LL-37 news BPi --- Genetics-- DNA-- P & YOU
randall
The P HOT Zone?...in this next abstract.
Has It all come together now?
We have LL-37 and BPi protein in the uPPer Gi tract. Please
recall how the LPS thing got going in this newsgroup.
It was when JXStern (JP etc et al) posted the Xoma link
to the now defunct linkages to the *Bacterial Endotoxin
In Human Disease* paper (pdf), by Michael Silverman and
Marc Ostro.
See this link on this group for links to the full paper:
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?group=alt.support.skin-diseases.psoriasis&q=ostro+silverman+LPS&qt_g=Search+this+group
With that in mind, this Gi tract, LPS P grail cure Quest is STILL
alive after
nearly six years.
http://www.ncbi.nlm.nih.gov/pubmed/18989140?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Antimicrobial host defense in the upper gastrointestinal tract.
Hosaka Y, Koslowski M, Nuding S, Wang G, Schlee M, Schäfer C, Saigenji
K, Stange EF, Wehkamp J.
Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart,
Germany.
BACKGROUND: With the exception of fungi, microbial infections are rare
in the oesophagus. Herein, we aimed to systematically assess the
distribution and quantity of different antimicrobial host factors as
well as, for the first time, functional mucosal antimicrobial activity
in the upper gastrointestinal tract. METHODS: We investigated biopsies
from the healthy oesophagus, three different locations in the stomach
and the duodenum in a total of 12 individuals. Using real-time PCR
with external standards, we compared absolute expression of mRNA
encoding antimicrobial peptides including defensins, cathelicidin,
bactericidal/permeability-increasing protein, psoriasin, and elafin.
In addition, we performed immunostaining for human-beta-defensin-1
(HBD1), elafin, and psoriasin. To test functional relevance, we
assessed antimicrobial as well as antifungal activity of cationic
extracts from biopsies against E. coli ATCC 25922 and a clinical
isolate of Candida albicans. RESULTS: In contrast to HBD1 which was
similarly expressed in all tissues, inducible beta-defensins in the
healthy oesophagus were much higher compared with the stomach and
duodenum (for HBD2-4: P<0.01). In addition, the antiproteases elafin
and psoriasin were also predominantly expressed in the oesophagus
(P<0.005). In contrast, LL-37 and bactericidal/permeability-increasing
protein were only marginally expressed. Cationic tissue extracts from
both the oesophagus as well as the stomach showed potent antibacterial
activity against E. coli. Consistent with susceptibility to Candida
infection, the esophageal extracts exhibited a weaker activity against
C. albicans (P=0.026). CONCLUSION: Despite dominant expression of
antimicrobial host peptides, oesophageal tissue shows a weakened
potency to kill C. albicans. These data suggest an important role of
yet unknown antimicrobial molecules.
PMID: 18989140
OH?
Low levels of ll37 and BPi?
Bummer. How can we get those dudes uP?
BPi
http://en.wikipedia.org/wiki/Bactericidal/permeability_increasing_protein
Bactericidal/permeability increasing protein (BPI) is a 456 residue
(~50kDa) protein which is part of the innate immune system.[1]
Distribution and function
BPI was initially identified in neutrophils, but is found in other
tissues including the epithelial lining of mucus membranes.[2] It is
an endogenous antibiotic protein with potent killing activity against
some bacteria (Gram-negative bacteria). It binds to compounds called
lipopolysaccharides produced by Gram-negative bacteria.
Lipolysaccharides are potent activators of the immune system, however
BPI at certain concentrations can prevent this activation.
BPI was discovered by Jerrold Weiss and Peter Elsbach at New York
University Medical School.
rBPI21
Because lipopolysaccharides are potent inflammatory agents, and the
action of antibiotics can result in the the release of these
compounds, the binding capacity of BPI was explored as a possible
means of reducing injury. Xoma Ltd. developed a recombinant 25kDa
portion of the BPI molecule called rBPI21, NEUPREX or opebecan. It was
given as trial has been found to have decrease the mortality in Gram-
negative bacterial induced sepsis.[3] Studies suggest that its binding
activity is not the means by which it mediates its protective effect.
[4] Studies show biological effects with Gram-positive bacteria[5] and
even in infection by the protozoan, Toxoplasma gondii.[6]
<sniP>
----------------------
I guess this isn't exactly what I wanted.
But hey, their working in the right area and that's a steP in the
right direction.
Cool...but I thought the candida was coming back uP from the other
direction?
Maybe it's invasive from both sides in this uPside down gut thing?
How come I don't read this crap before i toss it all together?
What's wrong with me???
Am I so demented I think the CURE for Psoriasis is right around the
corner?
Oh well... never mind.
My mistake.
Here listen to player singing baby come back on youtube:
http://www.youtube.com/watch?v=Hn-enjcgV1o
Now forget my obvious false exhilaration.
=========================================
Let's work the P GENE angle instead for a while.
What do P genes have to do with this skinny deal?
Are you like that goldfish swimming around in H2O wondering
what air is like?
Isn't life what it is?
Cept for folks with P?
http://www.cartoonstock.com/lowres/dre0387l.jpg
http://www.cartoonstock.com/lowres/dre0385l.jpg
With enough O2 you can figure it out:
http://seoblog.intrapromote.com/Google_MSN_Yahoo%20Fish%20Cartoon.jpg
This next link has a craP load of links for DNA:
http://www.nature.com/nature/journal/v456/n7218/edsumm/e081106-01.html
http://www.nature.com/news/2008/081105/full/456011a.html
How to get the most from a gene test
New tools squeeze more research out of personal genomics.
According to two commercial gene-testing services — 23andMe and
deCODEme — US Army medic Timothy Richard Gall of Fort Belvoir,
Virginia, has a higher-than-average risk of basal cell carcinoma, type
2 diabetes and ________psoriasis______. But much more enlightening
than these results, which cost Gall more than $1,400, was a free
online program called Promethease that he used to further analyse the
data. By offering more in-depth information and interpreting of more
of his genetic variants, Promethease "gives a much more realistic view
of the usefulness of the information", Gall says.
Start-ups and services such as Promethease are now developing ways to
improve the limited value of information provided by personal genomics
companies for consumers and scientists alike.
For instance, Omicia, based in Emeryville, California, is designing
software to make sense of entire genome sequences, such as those of
the individuals published in this issue (see pages 53 and 60). At
present, firms offering genetic testing look only at small variations
called single nucleotide polymorphisms, or SNPs. But people looking at
their whole genomes will also want to know the meaning of all the
different types of variation within them, such as extra copies of
genes or flipped sections of DNA. Omicia examines each location in a
person's genome and compares it to the company's own analysis of
disease risks linked to all the types of variation known to exist.
"We've always had the full genome in mind, so for us, any kind of
position somebody finds we can link to their genome and to our
system," says company co-founder Martin Reese.
Of course, most consumers are still stuck with SNPs, and Promethease
attempts to squeeze as much information as possible out of these. The
program uses data compiled in a wiki called SNPedia, launched in 2006
and run in the spare time of bioinformatician Mike Cariaso and
scientist/entrepeneur Greg Lennon. Their wiki contains information
selected from the vast public databases commonly used for research,
such as dbSNP, and tries to make it more useful by, for instance,
including short written interpretations of the SNPs' importance in
various health conditions on the basis of published studies. Compared
with reports delivered by gene-testing companies, Promethease reports
are more detailed and nuanced — containing information on, for
example, more SNPs, how common each of a person's particular genetic
variants are and the magnitude of the likely impact of each variant.
Cariaso, who lives in Bethesda, Maryland, says that the ability to
link genes to traits through SNPedia will become more useful with more
individuals' data — so he has begun analysing data from the Personal
Genome Project (PGP). This aims to sequence and post the genomes of as
many people as possible, along with data about their medical, mental
and physical characteristics. PGP released its first batch of data on
21 October, to grumblings about its quality. Two days later, Daniel
MacArthur, a postdoc at the Wellcome Trust Sanger Institute in
Cambridge, UK, wrote in his blog that the data were "pretty
underwhelming", containing mostly low-quality sequence information on
just four people that covers only 0.13% of the entire genome. "Given
the hype surrounding this data release I'm a little disappointed by
the data itself," he wrote.
George Church, a Harvard University molecular geneticist who runs the
PGP, doesn't disagree. "You should be underwhelmed" by the first data
release, he says. He calls it "really more of a social engineering
event than a true production announcement". Right now, Church says,
the main focus is recruiting more study participants to improve the
project's scope and its data quality; he adds that 9,500 people have
now volunteered.
Already, Church's 'social engineering event' has stirred a public
dialogue about the usefulness of linked genetic and medical data. For
instance, Gall is one of seven people who have released their
Promethease reports publicly on SNPedia independently of any research
project.
Gall says he posted his data in part because he knows its value today
is still limited, and he wants that to change: "By making it public, I
hope that I will only increase its usefulness to me personally," Gall
says. That shouldn't be too hard: Gall notes that his SNPs didn't even
reveal the makeup of some medically crucial genes — such as those that
determine his compatibility for organ donations — whose composition he
can learn for free as a member of the military: "In that sense,
23andMe and deCODEme are not worth the price," he says.
---------------------
OH? Another bummer...
----------------------------
More genetics:
[...]
With the help of the genetic samples from patients living with
pediatric glaucoma, the research team studied the locations where
extra or missing pieces of DNA begin and end.
They examined these points closely and determined how these copy
number variations occur.
“Our findings broaden the mechanisms known to cause copy number
variations, which improves our understanding not only of pediatric
glaucoma, but also of the growing number of genetic diseases linked to
copy number variations, including heart disease and psoriasis,” said
Dr. Ordan Lehmann, an associate professor with the Faculty of Medicine
& Dentistry at the University of Alberta and an ophthalmologist with
Alberta Health Services.
“We’re really only looking at the tip of the iceberg in terms of how
CNVs cause disease.
<sniP>
=====================
GENETIc Variation:: [ keywords:: genetic variation + psoriasis ] 544
hits on pubmed
http://www.ncbi.nlm.nih.gov/pubmed/18923449?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Further Genetic Evidence for Three Psoriasis-Risk Genes: ADAM33,
CDKAL1, and PTPN22.
Li Y, Liao W, Chang M, Schrodi SJ, Bui N, Catanese JJ, Poon A,
Matsunami N, Callis-Duffin KP, Leppert MF, Bowcock AM, Kwok PY,
Krueger GG, Begovich AB.
1Celera, Alameda, California, USA.
Predisposition to psoriasis is known to be affected by genetic
variation in HLA-C, IL12B, and IL23R, and although other psoriasis-
associated variants have been identified, incontrovertible statistical
evidence for these markers has not yet been obtained. To help resolve
this issue, we tested 15 single-nucleotide polymorphisms (SNPs) from 7
putative psoriasis-risk genes in 1,448 psoriasis patients and 1,385
control subjects; 3 SNPs, rs597980 in ADAM33, rs6908425 in CDKAL1 and
rs3789604 in PTPN22, were significant with the same risk allele as in
prior reports (one-sided P<0.05, false discovery rate<0.15). These
three markers were tested in a fourth sample set (599 cases and 299
controls); one marker, rs597980, replicated (one-sided P<0.05) and the
other two had odds ratios with the same directionality as in the
original sample sets. Mantel-Haenszel meta-analyses of all available
case-control data, including those published by other groups, showed
that these three markers were highly significant (rs597980: P=0.0057
(2,025 cases and 1,597 controls), rs6908425: P=1.57 x 10(-5) (3,206
cases and 4,529 controls), and rs3789604: P=3.45 x 10(-5) (2,823 cases
and 4,066 controls)). These data increase the likelihood that ADAM33,
CDKAL1, and PTPN22 are true psoriasis-risk genes.Journal of
Investigative Dermatology advance online publication, 16 October 2008;
doi:10.1038/jid.2008.297.
PMID: 18923449
More GENETIC Variation:
http://www.ncbi.nlm.nih.gov/pubmed/18833071?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Genetic variation and psoriasis.
Gudjonsson JE.
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
joh...@med.umich.edu.
Psoriasis is a common chronic inflammatory skin disease with a strong
genetic basis, characterized by complex alteration in epidermal growth
and differentiation. The genetic basis of psoriasis has been
appreciated for nearly 100 years, but only recently have several of
the genetic variants involved in psoriasis pathogenesis been
identified. These genetic variants so far identified are the HLA-
Cw*0602 allele of the HLA-C gene on chromosome 6, the p40 subunit of
the IL-12 and IL-23 cytokines (IL12B), the IL-23 receptor and SNF313,
a gene implicated in protein ubiquitinylation. Psoriasis patients have
also been shown to have an increased number of copies of the beta-
defensin gene cluster on chromosome 8. Beta-defensin 2, which is
located in this region, is amongst the most highly up-regulated
proteins in lesional skin and has cytokine-like properties in addition
to potent antimicrobial activity. Although several additional genes
remain to be identified, the variants that have so far been described
support the autoimmune basis of psoriasis indicating that the disease
may be mediated by T-cells reacting against (self)antigen(s) in the
binding pocket of HLA-C, with contribution from the recently described
Th17 subset of T-cells which are maintained by the IL-23 cytokine
axis. These genetic variants together with pro-inflammatory
environment caused by exaggerated antimicrobial response (beta-
defensins) and dysregulation of signaling pathways (ubiquination),
suggest the type of mechanism by which psoriasis can arise.
Elucidation of the genetic basis of psoriasis and the underlying
pathogenic mechanisms hold the potential for eventual cure of this
enigmatic disorder.
PMID: 18833071
===================================
I should spend a week understanding this one.
http://www.ncbi.nlm.nih.gov/pubmed/18981132?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-
dependent antimicrobial pathway.
Krutzik SR, Hewison M, Liu PT, Robles JA, Stenger S, Adams JS, Modlin
RL.
Division of Dermatology, David Geffen School of Medicine at University
of California Los Angeles, CA 90095, USA.
An essential function of the innate immune system is to directly
trigger antimicrobial mechanisms to defend against invading pathogens.
In humans, one such pathway involves activation by TLR2/1L leading to
the vitamin D-dependent induction of antimicrobial peptides. In this
study, we found that TLR2/1-induced IL-15 was required for induction
of CYP27b1, the VDR and the downstream antimicrobial peptide
cathelicidin. Although both IL-15 and IL-4 triggered macrophage
differentiation, only IL-15 was sufficient by itself to induce CYP27b1
and subsequent bioconversion of 25-hydroxyvitamin D3 (25D3) into
bioactive 1,25D3, leading to VDR activation and induction of
cathelicidin. Finally, IL-15-differentiated macrophages could be
triggered by 25D3 to induce an antimicrobial activity against
intracellular Mycobacterium tuberculosis. Therefore, IL-15 links
TLR2/1-induced macrophage differentiation to the vitamin D-dependent
antimicrobial pathway.
PMID: 18981132