Google Groups no longer supports new Usenet posts or subscriptions. Historical content remains viewable.
Dismiss
Strange BREW (Lavender) - Nestin - More H2S in SkIN - & IL-22 - CAVEat mTOR? -- SNP's on CRACK - PON1 - Autism Re-ducks - Skin GAME beYOND Gut -- MicroBEs en Masse -- Hidden Hordes --
9 views
Skip to first unread message
randall
Aug 7, 2012, 3:13:21 PM8/7/12
to
hi
I just looked the last thread. it's..
in my head:
Tues, Aug 7 2012 11:36 am
Subject: A ROSE or LaVENDER is NOT a FART -- Hydrogen Sulfide Heart
Fiend-LY? PLC to GUT RESCUE? WILL BLOCK-> Propionyl L-Carnitine & IBD
-- Liar on Fire -- Ei24 and ER with P53 (cancer skew Th2 inside of
YOU?)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/2543ce09927d056d
and stRange brew came in to my HEAD.
Cream - Strange Brew
http://www.youtube.com/watch?v=m_NholHANoY
Kewl hip daddy....
I know... it's so so so.. what you gonna do?
Strange brew what's inside of you-- some kind of demon-- stick to
glue.
what kinda fool are u?
OK... so whatz on the outside of YOU?
Does your skin act like GLUE so you don't fall to pieces?
Whats you sign?
Scales?
Libra?
LOL
Eat a Pisces or eat a pi? Just don't die drinking strange lavender
brew? LOL
OK... back to weird science:
but the dow is at 13196 and obama gets credit, right?
Yep.. he did it and not BUSH... and a partisan left wing ding a ling
did it and he built it
all by his big boy self..LOL
He's like so 1/2 and 1/2.... and half marxist and half capitalist tar
baby?
Who knows?? oNly his school transcript will tell the TALE of what he
took... or forsook?
But make no misTEAK... his mooooooooooochele will eat that filet and
fly the 747 friendly sky.
or fiendly skies of lies tar baby?
id squid let's stick to the topic du jour and skin please?
OK...sorry already...
Nestin in skin:
http://www.ncbi.nlm.nih.gov/pubmed/22854836
Acta Derm Venereol. 2012 Aug 1. doi: 10.2340/00015555-1420. [Epub
ahead of print]
Nestin Expression is Increased in the Suprabasal Epidermal Layer in
Psoriasis Vulgaris.
Watarai A, Amoh Y, Maejima H, Hamada Y, Katsuoka K.
Source
Department of Dermatology, Kitasato University School of Medicine,
1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan. E-
mail: wat...@med.kitasato-u.ac.jp.
Abstract
We investigated the expression of both epidermal fatty acid-binding
protein (FABP5), a marker of transit amplifying cells, and nestin, a
putative marker of epidermal stem cells, in psoriatic epidermis and in
normal human cultured keratinocytes. In lesional psoriatic epidermis,
immunostaining showed that the suprabasal layer was positive for
nestin, with some cells co-expressing FABP5. Flow cytometric analysis
revealed that the expression of both nestin and FABP5 were increased
in keratinocytes cultured in a low concentration of calcium relative
to those cultured in a high concentration of calcium. These results
suggest that nestin and FABP5 are expressed in actively proliferating
keratinocytes in vitro and in the suprabasal layer in lesional
psoriatic epidermis, and that double-positive cells may identify
transit amplifying cells in the epidermis.
PMID: 22854836
full text
http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1420&preview=1
http://en.wikipedia.org/wiki/Nestin_(protein)
Nestin is a type VI intermediate filament (IF) protein.[1][2] These
intermediate filament proteins are expressed mostly in nerve cells
where they are implicated in the radial growth of the axon. Seven
genes encode for the heavy (NF-H), medium (NF-M) and light
neurofilament (NF-L) proteins, nestin and α-internexin in nerve cells,
synemin α and desmuslin/synemin β (two alternative transcripts of the
DMN gene) in muscle cells, and syncoilin (also in muscle cells).
Members of this group mostly preferentially coassemble as
heteropolymers in tissues. Steinert et al. has shown that nestin forms
homodimers and homotetramers but does not form IF by itself in vitro.
In mixtures, nestin preferentially co-assembles with purified vimentin
or the type IV IF protein -internexin to form heterodimer coiled-coil
molecules.[3]
[...] Nestin has recently received attention as a marker for detecting
newly formed endothelial cells. In a study, Teranishi et al. examined
and came to the conclusion that nestin is a novel angiogenesis marker
of proliferating endothelial cells in colorectal cancer tissue.[7]
<snip>
zero hits: nestin - p ng / and 5 hits: FABP5 - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=FABP5&start=0&
14 hits: psoria* + FABP5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20fabp5
137 hits: nestin skin -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=nestin%20skin%20&itool=QuerySuggestion
4 hits: nestin + FABP5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=nestin%20fabp5
457 hits -fabp5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=fabp5
For pancan this is salient:
fabp5 crabp2 - 9 hits - pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=fabp5%20crabp2
http://www.ncbi.nlm.nih.gov/pubmed/22010213
Molecular determinants of retinoic acid sensitivity in pancreatic
cancer.
Gupta S, Pramanik D, Mukherjee R, Campbell NR, Elumalai S, de Wilde
RF, Hong SM, Goggins MG, De Jesus-Acosta A, Laheru D, Maitra A.
Clin Cancer Res. 2012 Jan 1;18(1):280-9. Epub 2011 Oct 18.
PMID: 22010213
http://www.ncbi.nlm.nih.gov/pubmed/19554024
J Invest Dermatol. 2009 Nov;129(11):2711-20. Epub 2009 Jun 25.
Nestin in human skin: exclusive expression in intramesenchymal skin
compartments and regulation by leptin.
Tiede S, Kloepper JE, Ernst N, Poeggeler B, Kruse C, Paus R.
Source
Department of Dermatology, Allergology and Venerology, University of
Lübeck, Lübeck, Germany.
Abstract
Cutaneous nestin+ cells are of substantial interest in regenerative
medicine. However, the location of nestin+ cells in situ remains
controversial. We therefore sought to determine their location in
female human scalp skin, using stringently controlled
immunohistochemical techniques, Western blot analysis, and in situ
hybridization and complementing those techniques with relative and
quantitative reverse transcriptase-PCR of enzymatically digested or
laser-capture microdissected human hair follicle (HF) compartments. We
show here that the immunoreactivity (IR) patterns obtained with anti-
nestin antibodies are highly dependent on the tissue-fixation and
immunohistochemical methods used. NESTIN mRNA could not be detected
within HF-associated epithelial cells in situ or in RNA extracts of
the microdissected HF epithelium. Instead, NESTIN transcripts were
found only in intramesenchymal skin compartments. Individual cells
showing both, specific nestin IR and NESTIN mRNA were detectable in
the connective-tissue sheaths of human HFs, sebaceous and sweat
glands. Moreover, stimulation of organ-cultured human scalp skin with
the adipokine leptin increased the number of nestin+ cells in these
intramesenchymal skin locations, whereas no specific nestin IR could
be induced by leptin within the HF epithelium, including the bulge.
Therefore, nestin expression at the gene and protein levels in human
scalp skin is restricted to the periappendage mesenchyme and can be
stimulated by leptin.
PMID: 19554024
Free full text
==================
more fart gas?
It's a gas gas gas?
yikes.
The Rolling Stones - Jumpin Jack Flash-HQ
http://www.youtube.com/watch?v=eQSGw0hMd_I
he was borrrrrn ... and howled at the drive in rain... and all right
now and in
fact it's a gas.... gas gas... jumping human bean with 4000 love
affairs...LOL
WELL my heart couldn't take what mick does... for more then a
year...about 25 fears aglow... you know?
http://www.ncbi.nlm.nih.gov/pubmed/22840496
Pharmacol Res. 2012 Jul 26.
Hydrogen sulfide modulates the release of nitric oxide and VEGF in
human keratinocytes
Merighi S, Gessi S, Varani K, Fazzi D, Borea PA.
Source
Department of Clinical and Experimental Medicine, Pharmacology Section
and Interdisciplinary Center for the Study of Inflammation, University
of Ferrara, Via Fossato di Mortara, 17/19, 44100, Ferrara, Italy.
Abstract
Hydrogen sulphide (H(2)S) is a novel signaling molecule with both pro-
or anti-inflammatory effect. The present study aimed to: i-
characterize the in vitro effects of H(2)S on human keratinocyte's
proliferation and death; ii- investigate the ability of H(2)S to
modulate VEGF and NO production; iii- examine the intracellular
signaling pathways involved in VEGF and NO modulatory effect. We found
that exogenous application of H(2)S (NaHS and GYY4137 as H(2)S donors)
significantly enhances NO through increase of iNOS, in a manner Akt-
dependent. The increment in NO down-regulates ERK1/2 activation
thereby resulting in the decrease of VEGF release. We suggest that
H(2)S-releasing agents may be promising therapeutics for chronic
inflammatory disorders of the skin, i.e. psoriasis, in which NO
increases as well as anti-VEGF treatments have been suggested to be
novel effective approaches.
PMID: 22842066
http://www.ncbi.nlm.nih.gov/pubmed/22840496
Cytokine. 2012 Jul 25.
IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR
signaling cascade.
Mitra A, Raychaudhuri SK, Raychaudhuri SP.
Source
Dermatology, University of California School of Medicine, Davis, CA,
USA; VA Medical Center Sacramento, CA, USA.
Abstract
OBJECTIVE:
Interleukin 22 (IL-22), a relatively new cytokine has been found to
induce significant proliferation of human keratinocytes and fibroblast
like synoviocytes (FLS) and thus plays an important role in the
pathogenesis of autoimmune diseases like psoriasis and rheumatoid
arthritis (RA) which are characterized by hyperproliferation of
keratinocytes and FLS respectively. PI3K/Akt/mTOR signaling cascade
plays crucial role in cell growth and survival. Therefore our
objective was to see the regulatory role of PI3K/Akt/mTOR signaling
cascade in IL-22 induced proliferation of keratinocytes and FLS.
METHODS:
Normal human epidermal keratinocytes (NHEK) and FLS were isolated from
skin of healthy volunteer's undergone plastic surgery and synovial
tissue of psoriatic arthritis (PsA) and RA patients respectively.
IL-22 induced proliferation of NHEK and FLS was measured by MTT assay.
Phosphorylation of Akt/mTOR was determined by western blot assay and
further confirmed by real time polymerase chain reaction (RT-PCR).
RESULTS:
We observed that IL-22 induced significant proliferation of NHEK and
FLS which was effectively inhibited by dual kinase (PI3K/mTOR)
inhibitor, NVP-BEZ235 and specific mTOR inhibitor, Rapamycin. In NHEK
and FLS, IL-22 significantly induced phosphorylation of Akt and mTOR
which was effectively blocked by Rapamycin and NVP-BEZ235. Further we
did RT-PCR in NHEK and found that IL-22 significantly upregulated AKT1
and MTOR gene.
CONCLUSION:
These results show that IL-22 induced proliferation of NHEK and FLS is
dependent on PI3K/Akt/mTOR signaling pathway. This novel observation
provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR
signaling pathway in autoimmune diseases like psoriasis and rheumatoid
arthritis.
PMID: 22840496
http://www.ncbi.nlm.nih.gov/pubmed/22837380
Am J Respir Crit Care Med. 2012 Jul 26.
A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1.
Fischer A, Schmid B, Ellinghaus D, Nothnagel M, Gaede KI, Schürmann M,
Lipinski S, Rosenstiel P, Zissel G, Höhne K, Petrek M, Kolek V, Pabst
S, Grohé C, Grunewald J, Ronninger M, Eklund A, Padyukov L, Gieger C,
Wichmann HE, Nebel A, Franke A, Müller-Quernheim J, Hofmann S,
Schreiber S.
Source
Institute of Clinical Molecular Biology, Christian-Albrechts
University, Kiel, Germany.
Abstract
RATIONALE:
Sarcoidosis is a complex inflammatory disease with a heterogeneous
clinical picture. Amongst others, an acute and chronic clinical course
can be distinguished, for which specific genetic risk factors are
known.
OBJECTIVES:
In order to identify additional risk loci for sarcoidosis and its
acute and chronic subforms, we analyzed imputed data from a genome-
wide association scan (GWAS) for these phenotypes.
METHODS:
After quality control, the GWAS comprised nearly 1.3 million imputed
single nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip
dataset of 564 German sarcoidosis cases, including 176 acute and 354
chronic cases and 1575 controls.
MAIN RESULTS:
We identified chromosome 11q13.1 (rs479777) as a novel locus
influencing susceptibility to sarcoidosis with genome-wide
significance. The marker was significantly associated in three
distinct German case-control populations and in an additional German
family sample with ORs ranging from 0.67 to 0.77. This finding was
further replicated in two independent European case-control
populations from the Czech Republic (OR = 0.75) and from Sweden (OR =
0.79). In a meta-analysis of the included European case-control
samples the marker yielded a p value of 2.68x10(-18). The locus was
previously reported to be associated with Crohn´s disease, alopecia
areata, leprosy and psoriasis. For sarcoidosis, fine-mapping and
expression analysis suggest KCNK4, PRDX5, PCLB3 and, most promising,
CCDC88B, as candidates for the underlying risk gene in the associated
region.
CONCLUSION:
This study provides striking evidence for association of chromosome
11q13.1 with sarcoidosis in Europeans, and thus identified a further
genetic risk locus shared by sarcoidosis, Crohn´s disease and
psoriasis.
PMID: 22837380
http://www.ncbi.nlm.nih.gov/pubmed/22837109
Hum Mutat. 2012 Jul 26. doi: 10.1002/humu.22172.
Correlating multi-allelic copy number polymorphisms with disease
susceptibility.
Cantsilieris S, White SJ.
Source
Centre for Reproduction and Development, Monash Institute of Medical
Research, Monash University, Melbourne, Victoria, Australia; Centre
for Eye Research Australia, University of Melbourne, Royal Victorian
Eye and Ear Hospital, East Melbourne, Victoria, Australia.
Abstract
The human genome contains a significant amount of sequence variation,
from single nucleotide polymorphisms to large stretches of DNA that
may be present in a range of different copies between individuals.
Several such regions are variable in >1% of the population (referred
to as copy number polymorphisms or CNPs), and many studies have looked
for associations between the copy number of genes within multi-allelic
CNPs and disease susceptibility. Associations have indeed been
described for several genes, including the Beta-defensins (DEFB4,
DEFB103, DEFB104), Chemokine ligand 3 like 1 (CCL3L1), Fc Gamma
Receptor 3B (FCGR3B) and Complement Component C4 (C4). However, follow
up replication in independent cohorts has failed to reproduce a number
of these associations. It is clear that replicated associations such
as those between C4 and Systemic Lupus Erythamatosis, and Beta-
defensin and Psoriasis, have used robust genotyping methodologies.
Technical issues associated with genotyping sequences of high identity
may therefore account for failure to replicate other associations.
Here we compare and contrast the most popular approaches that have
been used to genotype CNPs, describe how they have been applied in
different situations, and discuss potential reasons for the difficulty
in reproducibly linking multi-allelic CNPs to complex diseases.
PMID: 22837109
http://www.ncbi.nlm.nih.gov/pubmed/22835076
Br J Dermatol. 2012 Jul 27. doi: 10.1111/j.1365-2133.2012.11170.x.
Paraoxonase (PON1) 55 polymorphism, lipid profiles and psoriasis
Asefi M, Vaisi-Raygani A, Bahrehmand F, Kiani A, Rahimi Z, Nomani H,
Ebrahimi A, Tavilani H, Pourmotabbed T.
Source
Molecular Diagnostic Research Center Kermanshah University of Medical
Sciences, Kermanshah, Iran Fertility and Infertility Research Center,
Kermanshah University of Medical Sciences, Kermanshah, Iran Department
of Clinical Biochemistry, Kermanshah University of Medical Sciences,
Kermanshah, Iran Medical Biology Research Center, Kermanshah
University of Medical Sciences, Kermanshah, Iran. Department of
Dermatology, Kermanshah University of Medical Sciences, Kermanshah,
Iran. Department of Clinical Biochemistry, Hamadan University of
Medical Sciences, Hamadan, Iran Department of Microbiology, Immunology
and Biochemistry, University of Tennessee Health Science Center, USA.
Abstract
Background: Paraoxonase (PON1) is a serum HDL-bound enzyme with an
antioxidant function. It hydrolyzes lipid peroxides protecting LDL
from oxidative modifications. Psoriatic patients are at greater risk
of oxidative stress, which is associated with abnormal plasma lipid
metabolism. Objectives: In this study, association of PON 55 M allele
with serum arylesterase (ARE) activity, Malondialdehyde (MDA), lipids
profiles and psoriasis was investigated. Methods: The present case-
control study consisted of 100 psoriatic patients with and without
cardiovascular diseases (CVD; mean age, 35.3 years) and 100 gender-
and age-matched unrelated healthy controls (mean age, 35.7 years) from
west population of Iran. PON Met 55 Leu polymorphism was detected by
PCR-RFLP, serum ARE activity, MDA, lipid and apolipoprotein levels
were determined spectrophotometrically, by HPLC and by enzyme assay,
respectively. Results: The presence of PON 55 M allele was found to
be associated with psoriasis (OR=1.96,p=0.017). The psoriasis patients
with PON M (M/L+M/M) allele had higher levels of MDA (4.12±0.88 vs.
2.24 ± 0.55 μmol/l, p<0.001), APOB/APOA1ratio(0.91 ± 0.66 vs. 0.66 ±
0.35,p=0.004), APOB(111 ± 38.7 vs. 88.3 ± 22.5 mg/ml, p=0.001), LP(a)
(21.9 ± 18.4 vs. 15.8 ± 16.6 mg/ml, p=0.034) but lower ARE activity
(39.6±11vs.45.9±11.8 IU/mL,p=0.031) than the control subjects. There
was a significant positive correlation between ARE activity with APOA1
and a negative correlation with MDA concentration in psoriatic
patients. Conclusions: PON55 M allele is a risk factor for psoriasis.
The carriers of this allele has high levels of MDA, APOB, LP(a), APOB/
APA1 and lower ARE activity. These results indicated that oxidative
stress, impairment of antioxidant system and abnormal lipid metabolism
may play a role in the pathogenesis and progression of psoriasis and
its related complications. These data suggest that psoriatic patients
are more susceptible to vascular diseases.
PMID: 22835076
4 hits: psoria* Paraoxonase -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20Paraoxonase%20
7 hits: Paraoxonase - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=Paraoxonase+&start=0&scoring=d&
************************************
http://www.ncbi.nlm.nih.gov/pubmed/22802640
Proc Natl Acad Sci U S A. 2012 Jul 16.
Modeling an autism risk factor in mice leads to permanent immune
dysregulation.
Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH.
Source
Biology Division, California Institute of Technology, Pasadena, CA
91125.
Abstract
Increasing evidence highlights a role for the immune system in the
pathogenesis of autism spectrum disorder (ASD), as immune
dysregulation is observed in the brain, periphery, and
gastrointestinal tract of ASD individuals. Furthermore, maternal
infection (maternal immune activation, MIA) is a risk factor for ASD.
Modeling this risk factor in mice yields offspring with the cardinal
behavioral and neuropathological symptoms of human ASD. In this study,
we find that offspring of immune-activated mothers display altered
immune profiles and function, characterized by a systemic deficit in
CD4(+) TCRβ(+) Foxp3(+) CD25(+) T regulatory cells, increased IL-6 and
IL-17 production by CD4(+) T cells, and elevated levels of peripheral
Gr-1(+) cells. In addition, hematopoietic stem cells from MIA
offspring exhibit altered myeloid lineage potential and
differentiation. Interestingly, repopulating irradiated control mice
with bone marrow derived from MIA offspring does not confer MIA-
related immunological deficits, implicating the peripheral
environmental context in long-term programming of immune dysfunction.
Furthermore, behaviorally abnormal MIA offspring that have been
irradiated and transplanted with immunologically normal bone marrow
from either MIA or control offspring no longer exhibit deficits in
stereotyped/repetitive and anxiety-like behaviors, suggesting that
immune abnormalities in MIA offspring can contribute to ASD-related
behaviors. These studies support a link between cellular immune
dysregulation and ASD-related behavioral deficits in a mouse model of
an autism risk factor.
PMID: 22802640
26 hits: maternal immune activation autism -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=maternal%20immune%20activation%20autism
---------------------
super duper enterotypes/microbiome link from nature:
http://www.nature.com/nature/focus/humanmicrobiota/index.html
Or from mother nurture depending on how you look or think about it?
Skin in the Buggy GAME:
http://www.nature.com/news/the-skin-s-secret-surveillance-system-1.11075
The skin’s secret surveillance system
Microorganisms that reside on the skin found to influence host
immunity.
Virginia Gewin
26 July 2012
The skin has long been thought of as a mere physical barrier to attack
by pathogens. Now, however, researchers are starting to realize that
this simplistic view needs a radical rethink.
The folds, follicles and tiny oil-producing glands on the skin's
surface create a multitude of diverse habitats, each with its own
community of microbes1. Most of these 'commensals' live harmlessly on
the skin, and their presence is thought to stop pathogenic microbes
from invading the skin's habitats. But these benign residents are not
just innocent bystanders — according to a paper published today in
Science, skin-specific bacteria also influence the response from the
host's immune system to help fight off infection2.
----
http://www.nature.com/polopoly_fs/7.5544.1343318235!/image/1.11075_naik4HR.jpg_gen/derivatives/landscape_300/1.11075_naik4HR.jpg
Microorganisms (blue) living around a hair follicle in the skin can
alter the responses of immune cells.
----
Immunologist Yasmine Belkaid and her team at the National Institute of
Allergy and Infectious Diseases in Bethesda, Maryland, decided to
investigate the immunological role of the skin's resident
microorganisms, known collectively as the skin microbiome. “For the
first time, we’ve shown that the skin needs microbial signals for
proper immune-cell function,” says study author Shruti Naik, a
graduate student at the University of Pennsylvania, Philadelphia, who
is based in Belkaid's lab.
Most studies of how resident microorganisms regulate the immune system
and inflammation have focused on the gut microbiome, largely because
it is the site of greatest exposure and contains a wide diversity of
microbes. But Belkaid and her colleagues wanted to determine whether
the skin microbiome performed a similar function.
“No one had any idea of the relative magnitude of the immunological
effect in skin, or how similar any mechanisms found outside the gut
would be to those occurring inside the gut,” says Curtis Huttenhower,
a computational biologist at the Harvard School of Public Health in
Boston, Massachusetts, who is involved in the Human Microbiome
Project. “This paper is the first good demonstration I’ve seen that
shows the skin microbiome has a parallel immunological response to
that seen in the gut.”
Skin signals
To investigate these effects, Belkaid's team compared the production
of inflammatory molecules by a subset of immune cells known as T cells
from two groups of mice — one that was 'germ-free', having been raised
in a sterile environment, and another that had microbes present on the
skin. The T cells of germ-free mice produced lower levels of
inflammatory molecules than those of the control mice, suggesting that
skin bacteria are needed for proper immune cell function.
Next, to confirm that the skin microbiota rather than gut microbes
were responsible for this effect, the researchers gave normal mice
oral antibiotics that altered only gut microbes and showed that there
was no effect on the ability of skin T cells to produce inflammatory
signals.
Related stories
Microbes en masse: The sequencing machine
http://www.nature.com/news/microbes-en-masse-the-sequencing-machine-1.10985
Microbiome sequencing offers hope for diagnostics
http://www.nature.com/doifinder/10.1038/nature.2012.10299
Nature's Human Microbiota special
http://www.nature.com/nature/focus/humanmicrobiota/index.html
More related stories
http://www.nature.com/news/the-skin-s-secret-surveillance-system-1.11075#related-links
The team then colonized the germ-free mice with a bacterium often
found on human skin, Staphylococcus epidermidis. The addition of this
one species was enough to reinstate the production of an inflammatory
protein by T cells in the skin — but not in the gut. The germ-free
mice were also unable to mount an immune response to the pathogen
Leishmania major, but the addition of S. epidermidis restored their
immune response. “We showed that skin flora drive local immunity,”
says Naik.
Finally, to confirm the mechanism underpinning this cross-talk between
skin microbes and the immune system, the researchers tested mice that
were deficient in a signalling pathway known as MYD88 and found that
although it is dispensible in the gut, it is required in the skin.
“This paper takes previous observations that commensal bacteria can
have an anti-inflammatory role in the skin one step further and shows
how these organisms can affect T-cell maturation,” says Richard Gallo,
chief of dermatology at the University of California, San Diego. In
essence, commensal bacteria help to fine-tune host immune-cell
responses.
Beyond the gut
“The fact that we found that protective immunity is dependent on skin,
rather than gut, microbiota gives their role a specificity that was
lacking previously,” says study co-author Julie Segre, a skin-
microbiome researcher at the National Human Genome Research Institute
in Bethesda. There may be commonalities in how gut and skin microbiota
work, but, she adds, there will also be important differences.
Huttenhower says that this work is a timely reminder that the research
community needs to look beyond the gut to fully understand
immunological responses.
Segre notes that the findings are a first step towards detailing
whether the gut, skin or oral microbial communities communicate
directly with each other or if the skin microbiome simply primes the
immune system. “The gut microbiome has been the focus for the last ten
years,” she says. “Now it’s the skin’s turn.”
Nature doi:10.1038/nature.2012.11075
^^^^^^^^^^^^
http://www.nature.com/news/microbes-en-masse-the-sequencing-machine-1.10985
Microbes en masse: The sequencing machine
Faeces, lizards, keyboards, faces — Rob Knight likes to sequence the
microbes on anything and everything. Next, he plans to sequence Earth.
Virginia Gewin
11 July 2012
Rob Knight wants the spit of a komodo dragon. But he is unsure whether
Bintang, a metre-long juvenile of this endangered lizard species, will
oblige. Wielding a white cotton swab, Knight cautiously approaches the
creature, which is squirming in its keeper's arms at the Denver Zoo in
Colorado. With an inquisitive flick of the tongue, Bintang deposits a
dab of saliva on the swab.
Knight pops the swab into a sterile plastic tube, opens another tube
and goes on to collect samples from the lizard's head and belly. He
also swabs the enclosure, which is part of the world's most successful
facility for the captive breeding of komodo dragons (Varanus
komodoensis). The samples are teeming with the bacteria and viruses
that live in the reptile's mouth, gut and skin. Back in his lab at the
University of Colorado Boulder, Knight will sequence the DNA of these
microorganisms — and eventually compare the microbes with those found
on komodo dragons in the wild and at other facilities, to try to find
out whether and how they affect the animals' survival and why captive
females tend to die young.
If there is a link between this species' microbes and its health,
Knight is the one to find it. He is a leader in the burgeoning field
of microbiome research, which aims to sequence the mass of genes from
microbial communities and use computational tools to count and compare
species. Knight has helped to reveal differences between the gut
microbes in obese and lean people1; to show that people's intestinal
microbes differ dramatically depending on where in the world they
live2; and to document the wide differences between the microbes
acquired by babies born by Caesarean section and those delivered
vaginally3. Outside the human body, Knight has probed the microbes
that blanket various natural and man-made environments, from freshly
fallen snow to computer keyboards and bathroom floors. He does all
this at a restless, relentless pace; he co-authored 49 publications in
2011 alone.
Related stories
Microbiology: Learning about who we are
The human microbiome: at the interface of health and disease
Social network wants to sequence your gut
More related stories
Knight is sensitive to the charge that all this is an exercise in
microbial surveying, rather than in hard hypothesis-testing. “We don't
take on projects if the scientific value isn't clear,” he says. “What
motivates me, from a pragmatic standpoint, is how understanding the
microbial world might help us improve human and environmental health.”
The microbiota hold clues, he says, to solving major societal problems
— preserving endangered species, for example, or treating obesity or
malnutrition.
Since 2010, Knight has been involved with the most ambitious effort
yet to probe the microbiota: the Earth Microbiome Project, a
collaborative effort to sequence and characterize the microbial
communities in at least 200,000 environmental samples such as soils
and water collected from around the world. He says that the project,
which is led by Jack Gilbert, an environmental microbiologist at the
US Department of Energy's Argonne National Laboratory in Illinois,
will yield a master list of the proteins required to sustain microbial
life across the planet; about 500,000 reconstructed microbial genomes;
and the makings of a global-scale model of microbial metabolism.
“Knight and Gilbert literally talk about sampling the entire planet.
It is ludicrous and not feasible — yet they are doing it,” says
Jonathan Eisen, an evolutionary biologist at the University of
California, Davis. “Rob is one of the few people who are surfing the
exponential curve of increased sequencing power,” Eisen adds, “and
planning where the wave will take him next.”
Everything of interest
A tall, lanky 35-year-old, Knight doesn't look the part of a tenured
professor. He speaks so rapidly that he can be difficult to follow,
and his ideas erupt at a similar rate. The conversation can swerve
from using microbes to estimate time of death to his hopes of one day
swabbing the International Space Station to reveal its hidden
microbial life. “I've never been interested in just one thing,” he
says.
As a youth growing up in New Zealand, Knight had interests ranging
from fossils to chemistry and computers. “I didn't really have this
idea that science should be compartmentalized into biology or
physics,” he says. He was soon dabbling in both at Princeton
University in New Jersey, as he worked on a PhD project analysing the
evolution of the genetic code. He went on a self-taught computer-
programming binge, logging 12–20 hours of screen time per day, writing
code, testing programs and working out bugs.
Cathy Lozupone, a technician in the Princeton lab at the time, recalls
one night in 2000 when Knight, who was in between apartments, was
briefly staying with her. She woke at 2 a.m. to find him trembling
with excitement after solving a thorny computational problem. The
program he had devised crunched through protein-coding sequences from
600 species spanning all domains of life to show that very simple
rules involving mutation and selection could explain a major puzzle
about DNA: why different organisms prefer different coding sequences
for the same amino acid4.
“Knight and Gilbert literally talk about sampling the entire planet.
It is ludicrous and not feasible — yet they are doing it”
Knight moved to Boulder as a postdoc in 2001, and went on to run his
own group. He began attending lab meetings with famed microbiologist
Norm Pace, whose group was studying microbial diversity by sequencing
16S ribosomal RNA, a stretch of 1,500 nucleotides used for studying
evolutionary relationships. Knight saw that mass sequencing of
microbes was taking off, but that it was enormously challenging to
make sense of so much data. He developed a software tool dubbed
UniFrac (unique fraction)5, which provides a measure of the difference
between two microbial communities by constructing evolutionary trees
from the sequences in each sample and calculating the fraction of
branches that are unique to each.
UniFrac received a high-profile test when Knight teamed up with Jeff
Gordon, a leader in microbiome research at Washington University in St
Louis, Missouri, and his postdoc Ruth Ley. The researchers used
UniFrac to show that microbial populations in the guts of obese mice
differ from those in lean ones6. That paper has now been cited more
than 500 times, and the program has become a standard analytical tool
in the field. “Before UniFrac we had simply been tallying species, but
understanding whether the species were related or not gave us deeper
insights into the biology of communities,” says Ley, now a
microbiologist at Cornell University in Ithaca, New York.
Up close and personal
Fascinated by the gut's inhabitants, Knight was soon helping to chart
a course for the Human Microbiome Project (HMP) — a US$115-million
effort funded by the US National Institutes of Health to sequence the
tens of trillions of microbes that live in and on humans — which
published its major results in June7.
He also plunged into data: Knight and his colleagues showed that the
human body's bacteria vary dramatically between the gut, skin, mouth,
ears and other locations8. And by exploring the faeces of mammals
ranging from kangaroos to lemurs and zebras, Knight's team showed that
microbiota adapt to diet — be it carnivorous, herbivorous or
omnivorous — in a similar way across all mammalian lineages9. With a
rapid succession of high-profile papers, “Rob exploded onto the scene
— he went from no profile to being everywhere”, says Phil Hugenholtz,
a microbial ecologist at the Australian Centre for Ecogenomics in
Brisbane.
Knight has continued to develop software for handling the increasingly
giant data sets generated by modern sequencing technology. One
package, called QIIME (quantitative insights into microbial ecology)10
uses tools developed by Knight's group and others to simultaneously
compare millions of raw sequences, assign species names when possible,
build phylogenetic trees and visualize the data in many different
ways.
During the HMP, Knight was vocal about his concerns that the tools and
data weren't being shared effectively with the wider community. In one
case, he “challenged in a very public way” a rule that was slowing
down publication, says Owen White, associate director of the Institute
for Genome Sciences in Baltimore, Maryland, who oversees the central
data repository for the HMP. The rule was later overturned. White says
that Knight was also instrumental in shifting the centre of
intellectual power in genomic analysis from larger sequencing centres
to smaller labs. Knight says that he wants to “democratize” the data
and tools. “To maximize the output of science, it makes more sense to
do things that are good for the field overall,” he says.
http://www.nature.com/polopoly_fs/7.5296.1341936545!/image/Knight-graphic1.jpg_gen/derivatives/fullsize/Knight-graphic1.jpg
Another of his innovations lies in working out how to link sequence
data to the sample's metadata — environmental details such as pH,
temperature, salinity and collection time — so that the maximum amount
of information can be stored and extracted. “He strongly encouraged
people to get organized and put their data in a standard format so
that studies could be compared,” says Ley.
Knight has ruffled some feathers — perhaps owing to his meteoric rise
at an envy-inducing young age, or his unflinching criticism when he
thinks something is being done in the wrong way. “He's not always
terribly diplomatic,” says Ley. Some complain of “superficial, catchy”
studies, says one colleague who preferred not to be named. Knight's
work certainly can make a splash: in 2010, the popular detective
television programme CSI: Miami featured a technique developed by
Knight and Noah Fierer, a microbial ecologist at Boulder, with which
they matched individuals to the unique bacterial fingerprints that
they left on computer keyboards11 (see 'CSI: Microbes'). Knight's team
also attracted attention with as-yet unpublished work mapping the
microbes that carpet the human face from forehead to lips, and a study
documenting how the gut microbiota of a Burmese python (Python
molurus) shifted from famine to feast mode as the snake digested a rat
over three days12.
Serious business
Knight doesn't deny that he is one of two “healthy subjects” involved
in generating the largest time series of human microbiota yet
collected13: he swabbed his palms, mouth and faeces every day for 15
months for the cause. And he relishes the story of an airport official
who briefly confiscated the thermos of dry ice he was carrying to
transport the samples. Six hours later, in Knight's office, the
thermos exploded because the official had cinched down the lid too
tightly.
Knight says that all his studies have a serious intent. The time-
series data, for example, showed that there was vastly more variation
within one person's microbiota than expected. He hopes that the
finding will convince clinicians that monitoring people's microbiomes
over time could be useful in a clinical trial, allowing investigators
to, for example, test whether variations in microbiota correlate with
a drug response. “It's the kind of thing where you wouldn't want to
ask someone else to go through the trouble if you haven't demonstrated
the feasibility yourself,” he says.
Knight says he currently has about 70 papers in draft form, involving
roughly 50 principal investigators. But that looks set to increase
thanks to the Earth Microbiome Project. Knight, Gilbert and Janet
Jansson, a microbial ecologist at the Lawrence Berkeley National
Laboratory in Berkeley, California, are encouraging microbiologists
worldwide to send in samples. They have already received some 60,000,
ranging from deep-sea sediments from the Pacific Ocean to owl nests
from Alaska. The researchers, funded so far on about $3 million from
the US Department of Energy, as well as scraps from private sponsors
and their own and their contributors' funds, have sequenced around
15,000 of them. They are making all the data and tools — many of which
Knight developed or is developing — openly available.
“The Earth Microbiome Project is not a purely exploratory project,”
Knight emphasizes. The plan, he says, is to collect a number of
hypothesis-driven data sets, such as samples collected in pristine and
disturbed areas of the Australia coastline to determine whether the
disease-driven decline of algae has knock-on effects for other
organisms. By combining data sets, the team should also be able to
test broader hypotheses — such as whether the dominant microbes in a
sample always have the most important functions.
To that end, Knight continues to collect samples whenever he has the
chance; later this month, for example, he will be scraping up
microbial 'mats', which are among the most diverse communities known,
from hypersaline waters off the Californian coast. The komodo-dragon
samples are going into the project, and Knight now has approval to
sample these and other species at a further three zoos.
Knight has other ventures on the boil. In one project, he is exploring
whether gut microbial communities can influence mental health by, for
example, changing the signalling patterns between the gut and brain.
“My family has schizophrenia on one side and bipolar disorder on the
other,” he says, “which has led to my interest in trying to figure out
whether we could potentially address those conditions.” With Gordon
and Lozupone, he is also part of a global network for the study of
malnutrition and intestinal diseases, funded by the Bill & Melinda
Gates Foundation in Seattle, Washington. Working in Bangladesh, the
team hopes to identify the microbes associated with malnutrition, and
to explore potential probiotic or other microbial treatments.
Knight struggles to explain how he sustains his eclectic interests and
level of intensity. With so much to sequence, over-commitment is an
occupational hazard for everyone in microbiome research, he says.
But Gilbert says that the research community faces a challenge in
keeping up with Knight. “Unless he burns out in the next 20 years,”
says Gilbert, “I think we'll look back at him as a pioneer.”
Nature 487, 156–158 (12 July 2012) doi:10.1038/487156a
References
<snip>
^^^^^^^^^^^^^^^^^^^^^^^^^^^^
http://www.nature.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299
Microbiome sequencing offers hope for diagnostics
Scientists try to avoid the hype that dogs human-genome research.
Ed Yong
23 March 2012
Microbes have hit the big time. Results from major projects that aim
to sequence the metagenome — the trillions of microbial cells and
genes in the human body — potentially offer new ways of diagnosing and
treating a wide range of health problems. But some researchers are
warning against the dangers of hyping the data too soon.
In 2007, the US National Institutes of Health (NIH) committed US$140
million to the Human Microbiome Project, which examines all the
microorganisms in the human body. The following year, the European
Commission established the €22-million (US$29-million) Metagenomics of
the Human Intestinal Tract project (MetaHIT), which focuses on gut
bacteria. Findings from both efforts were presented at the
International Human Microbiome Congress in Paris this week.
------
http://www.nature.com/polopoly_fs/7.3528.1332512425!/image/HI-RES%20B2201377-Tongue_bacteria%2C_SEM-SPL.jpg_gen/derivatives/landscape_300/HI-RES%20B2201377-Tongue_bacteria%2C_SEM-SPL.jpg
The genetic codes of microbes in the human body, such as these tongue
bacteria (seen in a coloured scanning electron micrograph) could be
the key to more accurate diagnosis.
STEVE GSCHMEISSNER/SPL
------
Speaking at the conference, Julian Davies, a microbiologist at the
University of British Columbia in Vancouver, described the quest to
understand the microbiome as “the biggest life science project of all
time”. He added, “Everyone will benefit if this project goes well and
is done properly.”
Managing expectations
These claims echo the enthusiasm that once surrounded another ‘big
science’ initiative — the international Human Genome Project, which
published its first draft of the human genetic sequence in 20011. In
1999, Francis Collins, then director of the US National Human Genome
Research Institute in Bethesda, Maryland, and now director of the NIH,
had written2 that the human genome sequence would allow researchers to
“uncover the hereditary factors in virtually every disease”, “foretell
future disease” and “adapt therapies to the individual patient”.
But the promised advances have been slow to arrive. On the tenth
anniversary of the publication of the draft, an editorial in Nature
noted that its promise is “still to be fulfilled” (see ‘Best is yet to
come’).
Jonathan Eisen, a microbiologist at University of California, Davis,
is worried that microbiome research will eventually encounter the same
backlash. “Without a doubt we are running into some of the same
problems as the Human Genome Project,” he says. “There are many people
who have oversold the human microbiome as the cause or cure of
everything.” Eisen worries that although numerous connections have
been discovered between the microbiome and diseases, it is usually
unclear whether the microbes caused the conditions or merely exploited
a new environment.
“There’s sensitivity about the expected returns,” says David Relman,
who studies infectious disease at Stanford University in Palo Alto,
California. “We need to be grounded about what it is we’ll be able to
gain at what point in time. I think the shorter-term gains may be
around diagnostics, and novel ways of classifying both health and
disease.”
-----
Related stories
Gut microbial 'enterotypes' become less clear-cut
http://www.nature.com/doifinder/10.1038/nature.2012.10276
Bursting the genomics bubble
http://www.nature.com/doifinder/10.1038/news.2010.145
Microbiology: Straight from the gut
http://www.nature.com/doifinder/10.1038/453581a
More related stories
http://www.nature.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299#related-links
or
http://www.nature.com/nature/focus/humanmicrobiota/index.html
-----
These gains are already becoming apparent. At the Paris conference,
Jens Nielsen, a systems biologist at Chalmers University of Technology
in Gothenburg, Sweden, showed that the gut’s microbial genes may be a
better predictor of type 2 diabetes than established risk factors such
as waist–hip ratio or body mass index. Other researchers presented
results from MetaHIT that suggest that gut bacteria are more accurate
markers for leanness or obesity than any of our own genetic variants.
Rob Knight, a microbiologist at the University of Colorado Boulder,
hopes that microbiome will be similarly effective at classifying
inflammatory bowel diseases such as Crohn’s disease or ulcerative
colitis, in which “gradations are subtle and people are often
misdiagnosed”.
All the difference
The metagenome differs from person to person much more than the genome
does, which may be the key to its diagnostic potential. “There’s a
0.1% difference in our genomes, but there may be a 50% difference in
our metagenome,” says Dusko Ehrlich, a project coordinator for
MetaHIT. “If the variability is higher, you’re more likely to find a
relevant signal.”
Knight predicts that the microbiome will also prove easier to
influence than the genome. “If you want to get rid of bacteria,
pharmaceutical companies have thousands of compounds that could target
them,” he says. By contrast, finding drugs that target disease-related
genes, or altering those genes outright, is more difficult.
Attempts to modulate the microbiome are already under way, although
big advances have not yet arrived. One study published last year3
showed that probiotic yoghurt affects gut bacteria only subtly (see
‘Friendly bacteria move in mysterious ways’). "Cocktails of classic
probiotics, which people have been trying for years, may have some
benefit but the effect seems to be quite small,” says Relman. A
targeted approach that manipulates specific species could be more
effective, but, Relman adds, “I don’t think we’re there yet”.
“Let’s be careful and cautious,” agrees Ehrlich. “These are early
days, but I think there is great potential in what we see now.” He
adds, “But you can never, ever avoid disappointing people because they
always want more.”
Nature doi:10.1038/nature.2012.10299
<snip>
^^^^^^^^^^^^^
http://www.nature.com/nrmicro/journal/v10/n8/full/nrmicro2849.html
The hidden hordes
With funding for the HMP and Meta-HIT consortia now ending, what's
next for these large-scale efforts to map the hidden microbial hordes
associated with the human body?
If asked, could you immediately point to your left, or indeed your
right, retroauricular crease? How about your antecubital fossae? These
niches — behind the ears and in the crooks of the elbows, naturally —
are just two of the bodily locations examined in an investigation into
the structure, function and diversity of the microbiome in healthy
humans, which was published recently in Nature1. Along with an
accompanying framework document2, plus 15 other papers published
simultaneously in three PLoS journals and available in the PLoS Human
Microbiome Project Collection, this represents the first collective
major research output from the Human Microbiome Project (HMP)
Consortium.
there is no such thing as an overall 'core' human microbiome
Presciently termed the “second human genome” by David Relman and
Stanley Falkow back in 2001 (Ref. 3), the microbiome has been one of
the hottest topics in microbiology in recent years. The ability to
analyse human samples using the culture-independent metagenomic
sequencing techniques that were pioneered by environmental
microbiologists working in soil and marine environments was
demonstrated in 2006 (Ref. 4) by the first metagenomic analysis of the
gut microbiome in healthy humans. Since then, however, although there
have been many fascinating studies on the microbiome, the majority
have focused less on its composition and role in maintaining health
and more on its influence in diseases such as inflammatory bowel
disease and obesity, as well as its role in fundamental processes such
as the development and homeostasis of the immune system.
This balance has now begun to be redressed. The HMP study
characterized the microorganisms present at up to 18 different body
sites on the skin, oral cavity, vagina and nostrils, as well as in
faecal samples, for 242 healthy individuals aged 18–40 and living in
two different geographical locations in the United States. The general
take-home message from the work, which combined 16S rRNA profiling
with metagenomic and whole-genome sequencing, is that each
individual's microbiome is unique, suggesting that there is no such
thing as an overall 'core' human microbiome. Each niche was
characterized by one or a few signature taxa and, overall, diversity
was greatest in the gut and oral cavity, and least in the vagina. Just
over half of the volunteers were sampled at more than one time point,
and there appeared to be little variation over time.
Officially launched in 2008, and funded to the tune of ~US$150 million
by the US National Institutes of Health (NIH) Common Fund, the HMP
received funding for a 5-year period, which is now coming to an end.
There are, of course, other major consortia working on the microbiome,
the largest of which is Meta-HIT (Metagenomics of the Human Intestinal
Tract), which, as the name suggests, has focused exclusively on the
intestine. Meta-HIT, which involves researchers from the European
Union and China, was launched in 2008 and received [euro]22 million
from the European Commission Seventh Framework Programme over a 4-year
period, which has also just ended. The main research finding from Meta-
HIT was that in European adults the gut microbiota segregates into
three main enterotypes5, although subsequent studies involving larger
sample sizes — including one of the recent HMP papers6 — have
suggested that this segregation is less discrete and more of a
continuum.
The amount of data associated with these projects is staggering. The
HMP has generated 3.5 terabytes, more than 1,000 times that generated
by the Human Genome Project. But so far the data have raised more
questions than answers, and most investigators are clear that there is
an urgent need for broader, more multicultural analyses that track
individuals over a much longer period of time. Although there is still
a definite need for consortia, a combination of this top-down approach
with more bottom-up, investigator- and hypothesis-led approaches is
the most desirable way forward for many. The NIH Common Fund office is
currently investigating possible funding options for an HMP2, and a
first call for proposals in health-related research under the next
European Framework Programme is expected in January 2014.
The results of all the microbiome-related research so far have
emphasized the pervasive influence of the hidden hordes within. It is
to be hoped that, even in these straitened times, the crucial
importance of this work will be realized and it will continue to be
funded.
<snip>
OK this was FUN... hidden hordes of bugs and i'm gonna get autistic
skin in this game and drink lavender and then di or eat pi?
pass the pi... please.
randall... is there lavender in this pi(e)?
I just looked the last thread. it's..
in my head:
Tues, Aug 7 2012 11:36 am
Subject: A ROSE or LaVENDER is NOT a FART -- Hydrogen Sulfide Heart
Fiend-LY? PLC to GUT RESCUE? WILL BLOCK-> Propionyl L-Carnitine & IBD
-- Liar on Fire -- Ei24 and ER with P53 (cancer skew Th2 inside of
YOU?)
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/msg/2543ce09927d056d
and stRange brew came in to my HEAD.
Cream - Strange Brew
http://www.youtube.com/watch?v=m_NholHANoY
Kewl hip daddy....
I know... it's so so so.. what you gonna do?
Strange brew what's inside of you-- some kind of demon-- stick to
glue.
what kinda fool are u?
OK... so whatz on the outside of YOU?
Does your skin act like GLUE so you don't fall to pieces?
Whats you sign?
Scales?
Libra?
LOL
Eat a Pisces or eat a pi? Just don't die drinking strange lavender
brew? LOL
OK... back to weird science:
but the dow is at 13196 and obama gets credit, right?
Yep.. he did it and not BUSH... and a partisan left wing ding a ling
did it and he built it
all by his big boy self..LOL
He's like so 1/2 and 1/2.... and half marxist and half capitalist tar
baby?
Who knows?? oNly his school transcript will tell the TALE of what he
took... or forsook?
But make no misTEAK... his mooooooooooochele will eat that filet and
fly the 747 friendly sky.
or fiendly skies of lies tar baby?
id squid let's stick to the topic du jour and skin please?
OK...sorry already...
Nestin in skin:
http://www.ncbi.nlm.nih.gov/pubmed/22854836
Acta Derm Venereol. 2012 Aug 1. doi: 10.2340/00015555-1420. [Epub
ahead of print]
Nestin Expression is Increased in the Suprabasal Epidermal Layer in
Psoriasis Vulgaris.
Watarai A, Amoh Y, Maejima H, Hamada Y, Katsuoka K.
Source
Department of Dermatology, Kitasato University School of Medicine,
1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan. E-
mail: wat...@med.kitasato-u.ac.jp.
Abstract
We investigated the expression of both epidermal fatty acid-binding
protein (FABP5), a marker of transit amplifying cells, and nestin, a
putative marker of epidermal stem cells, in psoriatic epidermis and in
normal human cultured keratinocytes. In lesional psoriatic epidermis,
immunostaining showed that the suprabasal layer was positive for
nestin, with some cells co-expressing FABP5. Flow cytometric analysis
revealed that the expression of both nestin and FABP5 were increased
in keratinocytes cultured in a low concentration of calcium relative
to those cultured in a high concentration of calcium. These results
suggest that nestin and FABP5 are expressed in actively proliferating
keratinocytes in vitro and in the suprabasal layer in lesional
psoriatic epidermis, and that double-positive cells may identify
transit amplifying cells in the epidermis.
PMID: 22854836
full text
http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-1420&preview=1
http://en.wikipedia.org/wiki/Nestin_(protein)
Nestin is a type VI intermediate filament (IF) protein.[1][2] These
intermediate filament proteins are expressed mostly in nerve cells
where they are implicated in the radial growth of the axon. Seven
genes encode for the heavy (NF-H), medium (NF-M) and light
neurofilament (NF-L) proteins, nestin and α-internexin in nerve cells,
synemin α and desmuslin/synemin β (two alternative transcripts of the
DMN gene) in muscle cells, and syncoilin (also in muscle cells).
Members of this group mostly preferentially coassemble as
heteropolymers in tissues. Steinert et al. has shown that nestin forms
homodimers and homotetramers but does not form IF by itself in vitro.
In mixtures, nestin preferentially co-assembles with purified vimentin
or the type IV IF protein -internexin to form heterodimer coiled-coil
molecules.[3]
[...] Nestin has recently received attention as a marker for detecting
newly formed endothelial cells. In a study, Teranishi et al. examined
and came to the conclusion that nestin is a novel angiogenesis marker
of proliferating endothelial cells in colorectal cancer tissue.[7]
<snip>
zero hits: nestin - p ng / and 5 hits: FABP5 - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=FABP5&start=0&
14 hits: psoria* + FABP5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20fabp5
137 hits: nestin skin -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=nestin%20skin%20&itool=QuerySuggestion
4 hits: nestin + FABP5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=nestin%20fabp5
457 hits -fabp5 -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=fabp5
For pancan this is salient:
fabp5 crabp2 - 9 hits - pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=fabp5%20crabp2
http://www.ncbi.nlm.nih.gov/pubmed/22010213
Molecular determinants of retinoic acid sensitivity in pancreatic
cancer.
Gupta S, Pramanik D, Mukherjee R, Campbell NR, Elumalai S, de Wilde
RF, Hong SM, Goggins MG, De Jesus-Acosta A, Laheru D, Maitra A.
Clin Cancer Res. 2012 Jan 1;18(1):280-9. Epub 2011 Oct 18.
PMID: 22010213
http://www.ncbi.nlm.nih.gov/pubmed/19554024
J Invest Dermatol. 2009 Nov;129(11):2711-20. Epub 2009 Jun 25.
Nestin in human skin: exclusive expression in intramesenchymal skin
compartments and regulation by leptin.
Tiede S, Kloepper JE, Ernst N, Poeggeler B, Kruse C, Paus R.
Source
Department of Dermatology, Allergology and Venerology, University of
Lübeck, Lübeck, Germany.
Abstract
Cutaneous nestin+ cells are of substantial interest in regenerative
medicine. However, the location of nestin+ cells in situ remains
controversial. We therefore sought to determine their location in
female human scalp skin, using stringently controlled
immunohistochemical techniques, Western blot analysis, and in situ
hybridization and complementing those techniques with relative and
quantitative reverse transcriptase-PCR of enzymatically digested or
laser-capture microdissected human hair follicle (HF) compartments. We
show here that the immunoreactivity (IR) patterns obtained with anti-
nestin antibodies are highly dependent on the tissue-fixation and
immunohistochemical methods used. NESTIN mRNA could not be detected
within HF-associated epithelial cells in situ or in RNA extracts of
the microdissected HF epithelium. Instead, NESTIN transcripts were
found only in intramesenchymal skin compartments. Individual cells
showing both, specific nestin IR and NESTIN mRNA were detectable in
the connective-tissue sheaths of human HFs, sebaceous and sweat
glands. Moreover, stimulation of organ-cultured human scalp skin with
the adipokine leptin increased the number of nestin+ cells in these
intramesenchymal skin locations, whereas no specific nestin IR could
be induced by leptin within the HF epithelium, including the bulge.
Therefore, nestin expression at the gene and protein levels in human
scalp skin is restricted to the periappendage mesenchyme and can be
stimulated by leptin.
PMID: 19554024
Free full text
==================
more fart gas?
It's a gas gas gas?
yikes.
The Rolling Stones - Jumpin Jack Flash-HQ
http://www.youtube.com/watch?v=eQSGw0hMd_I
he was borrrrrn ... and howled at the drive in rain... and all right
now and in
fact it's a gas.... gas gas... jumping human bean with 4000 love
affairs...LOL
WELL my heart couldn't take what mick does... for more then a
year...about 25 fears aglow... you know?
http://www.ncbi.nlm.nih.gov/pubmed/22840496
Pharmacol Res. 2012 Jul 26.
Hydrogen sulfide modulates the release of nitric oxide and VEGF in
human keratinocytes
Merighi S, Gessi S, Varani K, Fazzi D, Borea PA.
Source
Department of Clinical and Experimental Medicine, Pharmacology Section
and Interdisciplinary Center for the Study of Inflammation, University
of Ferrara, Via Fossato di Mortara, 17/19, 44100, Ferrara, Italy.
Abstract
Hydrogen sulphide (H(2)S) is a novel signaling molecule with both pro-
or anti-inflammatory effect. The present study aimed to: i-
characterize the in vitro effects of H(2)S on human keratinocyte's
proliferation and death; ii- investigate the ability of H(2)S to
modulate VEGF and NO production; iii- examine the intracellular
signaling pathways involved in VEGF and NO modulatory effect. We found
that exogenous application of H(2)S (NaHS and GYY4137 as H(2)S donors)
significantly enhances NO through increase of iNOS, in a manner Akt-
dependent. The increment in NO down-regulates ERK1/2 activation
thereby resulting in the decrease of VEGF release. We suggest that
H(2)S-releasing agents may be promising therapeutics for chronic
inflammatory disorders of the skin, i.e. psoriasis, in which NO
increases as well as anti-VEGF treatments have been suggested to be
novel effective approaches.
PMID: 22842066
http://www.ncbi.nlm.nih.gov/pubmed/22840496
Cytokine. 2012 Jul 25.
IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR
signaling cascade.
Mitra A, Raychaudhuri SK, Raychaudhuri SP.
Source
Dermatology, University of California School of Medicine, Davis, CA,
USA; VA Medical Center Sacramento, CA, USA.
Abstract
OBJECTIVE:
Interleukin 22 (IL-22), a relatively new cytokine has been found to
induce significant proliferation of human keratinocytes and fibroblast
like synoviocytes (FLS) and thus plays an important role in the
pathogenesis of autoimmune diseases like psoriasis and rheumatoid
arthritis (RA) which are characterized by hyperproliferation of
keratinocytes and FLS respectively. PI3K/Akt/mTOR signaling cascade
plays crucial role in cell growth and survival. Therefore our
objective was to see the regulatory role of PI3K/Akt/mTOR signaling
cascade in IL-22 induced proliferation of keratinocytes and FLS.
METHODS:
Normal human epidermal keratinocytes (NHEK) and FLS were isolated from
skin of healthy volunteer's undergone plastic surgery and synovial
tissue of psoriatic arthritis (PsA) and RA patients respectively.
IL-22 induced proliferation of NHEK and FLS was measured by MTT assay.
Phosphorylation of Akt/mTOR was determined by western blot assay and
further confirmed by real time polymerase chain reaction (RT-PCR).
RESULTS:
We observed that IL-22 induced significant proliferation of NHEK and
FLS which was effectively inhibited by dual kinase (PI3K/mTOR)
inhibitor, NVP-BEZ235 and specific mTOR inhibitor, Rapamycin. In NHEK
and FLS, IL-22 significantly induced phosphorylation of Akt and mTOR
which was effectively blocked by Rapamycin and NVP-BEZ235. Further we
did RT-PCR in NHEK and found that IL-22 significantly upregulated AKT1
and MTOR gene.
CONCLUSION:
These results show that IL-22 induced proliferation of NHEK and FLS is
dependent on PI3K/Akt/mTOR signaling pathway. This novel observation
provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR
signaling pathway in autoimmune diseases like psoriasis and rheumatoid
arthritis.
PMID: 22840496
http://www.ncbi.nlm.nih.gov/pubmed/22837380
Am J Respir Crit Care Med. 2012 Jul 26.
A Novel Sarcoidosis Risk Locus for Europeans on Chromosome 11q13.1.
Fischer A, Schmid B, Ellinghaus D, Nothnagel M, Gaede KI, Schürmann M,
Lipinski S, Rosenstiel P, Zissel G, Höhne K, Petrek M, Kolek V, Pabst
S, Grohé C, Grunewald J, Ronninger M, Eklund A, Padyukov L, Gieger C,
Wichmann HE, Nebel A, Franke A, Müller-Quernheim J, Hofmann S,
Schreiber S.
Source
Institute of Clinical Molecular Biology, Christian-Albrechts
University, Kiel, Germany.
Abstract
RATIONALE:
Sarcoidosis is a complex inflammatory disease with a heterogeneous
clinical picture. Amongst others, an acute and chronic clinical course
can be distinguished, for which specific genetic risk factors are
known.
OBJECTIVES:
In order to identify additional risk loci for sarcoidosis and its
acute and chronic subforms, we analyzed imputed data from a genome-
wide association scan (GWAS) for these phenotypes.
METHODS:
After quality control, the GWAS comprised nearly 1.3 million imputed
single nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip
dataset of 564 German sarcoidosis cases, including 176 acute and 354
chronic cases and 1575 controls.
MAIN RESULTS:
We identified chromosome 11q13.1 (rs479777) as a novel locus
influencing susceptibility to sarcoidosis with genome-wide
significance. The marker was significantly associated in three
distinct German case-control populations and in an additional German
family sample with ORs ranging from 0.67 to 0.77. This finding was
further replicated in two independent European case-control
populations from the Czech Republic (OR = 0.75) and from Sweden (OR =
0.79). In a meta-analysis of the included European case-control
samples the marker yielded a p value of 2.68x10(-18). The locus was
previously reported to be associated with Crohn´s disease, alopecia
areata, leprosy and psoriasis. For sarcoidosis, fine-mapping and
expression analysis suggest KCNK4, PRDX5, PCLB3 and, most promising,
CCDC88B, as candidates for the underlying risk gene in the associated
region.
CONCLUSION:
This study provides striking evidence for association of chromosome
11q13.1 with sarcoidosis in Europeans, and thus identified a further
genetic risk locus shared by sarcoidosis, Crohn´s disease and
psoriasis.
PMID: 22837380
http://www.ncbi.nlm.nih.gov/pubmed/22837109
Hum Mutat. 2012 Jul 26. doi: 10.1002/humu.22172.
Correlating multi-allelic copy number polymorphisms with disease
susceptibility.
Cantsilieris S, White SJ.
Source
Centre for Reproduction and Development, Monash Institute of Medical
Research, Monash University, Melbourne, Victoria, Australia; Centre
for Eye Research Australia, University of Melbourne, Royal Victorian
Eye and Ear Hospital, East Melbourne, Victoria, Australia.
Abstract
The human genome contains a significant amount of sequence variation,
from single nucleotide polymorphisms to large stretches of DNA that
may be present in a range of different copies between individuals.
Several such regions are variable in >1% of the population (referred
to as copy number polymorphisms or CNPs), and many studies have looked
for associations between the copy number of genes within multi-allelic
CNPs and disease susceptibility. Associations have indeed been
described for several genes, including the Beta-defensins (DEFB4,
DEFB103, DEFB104), Chemokine ligand 3 like 1 (CCL3L1), Fc Gamma
Receptor 3B (FCGR3B) and Complement Component C4 (C4). However, follow
up replication in independent cohorts has failed to reproduce a number
of these associations. It is clear that replicated associations such
as those between C4 and Systemic Lupus Erythamatosis, and Beta-
defensin and Psoriasis, have used robust genotyping methodologies.
Technical issues associated with genotyping sequences of high identity
may therefore account for failure to replicate other associations.
Here we compare and contrast the most popular approaches that have
been used to genotype CNPs, describe how they have been applied in
different situations, and discuss potential reasons for the difficulty
in reproducibly linking multi-allelic CNPs to complex diseases.
PMID: 22837109
http://www.ncbi.nlm.nih.gov/pubmed/22835076
Br J Dermatol. 2012 Jul 27. doi: 10.1111/j.1365-2133.2012.11170.x.
Paraoxonase (PON1) 55 polymorphism, lipid profiles and psoriasis
Asefi M, Vaisi-Raygani A, Bahrehmand F, Kiani A, Rahimi Z, Nomani H,
Ebrahimi A, Tavilani H, Pourmotabbed T.
Source
Molecular Diagnostic Research Center Kermanshah University of Medical
Sciences, Kermanshah, Iran Fertility and Infertility Research Center,
Kermanshah University of Medical Sciences, Kermanshah, Iran Department
of Clinical Biochemistry, Kermanshah University of Medical Sciences,
Kermanshah, Iran Medical Biology Research Center, Kermanshah
University of Medical Sciences, Kermanshah, Iran. Department of
Dermatology, Kermanshah University of Medical Sciences, Kermanshah,
Iran. Department of Clinical Biochemistry, Hamadan University of
Medical Sciences, Hamadan, Iran Department of Microbiology, Immunology
and Biochemistry, University of Tennessee Health Science Center, USA.
Abstract
Background: Paraoxonase (PON1) is a serum HDL-bound enzyme with an
antioxidant function. It hydrolyzes lipid peroxides protecting LDL
from oxidative modifications. Psoriatic patients are at greater risk
of oxidative stress, which is associated with abnormal plasma lipid
metabolism. Objectives: In this study, association of PON 55 M allele
with serum arylesterase (ARE) activity, Malondialdehyde (MDA), lipids
profiles and psoriasis was investigated. Methods: The present case-
control study consisted of 100 psoriatic patients with and without
cardiovascular diseases (CVD; mean age, 35.3 years) and 100 gender-
and age-matched unrelated healthy controls (mean age, 35.7 years) from
west population of Iran. PON Met 55 Leu polymorphism was detected by
PCR-RFLP, serum ARE activity, MDA, lipid and apolipoprotein levels
were determined spectrophotometrically, by HPLC and by enzyme assay,
respectively. Results: The presence of PON 55 M allele was found to
be associated with psoriasis (OR=1.96,p=0.017). The psoriasis patients
with PON M (M/L+M/M) allele had higher levels of MDA (4.12±0.88 vs.
2.24 ± 0.55 μmol/l, p<0.001), APOB/APOA1ratio(0.91 ± 0.66 vs. 0.66 ±
0.35,p=0.004), APOB(111 ± 38.7 vs. 88.3 ± 22.5 mg/ml, p=0.001), LP(a)
(21.9 ± 18.4 vs. 15.8 ± 16.6 mg/ml, p=0.034) but lower ARE activity
(39.6±11vs.45.9±11.8 IU/mL,p=0.031) than the control subjects. There
was a significant positive correlation between ARE activity with APOA1
and a negative correlation with MDA concentration in psoriatic
patients. Conclusions: PON55 M allele is a risk factor for psoriasis.
The carriers of this allele has high levels of MDA, APOB, LP(a), APOB/
APA1 and lower ARE activity. These results indicated that oxidative
stress, impairment of antioxidant system and abnormal lipid metabolism
may play a role in the pathogenesis and progression of psoriasis and
its related complications. These data suggest that psoriatic patients
are more susceptible to vascular diseases.
PMID: 22835076
4 hits: psoria* Paraoxonase -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=psoria*%20Paraoxonase%20
7 hits: Paraoxonase - p ng
https://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?q=Paraoxonase+&start=0&scoring=d&
************************************
http://www.ncbi.nlm.nih.gov/pubmed/22802640
Proc Natl Acad Sci U S A. 2012 Jul 16.
Modeling an autism risk factor in mice leads to permanent immune
dysregulation.
Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH.
Source
Biology Division, California Institute of Technology, Pasadena, CA
91125.
Abstract
Increasing evidence highlights a role for the immune system in the
pathogenesis of autism spectrum disorder (ASD), as immune
dysregulation is observed in the brain, periphery, and
gastrointestinal tract of ASD individuals. Furthermore, maternal
infection (maternal immune activation, MIA) is a risk factor for ASD.
Modeling this risk factor in mice yields offspring with the cardinal
behavioral and neuropathological symptoms of human ASD. In this study,
we find that offspring of immune-activated mothers display altered
immune profiles and function, characterized by a systemic deficit in
CD4(+) TCRβ(+) Foxp3(+) CD25(+) T regulatory cells, increased IL-6 and
IL-17 production by CD4(+) T cells, and elevated levels of peripheral
Gr-1(+) cells. In addition, hematopoietic stem cells from MIA
offspring exhibit altered myeloid lineage potential and
differentiation. Interestingly, repopulating irradiated control mice
with bone marrow derived from MIA offspring does not confer MIA-
related immunological deficits, implicating the peripheral
environmental context in long-term programming of immune dysfunction.
Furthermore, behaviorally abnormal MIA offspring that have been
irradiated and transplanted with immunologically normal bone marrow
from either MIA or control offspring no longer exhibit deficits in
stereotyped/repetitive and anxiety-like behaviors, suggesting that
immune abnormalities in MIA offspring can contribute to ASD-related
behaviors. These studies support a link between cellular immune
dysregulation and ASD-related behavioral deficits in a mouse model of
an autism risk factor.
PMID: 22802640
26 hits: maternal immune activation autism -pubmed
http://www.ncbi.nlm.nih.gov/pubmed?term=maternal%20immune%20activation%20autism
---------------------
super duper enterotypes/microbiome link from nature:
http://www.nature.com/nature/focus/humanmicrobiota/index.html
Or from mother nurture depending on how you look or think about it?
Skin in the Buggy GAME:
http://www.nature.com/news/the-skin-s-secret-surveillance-system-1.11075
The skin’s secret surveillance system
Microorganisms that reside on the skin found to influence host
immunity.
Virginia Gewin
26 July 2012
The skin has long been thought of as a mere physical barrier to attack
by pathogens. Now, however, researchers are starting to realize that
this simplistic view needs a radical rethink.
The folds, follicles and tiny oil-producing glands on the skin's
surface create a multitude of diverse habitats, each with its own
community of microbes1. Most of these 'commensals' live harmlessly on
the skin, and their presence is thought to stop pathogenic microbes
from invading the skin's habitats. But these benign residents are not
just innocent bystanders — according to a paper published today in
Science, skin-specific bacteria also influence the response from the
host's immune system to help fight off infection2.
----
http://www.nature.com/polopoly_fs/7.5544.1343318235!/image/1.11075_naik4HR.jpg_gen/derivatives/landscape_300/1.11075_naik4HR.jpg
Microorganisms (blue) living around a hair follicle in the skin can
alter the responses of immune cells.
----
Immunologist Yasmine Belkaid and her team at the National Institute of
Allergy and Infectious Diseases in Bethesda, Maryland, decided to
investigate the immunological role of the skin's resident
microorganisms, known collectively as the skin microbiome. “For the
first time, we’ve shown that the skin needs microbial signals for
proper immune-cell function,” says study author Shruti Naik, a
graduate student at the University of Pennsylvania, Philadelphia, who
is based in Belkaid's lab.
Most studies of how resident microorganisms regulate the immune system
and inflammation have focused on the gut microbiome, largely because
it is the site of greatest exposure and contains a wide diversity of
microbes. But Belkaid and her colleagues wanted to determine whether
the skin microbiome performed a similar function.
“No one had any idea of the relative magnitude of the immunological
effect in skin, or how similar any mechanisms found outside the gut
would be to those occurring inside the gut,” says Curtis Huttenhower,
a computational biologist at the Harvard School of Public Health in
Boston, Massachusetts, who is involved in the Human Microbiome
Project. “This paper is the first good demonstration I’ve seen that
shows the skin microbiome has a parallel immunological response to
that seen in the gut.”
Skin signals
To investigate these effects, Belkaid's team compared the production
of inflammatory molecules by a subset of immune cells known as T cells
from two groups of mice — one that was 'germ-free', having been raised
in a sterile environment, and another that had microbes present on the
skin. The T cells of germ-free mice produced lower levels of
inflammatory molecules than those of the control mice, suggesting that
skin bacteria are needed for proper immune cell function.
Next, to confirm that the skin microbiota rather than gut microbes
were responsible for this effect, the researchers gave normal mice
oral antibiotics that altered only gut microbes and showed that there
was no effect on the ability of skin T cells to produce inflammatory
signals.
Related stories
Microbes en masse: The sequencing machine
http://www.nature.com/news/microbes-en-masse-the-sequencing-machine-1.10985
Microbiome sequencing offers hope for diagnostics
http://www.nature.com/doifinder/10.1038/nature.2012.10299
Nature's Human Microbiota special
http://www.nature.com/nature/focus/humanmicrobiota/index.html
More related stories
http://www.nature.com/news/the-skin-s-secret-surveillance-system-1.11075#related-links
The team then colonized the germ-free mice with a bacterium often
found on human skin, Staphylococcus epidermidis. The addition of this
one species was enough to reinstate the production of an inflammatory
protein by T cells in the skin — but not in the gut. The germ-free
mice were also unable to mount an immune response to the pathogen
Leishmania major, but the addition of S. epidermidis restored their
immune response. “We showed that skin flora drive local immunity,”
says Naik.
Finally, to confirm the mechanism underpinning this cross-talk between
skin microbes and the immune system, the researchers tested mice that
were deficient in a signalling pathway known as MYD88 and found that
although it is dispensible in the gut, it is required in the skin.
“This paper takes previous observations that commensal bacteria can
have an anti-inflammatory role in the skin one step further and shows
how these organisms can affect T-cell maturation,” says Richard Gallo,
chief of dermatology at the University of California, San Diego. In
essence, commensal bacteria help to fine-tune host immune-cell
responses.
Beyond the gut
“The fact that we found that protective immunity is dependent on skin,
rather than gut, microbiota gives their role a specificity that was
lacking previously,” says study co-author Julie Segre, a skin-
microbiome researcher at the National Human Genome Research Institute
in Bethesda. There may be commonalities in how gut and skin microbiota
work, but, she adds, there will also be important differences.
Huttenhower says that this work is a timely reminder that the research
community needs to look beyond the gut to fully understand
immunological responses.
Segre notes that the findings are a first step towards detailing
whether the gut, skin or oral microbial communities communicate
directly with each other or if the skin microbiome simply primes the
immune system. “The gut microbiome has been the focus for the last ten
years,” she says. “Now it’s the skin’s turn.”
Nature doi:10.1038/nature.2012.11075
^^^^^^^^^^^^
http://www.nature.com/news/microbes-en-masse-the-sequencing-machine-1.10985
Microbes en masse: The sequencing machine
Faeces, lizards, keyboards, faces — Rob Knight likes to sequence the
microbes on anything and everything. Next, he plans to sequence Earth.
Virginia Gewin
11 July 2012
Rob Knight wants the spit of a komodo dragon. But he is unsure whether
Bintang, a metre-long juvenile of this endangered lizard species, will
oblige. Wielding a white cotton swab, Knight cautiously approaches the
creature, which is squirming in its keeper's arms at the Denver Zoo in
Colorado. With an inquisitive flick of the tongue, Bintang deposits a
dab of saliva on the swab.
Knight pops the swab into a sterile plastic tube, opens another tube
and goes on to collect samples from the lizard's head and belly. He
also swabs the enclosure, which is part of the world's most successful
facility for the captive breeding of komodo dragons (Varanus
komodoensis). The samples are teeming with the bacteria and viruses
that live in the reptile's mouth, gut and skin. Back in his lab at the
University of Colorado Boulder, Knight will sequence the DNA of these
microorganisms — and eventually compare the microbes with those found
on komodo dragons in the wild and at other facilities, to try to find
out whether and how they affect the animals' survival and why captive
females tend to die young.
If there is a link between this species' microbes and its health,
Knight is the one to find it. He is a leader in the burgeoning field
of microbiome research, which aims to sequence the mass of genes from
microbial communities and use computational tools to count and compare
species. Knight has helped to reveal differences between the gut
microbes in obese and lean people1; to show that people's intestinal
microbes differ dramatically depending on where in the world they
live2; and to document the wide differences between the microbes
acquired by babies born by Caesarean section and those delivered
vaginally3. Outside the human body, Knight has probed the microbes
that blanket various natural and man-made environments, from freshly
fallen snow to computer keyboards and bathroom floors. He does all
this at a restless, relentless pace; he co-authored 49 publications in
2011 alone.
Related stories
Microbiology: Learning about who we are
The human microbiome: at the interface of health and disease
Social network wants to sequence your gut
More related stories
Knight is sensitive to the charge that all this is an exercise in
microbial surveying, rather than in hard hypothesis-testing. “We don't
take on projects if the scientific value isn't clear,” he says. “What
motivates me, from a pragmatic standpoint, is how understanding the
microbial world might help us improve human and environmental health.”
The microbiota hold clues, he says, to solving major societal problems
— preserving endangered species, for example, or treating obesity or
malnutrition.
Since 2010, Knight has been involved with the most ambitious effort
yet to probe the microbiota: the Earth Microbiome Project, a
collaborative effort to sequence and characterize the microbial
communities in at least 200,000 environmental samples such as soils
and water collected from around the world. He says that the project,
which is led by Jack Gilbert, an environmental microbiologist at the
US Department of Energy's Argonne National Laboratory in Illinois,
will yield a master list of the proteins required to sustain microbial
life across the planet; about 500,000 reconstructed microbial genomes;
and the makings of a global-scale model of microbial metabolism.
“Knight and Gilbert literally talk about sampling the entire planet.
It is ludicrous and not feasible — yet they are doing it,” says
Jonathan Eisen, an evolutionary biologist at the University of
California, Davis. “Rob is one of the few people who are surfing the
exponential curve of increased sequencing power,” Eisen adds, “and
planning where the wave will take him next.”
Everything of interest
A tall, lanky 35-year-old, Knight doesn't look the part of a tenured
professor. He speaks so rapidly that he can be difficult to follow,
and his ideas erupt at a similar rate. The conversation can swerve
from using microbes to estimate time of death to his hopes of one day
swabbing the International Space Station to reveal its hidden
microbial life. “I've never been interested in just one thing,” he
says.
As a youth growing up in New Zealand, Knight had interests ranging
from fossils to chemistry and computers. “I didn't really have this
idea that science should be compartmentalized into biology or
physics,” he says. He was soon dabbling in both at Princeton
University in New Jersey, as he worked on a PhD project analysing the
evolution of the genetic code. He went on a self-taught computer-
programming binge, logging 12–20 hours of screen time per day, writing
code, testing programs and working out bugs.
Cathy Lozupone, a technician in the Princeton lab at the time, recalls
one night in 2000 when Knight, who was in between apartments, was
briefly staying with her. She woke at 2 a.m. to find him trembling
with excitement after solving a thorny computational problem. The
program he had devised crunched through protein-coding sequences from
600 species spanning all domains of life to show that very simple
rules involving mutation and selection could explain a major puzzle
about DNA: why different organisms prefer different coding sequences
for the same amino acid4.
“Knight and Gilbert literally talk about sampling the entire planet.
It is ludicrous and not feasible — yet they are doing it”
Knight moved to Boulder as a postdoc in 2001, and went on to run his
own group. He began attending lab meetings with famed microbiologist
Norm Pace, whose group was studying microbial diversity by sequencing
16S ribosomal RNA, a stretch of 1,500 nucleotides used for studying
evolutionary relationships. Knight saw that mass sequencing of
microbes was taking off, but that it was enormously challenging to
make sense of so much data. He developed a software tool dubbed
UniFrac (unique fraction)5, which provides a measure of the difference
between two microbial communities by constructing evolutionary trees
from the sequences in each sample and calculating the fraction of
branches that are unique to each.
UniFrac received a high-profile test when Knight teamed up with Jeff
Gordon, a leader in microbiome research at Washington University in St
Louis, Missouri, and his postdoc Ruth Ley. The researchers used
UniFrac to show that microbial populations in the guts of obese mice
differ from those in lean ones6. That paper has now been cited more
than 500 times, and the program has become a standard analytical tool
in the field. “Before UniFrac we had simply been tallying species, but
understanding whether the species were related or not gave us deeper
insights into the biology of communities,” says Ley, now a
microbiologist at Cornell University in Ithaca, New York.
Up close and personal
Fascinated by the gut's inhabitants, Knight was soon helping to chart
a course for the Human Microbiome Project (HMP) — a US$115-million
effort funded by the US National Institutes of Health to sequence the
tens of trillions of microbes that live in and on humans — which
published its major results in June7.
He also plunged into data: Knight and his colleagues showed that the
human body's bacteria vary dramatically between the gut, skin, mouth,
ears and other locations8. And by exploring the faeces of mammals
ranging from kangaroos to lemurs and zebras, Knight's team showed that
microbiota adapt to diet — be it carnivorous, herbivorous or
omnivorous — in a similar way across all mammalian lineages9. With a
rapid succession of high-profile papers, “Rob exploded onto the scene
— he went from no profile to being everywhere”, says Phil Hugenholtz,
a microbial ecologist at the Australian Centre for Ecogenomics in
Brisbane.
Knight has continued to develop software for handling the increasingly
giant data sets generated by modern sequencing technology. One
package, called QIIME (quantitative insights into microbial ecology)10
uses tools developed by Knight's group and others to simultaneously
compare millions of raw sequences, assign species names when possible,
build phylogenetic trees and visualize the data in many different
ways.
During the HMP, Knight was vocal about his concerns that the tools and
data weren't being shared effectively with the wider community. In one
case, he “challenged in a very public way” a rule that was slowing
down publication, says Owen White, associate director of the Institute
for Genome Sciences in Baltimore, Maryland, who oversees the central
data repository for the HMP. The rule was later overturned. White says
that Knight was also instrumental in shifting the centre of
intellectual power in genomic analysis from larger sequencing centres
to smaller labs. Knight says that he wants to “democratize” the data
and tools. “To maximize the output of science, it makes more sense to
do things that are good for the field overall,” he says.
http://www.nature.com/polopoly_fs/7.5296.1341936545!/image/Knight-graphic1.jpg_gen/derivatives/fullsize/Knight-graphic1.jpg
Another of his innovations lies in working out how to link sequence
data to the sample's metadata — environmental details such as pH,
temperature, salinity and collection time — so that the maximum amount
of information can be stored and extracted. “He strongly encouraged
people to get organized and put their data in a standard format so
that studies could be compared,” says Ley.
Knight has ruffled some feathers — perhaps owing to his meteoric rise
at an envy-inducing young age, or his unflinching criticism when he
thinks something is being done in the wrong way. “He's not always
terribly diplomatic,” says Ley. Some complain of “superficial, catchy”
studies, says one colleague who preferred not to be named. Knight's
work certainly can make a splash: in 2010, the popular detective
television programme CSI: Miami featured a technique developed by
Knight and Noah Fierer, a microbial ecologist at Boulder, with which
they matched individuals to the unique bacterial fingerprints that
they left on computer keyboards11 (see 'CSI: Microbes'). Knight's team
also attracted attention with as-yet unpublished work mapping the
microbes that carpet the human face from forehead to lips, and a study
documenting how the gut microbiota of a Burmese python (Python
molurus) shifted from famine to feast mode as the snake digested a rat
over three days12.
Serious business
Knight doesn't deny that he is one of two “healthy subjects” involved
in generating the largest time series of human microbiota yet
collected13: he swabbed his palms, mouth and faeces every day for 15
months for the cause. And he relishes the story of an airport official
who briefly confiscated the thermos of dry ice he was carrying to
transport the samples. Six hours later, in Knight's office, the
thermos exploded because the official had cinched down the lid too
tightly.
Knight says that all his studies have a serious intent. The time-
series data, for example, showed that there was vastly more variation
within one person's microbiota than expected. He hopes that the
finding will convince clinicians that monitoring people's microbiomes
over time could be useful in a clinical trial, allowing investigators
to, for example, test whether variations in microbiota correlate with
a drug response. “It's the kind of thing where you wouldn't want to
ask someone else to go through the trouble if you haven't demonstrated
the feasibility yourself,” he says.
Knight says he currently has about 70 papers in draft form, involving
roughly 50 principal investigators. But that looks set to increase
thanks to the Earth Microbiome Project. Knight, Gilbert and Janet
Jansson, a microbial ecologist at the Lawrence Berkeley National
Laboratory in Berkeley, California, are encouraging microbiologists
worldwide to send in samples. They have already received some 60,000,
ranging from deep-sea sediments from the Pacific Ocean to owl nests
from Alaska. The researchers, funded so far on about $3 million from
the US Department of Energy, as well as scraps from private sponsors
and their own and their contributors' funds, have sequenced around
15,000 of them. They are making all the data and tools — many of which
Knight developed or is developing — openly available.
“The Earth Microbiome Project is not a purely exploratory project,”
Knight emphasizes. The plan, he says, is to collect a number of
hypothesis-driven data sets, such as samples collected in pristine and
disturbed areas of the Australia coastline to determine whether the
disease-driven decline of algae has knock-on effects for other
organisms. By combining data sets, the team should also be able to
test broader hypotheses — such as whether the dominant microbes in a
sample always have the most important functions.
To that end, Knight continues to collect samples whenever he has the
chance; later this month, for example, he will be scraping up
microbial 'mats', which are among the most diverse communities known,
from hypersaline waters off the Californian coast. The komodo-dragon
samples are going into the project, and Knight now has approval to
sample these and other species at a further three zoos.
Knight has other ventures on the boil. In one project, he is exploring
whether gut microbial communities can influence mental health by, for
example, changing the signalling patterns between the gut and brain.
“My family has schizophrenia on one side and bipolar disorder on the
other,” he says, “which has led to my interest in trying to figure out
whether we could potentially address those conditions.” With Gordon
and Lozupone, he is also part of a global network for the study of
malnutrition and intestinal diseases, funded by the Bill & Melinda
Gates Foundation in Seattle, Washington. Working in Bangladesh, the
team hopes to identify the microbes associated with malnutrition, and
to explore potential probiotic or other microbial treatments.
Knight struggles to explain how he sustains his eclectic interests and
level of intensity. With so much to sequence, over-commitment is an
occupational hazard for everyone in microbiome research, he says.
But Gilbert says that the research community faces a challenge in
keeping up with Knight. “Unless he burns out in the next 20 years,”
says Gilbert, “I think we'll look back at him as a pioneer.”
Nature 487, 156–158 (12 July 2012) doi:10.1038/487156a
References
<snip>
^^^^^^^^^^^^^^^^^^^^^^^^^^^^
http://www.nature.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299
Microbiome sequencing offers hope for diagnostics
Scientists try to avoid the hype that dogs human-genome research.
Ed Yong
23 March 2012
Microbes have hit the big time. Results from major projects that aim
to sequence the metagenome — the trillions of microbial cells and
genes in the human body — potentially offer new ways of diagnosing and
treating a wide range of health problems. But some researchers are
warning against the dangers of hyping the data too soon.
In 2007, the US National Institutes of Health (NIH) committed US$140
million to the Human Microbiome Project, which examines all the
microorganisms in the human body. The following year, the European
Commission established the €22-million (US$29-million) Metagenomics of
the Human Intestinal Tract project (MetaHIT), which focuses on gut
bacteria. Findings from both efforts were presented at the
International Human Microbiome Congress in Paris this week.
------
http://www.nature.com/polopoly_fs/7.3528.1332512425!/image/HI-RES%20B2201377-Tongue_bacteria%2C_SEM-SPL.jpg_gen/derivatives/landscape_300/HI-RES%20B2201377-Tongue_bacteria%2C_SEM-SPL.jpg
The genetic codes of microbes in the human body, such as these tongue
bacteria (seen in a coloured scanning electron micrograph) could be
the key to more accurate diagnosis.
STEVE GSCHMEISSNER/SPL
------
Speaking at the conference, Julian Davies, a microbiologist at the
University of British Columbia in Vancouver, described the quest to
understand the microbiome as “the biggest life science project of all
time”. He added, “Everyone will benefit if this project goes well and
is done properly.”
Managing expectations
These claims echo the enthusiasm that once surrounded another ‘big
science’ initiative — the international Human Genome Project, which
published its first draft of the human genetic sequence in 20011. In
1999, Francis Collins, then director of the US National Human Genome
Research Institute in Bethesda, Maryland, and now director of the NIH,
had written2 that the human genome sequence would allow researchers to
“uncover the hereditary factors in virtually every disease”, “foretell
future disease” and “adapt therapies to the individual patient”.
But the promised advances have been slow to arrive. On the tenth
anniversary of the publication of the draft, an editorial in Nature
noted that its promise is “still to be fulfilled” (see ‘Best is yet to
come’).
Jonathan Eisen, a microbiologist at University of California, Davis,
is worried that microbiome research will eventually encounter the same
backlash. “Without a doubt we are running into some of the same
problems as the Human Genome Project,” he says. “There are many people
who have oversold the human microbiome as the cause or cure of
everything.” Eisen worries that although numerous connections have
been discovered between the microbiome and diseases, it is usually
unclear whether the microbes caused the conditions or merely exploited
a new environment.
“There’s sensitivity about the expected returns,” says David Relman,
who studies infectious disease at Stanford University in Palo Alto,
California. “We need to be grounded about what it is we’ll be able to
gain at what point in time. I think the shorter-term gains may be
around diagnostics, and novel ways of classifying both health and
disease.”
-----
Related stories
Gut microbial 'enterotypes' become less clear-cut
http://www.nature.com/doifinder/10.1038/nature.2012.10276
Bursting the genomics bubble
http://www.nature.com/doifinder/10.1038/news.2010.145
Microbiology: Straight from the gut
http://www.nature.com/doifinder/10.1038/453581a
More related stories
http://www.nature.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299#related-links
or
http://www.nature.com/nature/focus/humanmicrobiota/index.html
-----
These gains are already becoming apparent. At the Paris conference,
Jens Nielsen, a systems biologist at Chalmers University of Technology
in Gothenburg, Sweden, showed that the gut’s microbial genes may be a
better predictor of type 2 diabetes than established risk factors such
as waist–hip ratio or body mass index. Other researchers presented
results from MetaHIT that suggest that gut bacteria are more accurate
markers for leanness or obesity than any of our own genetic variants.
Rob Knight, a microbiologist at the University of Colorado Boulder,
hopes that microbiome will be similarly effective at classifying
inflammatory bowel diseases such as Crohn’s disease or ulcerative
colitis, in which “gradations are subtle and people are often
misdiagnosed”.
All the difference
The metagenome differs from person to person much more than the genome
does, which may be the key to its diagnostic potential. “There’s a
0.1% difference in our genomes, but there may be a 50% difference in
our metagenome,” says Dusko Ehrlich, a project coordinator for
MetaHIT. “If the variability is higher, you’re more likely to find a
relevant signal.”
Knight predicts that the microbiome will also prove easier to
influence than the genome. “If you want to get rid of bacteria,
pharmaceutical companies have thousands of compounds that could target
them,” he says. By contrast, finding drugs that target disease-related
genes, or altering those genes outright, is more difficult.
Attempts to modulate the microbiome are already under way, although
big advances have not yet arrived. One study published last year3
showed that probiotic yoghurt affects gut bacteria only subtly (see
‘Friendly bacteria move in mysterious ways’). "Cocktails of classic
probiotics, which people have been trying for years, may have some
benefit but the effect seems to be quite small,” says Relman. A
targeted approach that manipulates specific species could be more
effective, but, Relman adds, “I don’t think we’re there yet”.
“Let’s be careful and cautious,” agrees Ehrlich. “These are early
days, but I think there is great potential in what we see now.” He
adds, “But you can never, ever avoid disappointing people because they
always want more.”
Nature doi:10.1038/nature.2012.10299
<snip>
^^^^^^^^^^^^^
http://www.nature.com/nrmicro/journal/v10/n8/full/nrmicro2849.html
The hidden hordes
With funding for the HMP and Meta-HIT consortia now ending, what's
next for these large-scale efforts to map the hidden microbial hordes
associated with the human body?
If asked, could you immediately point to your left, or indeed your
right, retroauricular crease? How about your antecubital fossae? These
niches — behind the ears and in the crooks of the elbows, naturally —
are just two of the bodily locations examined in an investigation into
the structure, function and diversity of the microbiome in healthy
humans, which was published recently in Nature1. Along with an
accompanying framework document2, plus 15 other papers published
simultaneously in three PLoS journals and available in the PLoS Human
Microbiome Project Collection, this represents the first collective
major research output from the Human Microbiome Project (HMP)
Consortium.
there is no such thing as an overall 'core' human microbiome
Presciently termed the “second human genome” by David Relman and
Stanley Falkow back in 2001 (Ref. 3), the microbiome has been one of
the hottest topics in microbiology in recent years. The ability to
analyse human samples using the culture-independent metagenomic
sequencing techniques that were pioneered by environmental
microbiologists working in soil and marine environments was
demonstrated in 2006 (Ref. 4) by the first metagenomic analysis of the
gut microbiome in healthy humans. Since then, however, although there
have been many fascinating studies on the microbiome, the majority
have focused less on its composition and role in maintaining health
and more on its influence in diseases such as inflammatory bowel
disease and obesity, as well as its role in fundamental processes such
as the development and homeostasis of the immune system.
This balance has now begun to be redressed. The HMP study
characterized the microorganisms present at up to 18 different body
sites on the skin, oral cavity, vagina and nostrils, as well as in
faecal samples, for 242 healthy individuals aged 18–40 and living in
two different geographical locations in the United States. The general
take-home message from the work, which combined 16S rRNA profiling
with metagenomic and whole-genome sequencing, is that each
individual's microbiome is unique, suggesting that there is no such
thing as an overall 'core' human microbiome. Each niche was
characterized by one or a few signature taxa and, overall, diversity
was greatest in the gut and oral cavity, and least in the vagina. Just
over half of the volunteers were sampled at more than one time point,
and there appeared to be little variation over time.
Officially launched in 2008, and funded to the tune of ~US$150 million
by the US National Institutes of Health (NIH) Common Fund, the HMP
received funding for a 5-year period, which is now coming to an end.
There are, of course, other major consortia working on the microbiome,
the largest of which is Meta-HIT (Metagenomics of the Human Intestinal
Tract), which, as the name suggests, has focused exclusively on the
intestine. Meta-HIT, which involves researchers from the European
Union and China, was launched in 2008 and received [euro]22 million
from the European Commission Seventh Framework Programme over a 4-year
period, which has also just ended. The main research finding from Meta-
HIT was that in European adults the gut microbiota segregates into
three main enterotypes5, although subsequent studies involving larger
sample sizes — including one of the recent HMP papers6 — have
suggested that this segregation is less discrete and more of a
continuum.
The amount of data associated with these projects is staggering. The
HMP has generated 3.5 terabytes, more than 1,000 times that generated
by the Human Genome Project. But so far the data have raised more
questions than answers, and most investigators are clear that there is
an urgent need for broader, more multicultural analyses that track
individuals over a much longer period of time. Although there is still
a definite need for consortia, a combination of this top-down approach
with more bottom-up, investigator- and hypothesis-led approaches is
the most desirable way forward for many. The NIH Common Fund office is
currently investigating possible funding options for an HMP2, and a
first call for proposals in health-related research under the next
European Framework Programme is expected in January 2014.
The results of all the microbiome-related research so far have
emphasized the pervasive influence of the hidden hordes within. It is
to be hoped that, even in these straitened times, the crucial
importance of this work will be realized and it will continue to be
funded.
<snip>
OK this was FUN... hidden hordes of bugs and i'm gonna get autistic
skin in this game and drink lavender and then di or eat pi?
pass the pi... please.
randall... is there lavender in this pi(e)?
0 new messages