Nature. 2009 Mar 12;458(7235):165-71.
9202...1
‫אלקסאנדר‬
Comment in: Nature. 2009 Mar 12;458(7235):156-7.
The neural basis of Drosophila gravity-sensing and hearing.
Kamikouchi A, Inagaki HK, Effertz T, Hendrich O, Fiala A, Göpfert MC, Ito K.
The neural substrates that the fruitfly Drosophila uses to sense smell, taste and
light share marked structural and functional similarities with ours, providing attractive
models to dissect sensory stimulus processing. Here we focus on two of the remaining
and less understood prime sensory modalities: graviception and hearing. We show that
the fly has implemented both sensory modalities into a single system, Johnston's organ,
which houses specialized clusters of mechanosensory neurons, each of which monitors
specific movements of the antenna. Gravity- and sound-sensitive neurons differ in their
response characteristics, and only the latter express the candidate mechanotransducer
channel NompC. The two neural subsets also differ in their central projections, feeding
into neural pathways that are reminiscent of the vestibular and auditory pathways in our
brain. By establishing the Drosophila counterparts of these sensory systems, our findings
provide the basis for a systematic functional and molecular dissection of how different
mechanosensory stimuli are detected and processed.
PMID: 19279630
Nature. 2009 Mar 1. [Epub ahead of print].
9202...1
‫איתן‬
Toxin B is essential for virulence of Clostridium difficile.
Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R,
Adams V, Vedantam G, Johnson S, Gerding DN, Rood JI.
Clostridium difficile is the leading cause of infectious diarrhoea in hospitals
worldwide, because of its virulence, spore-forming ability and persistence. C. difficileassociated diseases are induced by antibiotic treatment or disruption of the normal
gastrointestinal flora. Recently, morbidity and mortality resulting from C. difficileassociated diseases have increased significantly due to changes in the virulence of the
causative strains and antibiotic usage patterns. Since 2002, epidemic toxinotype III
NAP1/027 strains, which produce high levels of the major virulence factors, toxin A and
toxin B, have emerged. These toxins have 63% amino acid sequence similarity and are
members of the large clostridial glucosylating toxin family, which are monoglucosyltransferases that are pro-inflammatory, cytotoxic and enterotoxic in the human colon.
Inside host cells, both toxins catalyse the transfer of glucose onto the Rho family of
GTPases, leading to cell death. However, the role of these toxins in the context of a C.
difficile infection is unknown. Here we describe the construction of isogenic tcdA and tcdB
(encoding toxin A and B, respectively) mutants of a virulent C. difficile strain and their use
in the hamster disease model to show that toxin B is a key virulence determinant. Previous
studies showed that purified toxin A alone can induce most of the pathology observed after
infection of hamsters with C. difficile and that toxin B is not toxic in animals unless it is
co-administered with toxin A, suggesting that the toxins act synergistically. Our work
provides evidence that toxin B, not toxin A, is essential for virulence. Furthermore, it is
clear that the importance of these toxins in the context of infection cannot be predicted
exclusively from studies using purified toxins, reinforcing the importance of using the
natural infection process to dissect the role of toxins in disease.
PMID: 19252482
Nat Genet. 2009 Feb;41(2):251-7.
9202...1
‫איילת‬
Comment in:
Nat Genet. 2009 Feb;41(2):142-3.
Experimental evolution reveals natural selection on standing genetic variation.
Teotónio H, Chelo IM, Bradić M, Rose MR, Long AD.
Evolution depends on genetic variation generated by mutation or recombination
from standing genetic variation. In sexual organisms, little is known about the molecular
population genetics of adaptation and reverse evolution. We carry out 50 generations of
experimental reverse evolution in populations of Drosophila melanogaster, previously
differentiated by forward evolution, and follow changes in the frequency of SNPs in both
arms of the third chromosome. We characterize the effects of sampling finite population
sizes and natural selection at the genotype level. We demonstrate that selection has
occurred at several loci and further that there is no general loss or gain of allele diversity.
We also observe that despite the complete convergence to ancestral levels of adaptation,
allele frequencies only show partial return.
PMID: 19136954
Nature. 2009 Jan 15;457(7227):277-80.
90202...1
‫דפנה‬
Comment in: Nature. 2009 Jan 15;457(7227):269-70.
Induced pluripotent stem cells from a spinal muscular atrophy patient.
Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN.
Spinal muscular atrophy is one of the most common inherited forms of
neurological disease leading to infant mortality. Patients have selective loss of lower
motor neurons resulting in muscle weakness, paralysis and often death. Although patient
fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons
have a unique anatomy and physiology which may underlie their vulnerability to the
disease process. Here we report the generation of induced pluripotent stem cells from
skin fibroblast samples taken from a child with spinal muscular atrophy. These cells
expanded robustly in culture, maintained the disease genotype and generated motor
neurons that showed selective deficits compared to those derived from the child's
unaffected mother. This is the first study to show that human induced pluripotent stem
cells can be used to model the specific pathology seen in a genetically inherited disease.
As such, it represents a promising resource to study disease mechanisms, screen new
drug compounds and develop new therapies.
PMID: 19098894
Nature. 2009 Feb 22. [Epub ahead of print]
90202...1
‫אירנה‬
Inactivation of the Fto gene protects from obesity.
Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, Rüther U.
Several independent, genome-wide association studies have identified a strong
correlation between body mass index and polymorphisms in the human FTO gene.
Common variants in the first intron define a risk allele predisposing to obesity, with
homozygotes for the risk allele weighing approximately 3 kilograms more than
homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy
homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal
growth retardation and a significant reduction in adipose tissue and lean body mass. The
leanness of Fto-deficient mice develops as a consequence of increased energy
expenditure and systemic sympathetic activation, despite decreased spontaneous
locomotor activity and relative hyperphagia. Taken together, these experiments provide,
to our knowledge, the first direct demonstration that Fto is functionally involved in
energy homeostasis by the control of energy expenditure.
PMID: 19234441
Nature. 2009 Jan 22;457(7228):480-4.
90202...1
‫אלענה‬
A core gut microbiome in obese and lean twins.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML,
Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon
JI.
The human distal gut harbours a vast ensemble of microbes (the microbiota) that
provide important metabolic capabilities, including the ability to extract energy from
otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults
have revealed substantial diversity in their gut communities, as measured by sequencing
16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in
the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies
of lean and obese mice suggest that the gut microbiota affects energy balance by
influencing the efficiency of calorie harvest from the diet, and how this harvested energy
is used and stored. Here we characterize the faecal microbial communities of adult female
monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their
mothers, to address how host genotype, environmental exposure and host adiposity
influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length
and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their
microbiomes. The results reveal that the human gut microbiome is shared among family
members, but that each person's gut microbial community varies in the specific bacterial
lineages present, with a comparable degree of co-variation between adult monozygotic
and dizygotic twin pairs. However, there was a wide array of shared microbial genes
among sampled individuals, comprising an extensive, identifiable 'core microbiome' at
the gene, rather than at the organismal lineage, level. Obesity is associated with phylumlevel changes in the microbiota, reduced bacterial diversity and altered representation of
bacterial genes and metabolic pathways. These results demonstrate that a diversity of
organismal assemblages can nonetheless yield a core microbiome at a functional level,
and that deviations from this core are associated with different physiological states (obese
compared with lean).
PMID: 19043404
Nature. 2009 Mar 11. [Epub ahead of print]
0202...1
‫חני‬
Tumours with PI3K activation are resistant to dietary restriction.
Kalaany NY, Sabatini DM.
Dietary restriction delays the incidence and decreases the growth of various types
of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction
remain unknown. Here we show that certain human cancer cell lines, when grown as
tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary
restriction, whereas others are resistant. Cancer cells that form dietary-restrictionresistant tumours carry mutations that cause constitutive activation of the
phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of
insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K
with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN
expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restrictionresistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not
affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour
burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the
PI3K pathway is an important determinant of the sensitivity of tumours to dietary
restriction, and activating mutations in the pathway may influence the response of
cancers to dietary restriction-mimetic therapies.
PMID: 19279572
Science. 2009 Mar 6;323(5919):1339-43.
0202...1
‫דנה‬
Molecular and evolutionary history of melanism in North American gray wolves.
Anderson TM, vonHoldt BM, Candille SI, Musiani M, Greco C, Stahler DR, Smith DW,
Padhukasahasram B, Randi E, Leonard JA, Bustamante CD, Ostrander EA, Tang H,
Wayne RK, Barsh GS.
Morphological diversity within closely related species is an essential aspect of
evolution and adaptation. Mutations in the Melanocortin 1 receptor (Mc1r) gene
contribute to pigmentary diversity in natural populations of fish, birds, and many
mammals. However, melanism in the gray wolf, Canis lupus, is caused by a different
melanocortin pathway component, the K locus, that encodes a beta-defensin protein that
acts as an alternative ligand for Mc1r. We show that the melanistic K locus mutation in
North American wolves derives from past hybridization with domestic dogs, has risen to
high frequency in forested habitats, and exhibits a molecular signature of positive
selection. The same mutation also causes melanism in the coyote, Canis latrans, and in
Italian gray wolves, and hence our results demonstrate how traits selected in
domesticated species can influence the morphological diversity of their wild relatives.
PMID: 19197024
Neuron. 2009 Feb 12;61(3):373-84.
9.2.02...1
2‫שרון מ‬
Motor control in a Drosophila taste circuit.
Gordon MD, Scott K.
Tastes elicit innate behaviors critical for directing animals to ingest nutritious
substances and reject toxic compounds, but the neural basis of these behaviors is not
understood. Here, we use a neural silencing screen to identify neurons required for a
simple Drosophila taste behavior and characterize a neural population that controls a
specific subprogram of this behavior. By silencing and activating subsets of the defined
cell population, we identify the neurons involved in the taste behavior as a pair of motor
neurons located in the subesophageal ganglion (SOG). The motor neurons are activated
by sugar stimulation of gustatory neurons and inhibited by bitter compounds; however,
experiments utilizing split-GFP detect no direct connections between the motor neurons
and primary sensory neurons, indicating that further study will be necessary to elucidate
the circuitry bridging these populations. Combined, these results provide a general
strategy and a valuable starting point for future taste circuit analysis.
PMID: 19217375
Mol Cell. 2009 Feb 27;33(4):462-71.
9.202...1
2‫שרון ט‬
Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.
Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG, Farnebo M.
Antisense transcription is a widespread phenomenon in the mammalian genome.
It is thought to play a role in regulation of gene expression, but its exact functional
significance is largely unknown. We have identified a natural antisense transcript of p53,
designated Wrap53, that regulates endogenous p53 mRNA levels and further induction of
p53 protein by targeting the 5' untranslated region of p53 mRNA. siRNA knockdown of
Wrap53 results in significant decrease in p53 mRNA and suppression of p53 induction
upon DNA damage. Conversely, overexpression of Wrap53 increases p53 mRNA and
protein levels. Blocking of potential Wrap53/p53 RNA hybrids reduces p53 levels nearly
as efficiently as Wrap53 knockdown, strongly suggesting that Wrap53 regulates p53 via
Wrap53/p53 RNA interaction. Furthermore, induction of Wrap53 sensitizes cells for p53dependent apoptosis. This discovery not only reveals a regulatory pathway for controlling
p53, but also proposes a general mechanism for antisense-mediated gene regulation in
human cells.
PMID: 19250907
Immunity. 2009 Feb;30(2):218-27.
91202...1
‫נועה‬
Comment in: Immunity. 2009 Feb;30(2):171-3.
Selected Toll-like receptor ligands and viruses promote helper-independent cytotoxic T cell
priming by upregulating CD40L on dendritic cells.
Johnson S, Zhan Y, Sutherland RM, Mount AM, Bedoui S, Brady JL, Carrington EM,
Brown LE, Belz GT, Heath WR, Lew AM.
CD40L (CD154) on CD4(+) T cells has been shown to license dendritic cells
(DCs) via CD40 to prime cytotoxic T lymphocyte (CTL) responses. We found that the
converse (CD40L on DCs) was also important. Anti-CD40L treatment decreased
endogenous CTL responses to both ovalbumin and influenza infection even in the
absence of CD4(+) T cells. DCs expressed CD40L upon stimulation with agonists to
Toll-like receptor 3 (TLR3) and TLR9. Moreover, influenza infection, which stimulates
CTLs without help, upregulated CD40L on DCs, but herpes simplex infection, which
elicits CTLs through help, did not. CD40L-deficient (Cd40lg(-/-)) DCs are suboptimal
both in vivo in bone marrow chimera experiments and in vitro in mixed lymphocyte
reactions. In contrast, Cd40lg(-/-) CD8(+) T cells killed as effectively as wild-type cells.
Thus, CD40L upregulation on DCs promoted optimal priming of CD8(+) T cells without
CD4(+) T cells, providing a mechanism by which pathogens may elicit helperindependent CTL immunity.
PMID: 19200758
Nature. 2009 Feb 5;457(7230):731-5.
91202...1
‫צבי‬
Chlamydia causes fragmentation of the Golgi compartment to ensure reproduction.
Heuer D, Lipinski AR, Machuy N, Karlas A, Wehrens A, Siedler F, Brinkmann V, Meyer
TF.
The obligate intracellular bacterium Chlamydia trachomatis survives and
replicates within a membrane-bound vacuole, termed the inclusion, which intercepts host
exocytic pathways to obtain nutrients. Like many other intracellular pathogens, C.
trachomatis has a marked requirement for host cell lipids, such as sphingolipids and
cholesterol, produced in the endoplasmic reticulum and the Golgi apparatus. However,
the mechanisms by which intracellular pathogens acquire host cell lipids are not well
understood. In particular, no host cell protein responsible for transporting Golgi-derived
lipids to the chlamydial inclusions has yet been identified. Here we show that Chlamydia
infection in human epithelial cells induces Golgi fragmentation to generate Golgi
ministacks surrounding the bacterial inclusion. Ministack formation is triggered by the
proteolytic cleavage of the Golgi matrix protein golgin-84. Inhibition of golgin-84
truncation prevents Golgi fragmentation, causing a block in lipid acquisition and
maturation of C. trachomatis. Golgi fragmentation by means of RNA-interferencemediated knockdown of distinct Golgi matrix proteins before infection enhances bacterial
maturation. Our data functionally connect bacteria-induced golgin-84 cleavage, Golgi
ministack formation, lipid acquisition and intracellular pathogen growth. We show that C.
trachomatis subverts the structure and function of an entire host cell organelle for its own
advantage.
PMID: 19060882