bluuebunny/crossref_metadata_2025 huggingface dataset:
Against the CLOCK
Authors: Foley John F.
Published: September 2008

The feedback loop that controls the circadian clock includes the proteins CLOCK and BMAL1, which form a complex that binds to regulatory elements of circadian clock genes and drives their transcription. Two such genes are
Period
(
Per
) and
Cryptochrome
(
Cry
), whose products PER and CRY accumulate and then inhibit the activity of CLOCK-BMAL1. This feedback loop is entrained in the brain by light-dark cycles, but feeding behavior also seems to play some role. CLOCK was recently characterized as a histone acetyltransferase (HAT), which acetylates histone proteins to facilitate gene transcription, but CLOCK also acetylates nonhistone proteins, including BMAL1. Two groups have now identified the NAD
+
-dependent protein SIRT1 as the histone deacetylase (HDAC) that counteracts CLOCK. Asher
et al
. found that the abundance of SIRT1 was regulated in a circadian manner in mouse embryonic fibroblasts; that SIRT1 was necessary for the circadian expression of circadian clock genes; and that SIRT1 bound to CLOCK-BMAL1 and PER2 in a circadian manner. SIRT1 also deacetylated PER2, which promoted its degradation. Nakahata
et al
. found that the HDAC activity, but not the abundance, of SIRT1 was under circadian control and that knockout of
Sirt1
changed the circadian expression of circadian clock genes. SIRT1 was found in a chromatin complex with CLOCK-BMAL1 at the promoter of the circadian clock gene
Dbp
, where it contributed to the cyclical acetylation-deacetylation of histone H3 and BMAL1. As for PER2, deacetylation of BMAL1 led to its degradation. In commentary, Belden and Dunlap focus more on the similarities than on the differences between these two studies. Because its activity is dependent on NAD
+
and thus is affected by metabolism, SIRT1 may be the link that enables metabolic control of the circadian clock.

G. Asher, D. Gatfield, M. Stratmann, H. Reinke, C. Dibner, F. Kreppel, R. Mostoslavsky, F. W. Alt, U. Schibler, SIRT1 regulates circadian clock gene expression through PER2 deacetylation.
Cell
134
, 317-328 (2008).
[Online Journal]

Y. Nakahata, M. Kaluzova, B. Grimaldi, S. Sahar, J. Hirayama, D. Chen, L. P. Guarente, P. Sassone-Corsi, The NAD
+
-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control.
Cell
134
, 329-340 (2008).
[Online Journal]

W. J. Belden, J. C. Dunlap, SIRT1 is a circadian deacetylase for core clock components.
Cell
134
, 212-214 (2008).
[Online Journal]
Switching from Blue to Green
Authors: Gough Nancy R.
Published: September 2008

Fly larvae have "eyes" that help the larvae avoid light and contribute to entraining the circadian clock to light. Each eye is composed of four photoreceptor cells that sense blue light and eight photoreceptor cells that sense green light. The wavelength of light detected is controlled by the presence of particular rhodopsins, specifically Rh5 for blue light and Rh6 for green light. This larval eye metamorphoses into an organ called the eyelet that contains four Rh6 photoreceptors and is involved only in entraining the circadian clock in the adult. By tagging the eye cells in the larvae, Sprecher and Desplan found that the eight Rh6 photoreceptor cells died and the four Rh5 photoreceptor cells switched their
rhodopsin
expression profile to become Rh6 photoreceptor cells in the adult eyelet. The hormone ecdysone, which is a master regulator of metamorphosis, was required for the development of the eyelet. If the function of the ecdysone receptor (EcR) was compromised in the larval Rh6 cells, then an eyelet formed with 12 Rh6 photoreceptor cells. If EcR function was blocked only in the Rh5 cells, then these cells failed to undergo the switch to become Rh6 photoreceptor cells, thus producing a four-cell eyelet with Rh5 photoreceptors. The transcription factor Senseless (Sens), which was only present in the larval Rh5 photoreceptor cells, was required for survival of the Rh5 photoreceptor cells. If misexpressed in the larval Rh6 photoreceptor cells, those cells survived, producing the enlarged Rh6 photoreceptor eyelet with 12 cells. The change from Rh5 to Rh6 photoreceptor is an example of sensory plasticity and fate switching of differentiated cells.

S. G. Sprecher, C. Desplan, Switch of
rhodopsin
expression in terminally differentiated
Drosophila
sensory neurons.
Nature
454
, 533-537 (2008).
[PubMed]
Why Aging Muscles Don't Repair
Authors: Gough Nancy R.
Published: September 2008

As we get older, our muscles don't recover from even minor exercise-induced injury very well. Carlson
et al
. show that the muscles of young mice have higher Notch signaling than transforming growth factor-β (TGF-β) signaling and that in older mice this is reversed, with TGF-β signaling exceeding that of Notch. TGF-β and the abundance of phosphorylated Smad3 (pSmad3) were increased in aged muscle tissue that was not injured or after injury, compared with that in muscles from young animals. Knockdown of Smad3 in muscles in old mice resulted in enhanced regeneration of the muscle after injury. Further, knockdown of Smad3 resulted in decreased abundance of the cyclin-dependent kinase (CDK) inhibitors p15 and p21, which are encoded by genes regulated by Smad3. A function-blocking antibody against TGF-β also restored muscle repair in old muscles, and exposure of young muscles to recombinant TGF-β led to scarring. Satellite cells (muscle stem cells) isolated from injured muscle were cultured with TGF-β in the presence of conditions that activated Notch, and the TGF-β-mediated increase in CDK inhibitors was decreased by activation of Notch. pSmad3-specific chromatin immunoprecipitation assays in satellite cells exposed to conditions that activate Notch in the presence or absence of TGF-β showed that active Notch and pSmad3 interact at the promoters of the Smad3-regulated genes--
p15
,
p16
,
p21
, and
p27
. Forced activation of Notch decreased the presence of Smad3 at the target promoters, even in the presence of TGF-β. Thus, Notch appears to directly antagonize Smad3-mediated induction of genes encoding inhibitors of the cell cycle. The loss of this antagonism appears to contribute to the loss of regenerative potential of muscles in older animals.

M. E. Carlson, M. Hsu, I. M. Conboy, Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.
Nature
454
, 528-532 (2008).
[PubMed]
Brassinosteroid Signaling
Authors: Hines Pamela J.
Published: September 2008

Brassinosteroids, a type of steroid hormone in plants, regulate a variety of developmental processes. Some genetic targets and signaling components targeted by the brassinosteroids have been identified, but the full chain of command remains unclear. By focusing their attention on proteins in the plasma membrane or proteins modified by phosphorylation, Tang
et al
. were able to identify two previously unknown kinases (BSK1 and BSK2) that interact with the brassinosteroid receptor at the plasma membrane. BRI1 kinase, the brassinosteroid receptor, phosphorylates these two substrate kinases to activate downstream brassinosteroid signaling.

W. Tang, T.-W. Kim, J. A. Oses-Prieto, Y. Sun, Z. Deng, S. Zhu, R. Wang, A. L. Burlingame, Z.-Y. Wang, BSKs mediate signal transduction from the receptor kinase BRI1 in
Arabidopsis.
Science
321
, 557-560 (2008).
[Abstract]
[Full Text]
Human Immunity—Naturally
Authors: Kelner Katrina L.
Published: September 2008

Animal models continue to influence our understanding of immunity to infection, but how accurately do they predict how our own immune systems respond to different pathogens? Von Bernuth
et al
. continue a series of studies in which they use rare human immune deficiencies to help unpick the roles played by distinct innate immune pathways. The study focuses on MyD88, a signaling adaptor that is crucial in mice for protection against a wide range of pathogens by connecting key Toll-like receptor (TLR) and interleukin-1 (IL-1) pathways to the activation of immune response genes. In contrast to findings in mice, deficiency of the same protein in the human patients caused susceptibility to only a handful of pyogenic bacteria, despite leaving the subjects with broad deficits in their TLR and IL-1 responses.

H. von Bernuth, C. Picard, Z. Jin, R. Pankla, H. Xiao, C.-L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, J. Vasconcelos, N. Sirvent, M. Guedes, A. B. Vitor, M. J. Herrero-Mata, J. I. Aróstegui, C. Rodrigo, L. Alsina, E. Ruiz-Ortiz, M. Juan, C. Fortuny, J. Yagüe, J. Antón, M. Pascal, H.-H. Chang, L. Janniere, Y. Rose, B.-Z. Garty, H. Chapel, A. Issekutz, L. Maródi, C. Rodriguez-Gallego, J. Banchereau, L. Abel, X. Li, D. Chaussabel, A. Puel, J.-L. Casanova, Pyogenic bacterial infections in humans with MyD88 deficiency.
Science
321
, 691-696 (2008).
[Abstract]
[Full Text]
The Pain Specialists
Authors: Stern Peter
Published: September 2008

In pain research, it has been assumed that most nociceptive neurons are polymodal, responding to different damaging stimuli by means of a repertoire of cell surface receptors specialized for the detection of particular types of insult. Attempts to ascribe pain modalities and behavior to individual sensory neuron receptors have been problematic, probably because of the existence of multiple damage-sensing molecules. Now, however, by genetically ablating subsets of nociceptors, followed by behavioral and electrophysiological assays, Abrahamsen
et al.
have found that sensory neurons expressing a specific type of sodium channel (Na
v
1.8) have a modality-specific function in pain transmission. Na
v
1.8-expressing sensory neurons are essential for cold, mechanical, and inflammatory pain behavior. Strikingly, neuropathic and heat pain behavior do not require Na
v
1.8-expressing neurons.

B. Abrahamsen, J. Zhao, C. O. Asante, C. M. Cendan, S. Marsh, J. P. Martinez-Barbera, M. A. Nassar, A. H. Dickenson, J. N. Wood, The cell and molecular basis of mechanical, cold, and inflammatory pain.
Science
321
, 702-705 (2008).
[Abstract]
[Full Text]
pathFinder: A Static Network Analysis Tool for Pharmacological Analysis of Signal Transduction PathwaysA presentation from the Experimental Biology 2008 Meeting, San Diego, California, USA, 5 to 9 April 2008
Authors: Samal Babru B. , Eiden Lee E.
Published: September 2008

The study of signal transduction is becoming a de facto part of the analysis of gene expression and protein profiling techniques. Many online tools are used to cluster genes in various ways or to assign gene products to signal transduction pathways. Among these, pathFinder is a unique tool that can find signal transduction pathways between first, second, or nth messengers and their targets within the cell. pathFinder can identify qualitatively all possible signal transduction pathways connecting any starting component and target within a database of two-component pathways (directional dyads). One or more intermediate pathway components can be excluded to simulate the use of pharmacological inhibitors or genetic deletion (knockout). Missing elements in a pathway connecting the activator or initiator and target can also be inferred from a null pathway result. The value of this static network analysis tool is illustrated by the predication from pathFinder analysis of a novel cyclic AMP–dependent, protein kinase A–independent signaling pathway in neuroendocrine cells, which has been experimentally confirmed.
The Benefits of Exercise Without the Sweat
Authors: Gough Nancy R.
Published: September 2008

Skeletal muscle is one of the many organs that exhibit adaptations in response to exercise. Skeletal muscle undergoes a transcriptional reprogramming to increase mitochondrial biogenesis and oxidative phosphorylation, fatty acid oxidation, and slow-twitch contractile proteins, which not only contribute to enhanced performance and endurance but also contribute to protection from obesity and metabolic disorders. Overexpression of an activated form of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the skeletal muscles of mice appears to preprogram muscle fibers to an oxidative phenotype and increases running endurance in untrained mice. Treatment of adult mice with the PPARγ agonist GW1516 in combination with exercise increases endurance and reprograms skeletal muscle. Narkar
et al
. show that GW1516 does not increase endurance in the absence of exercise and that both are necessary to increase the proportion of slow-twitch muscle, increase mitochondrial biogenesis, and increase the transcription of genes involved in fatty acid storage and uptake. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is constitutively activated in the muscles of the transgenic mice overexpressing activated PPARγ. Treatment of mice with AICAR, an AMPK agonist, increased their endurance in the absence of any training. AMPK activation with AICAR combined with PPARγ activation with GW1516 in sedentary mice produced a transcriptional profile that was unique (189 genes), but 52 of these overlapped with many of the genes regulated by exercise combined with activation of PPARγ with GW1516 (130 genes). Primary muscle cultures from wild-type or PPARγ-null mice revealed that the effects of GW1516 and AICAR on gene expression required PPARγ. Transfected AD293 cells revealed that the α subunits of AMPK coimmunoprecipitated with PPARγ but did not appear to phosphorylate PPARγ. Thus, AMPK may promote PPARγ activity either through a protein-protein interaction or by phosphorylating coactivators. Although the ability of a single drug to mimic the effects of exercise in skeletal muscle in mice is tantalizing, it remains to be determined whether these results can be extrapolated to humans and what effects activation of AMPK may have on other organs that are important for mediating the health benefits of exercise (see Richter
et al
.).

V. A. Narkar, M. Downes, R. T. Yu, E. Embler, Y.-X. Wang, E. Banayo, M. M. Mihaylova, M. C. Nelson, Y. Zou, H. Juguilon, H. Kang, R. J. Shaw, R. M. Evans, AMPK and PPARγ agonists are exercise mimetics.
Cell
134
, 405-415 (2008).
[PubMed]

E. A. Richter, B. Kiens, J. F. P. Wojtaszewski, Can exercise mimetics substitute for exercise?
Cell Metab.
8
, 96-98 (2008).
[PubMed]
Fleeing Overexposure
Authors: Adler Elizabeth M.
Published: September 2008

Locomotion in the nematode
Caenorhabditis elegans
depends on neuronal Gα
q
and Gα
s
signaling pathways involved in synaptic function. Thus, worms in which either of these signaling pathways are nonfunctional are virtually paralyzed. Edwards
et al
. found that exposure to blue-violet light restored coordinated locomotion to worms with loss-of-function mutations affecting either Gα
q
or Gα
s
signaling pathways. Only short-wavelength light was effective in eliciting locomotion, through a mechanism that did not depend on temperature change, with the maximal response occurring with exposure to ultraviolet light. Prolonged exposure to short-wavelength light was lethal, and, given the option, wild-type worms avoided short-wavelength illumination. A forward genetic screen for motile worms that lacked a locomotive response to short-wavelength light implicated a protein that the authors called LITE-1. Intriguingly, LITE-1 is unrelated to any known photoreceptor protein but instead resembles an insect Gustatory receptor (Gr) protein. When
lite-1
was expressed in the neurons of
lite-1
-null mutant worms, it restored light-induced locomotion; when heterologously expressed in body wall and egg-laying muscles, it elicited light-induced contraction and egg expulsion. Thus, the authors conclude that LITE-1 represents a photoreceptor for ultraviolet light that may allow
C. elegans
to avoid lethal exposure to sunlight.

S. L. Edwards, N. K. Charlie, M. C. Milfort, B. S. Brown, C. N. Gravlin, J. E. Knecht, K. G. Miller, A novel molecular solution for ultraviolet light detection in
Caenorhabditis elegans
.
PLoS Biol.
6
, e198 (2008).
[PubMed]
Coupling Secretion with Transcription
Authors: Gough Nancy R.
Published: September 2008

Bacterial virulence factor secretion systems, which contribute to pathogenicity, are assembled when bacteria encounter host cells.
Mycobacterium tuberculosis
, which causes tuberculosis, produces a type VII secretion system (also called the ESX-1 protein secretion system). In a screen for ESX-1 secretion mutants, Raghavan
et al
. identified
Rv3849
, which encodes a secreted protein that they named EspR for ESX-1 secreted protein regulator. In wild-type bacteria, EspR was secreted by the secretion system. However, mutants defective in EspR function exhibited not only lack of EspR secretion but also diminished secretion of other factors, such as ESAT-6. Thus, EspR was not only a substrate of the secretion system but also required for proper function of the ESX-1 system. Secondary structure modeling suggested that EspR had a helix-turn-helix DNA binding domain and in the
Rv3849
−
cells three operons were activated and two operons were less active, including one
Rv3616c
-
Rv3612c
that encodes proteins that are necessary for the ESX-1 system. After phagocytosis by macrophages,
Rv3849
−
cells exhibited decreased induction of the
Rv3616c
-
Rv3612c
operon. Expression of
M. tuberculosis
EspR in a nonpathogenic relative that also expressed a
Rv3616c
promoter reporter showed that EspR stimulated transcription, and electrophoretic mobility shift assays confirmed that EspR bound the
Rv3616c
promoter. Forced expression of
Rv3616c
-
Rv3612c
using a constitutive promoter restored ESX-1 function in EspR-deficient bacteria, suggesting that the transcriptional activity is the relevant mechanism by which EspR contributes to ESX-1 secretion. Addition of an epitope tag to EspR blocked its secretion without compromising its transcriptional activity, and expression of the tagged EspR resulted in enhanced repression of EspR-inhibited genes and enhanced expression of EspR-activated genes. Thus, secretion of EspR appears to serve as a homeostatic mechanism to couple secretion with transcription of the genes encoding secretory system components.

S. Raghavan, P. Manzanillo, K. Chan, C. Dovey, J. S. Cox, Secreted transcription factor controls
Mycobacterium tuberculosis
virulence.
Nature
454
, 717-721 (2008).
[PubMed]
Avoiding a Traffic Jam
Authors: Adler Elizabeth M.
Published: September 2008

Proteins destined for secretion are delivered from the endoplasmic reticulum (ER) to the Golgi complex, which they must traverse en route to the plasma membrane. Noting that exit from the ER of procollagen-I is temperature-dependent, Pulvirenti
et al
. shifted the temperature of human skin fibroblasts from 40
o
C to 32
o
C to deliver a "pulse" of cargo to the Golgi and found that tyrosine phosphorylation in the Golgi region increased in parallel with the arrival and accumulation of procollagen-I after relief of ER export block. A combination of immunoblot and pharmacological analysis of cells homogenized during or after block indicated that trafficking was associated with the phosphorylation and activation of Src-family tyrosine kinases (SFKs). Immunofluorescence and immunoelectron microscopy confirmed localization of trafficking-induced phosphorylated SFK to the Golgi; trafficking did not, however, affect the total amount of Golgi-SFK. ER chaperones that accompany cargo proteins bind to the transmembrane KDEL receptor (KDEL-R) in the Golgi, triggering retrograde movement of KDEL-R and thereby recycling chaperones to the ER (see Asp and Nilsson), and the authors explored the role of KDEL-R in SFK activation in various cell types. Introduction of KDEL-R ligands (through endocytosis or transfection) stimulated phosphorylation of Golgi-associated SFKs, as did KDEL-R overexpression. In contrast, transfection of a KDEL-R dominant-negative mutant, microinjection of antibody directed against the KDEL-R cytosolic C-terminal tail, or depletion of KDEL-R with siRNA inhibited trafficking-induced activation of Golgi-localized SFKs. The KDEL-R C-terminal domain bound Src in a yeast two-hybrid assay; moreover, SFK inhibitors, depletion of Src with siRNA, and a Src dominant-negative mutant all inhibited intra-Golgi trafficking of a cargo protein. In contrast, a constitutively active Src mutant antagonized inhibition of trafficking by the KDEL-R dominant-negative. The authors thus conclude that KDEL-R binding by chaperones that accompany cargo initiates an SFK-mediated signaling cascade that stimulates Golgi trafficking.

T. Pulvirenti, M. Giannotta, M. Capestrano, M. Capitani, A. Pisanu, R. S. Polishchuk, E. San Pietro, G. V. Beznoussenko, A. A. Mironov, G. Turacchio, V. W. Hsu, M. Sallese, A. Luini, A traffic-activated Golgi-based signalling circuit coordinates the secretory pathway.
Nat. Cell Biol.
10
, 912-922 (2008).
[PubMed]

L. Asp, T. Nilsson, Golgi gets wired up.
Nat. Cell Biol.
10
, 885-887 (2008).
[PubMed]
Modulating Striatal Synapses
Authors: Stern Peter
Published: September 2008

The role of dopamine in plasticity at glutamatergic synapses in the striatum is central to our understanding of basal ganglia functions and dopamine-dependent reward mechanisms. Long-term potentiation (LTP) and long-term depression (LTD) at these synapses are thought to be dependent on D
1
and D
2
dopamine receptors, respectively. However, the mechanisms of LTP and LTD in the striatum are controversial. Using brain slices from transgenic mice, Shen
et al
. show that LTP and LTD can occur in both D
1
- and D
2
-expressing neurons but with different molecular mechanisms. Dopaminergic modulation of plasticity is receptor and cell-type specific. The findings suggest that the control of bidirectional plasticity is not exerted through a monolithic mechanism, as previously asserted, but by cell-type-specific mechanisms depending on the subtype of dopamine receptor expressed.

W. Shen, M. Flajolet, P. Greengard, D. J. Surmeier, Dichotomous dopaminergic control of striatal synaptic plasticity.
Science
321
, 848-851 (2008).
[Abstract]
[Full Text]
The Dynamic Z Bands of Striated Muscle Cells
Authors: Sanger Jean M. , Sanger Joseph W.
Published: September 2008

The distribution of proteins in the sarcomeres of skeletal and cardiac muscle gives rise to the striated pattern of these muscles. Sarcomeric protein localization is not, however, permanently fixed. There is dynamic exchange of proteins between a cytosolic pool and the sarcomere, addition of newly synthesized proteins during development and repair, and aberrant redistribution of proteins due to mutations. Recent studies have shown that two groups of proteins that localize in the sarcomere Z band can relocate, in one case to the A band, and in the other to the nucleus.
Food for Thought
Authors: Ray L. Bryan
Published: September 2008

The hormone ghrelin is produced in the gut and acts through heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors on neurons in the brain to stimulate food intake. Andrews
et al
. analyzed the effects of ghrelin on so-called NPY/AgRP neurons (named for their expression of two proteins—neuropeptide Y and agouti-related protein) of the hippocampus. In other tissues, including liver and adipose tissue, ghrelin influences metabolism by enhancing expression of uncoupling protein 2. Uncoupling protein 2 is a member of the anion carrier protein superfamily that exists in the inner membrane of mitochondria. Uncoupling refers to leaking of protons across the mitochondrial membrane that thus uncouples the electrochemical gradient across the membrane from formation of ATP (adenosine triphosphate) by altering the flow of electrons through the respiratory chain, a process that generates superoxide radicals in the mitochondria. The authors found that ghrelin also increased accumulation of UCP2 in the NPY/AgRP neurons, and studies with preparations from
Ucp2
–/–
mice showed that enhanced respiration in the neurons and neuronal firing in response to ghrelin required UCP2. The
Ucp2
–/–
animals also showed diminished feeding response to ghrelin. The authors further traced ghrelin’s actions through activation of adenosine monophosphate (AMP)–activated protein kinase and consequent increased activity of carnitine palmitoyltransferase, which enhances oxidation of long-chain fatty acids. Sustained metabolism of long-chain fatty acids increases production of reactive oxygen species (ROS), and ghrelin appeared to act through UCP2 to diminish accumulation of ROS. Limiting ROS allows continued fueling of firing of NPY/AgRP neurons and enhances their output, which, in turn, leads to increased feeding.

Z. B. Andrews, Z.-W. Liu, N. Wallingford, D. M. Erion, E. Borok, J. M. Friedman, M. H. Tschöp, M. Shanabrough, G. Cline, G. I. Shulman, A. Coppola, X.-B. Gao, T. L. Horvath, S. Diano, UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals.
Nature
454
, 846-851 (2008).
[PubMed]
Nuts and Bolts of Plant Pathogen Response
Authors: Zahn Laura M.
Published: September 2008

Changes in oxidation status somehow regulate pathogen resistance in plants. The
Arabidopsis
NPR1, a master regulator of salicylic acid (SA)–mediated defense genes, is held in an inactive multimeric state in the absence of SA and, when SA is released, is converted into a monomer before it is transported into the nucleus where it acts. Tada
et al.
show that NPR1 is sequestered in the cytoplasm as an oligomer through S-nitrosylation at residue Cys
156
, which facilitates the oligomerization. Conversely, the SA-induced NPR1 monomerization is catalyzed by reduced thioredoxins. Mutants in both NPR1 Cys
156
and thioredoxins compromised NPR1-mediated gene expression and disease resistance; this finding provides a missing link between pathogen-triggered cellular redox changes and gene regulation in plant immunity.

Y. Tada, S. H. Spoel, K. Pajerowska-Mukhtar, Z. Mou, J. Song, C. Wang, J. Zuo, X. Dong, Plant immunity requires conformational charges of NPR1 via S-nitrosylation and thioredoxins.
Science
321
, 952-956 (2008).
[Abstract]
[Full Text]
Dinucleotide-Sensing Proteins: Linking Signaling Networks and Regulating Transcription
Authors: Lamb Heather K. , Stammers David K. , Hawkins Alastair R.
Published: September 2008

Differential binding of dinucleotides to key regulatory proteins can modulate their interactions with other proteins and, in some cases, can signal fluctuations in the cellular redox state, to produce changes in transcription and physiological state. The dinucleotide-binding proteins human HSCARG and yeast transcription repressor Gal80p are examples that offer exciting glimpses into the potential for dinucleotide-sensing proteins to couple fluctuations in dinucleotide ratios to changes in transcription and to act as networking agents linking different classes of signaling molecules.
Great Times for Small Molecules: c-di-AMP, a Second Messenger Candidate in Bacteria and Archaea
Authors: Römling Ute
Published: September 2008

Successful cell division in pro- and eukaryotes is ensured by checkpoints that regulate cell cycle progression. Structural and biochemical analyses of the DNA integrity scanning protein (DisA) have recently shown that its domain of unknown function, DUF147 [renamed DAC (for diadenylate cyclase)], has diadenylate cyclase activity. This diadenylate cyclase activity is abolished when DisA binds to branched DNA substrates, which arise during DNA double-strand breaks that can spontaneously occur during DNA replication. This finding identifies cyclic di(3′→5′)-adenylic acid (c-di-AMP) as a second messenger candidate that signals DNA integrity in
Bacillus subtilis
during sporulation, a specialized cell division process that leads to formation of a dormant cell called a spore. The DAC domain is widespread in Bacteria and Archaea; moreover, it is found in proteins containing diverse domains, suggesting that c-di-AMP acts as a second messenger molecule in response to various signals besides branched DNA. To elucidate the biological importance and molecular mechanisms of action for c-di-AMP and the recently recognized second messenger c-di-GMP will require a multidisciplinary approach.
A Cryptic Response?
Authors: Adler Elizabeth M.
Published: September 2008

Newts, bees, migratory birds, and various other animals detect Earth’s magnetic field, which can provide cues used in orientation and navigation. One mechanism proposed to underlie this ability involves the modulation by a magnetic field of a chemical reaction initiated through light absorption by a photoreceptor. Gegear
et al
. investigated the role of cryptochrome--which in
Drosophila
is a photoreceptor sensitive to ultraviolet-A and blue light that functions to reset the circadian clock--in fruit fly magnetoreception. Using a behavioral assay in which flies could choose to enter either an arm of a T-maze in which they experienced a magnetic field or an arm in which no field was generated, the authors analyzed the responses of naive and trained flies. Whereas only some strains of flies showed a naive response to a magnetic field (avoidance), all strains tested preferred the arm with the magnetic field after being trained to associate the magnetic field with a sucrose reward. However, neither naive nor trained flies showed a preference when short-wavelength (ultraviolet-A and blue) light was blocked. Moreover, mutant flies that lacked cryptochrome failed to show either naive or trained responses to the presence of a magnetic field. In contrast, disruption of circadian clock function through exposure to constant light failed to abolish behavioral response to a magnetic field. Thus, cryptochrome appears to play a critical role in
Drosophila
magnetoreception. Rouyer provides commentary, noting that it is not clear why fruit flies (which don’t migrate) need to perceive Earth’s magnetic field.

R. J. Gegear, A. Casselman, S. Waddell, S. M. Reppert, Cryptochrome mediates light-dependent magnetosensitivity in
Drosophila
.
Nature
454
, 1014-1018 (2008).
[PubMed]

F. Rouyer, Mutant flies lack magnetic sense.
Nature
454
, 949-951 (2008).
[PubMed]
Application of Fluorescence Resonance Energy Transfer and Magnetic Twisting Cytometry to Quantify Mechanochemical Signaling Activities in a Living Cell
Authors: Na Sungsoo , Wang Ning
Published: September 2008

Mechanotransduction is the process by which living cells sense mechanical forces and then convert them into biochemical signaling. Recently, we showed that mechanical stress is transduced from the cell surface to remote cytoplasmic sites within 0.3 seconds, which is at least 40 to 50 times faster than soluble factor–induced signal transduction, and the sites of mechanotransduction colocalize with mechanical stress–induced microtubule displacements. These results suggest that mechanotransduction employs mechanisms different from those of soluble factor–induced signal transduction. Here, we describe a protocol that utilizes fluorescence resonance energy transfer (FRET) and a magnetic twisting cytometry (MTC) device to capture rapid mechanochemical signaling activities in living cells.
Defining Drug Targets in Yeast Haploinsufficiency Screens: Application to Human Translational PharmacologyA presentation from the American Society for Pharmacology and Experimental Therapeutics (ASPET) Centennial Meeting at the Experimental Biology 2008 Meeting, San Diego, California, 5 to 9 April 2008.
Authors: Roberge Michel
Published: September 2008

A major challenge in drug discovery is to identify the cellular targets responsible for the pharmacological activity of drug candidates. In the yeast
Saccharomyces cerevisiae
, a heterozygous diploid mutant collection of ~6000 strains, in each of which one copy of a single gene is deleted, is commercially available. With this collection, it is possible to evaluate the role of each gene product in the response of cells to a drug. Drug-induced haploinsufficiency refers to the situation where a heterozygous diploid mutant is more sensitive to a drug than is the wild-type strain. Drug-induced haploinsufficiency screening has the potential to reveal pharmacological targets of drugs and those that contribute to undesired side effects, as well as gene products involved in drug transport, metabolism, or resistance. Using published studies, I present advantages and limitations of this technique and discuss its value for predicting drug targets in human cells.
Memory Formation Enhanced by Circadian Signaling
Authors: Gough Nancy R.
Published: September 2008

Memory is improved in mice that learn during the circadian peak of ERK and cAMP signaling.
Maintaining Organ Integrity
Authors: VanHook Annalisa M.
Published: September 2008

FGF signaling directs both homeostatic and facultative regeneration in zebrafish fins.
VDAC-1 Structure in Solution
Authors: Vinson Valda J.
Published: September 2008

A channel that allows diffusion of metabolites across the mitochondrial outer membrane forms an unusual 19-stranded β barrel with a pore size of about 25 angstroms.
Ligand Not Required?
Authors: Gough Nancy R.
Published: September 2008

A ligand may not be necessary for the nuclear receptor PPARγ to promote adipogenesis.
New Insights in Bone Biology: Unmasking Skeletal Effects of the Extracellular Calcium–Sensing Receptor
Authors: Brown Edward M. , Lian Jane B.
Published: September 2008

Embryonic and postnatal development of the skeleton requires the functions of the extracellular calcium-sensing receptor (CaSR).
Alternative Wnt Signaling Is Initiated by Distinct Receptors
Authors: van Amerongen Renée , Mikels Amanda , Nusse Roel
Published: September 2008

The traditional classification of Wnts into canonical or noncanonical proteins may be misleading.
Getting to the Right Place
Authors: Adler Elizabeth M.
Published: September 2008

Neurogenin 2 transcriptionally activates the small GTP-binding protein Rnd2 to regulate migration of cortical neurons.
Promoting an Inactivating Partnership
Authors: Gough Nancy R.
Published: September 2008

The fimbriae of the bacteria that cause gingivitis promote the interaction of Toll-like receptor 2 (TLR2) and chemokine receptor CXCR4 to inhibit innate immunity.
A Missing Link in Cancer
Authors: Hurtley Stella M.
Published: September 2008

A tumor suppressor is shown to control the degradation of a central protein regulator of cell proliferation.
Receptor Trafficking Controls Signaling Strength
Authors: Gough Nancy R.
Published: September 2008

Differential requirements for receptor endocytosis and delivery to the perinuclear region for activation of STAT3.
Dynamic Visualization of Signaling Activities in Living CellsA presentation from the 102nd Annual Meeting of the American Society for Biochemistry and Molecular Biology (ASBMB) at Experimental Biology 2008, San Diego, CA, 6 to 9 April 2008.
Authors: Allen Michael D. , DiPilato Lisa M. , Ananthanarayanan Bharath , Newman Robert H. , Ni Qiang , Zhang Jin
Published: September 2008

Engineered fluorescent reporters allow researchers to follow subcellular activities of signaling components in real time in live cells.
Activity Around Plaques
Authors: Hurtley Stella M.
Published: September 2008

In a mouse model of Alzheimer's disease, neurons close to the characteristic deposits of amyloid show high activity, in contrast to the overall reduction in brain function.
Dopaminergic Synapse Plasticity
Authors: Stern Peter
Published: September 2008

When a rat learns to associate a cue with a reward, dopamine-containing neurons in the midbrain acquire an enhanced response to that cue through the action of glutamate.
XIST
ing Synergy
Authors: Riddihough Guy
Published: September 2008

X chromosome inactivation in stem cells is reversed, a step in allowing them to become pluripotent, when three factors repress the inactivation RNA.
Fat Talk
Authors: Ray L. Bryan
Published: September 2008

A fatty acid from adipose tissue acts as a hormone to control systemic metabolism.
Science Signaling
Podcast: 23 September 2008
Authors: Adler Elizabeth M. , Gough Nancy R. , VanHook Annalisa M.
Published: September 2008

Bacteria secrete factors that regulate genes that contribute to virulence.
Caspase-2: Vestigial Remnant or Master Regulator?
Authors: Troy Carol M. , Ribe Elena M.
Published: September 2008

Both mitochondrial-dependent and -independent cell death pathways are mediated by caspase-2.
Cymbidium Ringspot Virus Harnesses RNA Silencing To Control the Accumulation of Virus Parasite Satellite RNA
Authors: Pantaleo Vitantonio , Burgyán József
Published: September 2008

Cymbidium ringspot virus
(CymRSV) satellite RNA (satRNA) is a parasitic subviral RNA replicon that replicates and accumulates at the cost of its helper virus. This 621-nucleotide (nt) satRNA species has no sequence similarity to the helper virus, except for a 51-nt-long region termed the helper-satellite homology (HSH) region, which is essential for satRNA replication. We show that the accumulation of satRNA strongly depends on temperature and on the presence of the helper virus p19 silencing suppressor protein, suggesting that RNA silencing plays a crucial role in satRNA accumulation. We also demonstrate that another member of the
Tombusvirus
genus,
Carnation Italian ringspot virus
(CIRV), supports satRNA accumulation at a higher level than CymRSV. Our results suggest that short interfering RNA (siRNA) derived from CymRSV targets satRNA more efficiently than siRNA from CIRV, possibly because of the higher sequence similarity between the HSH regions of the helper and CIRV satRNAs. RNA silencing sensor RNA carrying the putative satRNA target site in the HSH region was efficiently cleaved when transiently expressed in CymRSV-infected plants but not in CIRV-infected plants. Strikingly, replacing the CymRSV HSH box2 sequence with that of CIRV restores satRNA accumulation both at 24°C and in the absence of the p19 suppressor protein. These findings demonstrate the extraordinary adaptation of this virus to its host in terms of harnessing the antiviral silencing response of the plant to control the virus parasite satRNA.
Behavioural and social correlates of sedentary time in young people
Authors: van Sluijs E M F , Page A , Ommundsen Y , Griffin S J
Published: September 2008

Objective

In this study, behavioural and social correlates of objectively measured sedentary time in young people were identified.

Design

Cross-sectional analysis of data from the European Youth Heart Study (EYHS).

Setting

Schools in Denmark, Estonia, Portugal and Norway.

Participants

Respondents were invited using a twostage cluster sampling procedure. Analyses include 2107 children (9–10 years old) and adolescents (14–15 years old).

Assessment of independent variables

Seven behavioural and 15 social variables assessed by parental and computerised child questionnaires.

Main outcome measure

Sedentary activity as assessed by accelerometry (10 min blocks at <200 counts/min). Analyses were stratified by country, and interactions with grade and sex were investigated.

Results

Adolescents were more sedentary than children (335.4 (90.4 min/day) vs 217.2 (75.6 min/day), p<0.001). Patterns of associations differed across countries. High computer use and no television viewing before school in Norway, and being sedentary during school breaks in Estonia were positively associated with sedentary time. No behavioural variables were associated with sedentary time in the Danish and Portuguese models. Socioeconomic position was positively associated with sedentary time in Portugal and Estonia, father's body mass index negatively in the Estonian model. Norwegian participants with a game console at home and Portuguese participants with a television in their bedroom were more sedentary.

Conclusions

A single strategy aimed at reducing sedentary behaviour is unlikely to be effective across Europe as the target populations and behaviours of focus differ between countries. Targeting high socioeconomic groups in Portugal and Estonia or focusing on reducing computer use in Norway might be effective intervention strategies to reduce overall sedentary time.
The reliability measurements of lateral scapular slide test at three different degrees of shoulder joint abduction
Authors: Shadmehr A , Bagheri H , Ansari N N , Sarafraz H
Published: September 2008

Background

Lateral scapular slide test (LSST) quantitatively measures the distance between thoracic spine (T7) and inferior angle of scapula.

Objective

In this study, the intra-rater reliability, inter-rater reliability and diagnostic accuracy of LSST were measured using a caliper.

Methods

Three measurements of each test position were obtained bilaterally. Intraclass correlation coefficient (ICC) (2.1), 95% CI and 2 SEMs were calculated for intra-rater and inter-rater reliability of the absolute scapular distance. Sensitivity, specificity, positive and negative likelihood ratios were determined.

Results

27 people with and 30 people without shoulder pain participated. The mean age (SD) for the participant was 47.7 (11.6) years and 33.5 (11.7) years, respectively. The ICCs for intra-rater reliability were high. A range of poor to good ICCs was found for inter-rater reliability. The 2 SEMs ranged from 4.6 to 7.9 mm for intra-rater reliability and from 6.8 to 13.4 mm for inter-rater reliability for people with shoulder pain. Positive and negative likelihood ratios from 0.94 to 1.22 and from 0.21 to 2.5, respectively, were demonstrated.

Conclusion

SST did not show a consistent high reliability. The diagnostic accuracy of the LSST was low, which questions the clinical importance of the tests outcomes.
Treatment of osteitis pubis and osteomyelitis of the pubic symphysis in athletes: a systematic review
Authors: Choi Haemi , McCartney Michael , Best Thomas M
Published: September 2008

Objectives

The authors examined the most current evidence for treatment options in athletes with osteitis pubis and osteomyelitis pubis, attempting to determine which options provide optimal pain relief with rapid return to sport and prevention of symptom reoccurrence.

Methods

Three databases—MEDLINE, Cochrane Database of Systematic Reviews and CINAHL—were searched using the OVID interface for all years between 1985 and May 2008. References were analysed from included studies, and additional relevant articles were obtained for inclusion. Inclusion criteria included (1) humans only, (2) subjects had no apparent risk factors for development of osteitis pubis or osteomyelitis of the pubic symphysis other than athletic involvement, (3) both physical exam findings and diagnostic imaging were used to confirm either diagnosis, and (4) a definitive treatment strategy was identifiable for management of osteitis pubis or osteomyelitis of the pubic symphysis. In total, 25 articles were included in the review.

Results

There were no randomised controlled trials identified with this study's search strategy. A total of 195 athletes were diagnosed as having osteitis pubis (186 males, nine females) and treated with either conservative measures/physical therapy, local injection with corticosteroids and/or local anaesthetic, dextrose prolotherapy, surgery or antibiotic therapy. Six case reports/series described conservative treatment measures (physical therapy, rest, non-steroid anti-inflammatory drugs). Four case series explored the use of corticosteroid injections in treatment. One case series described the use of dextrose prolotherapy as a treatment modality. Six case series described various surgical techniques (pubic symphysis curettage, polypropylene mesh placement and pubic bone stabilisation) in treatment. Ten case reports/series (10 subjects) outlined antibiotic treatment of osteomyelitis of the pubic symphysis.

Conclusions

The current medical literature shows only level 4 evidence of the treatment for osteitis pubis in 24 case reports/series in athletes. Without any direct comparison of treatment modalities, it is difficult to determine which individual treatment option is the most efficacious. Further study comparing the different treatment options is necessary to determine which modality provides the fastest return to sport.
Vibration therapy reduces plasma IL6 and muscle soreness after downhill running
Authors: Broadbent S , Rousseau J J , Thorp R M , Choate S L , Jackson F S , Rowlands D S
Published: September 2008

Objective

In this study, the effects of vibration therapy (VT) on delayed-onset muscle soreness (DOMS) and associated inflammatory markers after downhill running were determined.

Methods

29 male recreational runners (33 (8) years; Vo2peak 57 (6) ml kg−1min−1) completed a 40-min downhill run and were randomly allocated to a VT group or Control group. For 5 days post-run, the VT group underwent once-daily sessions of VT on the upper and lower legs. DOMS was assessed pre-run and for 5 days post-run by visual analogue scale. Immune cell subsets and plasma inflammatory markers were assessed pre-run, post-run, 24 and 120 h post-run by full differential cell count, and by ELISA and enzyme immunoassay, respectively. Data were analysed as per cent change from pre-run (ANOVA) and the magnitude of the treatment effect (Cohen's effect size statistics).

Results

VT significantly reduced calf pain 96 h post-run (−50% (40%), 90% confidence limits) and gluteal pain 96 h (−50% (40%)) and 120 h post-run (−30% (30%)); decreased interleukin 6 (IL6) 24 h (−46% (31%)) and 120 h post-run (−65% (30%)); substantially decreased histamine 24 h (−40% (50%)) and 120 h post-run (−37% (48%)); substantially increased neutrophils (8.6% (8.1%)) and significantly decreased lymphocytes (−17% (12%)) 24 h post-run. There were no clear substantial effects of VT on other leukocyte subsets and inflammatory markers.

Conclusion

VT reduces muscle soreness and IL6. It may stimulate lymphocyte and neutrophil responses and may be a useful modality in treating muscle inflammation.
FLAVOR SYMMETRIES, NEUTRINO MASSES AND NEUTRINO MIXING
Authors: FRITZSCH HARALD
Published: September 2008

We discuss the neutrino mixing, using the texture 0 mass matrices, which work very well for the quarks. The solar mixing angle is directly linked to the mass ratio of the first two neutrinos. The neutrino masses are hierarchical, but the mass ratios turn out to be much smaller than for quarks. The atmospheric mixing angle is 38°. The CP violation for leptons should be much smaller than for quarks.
ON THE SIGNIFICANCE OF RECENT LATTICE RESULTS FOR THE CHIRAL LAGRANGIAN
Authors: LEUTWYLER H.
Published: September 2008

The report concerns only one of the issues discussed in my talk at ICFP 2007: the significance of recent lattice results for our understanding of the nonperturbative phenomena in the low energy domain of QCD. All of these results are consistent with the phenomenological estimates for the coupling constants of the chiral SU (2)× SU (2) Lagrangian and thereby corroborate the predictions based on these. In the case of SU (3)× SU (3), the results also confirm the old estimates obtained from chiral perturbation theory. In particular, the first two terms in the expansion of the masses and decay constants in powers of ms appear to represent a decent approximation for the full series. Some of the lattice results indicate that the quark condensate violates the OZI-rule rather strongly, but as there are some discrepancies concerning this issue, it is too early to draw conclusions.
IMPACT OF POSITIVE PARITY HEAVY MESONS ON CHARM MESON DECAYS
Authors: FAJFER SVJETLANA , KAMENIK JERNEJ F.
Published: September 2008

We discuss strong decays of positive and negative parity charmed mesons within heavy meson chiral perturbation theory and study the impact of excited charm states on the determination of the effective meson couplings. Motivated by recent experimental results we also reconsider semileptonic D → Plνl and D → Vlνl decays within a model which combines heavy quark symmetry and properties of the chiral Lagrangian. Using limits of soft collinear effective theory and heavy quark effective theory we parametrize the semileptonic form factors. We include excited charm meson states in our Lagrangian and determine their impact on the charm meson semileptonic form factors.
CHIRAL RADIATIVE CORRECTIONS IN POTENTIAL MODEL AND THE P-WAVE STATES OF HEAVY-LIGHT MESONS
Authors: LEE TAEKOON
Published: September 2008

In relativistic potential model of heavy-light mesons it is essential to incorporate the chiral radiative corrections before comparing the model predictions with data. Once the radiative corrections are taken into account the potential model can explain the unusual mass spectra and absence of the spin orbit-inversion in P-wave states.