bluuebunny/crossref_metadata_2025 huggingface dataset:
The zebrafish
foxj1a
transcription factor regulates cilia function in response to injury and epithelial stretch
Authors: Hellman Nathan E. , Liu Yan , Merkel Erin , Austin Christina , Le Corre Stephanie , Beier David R. , Sun Zhaoxia , Sharma Neeraj , Yoder Bradley K. , Drummond Iain A.
Published: October 2010

Cilia are essential for normal organ function and developmental patterning, but their role in injury and regeneration responses is unknown. To probe the role of cilia in injury, we analyzed the function of foxj1, a transcriptional regulator of cilia genes, in response to tissue damage and renal cyst formation. Zebrafish
foxj1a
, but not
foxj1b
, was rapidly induced in response to epithelial distension and stretch, kidney cyst formation, acute kidney injury by gentamicin, and crush injury in spinal cord cells. Obstruction-induced up-regulation of
foxj1a
was not inhibited by cycloheximide, identifying
foxj1a
as a primary response gene to epithelial injury. Foxj1 was also dramatically up-regulated in murine cystic kidney disease epithelia [
jck/jck (nek8)
and

Ift88Tg737Rpw
−/−

] as well as in response to kidney ischemia-reperfusion injury. Obstruction of the zebrafish pronephric tubule caused a rapid increase in cilia beat rate that correlated tightly with expanded tubule diameter and epithelial stretch. Zebrafish
foxj1a
was specifically required for cilia motility. Enhanced
foxj1a
expression in obstructed tubules induced cilia motility target genes
efhc1
,
tektin-1
, and
dnahc9. foxj1a
-deficient embryos failed to up-regulate
efhc1
,
tektin-1
, and
dnahc9
and could not maintain enhanced cilia beat rates after obstruction, identifying an essential role for
foxj1
in modulating cilia function after injury. These studies reveal that activation of a Foxj1 transcriptional network of ciliogenic genes is an evolutionarily conserved response to multiple forms of tissue damage and highlight enhanced cilia function as a previously uncharacterized component of organ homeostasis.
p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation
Authors: Scherz-Shouval Ruth , Weidberg Hilla , Gonen Chagay , Wilder Sylvia , Elazar Zvulun , Oren Moshe
Published: October 2010

The p53 tumor suppressor is mutated in a high percentage of human tumors. However, many other tumors retain wild-type (wt) p53 expression, raising the intriguing possibility that they actually benefit from it. Recent studies imply a role for p53 in regulation of autophagy, a catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles, particularly under conditions of nutrient deprivation. Here, we show that, in many cell types, p53 confers increased survival in the face of chronic starvation. We implicate regulation of autophagy in this effect. In HCT116 human colorectal cancer cells exposed to prolonged nutrient deprivation, the endogenous wt p53 posttranscriptionally down-regulates LC3, a pivotal component of the autophagic machinery. This enables reduced, yet sustainable autophagic flux. Loss of p53 impairs autophagic flux and causes excessive LC3 accumulation upon starvation, culminating in apoptosis. Thus, p53 increases cell fitness by maintaining better autophagic homeostasis, adjusting the rate of autophagy to changing circumstances. We propose that some cancer cells retain wt p53 to benefit from the resultant increased fitness under limited nutrient supply.
Persistence of climate changes due to a range of greenhouse gases
Authors: Solomon Susan , Daniel John S. , Sanford Todd J. , Murphy Daniel M. , Plattner Gian-Kasper , Knutti Reto , Friedlingstein Pierre
Published: October 2010

Emissions of a broad range of greenhouse gases of varying lifetimes contribute to global climate change. Carbon dioxide displays exceptional persistence that renders its warming nearly irreversible for more than 1,000 y. Here we show that the warming due to non-CO
2
greenhouse gases, although not irreversible, persists notably longer than the anthropogenic changes in the greenhouse gas concentrations themselves. We explore why the persistence of warming depends not just on the decay of a given greenhouse gas concentration but also on climate system behavior, particularly the timescales of heat transfer linked to the ocean. For carbon dioxide and methane, nonlinear optical absorption effects also play a smaller but significant role in prolonging the warming. In effect, dampening factors that slow temperature increase during periods of increasing concentration also slow the loss of energy from the Earth’s climate system if radiative forcing is reduced. Approaches to climate change mitigation options through reduction of greenhouse gas or aerosol emissions therefore should not be expected to decrease climate change impacts as rapidly as the gas or aerosol lifetime, even for short-lived species; such actions can have their greatest effect if undertaken soon enough to avoid transfer of heat to the deep ocean.
Role of the synaptobrevin C terminus in fusion pore formation
Authors: Ngatchou Annita N. , Kisler Kassandra , Fang Qinghua , Walter Alexander M. , Zhao Ying , Bruns Dieter , Sørensen Jakob B. , Lindau Manfred
Published: October 2010

Neurotransmitter release is mediated by the SNARE proteins synaptobrevin II (sybII, also known as VAMP2), syntaxin, and SNAP-25, generating a force transfer to the membranes and inducing fusion pore formation. However, the molecular mechanism by which this force leads to opening of a fusion pore remains elusive. Here we show that the ability of sybII to support exocytosis is inhibited by addition of one or two residues to the sybII C terminus depending on their energy of transfer from water to the membrane interface, following a Boltzmann distribution. These results suggest that following stimulation, the SNARE complex pulls the C terminus of sybII deeper into the vesicle membrane. We propose that this movement disrupts the vesicular membrane continuity leading to fusion pore formation. In contrast to current models, the experiments suggest that fusion pore formation begins with molecular rearrangements at the intravesicular membrane leaflet and not between the apposed cytoplasmic leaflets.
Ecological convergence in a rocky intertidal shore metacommunity despite high spatial variability in recruitment regimes
Authors: Caro Andrés U. , Navarrete Sergio A. , Castilla Juan Carlos
Published: October 2010

In open ecological systems, community structure can be determined by physically modulated processes such as the arrival of individuals from a regional pool and by local biological interactions. There is debate centering on whether niche differentiation and local interactions among species are necessary to explain macroscopic community patterns or whether the patterns can be generated by the neutral interplay of dispersal and stochastic demography among ecologically identical species. Here we evaluate how much of the observed spatial variation within a rocky intertidal metacommunity along 800 km of coastline can be explained by drift in the structure of recruits across 15 local sites. Our results show that large spatial changes in recruitment do not explain the observed spatial variation in adult local structure and that, in comparison with the large drift in structure of recruits, local adult communities converged to a common, although not unique, structure across the region. Although there is no unique adult community structure in the entire region, the observed variation represents only a small subset of the possible structures that would be expected from passive recruitment drift. Thus, in this diverse system our results do not support the idea that rocky intertidal metacommunities are structured by neutral mechanisms.
Appropriation of the MinD protein-interaction motif by the dimeric interface of the bacterial cell division regulator MinE
Authors: Ghasriani Houman , Ducat Thierry , Hart Chris T. , Hafizi Fatima , Chang Nina , Al-Baldawi Ali , Ayed Saud H. , Lundström Patrik , Dillon Jo-Anne R. , Goto Natalie K.
Published: October 2010

MinE is required for the dynamic oscillation of Min proteins that restricts formation of the cytokinetic septum to the midpoint of the cell in gram negative bacteria. Critical for this oscillation is MinD-binding by MinE to stimulate MinD ATP hydrolysis, a function that had been assigned to the first ∼30 residues in MinE. Previous models based on the structure of an autonomously folded dimeric C-terminal fragment suggested that the N-terminal domain is freely accessible for interactions with MinD. We report here the solution NMR structure of the full-length MinE dimer from
Neisseria gonorrhoeae
, with two parts of the N-terminal domain forming an integral part of the dimerization interface. Unexpectedly, solvent accessibility is highly restricted for residues that were previously hypothesized to directly interact with MinD. To delineate the true MinD-binding region, in vitro assays for MinE-stimulated MinD activity were performed. The relative MinD-binding affinities obtained for full-length and N-terminal peptides from MinE demonstrated that residues that are buried in the dimeric interface nonetheless participate in direct interactions with MinD. According to results from NMR spin relaxation experiments, access to these buried residues may be facilitated by the presence of conformational exchange. We suggest that this concealment of MinD-binding residues by the MinE dimeric interface provides a mechanism for prevention of nonspecific interactions, particularly with the lipid membrane, to allow the free diffusion of MinE that is critical for Min protein oscillation.
Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa
Authors: Strettoi Enrica , Gargini Claudia , Novelli Elena , Sala Giusy , Piano Ilaria , Gasco Paolo , Ghidoni Riccardo
Published: October 2010

Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the rate-limiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10–20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.
Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel
Authors: Adams Paul J. , Rungta Ravi L. , Garcia Esperanza , van den Maagdenberg Arn M. J. M. , MacVicar Brian A. , Snutch Terrance P.
Published: October 2010

The dynamics, computational power, and strength of neural circuits are essential for encoding and processing information in the CNS and rely on short and long forms of synaptic plasticity. In a model system, residual calcium (Ca
2+
) in presynaptic terminals can act through neuronal Ca
2+
sensor proteins to cause Ca
2+
-dependent facilitation (CDF) of P/Q-type channels and induce short-term synaptic facilitation. However, whether this is a general mechanism of plasticity at intact central synapses and whether mutations associated with human disease affect this process have not been described to our knowledge. In this report, we find that, in both exogenous and native preparations, gain-of-function missense mutations underlying Familial Hemiplegic Migraine type 1 (FHM-1) occlude CDF of P/Q-type Ca
2+
channels. In FHM-1 mutant mice, the alteration of P/Q-type channel CDF correlates with reduced short-term synaptic facilitation at cerebellar parallel fiber-to-Purkinje cell synapses. Two-photon imaging suggests that P/Q-type channels at parallel fiber terminals in FHM-1 mice are in a basally facilitated state. Overall, the results provide evidence that FHM-1 mutations directly affect both P/Q-type channel CDF and synaptic plasticity and that together likely contribute toward the pathophysiology underlying FHM-1. The findings also suggest that P/Q-type channel CDF is an important mechanism required for normal synaptic plasticity at a fast synapse in the mammalian CNS.
Local DNA hypomethylation activates genes in rice endosperm
Authors: Zemach Assaf , Kim M. Yvonne , Silva Pedro , Rodrigues Jessica A. , Dotson Bradley , Brooks Matthew D. , Zilberman Daniel
Published: October 2010

Cytosine methylation silences transposable elements in plants, vertebrates, and fungi but also regulates gene expression. Plant methylation is catalyzed by three families of enzymes, each with a preferred sequence context: CG, CHG (H = A, C, or T), and CHH, with CHH methylation targeted by the RNAi pathway.
Arabidopsis thaliana
endosperm, a placenta-like tissue that nourishes the embryo, is globally hypomethylated in the CG context while retaining high non-CG methylation. Global methylation dynamics in seeds of cereal crops that provide the bulk of human nutrition remain unknown. Here, we show that rice endosperm DNA is hypomethylated in all sequence contexts. Non-CG methylation is reduced evenly across the genome, whereas CG hypomethylation is localized. CHH methylation of small transposable elements is increased in embryos, suggesting that endosperm demethylation enhances transposon silencing. Genes preferentially expressed in endosperm, including those coding for major storage proteins and starch synthesizing enzymes, are frequently hypomethylated in endosperm, indicating that DNA methylation is a crucial regulator of rice endosperm biogenesis. Our data show that genome-wide reshaping of seed DNA methylation is conserved among angiosperms and has a profound effect on gene expression in cereal crops.
Two abundant proteasome subtypes that uniquely process some antigens presented by HLA class I molecules
Authors: Guillaume Benoît , Chapiro Jacques , Stroobant Vincent , Colau Didier , Van Holle Benoît , Parvizi Grégory , Bousquet-Dubouch Marie-Pierre , Théate Ivan , Parmentier Nicolas , Van den Eynde Benoît J.
Published: October 2010

Most antigenic peptides presented by MHC class I molecules result from the degradation of intracellular proteins by the proteasome. In lymphoid tissues and cells exposed to IFNγ, the standard proteasome is replaced by the immunoproteasome, in which all of the standard catalytic subunits β1, β2, and β5 are replaced by their inducible counterparts β1i, β2i, and β5i, which have different cleavage specificities. The immunoproteasome thereby shapes the repertoire of antigenic peptides. The existence of additional forms of proteasomes bearing a mixed assortment of standard and inducible catalytic subunits has been suggested. Using a new set of unique subunit-specific antibodies, we have now isolated, quantified, and characterized human proteasomes that are intermediate between the standard proteasome and the immunoproteasome. They contain only one (β5i) or two (β1i and β5i) of the three inducible catalytic subunits of the immunoproteasome. These intermediate proteasomes represent between one-third and one-half of the proteasome content of human liver, colon, small intestine, and kidney. They are also present in human tumor cells and dendritic cells. We identified two tumor antigens of clinical interest that are processed exclusively either by intermediate proteasomes β5i (MAGE-A3271–279) or by intermediate proteasomes β1i-β5i (MAGE-A10254–262). The existence of these intermediate proteasomes broadens the repertoire of antigens presented to CD8 T cells and implies that the antigens presented by a given cell depend on their proteasome content.
Ion sensing in the RCK1 domain of BK channels
Authors: Zhang Guohui , Huang Sheng-You , Yang Junqiu , Shi Jingyi , Yang Xiao , Moller Alyssa , Zou Xiaoqin , Cui Jianmin
Published: October 2010

BK-type K
+
channels are activated by voltage and intracellular Ca
2+
, which is important in modulating muscle contraction, neural transmission, and circadian pacemaker output. Previous studies suggest that the cytosolic domain of BK channels contains two different Ca
2+
binding sites, but the molecular composition of one of the sites is not completely known. Here we report, by systematic mutagenesis studies, the identification of E535 as part of this Ca
2+
binding site. This site is specific for binding to Ca
2+
but not Cd
2+
. Experimental results and molecular modeling based on the X-ray crystallographic structures of the BK channel cytosolic domain suggest that the binding of Ca
2+
by the side chains of E535 and the previously identified D367 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, providing a basis to understand how Ca
2+
binding at this site opens the activation gate of the channel that is remotely located in the membrane.
Methionine sulfoxide reductase A down-regulation in human breast cancer cells results in a more aggressive phenotype
Authors: De Luca Antonella , Sanna Fabio , Sallese Michele , Ruggiero Carmen , Grossi Mauro , Sacchetta Paolo , Rossi Cosmo , De Laurenzi Vincenzo , Di Ilio Carmine , Favaloro Bartolo
Published: October 2010

Breast cancer is one of the most frequent of human malignacies, and it is therefore fundamental to identify the underlying molecular mechanisms leading to cancer transformation. Among other causative agents in the development of breast cancers, an important role for reactive oxygen species (ROS) has emerged. However, most studies on the role of ROS in cancer have not reached specific conclusions, and many issues remain controversial. In the present study, we show that methionine sulfoxide reductase A (MsrA), which is known to protect proteins from oxidation and which acts as a ROS scavenger, is down-regulated in a number of breast cancers. Moreover, levels of MsrA correlate with advanced tumor grade. We therefore investigated the functional role of MsrA in breast cancer cells. Our data show that reduction of MsrA levels results in increased cell proliferation and extracellular matrix degradation, and consequently in a more aggressive cellular phenotype, both in vivo and in vitro. We also show that the underlying molecular mechanisms involve increased ROS levels, resulting in reduction of phosphatase and tensin homolog deleted on chromosome ten protein (PTEN), and activation of the phosphoinositide 3-kinase pathway. In addition, MsrA down-regulation results in up-regulation of VEGF, providing additional support for tumor growth in vivo.
Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis
Authors: Guo Fukun , Hildeman David , Tripathi Pulak , Velu Chinavenmeni S. , Grimes H. Leighton , Zheng Yi
Published: October 2010

T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown. Here we demonstrate that T cell-specific deletion ofcell-division cycle 42(Cdc42) GTPase causes a profound loss of mature T cells. Deletion ofCdc42leads to a markedly increased expression of growth factor independence-1 (Gfi-1) and represses expression of IL-7Rα. In the absence ofCdc42, aberrant ERK1/2 MAP kinase activity results in enhanced, TCR-mediated T-cell proliferation. In vivo reconstitution of effector-binding–defective Cdc42 mutants and the effector p21 protein-activated kinase 1 (PAK1) intoCdc42-deficient T cells showed that PAK1 is both necessary and sufficient for Cdc42-regulated T-cell homeostasis. Thus, T-cell homeostasis is maintained through a concerted regulation of Gfi-1–IL-7R–controlled cytokine responsiveness and ERK-mediated TCR signaling strength by the Cdc42-PAK1 signaling axis.
SET DOMAIN GROUP2 is the major histone H3 lysine 4 trimethyltransferase in
Arabidopsis
Authors: Guo Lin , Yu Yanchun , Law Julie A. , Zhang Xiaoyu
Published: October 2010

Posttranslational modifications of histones play important roles in modulating chromatin structure and regulating gene expression. We have previously shown that more than two thirds of
Arabidopsis
genes contain histone H3 methylation at lysine 4 (H3K4me) and that trimethylation of H3K4 (H3K4me3) is preferentially located at actively transcribed genes. In addition, several
Arabidopsis
mutants with locus-specific loss of H3K4me have been found to display various developmental abnormalities. These findings suggest that H3K4me3 may play important roles in maintaining the normal expression of a large number of genes. However, the major enzyme(s) responsible for H3K4me3 has yet to be identified in plants, making it difficult to address questions regarding the mechanisms and functions of H3K4me3. Here we described the characterization of SET DOMAIN GROUP 2 (SDG2), a large
Arabidopsis
protein containing a histone lysine methyltransferase domain. We found that SDG2 homologs are highly conserved in plants and that the
Arabidopsis SDG2
gene is broadly expressed during development. In addition, the loss of SDG2 leads to severe and pleiotropic phenotypes, as well as the misregulation of a large number of genes. Consistent with our finding that SDG2 is a robust and specific H3K4 methyltransferase in vitro, the loss of SDG2 leads to a drastic decrease in H3K4me3 in vivo. Taken together, these results suggest that SDG2 is the major enzyme responsible for H3K4me3 in
Arabidopsis
and that SDG2-dependent H3K4m3 is critical for regulating gene expression and plant development.
Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir
Authors: Sevrioukova Irina F. , Poulos Thomas L.
Published: October 2010

Ritonavir is a HIV protease inhibitor routinely prescribed to HIV patients that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. By inhibiting CYP3A4, ritonavir increases plasma concentrations of other anti-HIV drugs oxidized by CYP3A4 thereby improving clinical efficacy. Despite the importance and wide use of ritonavir in anti-HIV therapy, the precise mechanism of CYP3A4 inhibition remains unclear. The available data are inconsistent and suggest that ritonavir acts as a mechanism-based, competitive or mixed competitive-noncompetitive CYP3A4 inactivator. To resolve this controversy and gain functional and structural insights into the mechanism of CYP3A4 inhibition, we investigated the ritonavir binding reaction by kinetic and equilibrium analysis, elucidated how the drug affects redox properties of the hemoprotein, and determined the 2.0 Å X-ray structure of the CYP3A4-ritonavir complex. Our results show that ritonavir is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase.
Crowding and hydrodynamic interactions likely dominate in vivo macromolecular motion
Authors: Ando Tadashi , Skolnick Jeffrey
Published: October 2010

To begin to elucidate the principles of intermolecular dynamics in the crowded environment of cells, employing Brownian dynamics (BD) simulations, we examined possible mechanism(s) responsible for the great reduction in diffusion constants of macromolecules in vivo from that at infinite dilution. In an
Escherichia coli
cytoplasm model comprised of 15 different macromolecule types at physiological concentrations, BD simulations of molecular-shaped and equivalent sphere representations were performed with a soft repulsive potential. At cellular concentrations, the calculated diffusion constant of GFP is much larger than experiment, with no significant shape dependence. Next, using the equivalent sphere system, hydrodynamic interactions (HI) were considered. Without adjustable parameters, the in vivo experimental GFP diffusion constant was reproduced. Finally, the effects of nonspecific attractive interactions were examined. The reduction in diffusivity is very sensitive to macromolecular radius with the motion of the largest macromolecules dramatically slowed down; this is not seen if HI dominate. In addition, long-lived clusters involving the largest macromolecules form if attractions dominate, whereas HI give rise to significant, size independent intermolecular dynamic correlations. These qualitative differences provide a testable means of differentiating the importance of HI vs. nonspecific attractive interactions on macromolecular motion in cells.
Human oral, gut, and plaque microbiota in patients with atherosclerosis
Authors: Koren Omry , Spor Aymé , Felin Jenny , Fåk Frida , Stombaugh Jesse , Tremaroli Valentina , Behre Carl Johan , Knight Rob , Fagerberg Björn , Ley Ruth E. , Bäckhed Fredrik
Published: October 2010

Periodontal disease has been associated with atherosclerosis, suggesting that bacteria from the oral cavity may contribute to the development of atherosclerosis and cardiovascular disease. Furthermore, the gut microbiota may affect obesity, which is associated with atherosclerosis. Using qPCR, we show that bacterial DNA was present in the atherosclerotic plaque and that the amount of DNA correlated with the amount of leukocytes in the atherosclerotic plaque. To investigate the microbial composition of atherosclerotic plaques and test the hypothesis that the oral or gut microbiota may contribute to atherosclerosis in humans, we used 454 pyrosequencing of 16S rRNA genes to survey the bacterial diversity of atherosclerotic plaque, oral, and gut samples of 15 patients with atherosclerosis, and oral and gut samples of healthy controls. We identified
Chryseomonas
in all atherosclerotic plaque samples, and
Veillonella
and
Streptococcus
in the majority. Interestingly, the combined abundances of
Veillonella
and
Streptococcus
in atherosclerotic plaques correlated with their abundance in the oral cavity. Moreover, several additional bacterial phylotypes were common to the atherosclerotic plaque and oral or gut samples within the same individual. Interestingly, several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels. Taken together, our findings suggest that bacteria from the oral cavity, and perhaps even the gut, may correlate with disease markers of atherosclerosis.
Bankruptcy risk model and empirical tests
Authors: Podobnik Boris , Horvatic Davor , Petersen Alexander M. , Urošević Branko , Stanley H. Eugene
Published: October 2010

We analyze the size dependence and temporal stability of firm bankruptcy risk in the US economy by applying Zipf scaling techniques. We focus on a single risk factor—the debt-to-asset ratioR—in order to study the stability of the Zipf distribution ofRover time. We find that the Zipf exponent increases during market crashes, implying that firms go bankrupt with larger values ofR. Based on the Zipf analysis, we employ Bayes’s theorem and relate the conditional probability that a bankrupt firm has a ratioRwith the conditional probability of bankruptcy for a firm with a givenRvalue. For 2,737 bankrupt firms, we demonstrate size dependence in assets change during the bankruptcy proceedings. Prepetition firm assets and petition firm assets follow Zipf distributions but with different exponents, meaning that firms with smaller assets adjust their assets more than firms with larger assets during the bankruptcy process. We compare bankrupt firms with nonbankrupt firms by analyzing the assets and liabilities of two large subsets of the US economy: 2,545 Nasdaq members and 1,680 New York Stock Exchange (NYSE) members. We find that both assets and liabilities follow a Pareto distribution. The finding is not a trivial consequence of the Zipf scaling relationship of firm size quantified by employees—although the market capitalization of Nasdaq stocks follows a Pareto distribution, the same distribution does not describe NYSE stocks. We propose a coupled Simon model that simultaneously evolves both assets and debt with the possibility of bankruptcy, and we also consider the possibility of firm mergers.
R
gene-controlled host specificity in the legume–rhizobia symbiosis
Authors: Yang Shengming , Tang Fang , Gao Muqiang , Krishnan Hari B. , Zhu Hongyan
Published: October 2010

Leguminous plants can enter into root nodule symbioses with nitrogen-fixing soil bacteria known as rhizobia. An intriguing but still poorly understood property of the symbiosis is its host specificity, which is controlled at multiple levels involving both rhizobial and host genes. It is widely believed that the host specificity is determined by specific recognition of bacterially derived Nod factors by the cognate host receptor(s). Here we describe the positional cloning of two soybean genes
Rj2
and
Rfg1
that restrict nodulation with specific strains of
Bradyrhizobium japonicum
and
Sinorhizobium fredii
, respectively. We show that
Rj2
and
Rfg1
are allelic genes encoding a member of the Toll-interleukin receptor/nucleotide-binding site/leucine-rich repeat (TIR-NBS-LRR) class of plant resistance (R) proteins. The involvement of host
R
genes in the control of genotype-specific infection and nodulation reveals a common recognition mechanism underlying symbiotic and pathogenic host–bacteria interactions and suggests the existence of their cognate avirulence genes derived from rhizobia. This study suggests that establishment of a root nodule symbiosis requires the evasion of plant immune responses triggered by rhizobial effectors.
Middle Pleistocene lower back and pelvis from an aged human individual from the Sima de los Huesos site, Spain
Authors: Bonmatí Alejandro , Gómez-Olivencia Asier , Arsuaga Juan-Luis , Carretero José Miguel , Gracia Ana , Martínez Ignacio , Lorenzo Carlos , Bérmudez de Castro José María , Carbonell Eudald
Published: October 2010

We report a nearly complete lumbar spine from the Middle Pleistocene site of the Sima de los Huesos (SH) that is assigned to the previously published SH male Pelvis 1 [Arsuaga JL, et al. (1999).
Nature
399: 255–258]. The “SH Pelvis 1 individual” is a unique nearly complete lumbo-pelvic complex from the human Middle Pleistocene fossil record, and offers a rare glimpse into the anatomy and past lifeways of
Homo heidelbergensis
. A revised reconstruction of Pelvis 1, together with the current fossil evidence, confirms our previous hypothesis that the morphology of this pelvis represents the primitive pattern within the genus
Homo
. Here we argue that this primitive pattern is also characterized by sexual dimorphism in the pelvic canal shape, implying complicated deliveries. In addition, this individual shows signs of lumbar kyphotic deformity, spondylolisthesis, and Baastrup disease. This suite of lesions would have postural consequences and was most likely painful. As a result, the individual’s daily physical activities would have been restricted to some extent. Reexamination of the age-at-death agrees with this individual being over 45 y old, relying on the modern human pattern of changes of the articular surfaces of the os coxae. The presence of degenerative pathological lesions and the advanced age-at-death of this individual make it the most ancient postcranial evidence of an aged individual in the human fossil record. Additional nonpathological SH lumbo-pelvic remains are consistent with previous hypotheses, suggesting a less-pronounced sagittal spinal curvature in Neandertals compared with
Homo sapiens
.
Clostridium thermocellum
cellulosomal genes are regulated by extracytoplasmic polysaccharides via alternative sigma factors
Authors: Nataf Yakir , Bahari Liat , Kahel-Raifer Hamutal , Borovok Ilya , Lamed Raphael , Bayer Edward A. , Sonenshein Abraham L. , Shoham Yuval
Published: October 2010

Clostridium thermocellum
produces a highly efficient cellulolytic extracellular complex, termed the cellulosome, for hydrolyzing plant cell wall biomass. The composition of the cellulosome is affected by the presence of extracellular polysaccharides; however, the regulatory mechanism is unknown. Recently, we have identified in
C. thermocellum
a set of putative σ and anti-σ factors that include extracellular polysaccharide-sensing components [Kahel-Raifer et al. (2010)
FEMS Microbiol Lett
308:84–93]. These factor-encoding genes are homologous to the
Bacillus subtilis
bicistronic operon
sigI-rsgI
, which encodes for an alternative σ
I
factor and its cognate anti-σ
I
regulator RsgI that is functionally regulated by an extracytoplasmic signal. In this study, the binding of
C. thermocellum
putative anti-σ
I
factors to their corresponding σ factors was measured, demonstrating binding specificity and dissociation constants in the range of 0.02 to 1 μM. Quantitative real-time RT-PCR measurements revealed three- to 30-fold up-expression of the alternative σ factor genes in the presence of cellulose and xylan, thus connecting their expression to direct detection of their extracellular polysaccharide substrates. Cellulosomal genes that are putatively regulated by two of these σ factors, σ
I1
or σ
I6
, were identified based on the sequence similarity of their promoters. The ability of σ
I1
to direct transcription from the
sigI1
promoter and from the promoter of
celS
(encodes the family 48 cellulase) was demonstrated in vitro by runoff transcription assays. Taken together, the results reveal a regulatory mechanism in which alternative σ factors are involved in regulating the cellulosomal genes via an external carbohydrate-sensing mechanism.
A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage
Authors: Chou Danny M. , Adamson Britt , Dephoure Noah E. , Tan Xu , Nottke Amanda C. , Hurov Kristen E. , Gygi Steven P. , Colaiácovo Monica P. , Elledge Stephen J.
Published: October 2010

Many proteins that respond to DNA damage are recruited to DNA lesions. We used a proteomics approach that coupled isotopic labeling with chromatin fractionation and mass spectrometry to uncover proteins that associate with damaged DNA, many of which are involved in DNA repair or nucleolar function. We show that polycomb group members are recruited by poly(ADP ribose) polymerase (PARP) to DNA lesions following UV laser microirradiation. Loss of polycomb components results in IR sensitivity of mammalian cells and
Caenorhabditis elegans
. PARP also recruits two components of the repressive nucleosome remodeling and deacetylase (NuRD) complex, chromodomain helicase DNA-binding protein 4 (CHD4) and metastasis associated 1 (MTA1), to DNA lesions. PARP plays a role in removing nascent RNA and elongating RNA polymerase II from sites of DNA damage. We propose that PARP sets up a transient repressive chromatin structure at sites of DNA damage to block transcription and facilitate DNA repair.
A triple
urocortin
knockout mouse model reveals an essential role for urocortins in stress recovery
Authors: Neufeld-Cohen Adi , Tsoory Michael M. , Evans Andrew K. , Getselter Dmitriy , Gil Shosh , Lowry Christopher A. , Vale Wylie W. , Chen Alon
Published: October 2010

Responding to stressful events requires numerous adaptive actions involving integrated changes in the central nervous and neuroendocrine systems. Numerous studies have implicated dysregulation of stress-response mechanisms in the etiology of stress-induced psychopathophysiologies. The urocortin neuropeptides are members of the corticotropin-releasing factor family and are associated with the central stress response. In the current study, a triple-knockout (tKO) mouse model lacking all three
urocortin
genes was generated. Intriguingly, these urocortin tKO mice exhibit increased anxiety-like behaviors 24 h following stress exposure but not under unstressed conditions or immediately following exposure to acute stress. The inability of these mutants to recover properly from the exposure to an acute stress was associated with robust alterations in the expression profile of amygdalar genes and with dysregulated serotonergic function in stress-related neurocircuits. These findings position the urocortins as essential factors in the stress-recovery process and suggest the tKO mouse line as a useful stress-sensitive mouse model.
Acceleration of wound healing by growth hormone-releasing hormone and its agonists
Authors: Dioufa Nikolina , Schally Andrew V. , Chatzistamou Ioulia , Moustou Evi , Block Norman L. , Owens Gary K. , Papavassiliou Athanasios G. , Kiaris Hippokratis
Published: October 2010

Despite the well-documented action of growth hormone-releasing hormone (GHRH) on the stimulation of production and release of growth hormone (GH), the effects of GHRH in peripheral tissues are incompletely explored. In this study, we show that GHRH plays a role in wound healing and tissue repair by acting primarily on wound-associated fibroblasts. Mouse embryonic fibroblasts (MEFs) in culture and wound-associated fibroblasts in mice expressed a splice variant of the receptors for GHRH (SV1). Exposure of MEFs to 100 nM and 500 nM GHRH or the GHRH agonist JI-38 stimulated the expression of α-smooth muscle actin (αSMA) based on immunoblot analyses as well as the expression of an αSMA-β-galactosidase reporter transgene in primary cultures of fibroblasts isolated from transgenic mice. Consistent with this induction of αSMA expression, results of transwell-based migration assays and in vitro wound healing (scratch) assays showed that both GHRH and GHRH agonist JI-38 stimulated the migration of MEFs in vitro. In vivo, local application of GHRH or JI-38 accelerated healing in skin wounds of mice. Histological evaluation of skin biopsies showed that wounds treated with GHRH and JI-38 were both characterized by increased abundance of fibroblasts during the early stages of wound healing and accelerated reformation of the covering epithelium at later stages. These results identify another function of GHRH in promoting skin tissue wound healing and repair. Our findings suggest that GHRH may have clinical utility for augmenting healing of skin wounds resulting from trauma, surgery, or disease.
Adaptation to diverse nitrogen-limited environments by deletion or extrachromosomal element formation of the
GAP1
locus
Authors: Gresham David , Usaite Renata , Germann Susanne Manuela , Lisby Michael , Botstein David , Regenberg Birgitte
Published: October 2010

To study adaptive evolution in defined environments, we performed evolution experiments with
Saccharomyces cerevisiae
(yeast) in nitrogen-limited chemostat cultures. We used DNA microarrays to identify copy-number variation associated with adaptation and observed frequent amplifications and deletions at the
GAP1
locus.
GAP1
encodes the general amino acid permease, which transports amino acids across the plasma membrane. We identified a self-propagating extrachromosomal circular DNA molecule that results from intrachromosomal recombination between long terminal repeats (LTRs) flanking
GAP1
. Extrachromosomal DNA circles (
GAP1
circle
) contain
GAP1
, the replication origin
ARS1116
, and a single hybrid LTR derived from recombination between the two flanking LTRs. Formation of the
GAP1
circle
is associated with deletion of chromosomal
GAP1
(
gap1Δ
) and production of a single hybrid LTR at the
GAP1
chromosomal locus. The
GAP1
circle
is selected following prolonged culturing in
l
-glutamine–limited chemostats in a manner analogous to the selection of oncogenes present on double minutes in human cancers. Clones carrying only the
gap1Δ
allele were selected under various non-amino acid nitrogen limitations including ammonium, urea, and allantoin limitation. Previous studies have shown that the rate of intrachromosomal recombination between tandem repeats is stimulated by transcription of the intervening sequence. The high level of
GAP1
expression in nitrogen-limited chemostats suggests that the frequency of
GAP1
circle
and
gap1Δ
generation may be increased under nitrogen-limiting conditions. We propose that this genomic architecture facilitates evolvability of
S. cerevisiae
populations exposed to variation in levels and sources of environmental nitrogen.
Release of Mps1 from kinetochores is crucial for timely anaphase onset
Authors: Jelluma Nannette , Dansen Tobias B. , Sliedrecht Tale , Kwiatkowski Nicholas P. , Kops Geert J.P.L.
Published: October 2010

Mps1 kinase activity is required for proper chromosome segregation during mitosis through its involvements in microtubule–chromosome attachment error correction and the mitotic checkpoint. Mps1 dynamically exchanges on unattached kinetochores but is largely removed from kinetochores in metaphase. Here we show that Mps1 promotes its own turnover at kinetochores and that removal of Mps1 upon chromosome biorientation is a prerequisite for mitotic checkpoint silencing. Inhibition of Mps1 activity increases its half-time of recovery at unattached kinetochores and causes accumulation of Mps1 protein at these sites. Strikingly, preventing dissociation of active Mps1 from kinetochores delays anaphase onset despite normal chromosome attachment and alignment, and high interkinetochore tension. This delay is marked by continued recruitment of Mad1 and Mad2 to bioriented chromosomes and is attenuated by Mad2 depletion, indicating chronic engagement of the mitotic checkpoint in metaphase. We propose that release of Mps1 from kinetochores is essential for mitotic checkpoint silencing and a fast metaphase-to-anaphase transition.
Tbata modulates thymic stromal cell proliferation and thymus function
Authors: Flomerfelt Francis A. , El Kassar Nahed , Gurunathan Chandra , Chua Kevin S. , League Stacy C. , Schmitz Sabrina , Gershon Timothy R. , Kapoor Veena , Yan Xiao-Yi , Schwartz Ronald H. , Gress Ronald E.
Published: October 2010

Niche availability provided by stromal cells is critical to thymus function. Thymi with diminished function contain fewer stromal cells, whereas thymi with robust function contain proliferating stromal cell populations. Here, we show that the thymus, brain, and testes–associated gene (Tbata; also known as SPATIAL) regulates thymic epithelial cell (TEC) proliferation and thymus size. Tbata is expressed in thymic stromal cells and interacts with the enzyme Uba3, thereby inhibiting the Nedd8 pathway and cell proliferation. Thymi from aged Tbata-deficient mice are larger and contain more dividing TECs than wild-type littermate controls. In addition, thymic reconstitution after bone marrow transplantation occurred more rapidly in Rag2−/−Tbata−/− mice than in Rag2−/−Tbata+/+ littermate controls. These findings suggest that Tbata modulates thymus function by regulating stromal cell proliferation via the Nedd8 pathway.
Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion
Authors: Xu Yingjie , Bismar Tarek A. , Su Jie , Xu Bin , Kristiansen Glen , Varga Zsuzsanna , Teng Lianghong , Ingber Donald E. , Mammoto Akiko , Kumar Rakesh , Alaoui-Jamali Moulay A.
Published: October 2010

The actin cross-linking protein filamin A (FLNa) functions as a scaffolding protein and couples cell cytoskeleton to extracellular matrix and integrin receptor signaling. In this study, we report that FLNa suppresses invasion of breast cancer cells and regulates focal adhesion (FA) turnover. Two large progression tissue microarrays from breast cancer patients revealed a significant decrease of FLNa levels in tissues from invasive breast cancer compared with benign disease and in lymph node–positive compared with lymph node–negative breast cancer. In breast cancer cells and orthotopic mouse breast cancer models, down-regulation of FLNa stimulated cancer cell migration, invasion, and metastasis formation. Time-lapse microscopy and biochemical assays after FLNa silencing and rescue with wild-type or mutant protein resistant to calpain cleavage revealed that FLNa regulates FA disassembly at the leading edge of motile cells. Moreover, FLNa down-regulation enhanced calpain activity through the mitogen-activated protein kinase–extracellular signal-regulated kinase cascade and stimulated the cleavage of FA proteins. These results document a regulation of FA dynamics by FLNa in breast cancer cells.
Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics
Authors: Arcisio-Miranda Manoel , Muroi Yukiko , Chowdhury Sandipan , Chanda Baron
Published: October 2010

The hallmark of many intracellular pore blockers such as tetra-alkylammonium compounds and local anesthetics is their ability to allosterically modify the movement of the voltage sensors in voltage-dependent ion channels. For instance, the voltage sensor of domain III is specifically stabilized in the activated state when sodium currents are blocked by local anesthetics. The molecular mechanism underlying this long-range interaction between the blocker-binding site in the pore and voltage sensors remains poorly understood. Here, using scanning mutagenesis in combination with voltage clamp fluorimetry, we systematically evaluate the role of the internal gating interface of domain III of the sodium channel. We find that several mutations in the S4–S5 linker and S5 and S6 helices dramatically reduce the stabilizing effect of lidocaine on the activation of domain III voltage sensor without significantly altering use-dependent block at saturating drug concentrations. In the wild-type skeletal muscle sodium channel, local anesthetic block is accompanied by a 21% reduction in the total gating charge. In contrast, point mutations in this critical intracellular region reduce this charge modification by local anesthetics. Our analysis of a simple model suggests that these mutations in the gating interface are likely to disrupt the various coupling interactions between the voltage sensor and the pore of the sodium channel. These findings provide a molecular framework for understanding the mechanisms underlying allosteric interactions between a drug-binding site and voltage sensors.
Asymptotic analysis of small-angle scattering intensities of plane columnar layers
Authors: Ciccariello Salvino
Published: October 2010

The asymptotic behaviour, at large scattering vectorq, of the small-angle scattering intensities of isotropic plane samples is similar to that of three-dimensional samples. In fact, its expression, limited to the first two leading terms, isc1γ(1)(0)/q3 + c3γ(3)(0)/q5, wherec1andc3are appropriate numerical constants, and γ(1)(0) and γ(3)(0) the values, at the origin, of the first and third derivatives, respectively, of the two-dimensional correlation function. These values are proportional to the specific length and to the mean square reciprocal curvature radius of the interface curve. The angularity of the latter can also be determined, while the presence of oscillations in the appropriate Porod plot is related to a parallelism condition obeyed by the interface curve. These results are useful for analysing the small-angle scattering intensities collected under grazing incidence and diffused by film samples that are a collection of homogeneous cylinders of arbitrary right sections.