bluuebunny/crossref_metadata_2025 huggingface dataset:
ERα-mediated repression of pro-inflammatory cytokine expression by glucocorticoids reveals a critical role for TNFα and IL1α in lumen formation and maintenance.
Authors: Eritja Nuria , Mirantes Cristina , Llobet David , Masip Gemma , Matias-Guiu Xavier , Dolcet Xavi
Published: February 2012

Most glandular tissues are comprised of polarized epithelial cells organized around a single central lumen. Although there is active research investigating the molecular networks involved in the regulation of lumenogenesis, little is known about the extracellular factors that influence lumen formation and maintenance. Using a three dimensional culture system of epithelial endometrial cells, we revealed a new role for pro-inflammatory cytokines such as TNFα and IL1α in formation and, more importantly, maintenance of a single central lumen. We have further studied the mechanism by which glucocorticoids repressed TNFα and IL1α expression. Interestingly, regulation of pro-inflammatory cytokine expression and subsequently lumen formation is mediated by Estrogen Receptor α but not by Glucocorticoid Receptor. Finally, we have investigated the signalling pathways involved in the regulation of lumen formation by pro-inflammatory cytokines. Our results demonstrate that activation ERK/MAPK signalling pathway, but not PI3K/Akt signalling pathway, is important for the formation and maintenance of a single central lumen. In summary, our results suggest a novel role for ERα-regulated of pro-inflammatory cytokine expression in lumen formation and maintenance.
Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation
Authors: Ngo Shyuan T. , Cole Rebecca N. , Sunn Nana , Phillips William D. , Noakes Peter G.
Published: February 2012

At neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signaling through the Muscle Specific Kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act via muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signaling can modulate n-agrin-induced AChR clustering independent of its effects on transcription. Here we report that when injected into muscles of embryonic mice, neuregulin-1increased the size of developing AChR clusters. We investigated this phenomenon using cultured myotubes, and found thatin the ongoing presence of n-agrin,neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. Thispotentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence may function as a second order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signaling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.
Cadherin-dependent differential cell adhesion in Xenopus causes cell sorting in vitro, but not in the embryo
Authors: Ninomiya Hiromasa , David Robert , Damm Erich W. , Fagotto Francois , Niessen Carien , Winklbauer Rudolf
Published: February 2012

Adhesion differences between cell populations are in principle a source of strong morphogenetic forces promoting cell sorting, boundary formation and tissue positioning, and cadherins are main mediators of cell adhesion. However, a direct link between cadherin expression, differential adhesion, and morphogenesis has not yet been determined for a specific process in vivo. To provide such a connection, we modulated the expression of C-cadherin in the Xenopus gastrula, and combined this with direct measurements of cell adhesion-related parameters. Our results show that gastrulation is surprisingly tolerant of overall changes in adhesion. Also, as expected, experimentally generated, cadherin-based adhesion differences promote cell sorting in vitro. Importantly, however, such differences do not lead to the sorting of cells in the embryo, showing that differential adhesion is not sufficient to drive morphogenesis in this system. Compensatory recruitment of cadherin protein to contacts between cadherin-deprived and -overexpressing cells could contribute to the prevention of sorting in vivo.
Peripheral Endoplasmic Reticulum Localization of Gp78 Ubiquitin Ligase Activity
Authors: St-Pierre Pascal , Dang Thao , Joshi Bharat , Nabi Ivan R.
Published: February 2012

Gp78 is an E3 ubiquitin ligase that targets proteins for proteasomal degradation through endoplasmic reticulum-associated degradation (ERAD). Here, we show that gp78-mediated ubiquitylation is initiated in the peripheral ER. Substrate monoubiquitylation and gp78 Cue domain integrity restrict substrate to the peripheral ER where Cue domain interactions and polyubiquitylation reduce gp78 mobility. Derlin-1 and derlin-2, involved in retrotranslocation of ERAD substrates, localize to a central, juxtanuclear ER domain where polyubiquitylated proteins accumulate upon proteasome inhibition. Transfer of polyubiquitylated substrate to the central ER is dependent on ubiquitin chain elongation and recruitment of the AAA ATPase p97. HT-1080 fibrosarcoma cells express elevated levels of endogenous gp78 that is associated with segregation of ubiquitylated substrate to the peripheral ER and its polyubiquitin-dependent redistribution to the central ER upon proteasome inhibition. The peripheral ER is therefore the site of gp78 ubiquitin ligase activity. Delivery of ubiquitylated substrate to the central ER is regulated by ubiquitin chain elongation and opposing actions of gp78 Cue domain interactions and p97 recruitment.
Mob1: defining cell polarity for proper cell division
Authors: Tavares Alexandra , Gonçalves João , Florindo Cláudia , Tavares Álvaro A. , Soares Helena
Published: February 2012

Mob1 is a component of both the mitotic exit network and Hippo pathway, being required for cytokinesis, control of cell proliferation and apoptosis. Cell division accuracy is crucial in maintaining cell ploidy and genomic stability and relies on the correct establishment of the cell division axis, which is under the control of the cell's environment and its intrinsic polarity. The ciliate Tetrahymena thermophila possesses a permanent anterior–posterior axis, left–right asymmetry and divides symmetrically. These unique features of Tetrahymena prompted us to investigate the role of Tetrahymena Mob1. Unexpectedly, we found that Mob1 accumulated in basal bodies at the posterior pole of the cell, and is the first molecular polarity marker so far described in Tetrahymena. In addition, Mob1 depletion caused the abnormal establishment of the cell division plane, providing clear evidence that Mob1 is important for its definition. Furthermore, cytokinesis was arrested and ciliogenesis delayed in Tetrahymena cells depleted of Mob1. This is the first evidence for an involvement of Mob1 in cilia biology. In conclusion, we show that Mob1 is an important cell polarity marker that is crucial for correct division plane placement, for cytokinesis completion and for normal cilia growth rates.
Stepwise androgen receptor dimerization
Authors: van Royen Martin E. , van Cappellen Wiggert A. , de Vos Carola , Houtsmuller Adriaan B. , Trapman Jan
Published: February 2012

Androgen-regulated gene expression is a highly coordinated dynamic process mediated by androgen receptor (AR) ligand-binding and DNA-binding, and by specific AR protein-protein interactions. The latter include DNA-binding domain (D-box) interactions in AR homodimers, and the interaction of the FQNLF-motif in the AR N-terminal domain and the coactivator groove in the ligand-binding domain (N/C interaction). Here we studied these interactions in AR homodimerization using quantitative imaging techniques. We show that the initial cytoplasmic intramolecular AR N/C interaction after ligand-binding is followed by a D-box-dimerization dependent transition to intermolecular N/C interaction in a proportion of nuclear ARs. The consecutive steps leading to homodimerization are initiated prior to DNA-binding. Our data indicate the presence of a nuclear pool of both AR homodimers and monomers. Based on AR-regulated reporter assays we propose specificity in regulation of gene expression by AR homodimers and monomers mediated by AR-domain interactions. Moreover, our findings elucidate important steps in the spatio-temporal organization of AR intra- and intermolecular interactions.
TPPP acts downstream of RhoA-ROCK-LIMK2 to regulate astral microtubule organization and spindle orientation
Authors: Heng Yi-Wen , Lim Hong-Hwa , Mina Theresia , Utomo Prayudi , Zhong Shaoping , Lim Chwee-Teck , Koh Cheng-Gee
Published: February 2012

The actin cytoskeleton in eukaryotic cells undergoes drastic rearrangement during mitosis. The actin cytoskeleton changes are most obvious in the adherent cells where the actin stress fibres are disassembled and the cortical actin network becomes more prominent with concomitant increase in cell rigidity as cells round up and enter mitosis. While the regulatory connections between the actin cytoskeleton and the early mitotic events are apparent, the mechanisms that govern these links are not well understood. Here, we report that LIMK1 and LIMK2, the downstream effectors of RhoA/ROCK, regulate centrosome integrity and astral microtubules organization respectively. Surprisingly, LIMK1 and cofilin are not involved downstream of RhoA/ROCK in the regulation of astral microtubule organization. Instead, we find LIMK2 acts via TPPP in the regulation of astral microtubule, while both LIMK1 and LIMK2 affect centrosome focusing. Both phenotypes are tightly coupled to spindle orientation in the mitotic cells. Thus, our results reveal a novel regulatory link between the actin cytoskeleton and the mitotic spindle during the early stages of mitosis.
Myo1c regulates lipid raft recycling to control cell spreading, migration and Salmonella invasion
Authors: Brandstaetter Hemma , Kendrick-Jones John , Buss Folma
Published: February 2012

A balance between endocytosis and membrane recycling regulates the composition and dynamics of the plasma membrane. Internalization and recycling of cholesterol and sphingolipid-enriched lipid rafts is an actin-dependent process that follows a specialized Arf6-dependent recycling pathway. Here we identify the first motor protein, myosin1c (Myo1c) that drives the formation of recycling tubules emanating from the perinuclear recycling compartment. We demonstrate that the single headed Myo1c is a lipid raft-associated motor protein, specifically involved in recycling of lipid raft-associated GPI-linked cargo proteins and their delivery to the cell surface. While Myo1c overexpression increases the levels of these raft proteins at the cell surface, in cells depleted of Myo1c function by RNA interference or by over-expression of a dominant-negative mutant, these tubular transport carriers of the recycling pathway are lost and GPI-linked raft markers are trapped in the perinuclear recycling compartment. Intriguingly, Myo1c selectively promotes delivery of only lipid raft membranes back to the cell surface and is not required for recycling of cargo such as the transferrin receptor using parallel pathways. The profound defect in lipid raft trafficking in Myo1c knockdown cells has a dramatic impact on cell spreading, cell migration and cholesterol-dependent Salmonella invasion; processes that require lipid raft transport to the cell surface to deliver signalling components and the extra membrane essential for cell surface expansion and remodelling. Thus, Myo1c plays a crucial role in the recycling of lipid raft membrane and proteins that regulate plasma membrane plasticity, cell motility and pathogen entry.
A Novel Binding Site for hERalpha and hARNT1 AF2 Domains in the C-terminus of SRC1e Up-regulates Estrogen Receptor Alpha and AhR/ARNT1 Related Responses
Authors: Endler Alexander , Chen Li , Zhang Jun , Xu Guo-Tong , Shibasaki Futoshi
Published: February 2012

Steroid receptor co-activator 1 (SRC1) is a transcriptional co-activator of numerous transcription factors involving nuclear receptors. Aryl hydrocarbon receptor nuclear translocator 1 (ARNT1) is an obligatory transcriptional partner of the aryl hydrocarbon receptor (AhR) and the hypoxia inducible factor-1α (HIF-1α) as well as a co-activator of estrogen receptors (ER). In order to initiate transcription, the activation function 2 (AF2) domains of estrogen-activated ERs interact with LxxLL motifs in the nuclear receptor interaction domain (NID) of SRC1. Here we report on a novel estrogen and LxxLL domain-independent hERalpha-AF2 binding to SRC1e-exon 21. In addition, we determined an unrecognized AF2 domain in hARNT1-exon 16, also binding to SRC1e-exon 21. Surprisingly, the interaction between SRC1e-exon 21 and the AF2 domain of hERalpha functions as a critical enhancer of estrogen-induced transcription. The hARNT1 AF2 binding to SRC1e-exon 21 enhances transcriptional response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but the up-regulation essentially depends on 2 cyclin destruction boxes (D-boxes), which are also located on exon 16 of ARNT1. Our findings reveal that a novel binding site for hERalpha and hARNT1 AF2 domains in the C-terminus of SRC1e up-regulates estrogen and TCDD related responses in mammalian cells.
Ror-family receptor tyrosine kinases regulate maintenance of neural progenitor cells in the developing neocortex
Authors: Endo Mitsuharu , Doi Ryosuke , Nishita Michiru , Minami Yasuhiro
Published: February 2012

The Ror-family of receptor tyrosine kinases (RTKs), Ror1 and Ror2, have been shown to play crucial roles in the developmental morphogenesis by acting as receptors or co-receptors to mediate Wnt5a-induced signaling. Although Ror1, Ror2, and Wnt5a are expressed in the developing brain, little is known about their roles in the neural development. Here we show that Ror1, Ror2, and their ligand Wnt5a are highly expressed in neocortical neural progenitor cells (NPCs). siRNA-mediated suppression of Ror1, Ror2, or Wnt5a in cultured NPCs isolated from embryonic neocortex results in the reduction of βIII-tubulin-positive neurons that are produced from NPCs possibly through the generation of T-box brain 2 (Tbr2)-positive intermediate progenitors. BrdU-labeling experiments further reveal that proportion of proliferative and neurogenic NPCs, that are positive for neural progenitor cell marker (Pax6), but negative for glial cell marker (glial fibrillary acidic protein; GFAP), is reduced within a few days in culture following knockdown of these molecules, suggesting that Ror1, Ror2, and Wnt5a regulate neurogenesis through the maintenance of NPCs. Moreover, we show that Dishevelled2 (Dvl2) is involved in Wnt5a–Ror1 and Wnt5a–Ror2 signalings in NPCs, and that suppressed expression of Dvl2 indeed reduces the proportion of proliferative and neurogenic NPCs. Interestingly, suppressed or forced expression of either Ror1 or Ror2 in NPCs in the developing neocortex results in their precocious or delayed differentiation into neurons, respectively. Collectively, these results indicate that Wnt5a–Ror1 and Wnt5a–Ror2 signalings play roles in maintaining proliferative and neurogenic NPCs during neurogenesis of the developing neocortex.
Disparate Ryanodine Receptor Association with the FK506-binding Proteins in Mammalian Heart
Authors: Zissimopoulos Spyros , Seifan Sara , Maxwell Chloe , Williams Alan J. , Lai F. Anthony
Published: February 2012

The FK506-binding proteins (FKBP12 and FKBP12.6) are accessory subunits of the ryanodine receptor-calcium release channel (RyR). Aberrant RyR2-FKBP12.6 interactions have been proposed to be the underlying cause of channel dysfunction in acquired and inherited cardiac disease. However, the stoichiometric RyR2 association with FKBP12/12.6 in mammalian heart is currently unknown. Here, we describe detailed quantitative analysis of cardiac RyR2:FKBP12/12.6 stoichiometry using immunoblot analysis and [3H]ryanodine binding assays, revealing striking disparities between four mammalian species. In mouse and pig heart, RyR2 is found complexed with both FKBP12 and FKBP12.6, although the former is the most abundant isoform. In rat heart, RyR2 is predominantly associated with FKBP12.6, whereas in rabbit it is associated with FKBP12 only. Co-immunoprecipitation experiments demonstrate RyR2-specific interaction with both FKBP isoforms in native cardiac tissue. Assuming four FKBP binding sites per RyR2 tetramer, only a small proportion of available sites are occupied by endogenous FKBP12.6. FKBP interactions with RyR2 are very strong and resistant to drug (FK506, rapamycin, cyclic ADPribose) and redox (H2O2, diamide) treatment. In contrast, the RyR1-FKBP12 association in skeletal muscle is readily disrupted under oxidative conditions. This is the first study to directly assess endogenous FKBP12 and FKBP12.6 associated with RyR2 in native cardiac tissue. Our results challenge the widespread perception that RyR2 associates exclusively with FKBP12.6 to near saturation, with important implications for the role of the FK506-binding proteins in RyR2 pathophysiology and cardiac disease.
GKAP-DLC2 interaction organizes postsynaptic scaffold complex to enhance synaptic NMDA receptor activity
Authors: Moutin Enora , Raynaud Fabrice , Fagni Laurent , Perroy Julie
Published: February 2012

At glutamatergic brain synapses, scaffolding proteins regulate receptor location and function. The targeting and organization of scaffolding proteins in the postsynaptic density (PSD) is poorly understood. A core protein of the glutamatergic receptor postsynaptic scaffold complex, GKAP, interacts with DLC2, a protein associated with molecular motors. In the present study, we combined BRET imaging, immuno-staining and electrophysiological recording to assess the role of GKAP-DLC2 interaction in the functional organization of the glutamatergic synapse. We found that GKAP-DLC2 interaction in dendritic spine stabilizes scaffolding protein expression at the PSD and enhances synaptic NMDA receptor activity. Moreover, the GKAP-DLC2 functional interaction is favored by sustained synaptic activity. These data provide a novel regulatory pathway of synaptic transmission that depends on activity-induced remodeling of the postsynaptic scaffold protein complex.
Identification of the amino-acid region involved in the intercellular interaction between the Na,K-ATPase β1 subunits
Authors: Tokhtaeva Elmira , Sachs George , Sun Haiying , Dada Laura A. , Sznajder Jacob I. , Vagin Olga
Published: February 2012

Epithelial junctions depend on intercellular interactions between the Na,K-ATPase β1 subunits of neighboring cells. The interaction between dog and rat subunits is less effective than the interaction between two dog β1 subunits, indicating the importance of species-specific regions for β1-β1 binding. To identify these regions, the species-specific amino-acid residues were mapped onto a high resolution structure of the Na,K-ATPase β1 subunit to select those exposed towards the β1 subunit of the neighboring cell. These exposed residues were mutated in both dog and rat YFP linked β1 subunits (YFP-β1) and also in the secreted extracellular domain of the dog β1 subunit. Five rat-like mutations in the 198–207 amino-acid region of the dog YFP-β1 expressed in Madin Darby canine kidney (MDCK) cells decreased co-precipitation of the endogenous dog β1 subunit with YFP-β1 to the level observed between dog β1 and rat YFP-β1. In parallel, these mutations impaired the recognition of YFP-β1 by the dog-specific antibody that inhibits cell adhesion between MDCK cells. Accordingly, dog-like mutations in rat YFP-β1 increased both (YFP-β1)-β1 interaction in MDCK cells and recognition by the antibody. Conversely, rat-like mutations in the secreted extracellular domain of the dog β1 subunit increased its interaction with rat YFP-β1 in vitro. In addition, these mutations resulted in reduction of intercellular adhesion between rat lung epithelial cells following addition of the secreted extracellular domain of the dog β1 subunit to a cell suspension. Therefore, the 198–207 amino-acid region is critical for both trans-dimerization of the Na,K-ATPase β1 subunits and cell-cell adhesion.
Dystrophin-compromised sarcoglycan-δ knockout diaphragm requires full wild type embryonic stem cell reconstitution for correction
Authors: Vitale Joseph M. , Schneider Joel S. , Beck Amanda J. , Zhao Qingshi , Chang Corey , Gordan Richard , Michaels Jennifer , Bhaumik Mantu , Fraidenraich Diego
Published: February 2012

Limb-girdle muscular dystrophy-2F (LGMD-2F) is an incurable degenerative muscle disorder caused by a mutation in the sarcoglycan-δ (SGδ) gene. The lack of SGδ results in the complete disruption of the sarcoglycan complex (SGC) in the skeletal and cardiac muscle within the larger dystrophin-glycoprotein complex (DGC). The long-term consequences of SGδ ablation on other members of the DGC are currently unknown. We produced mosaic mice through the injection of wild type (WT) embryonic stem cells (ESCs) into SGδ knockout (KO) blastocysts. ESC-SGδ was supplied to the sarcolemma of the 18-month old chimeric muscle, which resulted in the restoration of the SGC. Despite SGC rescue, and contrary to previous observations obtained with WT/mdx chimeras (a mouse rescue paradigm for Duchenne muscular dystrophy), low levels of ESC incorporation were insufficient to produce histological corrections in SGδ KO skeletal muscle or heart. The inefficient process of ESC rescue was more evident in the SGδ KO diaphragm, which had reduced levels of dystrophin and no compensatory utrophin, and needed almost full WT ESC reconstitution for histological improvement. The results suggest that the SGδ KO mouse model of LGMD is not amenable to ESC treatment.
In vivo cardiac anatomical and functional effects of wheel running in mice by magnetic resonance imaging
Authors: Aufradet Emeline , Bessaad Amine , Alsaid Hasan , Schäfer Florian , Sigovan Monica , De Souza Geneviève , Chirico Erica , Martin Cyril , Canet-Soulas Emmanuelle
Published: February 2012

Physical activity is frequently used as a strategy to decrease pathogenesis and improve outcomes in chronic pathologies such as metabolic or cardiac diseases. In mice, it has been shown that voluntary wheel running (VWR) could induce an aerobic training effect and may provide a means of exploring the relationship between physical activity and the progression of pathology, or the effect of a drug on locomotor activity. To the best of our knowledge, in vivo magnetic resonance imaging (MRI) and other non-invasive methods had not been investigated for training evaluation in mice; therefore, it was proposed to test an MRI method coupled with a cardiorespiratory gating system on C57Bl/6 mice for in vivo heart anatomical and functional characterization in both trained and untrained animals. Twenty mice were either assigned to a 12-week VWR program or to a control group (CON – no wheel in the cage). At week 12, MRI scans showed an increase in the left ventricular (LV) wall mass in the VWR group compared with the CON group. The ex vivo measurements also found an increase in the heart and LV weight, as well as an increase in oxidative enzyme activities (i.e. cytochrome c oxidase [COx] in the soleus). In addition, correlations have been observed between ex vivo LV/body weight ratio, COx activity in the soleus and in vivo MRI LV wall mass/body weight. In conclusion, mouse cardiac MRI methods coupled with a cardio-respiratory gating system are sufficiently effective and feasible for non-invasive, training-induced heart hypertrophy characterization, and may be used for longitudinal training level follow-up in mouse models of cardiovascular and metabolic diseases.
Daunorubicin therapy is associated with upregulation of E3 ubiquitin ligases in the heart
Authors: Sishi Balindiwe J N , Bester Dirk J , Wergeland Anita , Loos Benjamin , Jonassen Anne K , van Rooyen Jacques , Engelbrecht Anna-Mart
Published: February 2012

Daunorubicin (DNR) and doxorubicin (DOX) are two of the most effective anthracycline drugs known for the treatment of systemic neoplasms and solid tumors. However, their clinical use is hampered due to profound cardiotoxicity. The mechanism by which DNR injures the heart remains to be fully elucidated. Recent reports have indicated that DOX activates ubiquitin proteasome-mediated degradation of specific transcription factors; however, no reports exist on the effect of DNR on the E3 ubiquitin ligases, MURF-1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box). The aim of this study was to investigate the effect of DNR treatment on the protein and organelle degradation systems in the heart and to elucidate some of the signalling mechanisms involved. Adult rats were divided into two groups where one group received six intraperitoneal injections of 2 mg/kg DNR on alternate days and the other group received saline injections as control. Hearts were excised and perfused on a working heart system the day after the last injection and freeze-clamped for biochemical analysis. DNR treatment significantly attenuated cardiac function and increased apoptosis in the heart. DNR-induced cardiac cytotoxicity was associated with upregulation of the E3 ligases, MURF-1 and MAFbx and also caused significant increases in two markers of autophagy, beclin-1 and LC3. These changes observed in the heart were also associated with attenuation of the phosphoinositide 3-kinase/Akt signalling pathway.
Under-expression of the opioid growth factor receptor promotes progression of human ovarian cancer
Authors: Donahue Renee N , McLaughlin Patricia J , Zagon Ian S
Published: February 2012

The opioid growth factor (OGF) and its receptor, OGFr, serve as a tonically active inhibitory axis regulating the proliferation of human ovarian cancer cells. In the present study, we have investigated the repercussion on the progression of this deadly neoplasia when cells are engineered to molecularly under-express OGFr. shRNA constructs were used to knockdown OGFr in SKOV-3 cells; two clonal cell lines were examined. OGFr protein expression was decreased up to 73% in clones compared with wild-type (WT) and empty vector (EV) controls. OGFr-binding assays of clones revealed 50–55% decreases in binding capacity compared with control cells; binding affinity was comparable in all groups. Cell number in clones was increased 33–132%, and doubling times decreased 29–35%, compared with WT and EV cultures. Addition of exogenous OGF or naltrexone did not affect cell number in cultures with silenced OGFr. DNA synthesis of clonal cell lines was increased 136–146% from the WT and EV groups; no changes were noted in cell survival. Nude mice injected subcutaneously with cells under-expressing OGFr had an increased tumor incidence, decreased latency to tumor formation, increased tumor volume and decreased OGFr expression in tumors compared with WT and EV controls. OGF treatment in mice with WT or EV tumors, but not OGFr under-expressing tumors, inhibited tumor volume and weight. Collectively, these data demonstrate the critical nature of the OGF–OGFr axis as a determinant of the progression of human ovarian cancer, and suggest that attenuation of this system has an important bearing on the survival of these patients.
Analysis of stress granule assembly in Schizosaccharomyces pombe
Authors: Wang Chun-Yu , Wen Wei-Ling , Nilsson Daniel , Sunnerhagen Per , Chang Tien-Hsien , Wang Shao-Win
Published: February 2012

Stress granules (SGs) are cytoplasmic aggregates of RNA and proteins in eukaryotic cells that are rapidly induced in response to environmental stress, but are not seen in cells growing under favorable conditions. SGs have been primarily studied in mammalian cells. The existence of SGs in the fission yeast and the distantly related budding yeast was demonstrated only recently. In both species, they contain many orthologs of the proteins seen in mammalian SGs. In this study, we have characterized these proteins and determined their involvement in the assembly of fission yeast SGs, in particular, the homolog of human G3BP proteins. G3BP interacts with the deubiquitinating protease USP10 and plays an important role in the assembly of SGs. We have also identified Ubp3, an ortholog of USP10, as an interaction partner of the fission yeast G3BP-like protein Nxt3 and required for its stability. Under thermal stress, like their human orthologs, both Nxt3 and Ubp3 rapidly relocalize to cytoplasmic foci that contain the SG marker poly(A)-binding protein Pabp. However, in contrast to G3BP1 and USP10, neither deletion nor overexpression of nxt3+ or ubp3+ affected the assembly of fission yeast SGs as judged by the relocalization of Pabp. Similar results were observed in mutants defective in orthologs of SG components that are known to affect SG assembly in human and in budding yeast, such as ataxia-2 and TIA-like proteins. Together, our data indicate that despite similar protein compositions, the underlying molecular mechanisms for the assembly of SGs could be distinct between species.
Structure of the yeast U2/U6 snRNA complex
Authors: Burke Jordan E. , Sashital Dipali G. , Zuo Xiaobing , Wang Yun-Xing , Butcher Samuel E.
Published: February 2012

The U2/U6 snRNA complex is a conserved and essential component of the active spliceosome that interacts with the pre-mRNA substrate and essential protein splicing factors to promote splicing catalysis. Here we have elucidated the solution structure of a 111-nucleotide U2/U6 complex using an approach that integrates SAXS, NMR, and molecular modeling. The U2/U6 structure contains a three-helix junction that forms an extended “Y” shape. The U6 internal stem–loop (ISL) forms a continuous stack with U2/U6 Helices Ib, Ia, and III. The coaxial stacking of Helix Ib on the U6 ISL is a configuration that is similar to the Domain V structure in group II introns. Interestingly, essential features of the complex—including the U80 metal binding site, AGC triad, and pre-mRNA recognition sites—localize to one face of the molecule. This observation suggests that the U2/U6 structure is well-suited for orienting substrate and cofactors during splicing catalysis.
Consistency Judgments, Embeddedness, and Relationship Outcomes in Interorganizational Networks
Authors: Sa Vinhas Alberto , Heide Jan B. , Jap Sandy D.
Published: February 2012

Past research has shown how outcomes in interorganizational relationships are influenced by the characteristics of the individual relationship in question. Focusing on relationships between suppliers and their organizational buyers, we augment this perspective by positing that relationship outcomes are also influenced by social comparison processes involving perceptions of a supplier's practices across comparable buyer relationships. Based on past research on embedded ties and institutional theory, we propose that the effect of these comparison processes depends on the nature of a buyer's existing interorganizational ties and on the norms that are brought to bear on the relationship in question. We test our propositions based on 788 observations of organizational buyers who have relationships with the same supplier. Our findings paint a complex, multilevel picture of the process by which relationship outcomes come about in interorganizational networks.

This paper was accepted by Jesper Sørensen, organizations.
Streaks in Earnings Surprises and the Cross-Section of Stock Returns
Authors: Loh Roger K. , Warachka Mitch
Published: February 2012

The gambler's fallacy [Rabin, M. 2002. Inference by believers in the law of small numbers. Quart. J. Econom. 117(3) 775–816] predicts that trends bias investor expectations. Consistent with this prediction, we find that investors underreact to streaks of consecutive earnings surprises with the same sign. When the most recent earnings surprise extends a streak, post-earnings-announcement drift is strong and significant. In contrast, the drift is negligible following the termination of a streak. Indeed, streaks explain about half of the post-earnings-announcement drift in our sample. Our results are robust to more general definitions of trends than streaks and a battery of control variables including the magnitude of earnings surprises and their autocorrelation. Overall, post-earnings-announcement drift has a significant time-series component that is consistent with the gambler's fallacy.

This paper was accepted by Wei Xiong, finance.
OR Forum—Modeling the Impacts of Electricity Tariffs on Plug-In Hybrid Electric Vehicle Charging, Costs, and Emissions
Authors: Sioshansi Ramteen
Published: February 2012

Plug-in hybrid electric vehicles (PHEVs) have been touted as a transportation technology with lower fuel costs and emissions impacts than other vehicle types. Most analyses of PHEVs assume that the power system operator can either directly or indirectly control PHEV charging to coordinate it with power system operations. This paper examines the incentives of individual drivers making charging decisions with different electricity tariffs, and it compares the cost and emissions impacts of these charging patterns to the ideal case of charging controlled by the system operator. Our results show that real-time pricing performs worst among all of the tariffs we consider, because linear prices are inherently limited in signaling efficient use of resources in a system with nonconvexities. We also show that controlling overnight PHEV charging is significantly more important than limiting midday vehicle charging.
Spatial Updating Depends on Gaze Direction Even after Loss of Vision
Authors: Reuschel Johanna , Rösler Frank , Henriques Denise Y. P. , Fiehler Katja
Published: February 2012

Direction of gaze (eye angle + head angle) has been shown to be important for representing space for action, implying a crucial role of vision for spatial updating. However, blind people have no access to vision yet are able to perform goal-directed actions successfully. Here, we investigated the role of visual experience for localizing and updating targets as a function of intervening gaze shifts in humans. People who differed in visual experience (late blind, congenitally blind, or sighted) were briefly presented with a proprioceptive reach target while facing it. Before they reached to the target's remembered location, they turned their head toward an eccentric direction that also induced corresponding eye movements in sighted and late blind individuals. We found that reaching errors varied systematically as a function of shift in gaze direction only in participants with early visual experience (sighted and late blind). In the late blind, this effect was solely present in people with moveable eyes but not in people with at least one glass eye. Our results suggest that the effect of gaze shifts on spatial updating develops on the basis of visual experience early in life and remains even after loss of vision as long as feedback from the eyes and head is available.
Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury
Authors: Gupta Akshay , Elgammal Fatima S. , Proddutur Archana , Shah Samik , Santhakumar Vijayalakshmi
Published: February 2012

Brain injury is an etiological factor for temporal lobe epilepsy and can lead to memory and cognitive impairments. A recently characterized excitatory neuronal class in the dentate molecular layer, semilunar granule cell (SGC), has been proposed to regulate dentate network activity patterns and working memory formation. Although SGCs, like granule cells, project to CA3, their typical sustained firing and associational axon collaterals suggest that they are functionally distinct from granule cells. We find that brain injury results in an enhancement of SGC excitability associated with an increase in input resistance 1 week after trauma. In addition to prolonging miniature and spontaneous IPSC interevent intervals, brain injury significantly reduces the amplitude of tonic GABA currents in SGCs. The postinjury decrease in SGC tonic GABA currents is in direct contrast to the increase observed in granule cells after trauma. Although our observation that SGCs express Prox1 indicates a shared lineage with granule cells, data from control rats show that SGC tonic GABA currents are larger and sIPSC interevent intervals shorter than in granule cells, demonstrating inherent differences in inhibition between these cell types. GABAAreceptor antagonists selectively augmented SGC input resistance in controls but not in head-injured rats. Moreover, post-traumatic differences in SGC firing were abolished in GABAAreceptor blockers. Our data show that cell-type-specific post-traumatic decreases in tonic GABA currents boost SGC excitability after brain injury. Hyperexcitable SGCs could augment dentate throughput to CA3 and contribute substantively to the enhanced risk for epilepsy and memory dysfunction after traumatic brain injury.
Bias in the Brain: A Diffusion Model Analysis of Prior Probability and Potential Payoff
Authors: Mulder Martijn J. , Wagenmakers Eric-Jan , Ratcliff Roger , Boekel Wouter , Forstmann Birte U.
Published: February 2012

In perceptual decision-making, advance knowledge biases people toward choice alternatives that are more likely to be correct and more likely to be profitable. Accumulation-to-bound models provide two possible explanations for these effects: prior knowledge about the relative attractiveness of the alternatives at hand changes either the starting point of the decision process, or the rate of evidence accumulation. Here, we used model-based functional MRI to investigate whether these effects are similar for different types of prior knowledge, and whether there is a common neural substrate underlying bias in simple perceptual choices. We used two versions of the random-dot motion paradigm in which we manipulated bias by: (1) changing the prior likelihood of occurrence for two alternatives (“prior probability”) and (2) assigning a larger reward to one of two alternatives (“potential payoff”). Human subjects performed the task inside and outside a 3T MRI scanner. For each manipulation, bias was quantified by fitting the drift diffusion model to the behavioral data. Individual measurements of bias were then used in the imaging analyses to identify regions involved in biasing choice behavior. Behavioral results showed that subjects tended to make more and faster choices toward the alternative that was most probable or had the largest payoff. This effect was primarily due to a change in the starting point of the accumulation process. Imaging results showed that, at cue level, regions of the frontoparietal network are involved in changing the starting points in both manipulations, suggesting a common mechanism underlying the biasing effects of prior knowledge.
Variation in Teen Driver Education by State Requirements and Sociodemographics
Authors: Curry Allison E. , García-España J. Felipe , Winston Flaura K. , Ginsburg Kenneth , Durbin Dennis R.
Published: February 2012

OBJECTIVES:

There is renewed attention on national standardization of formal driver education (DE) instruction and momentum toward realigning DE with its original goal of producing safer teen drivers. However, teen DE participation rates and how they differ among sociodemographic groups and in states with and without DE requirements remain largely unknown. Thus, our objective was to estimate national teen participation rates in formal classroom and behind-the-wheel DE instruction in relevant demographic subgroups and also estimate subgroup-specific participation rates by presence of a state DE requirement.

METHODS:

Data were collected via the National Young Driver Survey, administered to a nationally representative sample of 5665 public school 9th- through 11th-graders in Spring 2006. Analyses were restricted to 1770 students with driver licenses. Survey data were weighted to reflect national prevalence estimates.

RESULTS:

Overall, 78.8% of students reported participating in formal DE. However, in states without DE requirements, more than 1 in 3 students had no formal DE before licensure, and more than half had no behind-the-wheel training. Hispanics, blacks, males, and students with lower academic achievement participated in DE at markedly lower levels than counterparts in states with requirements. Notably, 71% of Hispanic students in states with no requirement received a license without receiving formal DE.

CONCLUSIONS:

Considerable racial/ethnic, socioeconomic, and gender disparities in DE participation may exist in states with no DE requirements. State DE requirements may be an effective strategy to reduce these disparities.
In situ Structural Study of Organic Semiconductor Thin Films
Authors: Hosokai Takuya , Watanabe Takeshi , Koganezawa Tomoyuki , Ackermann Jorg , Brisset Hugues , Videlot-Ackermann Christine , Yoshimoto Noriyuki
Published: February 2012

A new class of high-vacuum organic deposition chamber was developed to study the structure and growth of organic semiconductor thin films. Using the chamber in situ real-time 2-dimensional grazing incidence x-ray diffraction (2D-GIXD) was measured during thin film growth of distyryl-oligothiophenes derivatives (DS2T) on SiO2 surface. An evolution of 2D-GIXD pattern was clearly observed during the growth due to the crystallization of the molecular domains consisting of standing-up orientation. A theoretical simulation on the experimental 2D-GIXD map provided a potential use of this system to determine the unit cell parameters in thin films. Thickness dependence and influence of air exposure on the film structure were also studied.
Carrier Transport Dependence on Phosphorescent Materials in Polymer Based OLEDs
Authors: Motomura Genichi , Suzuki Mitsunori , Shimizu Takahisa , Fujikake Hideo
Published: February 2012

The carrier transport properties in the emissive layer of phosphorescent polymer organic light-emitting diodes (OLEDs) were observed by time-of-flight (TOF) mobility measurements. The hole and electron mobilities in carrier transport polymer without iridium complexes were measured with high levels, 3 × 10-4 cm2/Vs (hole) and 1 × 10-3 cm2/Vs (electron), of non-dispersive transport. The hole and/or electron transport properties were degraded when the iridium complexes were included in the phosphorescent polymers. The complexes acted as a trap in the phosphorescent polymers when the energy levels of the iridium complexes were lower than that of the carrier transport polymer.
Relentless Progress: ASCO Responds
Authors: Lichter Allen S.
Published: February 2012

Efforts by the American Society of Clinical Oncology to keep oncologists apprised of the latest developments in cancer research, including its new interactive website CancerProgress.net and its Quality Oncology Practice Initiative, are highlighted.
Advances in Surveillance of Periodontitis: The Centers for Disease Control and Prevention Periodontal Disease Surveillance Project
Authors: Eke Paul I. , Thornton‐Evans Gina , Dye Bruce , Genco Robert
Published: February 2012

The Centers for Disease Control and Prevention (CDC) has as one of its strategic goals to support and improve surveillance of periodontal disease. In 2003, the CDC initiated the CDC Periodontal Disease Surveillance Project in collaboration with the American Academy of Periodontology to address population‐based surveillance of periodontal disease at the local, state, and national levels. This initiative has made significant advancements toward the goal of improved surveillance, including developing valid self‐reported measures that can be obtained from interview‐based surveys to predict prevalence of periodontitis in populations. This will allow surveillance of periodontitis at the state and local levels and in countries where clinical resources for surveillance are scarce. This work has produced standard case definitions for surveillance of periodontitis that are now widely recognized and applied in population studies and research. At the national level, this initiative has evaluated the validity of previous clinical examination protocols and tested new protocols on the National Health and Nutrition Examination Survey (NHANES), recommending and supporting funding for the gold‐standard full‐mouth periodontal examination in NHANES 2009 to 2012. These examinations will generate accurate estimates of the prevalence of periodontitis in the US adult population and provide a superior dataset for surveillance and research. Also, this data will be used to generate the necessary coefficients for our self‐report questions for use in subsets of the total US population. The impact of these findings on population‐based surveillance of periodontitis and future directions of the project are discussed along with plans for dissemination and translation efforts for broader public health use.
Hormetic Effects of Acute Methylmercury Exposure on GRP78 Expression in Rat Brain Cortex
Authors: Zhang Ye , Lu Rongzhu , Liu Wenshuai , Wu Ying , Qian Hai , Zhao Xiaowu , Wang Suhua , Xing Guangwei , Yu Feng , Aschner Michael
Published: February 2012

This study aims to explore the expression of GRP78, a marker of endoplasmic reticulum (ER) stress, in the cortex of rat brains acutely exposed to methylmercury (MeHg). Thirty Sprague-Dawley (SD) rats were randomly divided into six groups, and decapitated 6 hours (h) after intraperitoneal (i.p.) injection of MeHg (2, 4, 6, 8 or 10 mg/kg body weight) or normal saline. Protein and mRNA expression of Grp78 were detected by western blotting and real-time PCR, respectively. The results showed that a gradual increase in GRP78 protein expression was observed in the cortex of rats acutely exposed to MeHg (2, 4 or 6 mg/kg). Protein levels peaked in the 6 mg/kg group ( p < 0.05 vs. controls), decreased in the 8 mg/kg group, and bottomed below the control level in the 10 mg/kg group. Parallel changes were noted for Grp78 mRNA expression. It may be implied that acute exposure to MeHg induced hormetic dose-dependent changes in Grp78 mRNA and protein expression, suggesting that activation of ER stress is involved in MeHg-induced neurotoxicity. Low level MeHg exposure may induce GRP78 protein expression to stimulate endogenous cytoprotective mechanisms.
Byzantine and post-byzantine sources on medieval Bosnia, its area and position
Authors: Babic Boris
Published: February 2012

This article discusses the historical and geographical characteristics of
medieval Bosnia, its area and position presented in the perception of
Byzantine and post-Byzantine sources. It is characteristic that all these
sources, regardless of whether they originated in the 10th, 12th, or 15th
century or in the centuries after the collapse of the Byzantine Empire
offered testimony of the territory of Bosnia. The presentations are sometimes
a bit distorted and unrealistic, and their names are based on ancient
standards. Data provided by the source material speaking of the appearance of
Bosnia and medieval towns in its territory, were named differently in
Byzantine sources.
Manuel i Komnenos, „Carski san“ and „Samodrzci oblasti srpskog prestola“
Authors: Pirivatric Srdjan
Published: February 2012

This research examines the question of the so-called territorial
power-sharing rulers in Serbia during the reign of the Byzantine emperor
Manuel I Komnenos (1143-1180) based on the interpretations and
contextualisation of original data and of terms with the connotation of ruler
referring to Stefan Nemanja and his relatives.