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  1. Cocoa Procyanidins with Different Degrees of Polymerization Possess Distinct Activities in Models of Colonic Inflammation

    PubMed Central

    Bitzer, Zachary T.; Glisan, Shannon L.; Dorenkott, Melanie R.; Goodrich, Katheryn M.; Ye, Liyun; O’Keefe, Sean F.; Lambert, Joshua D.; Neilson, Andrew P.

    2015-01-01

    Procyanidins are available in the diet from sources such as cocoa and grapes. Procyanidins are unique in that they are comprised of repeating monomeric units and can exist in various degrees of polymerization. The degree of polymerization plays a role in determining the biological activities of procyanidins. However, generalizations cannot be made regarding the correlation between procyanidin structure and bioactivity, because the size-activity relationship appears to be system-dependent. Our aim was to screen fractions of procyanidins with differing degrees of polymerization in vitro for anti-inflammatory activities in models of colonic inflammation. Monomeric, oligomeric, and polymeric cocoa procyanidin fractions were screened using cell models of disrupted membrane integrity and inflammation in human colon cells. High molecular weight polymeric procyanidins were the most effective at preserving membrane integrity and reducing secretion of interleukin-8 in response to inflammatory stimuli. Conversely, oligomeric procyanidins appeared to be the least effective. These results suggest that polymeric cocoa procyanidins may be the most effective for preventing loss of gut barrier function and epithelial inflammation, which are critical steps in the pathogenesis of metabolic endotoxemia, inflammatory bowel disease, and colon cancer. Therefore, further investigations of the potential health-protective benefits of cocoa procyanidins with distinct degrees of polymerization, particularly high molecular weight procyanidins, are warranted. PMID:25869594

  2. Risk factors for spirit possession among school girls in southern Thailand.

    PubMed

    Trangkasombat, U; Su-Umpan, U; Churujiporn, V; Nukhew, O; Haruhanpong, V

    1998-07-01

    In September 1993, at a school in the south of Thailand, an outbreak of spirit possession suddenly afflicted 32 girls aged 9-14 years. A case-control study was done to investigate factors that predispose a child to spirit possession. Psychiatric evaluation was done on 32 cases and 34 matched controls. Parents were interviewed regarding the child's psychosocial history. Results of the study were as follows. Children with spirit possession were first-born and came from small families with 1-3 children. Compared with the controls their family life was characterized by more psychosocial stressors and there were significantly higher rates of psychiatric disorders, anxious and fearful character traits, histrionic character traits and history of recurrent trance states. The history of traumatic experiences and exposure to spirit possession ceremonies were more frequent in spirit-possessed children than in the control group but the difference was not significant. This study showed that being first-born from a small family, individual vulnerability especially psychiatric disorders, problematic character traits and dissociative tendency were significant risk factors in the development of possession states in children. PMID:9676093

  3. Odd perfect numbers have at least nine distinct prime factors

    NASA Astrophysics Data System (ADS)

    Nielsen, Pace P.

    2007-12-01

    An odd perfect number, N , is shown to have at least nine distinct prime factors. If 3nmid N then N must have at least twelve distinct prime divisors. The proof ultimately avoids previous computational results for odd perfect numbers.

  4. Strains of Burkholderia cenocepacia genomovar IIIA possessing the cblA gene that are distinct from ET12.

    PubMed

    Turton, Jane F; O'Brien, Emily; Megson, Brian; Kaufmann, Mary E; Pitt, Tyrone L

    2009-05-01

    Three strains of Burkholderia cenocepacia genomovar IIIA that were polymerase chain reaction positive for cblA, bcrA, and the epidemic strain marker, but were distinct from representatives of ET12 by pulsed-field gel electrophoresis, are described. One of these strains was shown to express cable pili by electron microscopy. PMID:19304435

  5. Leishmania parasites possess a platelet-activating factor acetylhydrolase important for virulence

    PubMed Central

    Pawlowic, Mattie C.; Zhang, Kai

    2012-01-01

    Leishmania parasites are intracellular protozoans capable of salvaging and remodeling lipids from the host. To understand the role of lipid metabolism in Leishmania virulence, it is necessary to characterize the enzymes involved in the uptake and turnover of phospholipids. This study focuses on a putative phospholipase A2 (PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) in L. major. In mammals, PAF-AH is a subgroup of PLA2 catalyzing the hydrolysis/inactivation of platelet-activating factor (PAF), a potent mediator of many leukocyte functions. By immunofluorescence microscopy, L. major PLA2/PAF-AH is predominantly localized in the ER. While wild type L. major parasites are able to hydrolyze PAF, this activity is completely absent in the PLA2/PAF-AH-null mutants. Meanwhile, deletion of PLA2/PAF-AH had no significant effect on the turnover of common glycerophospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. PLA2/PAF-AH is not required for the growth of L. major parasites in culture, or the production of GPI-anchored virulence factors. Nonetheless, it does play a key role in the mammalian host as the PLA2/PAF-AH null mutants exhibit attenuated virulence in BALB/c mice. In conclusion, these data suggest that Leishmania parasites possess a functional PAF-AH and the degradation of PAF or PAF-like lipids is an important step in infection. PMID:22954769

  6. The Expression of Possession in Medieval Russian Legal Language: Contextual Factors in the Selection of Alternatives

    ERIC Educational Resources Information Center

    Duraskovic, Ljiljana

    2012-01-01

    Russian legal-administrative documents from the early fourteenth through the mid-seventeenth century (Middle Russian) show extensive variation in expressing possessivity within the noun phrase. Possessor expressions can be conveyed by morphologically derived possessive adjectives, adnominal genitives, or by combinations of those constructions…

  7. When Does the Factor-Mixture Distinction Matter?

    ERIC Educational Resources Information Center

    Loken, Eric

    2012-01-01

    Von Davier, Naemi, and Roberts (this issue) present a nice summary of the statistical ambiguity often encountered in making distinctions between qualitative and quantitative constructs. In this commentary, the author begins with two broad points. The first is that the mixture/factor arguments are most intriguing when firmly embedded in a…

  8. Effectiveness of and Factors Related to Possession of a Mother and Child Health Handbook: An Analysis Using Propensity Score Matching

    ERIC Educational Resources Information Center

    Kawakatsu, Yoshito; Sugishita, Tomohiko; Oruenjo, Kennedy; Wakhule, Stephen; Kibosia, Kennedy; Were, Eric; Honda, Sumihisa

    2015-01-01

    Background: Mother and Child Health handbooks (MCH handbooks) serve as useful health education tools for mothers and sources of information that allow health care professionals to understand patient status. Therefore, it is necessary to clarify the effectiveness of and identify the factors related to possession of an MCH handbook among parents in…

  9. Reward and punishment act as distinct factors in guiding behavior

    PubMed Central

    Kubanek, Jan; Snyder, Lawrence H; Abrams, Richard A

    2015-01-01

    Behavior rests on the experience of reinforcement and punishment. It has been unclear whether reinforcement and punishment act as oppositely valenced components of a single behavioral factor, or whether these two kinds of outcomes play fundamentally distinct behavioral roles. To this end, we varied the magnitude of a reward or a penalty experienced following a choice using monetary tokens. The outcome of each trial was independent of the outcome of the previous trial, which enabled us to isolate and study the effect on behavior of each outcome magnitude in single trials. As expected, we found that a reward led to a repetition of the previous choice, whereas a penalty led to an avoidance of the previous choice. However, the effects of the reward magnitude and the penalty magnitude revealed a striking asymmetry. The choice repetition effect of a reward strongly scaled with the magnitude of the reward. In a marked contrast, the avoidance effect of a penalty was flat, not influenced by the magnitude of the penalty. These effects were mechanistically described using the Reinforcement Learning model after the model was updated to account for the penalty-based asymmetry. The asymmetry in the effects of the reward magnitude and the punishment magnitude was so striking that it is diffcult to conceive that one factor is just a weighted or transformed form of the other factor. Instead, the data suggest that rewards and penalties are fundamentally distinct factors in governing behavior. PMID:25824862

  10. Pseudomonas aeruginosa Possesses Two Putative Type I Signal Peptidases, LepB and PA1303, Each with Distinct Roles in Physiology and Virulence

    PubMed Central

    Rose, Ruth S.; Rangarajan, Minnie; Aduse-Opoku, Joseph; Hashim, Ahmed; Curtis, Michael A.

    2012-01-01

    Type I signal peptidases (SPases) cleave signal peptides from proteins during translocation across biological membranes and hence play a vital role in cellular physiology. SPase activity is also of fundamental importance to the pathogenesis of infection for many bacteria, including Pseudomonas aeruginosa, which utilizes a variety of secreted virulence factors, such as proteases and toxins. P. aeruginosa possesses two noncontiguous SPase homologues, LepB (PA0768) and PA1303, which share 43% amino acid identity. Reverse transcription (RT)-PCR showed that both proteases were expressed, while a FRET-based assay using a peptide based on the signal sequence cleavage region of the secreted LasB elastase showed that recombinant LepB and PA1303 enzymes were both active. LepB is positioned within a genetic locus that resembles the locus containing the extensively characterized SPase of E. coli and is of similar size and topology. It was also shown to be essential for viability and to have high sequence identity with SPases from other pseudomonads (≥78%). In contrast, PA1303, which is small for a Gram-negative SPase (20 kDa), was found to be dispensable. Mutation of PA1303 resulted in an altered protein secretion profile and increased N-butanoyl homoserine lactone production and influenced several quorum-sensing-controlled phenotypic traits, including swarming motility and the production of rhamnolipid and elastinolytic activity. The data indicate different cellular roles for these P. aeruginosa SPase paralogues; the role of PA1303 is integrated with the quorum-sensing cascade and includes the suppression of virulence factor secretion and virulence-associated phenotypes, while LepB is the primary SPase. PMID:22730125

  11. DNA methylation presents distinct binding sites for human transcription factors

    PubMed Central

    Hu, Shaohui; Wan, Jun; Su, Yijing; Song, Qifeng; Zeng, Yaxue; Nguyen, Ha Nam; Shin, Jaehoon; Cox, Eric; Rho, Hee Sool; Woodard, Crystal; Xia, Shuli; Liu, Shuang; Lyu, Huibin; Ming, Guo-Li; Wade, Herschel; Song, Hongjun; Qian, Jiang; Zhu, Heng

    2013-01-01

    DNA methylation, especially CpG methylation at promoter regions, has been generally considered as a potent epigenetic modification that prohibits transcription factor (TF) recruitment, resulting in transcription suppression. Here, we used a protein microarray-based approach to systematically survey the entire human TF family and found numerous purified TFs with methylated CpG (mCpG)-dependent DNA-binding activities. Interestingly, some TFs exhibit specific binding activity to methylated and unmethylated DNA motifs of distinct sequences. To elucidate the underlying mechanism, we focused on Kruppel-like factor 4 (KLF4), and decoupled its mCpG- and CpG-binding activities via site-directed mutagenesis. Furthermore, KLF4 binds specific methylated or unmethylated motifs in human embryonic stem cells in vivo. Our study suggests that mCpG-dependent TF binding activity is a widespread phenomenon and provides a new framework to understand the role and mechanism of TFs in epigenetic regulation of gene transcription. DOI: http://dx.doi.org/10.7554/eLife.00726.001 PMID:24015356

  12. DNA methylation presents distinct binding sites for human transcription factors.

    PubMed

    Hu, Shaohui; Wan, Jun; Su, Yijing; Song, Qifeng; Zeng, Yaxue; Nguyen, Ha Nam; Shin, Jaehoon; Cox, Eric; Rho, Hee Sool; Woodard, Crystal; Xia, Shuli; Liu, Shuang; Lyu, Huibin; Ming, Guo-Li; Wade, Herschel; Song, Hongjun; Qian, Jiang; Zhu, Heng

    2013-01-01

    DNA methylation, especially CpG methylation at promoter regions, has been generally considered as a potent epigenetic modification that prohibits transcription factor (TF) recruitment, resulting in transcription suppression. Here, we used a protein microarray-based approach to systematically survey the entire human TF family and found numerous purified TFs with methylated CpG (mCpG)-dependent DNA-binding activities. Interestingly, some TFs exhibit specific binding activity to methylated and unmethylated DNA motifs of distinct sequences. To elucidate the underlying mechanism, we focused on Kruppel-like factor 4 (KLF4), and decoupled its mCpG- and CpG-binding activities via site-directed mutagenesis. Furthermore, KLF4 binds specific methylated or unmethylated motifs in human embryonic stem cells in vivo. Our study suggests that mCpG-dependent TF binding activity is a widespread phenomenon and provides a new framework to understand the role and mechanism of TFs in epigenetic regulation of gene transcription. DOI:http://dx.doi.org/10.7554/eLife.00726.001. PMID:24015356

  13. A third distinct tumor necrosis factor receptor of orthopoxviruses.

    PubMed

    Loparev, V N; Parsons, J M; Knight, J C; Panus, J F; Ray, C A; Buller, R M; Pickup, D J; Esposito, J J

    1998-03-31

    Cowpox virus Brighton red strain (CPV) contains a gene, crmD, which encodes a 320-aa tumor necrosis factor receptor (TNFR) of 44% and 22% identity, respectively, to the CPV TNFR-like proteins, cytokine response modifiers (crm) CrmB and CrmC. The crmD gene was interrupted in three other cowpox strains examined and absent in various other orthopoxviruses; however, four strains of ectromelia virus (ECT) examined contained an intact crmD (97% identity to CPV crmD) and lacked cognates of crmB and crmC. The protein, CrmD, contains a transport signal; a 151-aa cysteine-rich region with 21 cysteines that align with human TNFRII ligand-binding region cysteines; and C-terminal region sequences that are highly diverged from cellular TNFR C-terminal region sequences involved in signal transduction. Bacterial maltose-binding proteins containing the CPV or ECT CrmD cysteine-rich region bound TNF and lymphotoxin-alpha (LTalpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTalpha and was detectable after the early stage of replication, using nonreducing conditions, as 60- to 70-kDa predominant and 90- to 250-kDa minor disulfide-linked complexes that were able to be reduced to a 46-kDa form and deglycosylated to a 38-kDa protein. Cells infected with CPV produced extremely low amounts of CrmD compared with ECT. Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses. PMID:9520445

  14. An avian retrovirus expressing chicken pp59c-myc possesses weak transforming activity distinct from v-myc that may be modulated by adjacent normal cell neighbors.

    PubMed Central

    Filardo, E J; Humphries, E H

    1991-01-01

    We demonstrate that EF168, an avian retrovirus that expresses the chicken pp59c-myc proto-oncogene, transforms quail embryo fibroblasts in vitro. An EF168-transformed quail clone, EF168-28, containing a single provirus, synthesizes several hundred copies of c-myc RNA and expresses elevated levels of the pp59c-myc gene product. The EF168 provirus in EF168-28 was isolated as a molecular clone, and the nucleotide sequence of its c-myc allele was confirmed as identical to that of exons 2 and 3 of the chicken c-myc proto-oncogene. Extended infection of quail embryo fibroblast cultures with EF168 induced a number of in vitro transformation-associated parameters similar to those elicited by the oncogenic v-myc-encoding retrovirus MC29, including alteration of cellular morphology, anchorage-independent growth, and induction of immortalized cell lines. Despite the fact that EF168 and MC29 shared these biological activities, further analysis revealed that EF168 initiated transformation in quail embryo fibroblasts, bone marrow, or adherent peripheral blood cultures 100- to 1,000-fold less efficiently than did MC29. Further, in contrast to MC29-induced foci, EF168 foci were smaller, morphologically diffuse, and less prominent. Analysis of newly infected cells demonstrated efficient expression of EF168 viral RNA in the absence of transformation. These differences suggest that while the pp59v-myc gene product can exert dominant transforming activity on quail embryo fibroblasts, its ability to initiate transformation is distinct from that of the pp110gag-v-myc gene product encoded by MC29 and may be suppressed by adjacent nontransformed cell neighbors. Images PMID:1942247

  15. GAGA Factor Isoforms Have Distinct but Overlapping Functions In Vivo

    PubMed Central

    Greenberg, Anthony J.; Schedl, Paul

    2001-01-01

    The Drosophila melanogaster GAGA factor (encoded by the Trithorax-like [Trl] gene) is required for correct chromatin architecture at diverse chromosomal sites. The Trl gene encodes two alternatively spliced isoforms of the GAGA factor (GAGA-519 and GAGA-581) that are identical except for the length and sequence of the C-terminal glutamine-rich (Q) domain. In vitro and tissue culture experiments failed to find any functional difference between the two isoforms. We made a set of transgenes that constitutively express cDNAs coding for either of the isoforms with the goal of elucidating their roles in vivo. Phenotypic analysis of the transgenes in Trl mutant background led us to the conclusion that GAGA-519 and GAGA-581 perform different, albeit largely overlapping, functions. We also expressed a fusion protein with LacZ disrupting the Q domain of GAGA-519. This LacZ fusion protein compensated for the loss of wild-type GAGA factor to a surprisingly large extent. This suggests that the Q domain either is not required for the essential functions performed by the GAGA protein or is exclusively used for tetramer formation. These results are inconsistent with a major role of the Q domain in chromatin remodeling or transcriptional activation. We also found that GAGA-LacZ was able to associate with sites not normally occupied by the GAGA factor, pointing to a role of the Q domain in binding site choice in vivo. PMID:11713290

  16. Increase in a distinct pulmonary macrophage subset possessing an antigen-presenting cell phenotype and in vitro APC activity following silica exposure

    SciTech Connect

    Migliaccio, Christopher T. . E-mail: christopher.migliaccio@umontana.edu; Hamilton, Raymond F.; Holian, Andrij

    2005-06-01

    Silica inhalation results in chronic lung inflammation and fibrosis. While the role of the alveolar macrophage (AM) is considered key to the effects of silica on lung pathology, the etiology is not completely understood. Evidence suggests an increase in antigen presenting cell (APC) activity as a contributing factor to this process, as well as potential roles for both AM and interstitial macrophages (IM) in silicosis. In order to study the effects of crystalline silica on the APC activity of pulmonary macrophages, mice were exposed intranasally and changes in pulmonary macrophage populations were assessed using flow cytometry. Following intranasal instillation of silica, a significant increase in the APC activity of AM was observed, as well as a significant increase in a subset of IM expressing classic APC markers (MHC class II, CD11c). In addition, an in vitro system using bone marrow-derived macrophages (BMDM) was generated to assess the effects of silica on the APC activity of macrophages in vitro. Data using BMDM in the in vitro APC assay demonstrated a significant increase in APC activity following silica exposure, but not following exposure to saline or a control particle (TiO{sub 2}). Using a combination of in vivo and in vitro experiments, the current study describes a significant increase in an interstitial macrophage subset with an APC phenotype, as well as an increase in the APC activity of both AM and BMDM, as a direct result of exposure to crystalline silica. These studies suggest a specific mechanism, macrophage subset activation, by which crystalline silica exposure results in chronic pulmonary inflammation and, eventually, fibrosis.

  17. The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells.

    PubMed

    Nelson, Shelley B; Schaffer, Ashleigh E; Sander, Maike

    2007-07-01

    Despite much progress in identifying transcriptional regulators that control the specification of the different pancreatic endocrine cell types, the spatiotemporal aspects of endocrine subtype specification have remained largely elusive. Here, we address the mechanism by which the transcription factors Nkx6.1 (Nkx6-1) and Nkx6.2 (Nkx6-2) orchestrate development of the endocrine alpha- and beta-cell lineages. Specifically, we assayed for the rescue of insulin-producing beta-cells in Nkx6.1 mutant mice upon restoring Nkx6 activity in select progenitor cell populations with different Nkx6-expressing transgenes. Beta-cell formation and maturation was restored when Nkx6.1 was expressed in multipotential Pdx1(+) pancreatic progenitors, whereas no rescue was observed upon expression in committed Ngn3(+) (Neurog3(+)) endocrine progenitors. Although not excluding additional roles downstream of Ngn3, this finding suggests a first requirement for Nkx6.1 in specifying beta-cell progenitors prior to Ngn3 activation. Surprisingly, although Nkx6.2 only compensates for Nkx6.1 in alpha-but not in beta-cell development in Nkx6.1(-/-) mice, a Pdx1-promoter-driven Nkx6.2 transgene had the same ability to rescue beta-cells as the Pdx1-Nkx6.1 transgene. This demonstrates that the distinct requirements for Nkx6.1 and Nkx6.2 in endocrine differentiation are a consequence of their divergent spatiotemporal expression domains rather than their biochemical activities and implies that both Nkx6.1 and Nkx6.2 possess alpha- and beta-cell-specifying activities. PMID:17537793

  18. Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1β and tumor necrosis factor α.

    PubMed

    Adamik, Juraj; Wang, Kent Z Q; Unlu, Sebnem; Su, An-Jey A; Tannahill, Gillian M; Galson, Deborah L; O'Neill, Luke A; Auron, Philip E

    2013-01-01

    Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. PMID:23936458

  19. The Latent Structure of Memory: A Confirmatory Factor-Analytic Study of Memory Distinctions.

    ERIC Educational Resources Information Center

    Herrman, Douglas J.; Schooler, Carmi; Caplan, Leslie J.; Lipman, Paula Darby; Grafman, Jordan; Schoenbach, Carrie; Schwab, Karen; Johnson, Marnie L.

    2001-01-01

    Used confirmatory factor analysis to study the nature of memory distinctions underlying the performance of two samples of Vietnam veterans. One sample (n=96) had received head injuries resulting in relatively small lesions; the other (n=85) had not. A four-component model with verbal-episodic, visual-episodic, semantic, and short-term memory…

  20. Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes.

    PubMed

    Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Šćepanović, Petar; Miretti, Silvia; Morotti, Alessandro; Shern, Jack F; Khan, Javed; Ala, Ugo; Provero, Paolo; Sala, Valentina; Crepaldi, Tiziana; Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo

    2016-01-01

    Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. PMID:26987019

  1. Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways

    PubMed Central

    Lawlor, Margaret A.; Feng, Xiuhong; Everding, Daniel R.; Sieger, Kerry; Stewart, Claire E. H.; Rotwein, Peter

    2000-01-01

    In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways. PMID:10757809

  2. Phytochrome-Interacting Factors Have Both Shared and Distinct Biological Roles

    PubMed Central

    Jeong, Jinkil; Choi, Giltsu

    2013-01-01

    Phytochromes are plant photoreceptors that perceive red and far-red light. Upon the perception of light in Arabidopsis, light-activated phytochromes enter the nucleus and act on a set of interacting proteins, modulating their activities and thereby altering the expression levels of ∼10% of the organism’s entire gene complement. Phytochrome-interacting factors (PIFs) belonging to Arabidopsis basic helix-loop-helix (bHLH) subgroup 15 are key interacting proteins that play negative roles in light responses. Their activities are post-translationally countered by light-activated phytochromes, which promote the degradation of PIFs and directly or indirectly inhibit their binding to DNA. The PIFs share a high degree of similarity, but examinations of pif single and multiple mutants have indicated that they have shared and distinct functions in various developmental and physiological processes. These are believed to stem from differences in both intrinsic protein properties and their gene expression patterns. In an effort to clarify the basis of these shared and distinct functions, we compared recently published genome-wide ChIP data, developmental gene expression maps, and responses to various stimuli for the various PIFs. Based on our observations, we propose that the biological roles of PIFs stem from their shared and distinct DNA binding targets and specific gene expression patterns. PMID:23708772

  3. Regulation of GATA factor expression is distinct between erythroid and mast cell lineages.

    PubMed

    Ohmori, Shin'ya; Takai, Jun; Ishijima, Yasushi; Suzuki, Mikiko; Moriguchi, Takashi; Philipsen, Sjaak; Yamamoto, Masayuki; Ohneda, Kinuko

    2012-12-01

    The zinc finger transcription factors GATA1 and GATA2 participate in mast cell development. Although the expression of these factors is regulated in a cell lineage-specific and differentiation stage-specific manner, their regulation during mast cell development has not been clarified. Here, we show that the GATA2 mRNA level was significantly increased while GATA1 was maintained at low levels during the differentiation of mast cells derived from mouse bone marrow (BMMCs). Unlike in erythroid cells, forced expression or small interfering RNA (siRNA)-mediated knockdown of GATA1 rarely affected GATA2 expression, and vice versa, in mast cells, indicating the absence of cross-regulation between Gata1 and Gata2 genes. Chromatin immunoprecipitation assays revealed that both GATA factors bound to most of the conserved GATA sites of Gata1 and Gata2 loci in BMMCs. However, the GATA1 hematopoietic enhancer (G1HE) of the Gata1 gene, which is essential for GATA1 expression in erythroid and megakaryocytic lineages, was bound only weakly by both GATA factors in BMMCs. Furthermore, transgenic-mouse reporter assays revealed that the G1HE is not essential for reporter expression in BMMCs and peritoneal mast cells. Collectively, these results demonstrate that the expression of GATA factors in mast cells is regulated in a manner quite distinct from that in erythroid cells. PMID:22988301

  4. Coordinate Control of Muscle Cell Survival by Distinct Insulin-like Growth Factor Activated Signaling Pathways

    PubMed Central

    Lawlor, Margaret A.; Rotwein, Peter

    2000-01-01

    Peptide growth factors control diverse cellular functions by regulating distinct signal transduction pathways. In cultured myoblasts, insulin-like growth factors (IGFs) stimulate differentiation and promote hypertrophy. IGFs also maintain muscle cell viability. We previously described C2 skeletal muscle lines lacking expression of IGF-II. These cells did not differentiate, but underwent progressive apoptotic death when incubated in differentiation medium. Viability could be sustained and differentiation enabled by IGF analogues that activated the IGF-I receptor; survival was dependent on stimulation of phosphatidylinositol 3-kinase (PI3-kinase). We now find that IGF action promotes myoblast survival through two distinguishable PI3-kinase–regulated pathways that culminate in expression of the cyclin-dependent kinase inhibitor, p21. Incubation with IGF-I or transfection with active PI3-kinase led to rapid induction of MyoD and p21, and forced expression of either protein maintained viability in the absence of growth factors. Ectopic expression of MyoD induced p21, and inhibition of p21 blocked MyoD-mediated survival, thus defining one PI3-kinase–dependent pathway as leading first to MyoD, and then to p21 and survival. Unexpectedly, loss of MyoD expression did not impede IGF-mediated survival, revealing a second pathway involving activation by PI3-kinase of Akt, and subsequent induction of p21. Since inhibition of p21 caused death even in the presence of IGF-I, these results establish a central role for p21 as a survival factor for muscle cells. Our observations also define a MyoD-independent pathway for regulating p21 in muscle, and demonstrate that distinct mechanisms help ensure appropriate expression of this key protein during differentiation. PMID:11121430

  5. Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes

    PubMed Central

    Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Šćepanović, Petar; Miretti, Silvia; Morotti, Alessandro; Shern, Jack F; Khan, Javed; Ala, Ugo; Provero, Paolo; Sala, Valentina; Crepaldi, Tiziana; Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo

    2016-01-01

    Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. DOI: http://dx.doi.org/10.7554/eLife.12116.001 PMID:26987019

  6. An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors.

    PubMed

    Jin, Jinpu; He, Kun; Tang, Xing; Li, Zhe; Lv, Le; Zhao, Yi; Luo, Jingchu; Gao, Ge

    2015-07-01

    Transcription factors (TFs) play key roles in both development and stress responses. By integrating into and rewiring original systems, novel TFs contribute significantly to the evolution of transcriptional regulatory networks. Here, we report a high-confidence transcriptional regulatory map covering 388 TFs from 47 families in Arabidopsis. Systematic analysis of this map revealed the architectural heterogeneity of developmental and stress response subnetworks and identified three types of novel network motifs that are absent from unicellular organisms and essential for multicellular development. Moreover, TFs of novel families that emerged during plant landing present higher binding specificities and are preferentially wired into developmental processes and these novel network motifs. Further unveiled connection between the binding specificity and wiring preference of TFs explains the wiring preferences of novel-family TFs. These results reveal distinct functional and evolutionary features of novel TFs, suggesting a plausible mechanism for their contribution to the evolution of multicellular organisms. PMID:25750178

  7. Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites.

    PubMed

    Kerekes, Krisztina; Bányai, László; Patthy, László

    2015-10-01

    Wnts have a structure resembling a hand with "thumb" and "index" fingers that grasp the cysteine rich domains of Frizzled receptors at two distinct binding sites. In the present work we show that the WIF domain of Wnt Inhibitory Factor 1 is also bound by Wnts at two sites. Using C-terminal domains of Wnt5a and Wnt7a and arginine-scanning mutagenesis of the WIF domain we demonstrate that, whereas the N-terminal, lipid-modified "thumb" of Wnts interacts with the alkyl-binding site of the WIF domain, the C-terminal domain of Wnts (Wnt-CTD) binds to a surface on the opposite side of the WIF domain. PMID:26342861

  8. MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation*

    PubMed Central

    Estrella, Nelsa L.; Desjardins, Cody A.; Nocco, Sarah E.; Clark, Amanda L.; Maksimenko, Yevgeniy; Naya, Francisco J.

    2015-01-01

    Skeletal muscle differentiation requires precisely coordinated transcriptional regulation of diverse gene programs that ultimately give rise to the specialized properties of this cell type. In Drosophila, this process is controlled, in part, by MEF2, the sole member of an evolutionarily conserved transcription factor family. By contrast, vertebrate MEF2 is encoded by four distinct genes, Mef2a, -b, -c, and -d, making it far more challenging to link this transcription factor to the regulation of specific muscle gene programs. Here, we have taken the first step in molecularly dissecting vertebrate MEF2 transcriptional function in skeletal muscle differentiation by depleting individual MEF2 proteins in myoblasts. Whereas MEF2A is absolutely required for proper myoblast differentiation, MEF2B, -C, and -D were found to be dispensable for this process. Furthermore, despite the extensive redundancy, we show that mammalian MEF2 proteins regulate a significant subset of nonoverlapping gene programs. These results suggest that individual MEF2 family members are able to recognize specific targets among the entire cohort of MEF2-regulated genes in the muscle genome. These findings provide opportunities to modulate the activity of MEF2 isoforms and their respective gene programs in skeletal muscle homeostasis and disease. PMID:25416778

  9. Distinct factors control histone variant H3.3 localization at specific genomic regions

    PubMed Central

    Goldberg, Aaron D.; Banaszynski, Laura A.; Noh, Kyung-Min; Lewis, Peter W.; Elsaesser, Simon J.; Stadler, Sonja; Dewell, Scott; Law, Martin; Guo, Xingyi; Li, Xuan; Wen, Duancheng; Chapgier, Ariane; DeKelver, Russell C.; Miller, Jeffrey C.; Lee, Ya-Li; Boydston, Elizabeth A.; Holmes, Michael C.; Gregory, Philip D.; Greally, John M.; Rafii, Shahin; Yang, Chingwen; Scambler, Peter J.; Garrick, David; Gibbons, Richard J.; Higgs, Douglas R.; Cristea, Ileana M.; Urnov, Fyodor D.; Zheng, Deyou; Allis, C. David

    2010-01-01

    Summary The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem (ES) cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence, and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres, and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells. PMID:20211137

  10. Clonal-Level Responses of Functionally Distinct Hematopoietic Stem Cells to Trophic Factors

    PubMed Central

    Mallaney, Cates; Kothari, Alok; Martens, Andrew; Challen, Grant A.

    2014-01-01

    Recent findings from several groups have identified distinct classes of hematopoietic stem cells (HSCs) in the bone marrow, each with inherent functional biases in terms of their differentiation, self-renewal, proliferation and lifespan. It has previously been demonstrated that myeloid- and lymphoid-biased HSCs can be prospectively enriched based on their degree of Hoechst dye efflux. In the present study, we used differential Hoechst efflux to enrich lineage-biased HSC subtypes and analyzed their functional potentials. Despite similar outputs in vitro, bone marrow transplantation assays revealed contrasting lineage differentiation in vivo. To stratify the molecular differences underlying these contrasting functional potentials at the clonal level, single-cell gene expression analysis was performed using the Fluidigm Biomark system and revealed dynamic expression of genes including Meis1, CEBP/α, Sfpi1 and Dnmt3a. Finally, single-cell gene expression analysis was used to unravel the opposing proliferative responses of lineage-biased HSCs to the growth factor TGFβ1, revealing a potential role for the cell cycle inhibitor Cdkn1c as molecular mediator. This work lends further credence to the concept of HSC heterogeneity and presents unprecedented molecular resolution of the HSC response to trophic factors using single-cell gene expression analysis. PMID:24373928

  11. Activated STAT1 Transcription Factors Conduct Distinct Saltatory Movements in the Cell Nucleus

    PubMed Central

    Speil, Jasmin; Baumgart, Eugen; Siebrasse, Jan-Peter; Veith, Roman; Vinkemeier, Uwe; Kubitscheck, Ulrich

    2011-01-01

    The activation of STAT transcription factors is a critical determinant of their subcellular distribution and their ability to regulate gene expression. Yet, it is not known how activation affects the behavior of individual STAT molecules in the cytoplasm and nucleus. To investigate this issue, we injected fluorescently labeled STAT1 in living HeLa cells and traced them by single-molecule microscopy. We determined that STAT1 moved stochastically in the cytoplasm and nucleus with very short residence times (<0.03 s) before activation. Upon activation, STAT1 mobility in the cytoplasm decreased ∼2.5-fold, indicating reduced movement of STAT1/importinα/β complexes to the nucleus. In the nucleus, activated STAT1 displayed a distinct saltatory mobility, with residence times of up to 5 s and intermittent diffusive motion. In this manner, activated STAT1 factors can occupy their putative chromatin target sites within ∼2 s. These results provide a better understanding of the timescales on which cellular signaling and regulated gene transcription operate at the single-molecule level. PMID:22261046

  12. Clonal-level responses of functionally distinct hematopoietic stem cells to trophic factors.

    PubMed

    Mallaney, Cates; Kothari, Alok; Martens, Andrew; Challen, Grant A

    2014-04-01

    Recent findings from several groups have identified distinct classes of hematopoietic stem cells (HSCs) in the bone marrow, each with inherent functional biases in terms of their differentiation, self-renewal, proliferation, and lifespan. It has previously been demonstrated that myeloid- and lymphoid-biased HSCs can be prospectively enriched based on their degree of Hoechst dye efflux. In the present study, we used differential Hoechst efflux to enrich lineage-biased HSC subtypes and analyzed their functional potentials. Despite similar outputs in vitro, bone marrow transplantation assays revealed contrasting lineage differentiation in vivo. To stratify the molecular differences underlying these contrasting functional potentials at the clonal level, single-cell gene expression analysis was performed using the Fluidigm BioMark system and revealed dynamic expression of genes including Meis1, CEBP/α, Sfpi1, and Dnmt3a. Finally, single-cell gene expression analysis was used to unravel the opposing proliferative responses of lineage-biased HSCs to the growth factor TGF-β1, revealing a potential role for the cell cycle inhibitor Cdkn1c as molecular mediator. This work lends further credence to the concept of HSC heterogeneity, and it presents unprecedented molecular resolution of the HSC response to trophic factors using single-cell gene expression analysis. PMID:24373928

  13. Three R2R3-MYB transcription factors regulate distinct floral pigmentation patterning in Phalaenopsis spp.

    PubMed

    Hsu, Chia-Chi; Chen, You-Yi; Tsai, Wen-Chieh; Chen, Wen-Huei; Chen, Hong-Hwa

    2015-05-01

    Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long-lasting flowers of various colors and pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3-hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus-induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp. PMID:25739699

  14. Distinct Properties of Hexameric but Functionally Conserved Mycobacterium tuberculosis Transcription-Repair Coupling Factor

    PubMed Central

    Prabha, Swayam; Rao, Desirazu N.; Nagaraja, Valakunja

    2011-01-01

    Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd) is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd) deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD) comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD) containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC) increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair. PMID:21559463

  15. Risk Factors for Fecal Colonization with Multiple Distinct Strains of Escherichia coli Among Long-Term Care Facility Residents

    PubMed Central

    Lautenbach, Ebbing; Tolomeo, Pam; Black, Nicole; Maslow, Joel N.

    2009-01-01

    Of 49 long-term care facility residents, 21 (43%) were colonized with two or more distinct strains of Escherichia coli. There were no significant risk factors for colonization with multiple strains of E. coli. These results suggest future efforts to efficiently identify diversity of colonizing strains will be challenging. PMID:19292660

  16. Risk factors for fecal colonization with multiple distinct strains of Escherichia coli among long-term care facility residents.

    PubMed

    Lautenbach, Ebbing; Tolomeo, Pam; Black, Nicole; Maslow, Joel N

    2009-05-01

    Of 49 long-term care facility residents, 21 (43%) were colonized with 2 or more distinct strains of Escherichia coli. There were no significant risk factors for colonization with multiple strains of E. coli. These results suggest that future efforts to efficiently identify the diversity of colonizing strains will be challenging. PMID:19292660

  17. Instant noodle intake and dietary patterns are associated with distinct cardiometabolic risk factors in Korea.

    PubMed

    Shin, Hyun Joon; Cho, Eunyoung; Lee, Hae-Jeung; Fung, Teresa T; Rimm, Eric; Rosner, Bernard; Manson, JoAnn E; Wheelan, Kevin; Hu, Frank B

    2014-08-01

    The consumption of instant noodles is relatively high in Asian populations. It is unclear whether a higher intake of instant noodles is associated with cardiometabolic risk independent of overall dietary patterns. We therefore investigated the association using the Korean National Health and Nutrition Examination Survey IV 2007-2009, a nationally representative cross-sectional survey of the Korean population with a clustered, multistage, stratified, and rolling sampling design. A total of 10,711 adults (54.5% women) 19-64 y of age were analyzed, with adjustment for sampling design complexity. Diet was assessed by using a 63-item food-frequency questionnaire. We identified 2 major dietary patterns with the use of principal components analysis: the "traditional dietary pattern" (TP), rich in rice, fish, vegetables, fruit, and potatoes, and the "meat and fast-food pattern" (MP), with less rice intake but rich in meat, soda, fried food, and fast food including instant noodles. The highest MP quintile was associated with increased prevalence of abdominal obesity (OR: 1.41; 95% CI: 1.05, 1.90), LDL cholesterol ≥130 mg/dL (1.3 g/L) (OR: 1.57, 95% CI 1.26, 1.95), decreased prevalence of low HDL cholesterol (OR: 0.65; 95% CI: 0.53, 0.80), and high triglycerides [≥150 mg/dL (1.5 g/L); OR: 0.73; 95% CI: 0.57, 0.93]. The highest quintile for the TP was associated with decreased prevalence of elevated blood pressure (OR: 0.73; 95% CI: 0.59, 0.90) and marginally lower trends for abdominal obesity (OR: 0.76; 95% CI: 0.58, 0.98; P-trend = 0.06), but neither of the dietary patterns was associated with prevalence of metabolic syndrome. The consumption of instant noodles ≥2 times/wk was associated with a higher prevalence of metabolic syndrome (OR: 1.68; 95% CI: 1.10, 2.55) in women but not in men (OR: 0.93; 95% CI: 0.58, 1.49; P-interaction = 0.04). The 2 major dietary patterns were associated with distinct cardiometabolic risk factors. The consumption of instant noodles was

  18. Schizophrenia or possession?

    PubMed

    Irmak, M Kemal

    2014-06-01

    Schizophrenia is typically a life-long condition characterized by acute symptom exacerbations and widely varying degrees of functional disability. Some of its symptoms, such as delusions and hallucinations, produce great subjective psychological pain. The most common delusion types are as follows: "My feelings and movements are controlled by others in a certain way" and "They put thoughts in my head that are not mine." Hallucinatory experiences are generally voices talking to the patient or among themselves. Hallucinations are a cardinal positive symptom of schizophrenia which deserves careful study in the hope it will give information about the pathophysiology of the disorder. We thought that many so-called hallucinations in schizophrenia are really illusions related to a real environmental stimulus. One approach to this hallucination problem is to consider the possibility of a demonic world. Demons are unseen creatures that are believed to exist in all major religions and have the power to possess humans and control their body. Demonic possession can manifest with a range of bizarre behaviors which could be interpreted as a number of different psychotic disorders with delusions and hallucinations. The hallucination in schizophrenia may therefore be an illusion-a false interpretation of a real sensory image formed by demons. A local faith healer in our region helps the patients with schizophrenia. His method of treatment seems to be successful because his patients become symptom free after 3 months. Therefore, it would be useful for medical professions to work together with faith healers to define better treatment pathways for schizophrenia. PMID:23269538

  19. Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury.

    PubMed

    Laskowski, Jennifer; Renner, Brandon; Le Quintrec, Moglie; Panzer, Sarah; Hannan, Jonathan P; Ljubanovic, Danica; Ruseva, Marieta M; Borza, Dorin-Bogdan; Antonioli, Alexandra H; Pickering, Matthew C; Holers, V Michael; Thurman, Joshua M

    2016-07-01

    Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location. PMID:27165610

  20. The mitochondrial elongation factors MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics

    SciTech Connect

    Liu, Tong; Yu, Rong; Jin, Shao-Bo; Han, Liwei; Lendahl, Urban; Zhao, Jian; Nistér, Monica

    2013-11-01

    Mitochondria are dynamic organelles whose morphology is regulated by a complex balance of fission and fusion processes, and we still know relatively little about how mitochondrial dynamics is regulated. MIEF1 (also called MiD51) has recently been characterized as a key regulator of mitochondrial dynamics and in this report we explore the functions of its paralog MIEF2 (also called MiD49), to learn to what extent MIEF2 is functionally distinct from MIEF1. We show that MIEF1 and MIEF2 have many functions in common. Both are anchored in the mitochondrial outer membrane, recruit Drp1 from the cytoplasm to the mitochondrial surface and cause mitochondrial fusion, and MIEF2, like MIEF1, can interact with Drp1 and hFis1. MIEF1 and MIEF2, however, also differ in certain aspects. MIEF1 and MIEF2 are differentially expressed in human tissues during development. When overexpressed, MIEF2 exerts a stronger fusion-promoting effect than MIEF1, and in line with this, hFis1 and Mff can only partially revert the MIEF2-induced fusion phenotype, whereas MIEF1-induced fusion is reverted to a larger extent by hFis1 and Mff. MIEF2 forms high molecular weight oligomers, while MIEF1 is largely present as a dimer. Furthermore, MIEF1 and MIEF2 use distinct domains for oligomerization: in MIEF1, the region from amino acid residues 109–154 is required, whereas oligomerization of MIEF2 depends on amino acid residues 1 to 49, i.e. the N-terminal end. We also show that oligomerization of MIEF1 is not required for its mitochondrial localization and interaction with Drp1. In conclusion, our data suggest that the mitochondrial regulators MIEF1 and MIEF2 exert partially distinct functions in mitochondrial dynamics. - Highlights: • MIEF1 and MIEF2 recruit Drp1 to mitochondria and cause mitochondrial fusion. • MIEF2, like MIEF1, can interact with Drp1 and hFis1. • MIEF1 and MIEF2 are differentially expressed in human tissues during development. • MIEF2 exerts a stronger fusion

  1. Chlamydia Infection Across Host Species Boundaries Promotes Distinct Sets of Transcribed Anti-Apoptotic Factors

    PubMed Central

    Messinger, Joshua E.; Nelton, Emmalin; Feeney, Colleen; Gondek, David C.

    2015-01-01

    Chlamydiae, obligate intracellular bacteria, cause significant human and veterinary associated diseases. Having emerged an estimated 700-million years ago, these bacteria have twice adapted to humans as a host species, causing sexually transmitted infection (C. trachomatis) and respiratory associated disease (C. pneumoniae). The principle mechanism of host cell defense against these intracellular bacteria is the induction of cell death via apoptosis. However, in the “arms race” of co-evolution, Chlamydiae have developed mechanisms to promote cell viability and inhibit cell death. Herein we examine the impact of Chlamydiae infection across multiple host species on transcription of anti-apoptotic genes. We found mostly distinct patterns of gene expression (Mcl1 and cIAPs) elicited by each pathogen-host pair indicating Chlamydiae infection across host species boundaries does not induce a universally shared host response. Understanding species specific host-pathogen interactions is paramount to deciphering how potential pathogens become emerging diseases. PMID:26779446

  2. Sperm and Spermatids Contain Different Proteins and Bind Distinct Egg Factors

    PubMed Central

    Teperek, Marta; Miyamoto, Kei; Simeone, Angela; Feret, Renata; Deery, Michael J.; Gurdon, John B.; Jullien, Jerome

    2014-01-01

    Spermatozoa are more efficient at supporting normal embryonic development than spermatids, their immature, immediate precursors. This suggests that the sperm acquires the ability to support embryonic development during spermiogenesis (spermatid to sperm maturation). Here, using Xenopus laevis as a model organism, we performed 2-D Fluorescence Difference Gel Electrophoresis (2D-DIGE) and mass spectrometry analysis of differentially expressed proteins between sperm and spermatids in order to identify factors that could be responsible for the efficiency of the sperm to support embryonic development. Furthermore, benefiting from the availability of egg extracts in Xenopus, we also tested whether the chromatin of sperm could attract different egg factors compared to the chromatin of spermatids. Our analysis identified: (1) several proteins which were present exclusively in sperm; but not in spermatid nuclei and (2) numerous egg proteins binding to the sperm (but not to the spermatid chromatin) after incubation in egg extracts. Amongst these factors we identified many chromatin-associated proteins and transcriptional repressors. Presence of transcriptional repressors binding specifically to sperm chromatin could suggest its preparation for the early embryonic cell cycles, during which no transcription is observed and suggests that sperm chromatin has a unique protein composition, which facilitates the recruitment of egg chromatin remodelling factors. It is therefore likely that the acquisition of these sperm-specific factors during spermiogenesis makes the sperm chromatin suitable to interact with the maternal factors and, as a consequence, to support efficient embryonic development. PMID:25244019

  3. Distinctive effect on nerve growth factor-induced PC12 cell neurite outgrowth by two unique neolignan enantiomers from Illicium merrillianum

    PubMed Central

    Tian, Xinhui; Yue, Rongcai; Zeng, Huawu; Li, Honglin; Shan, Lei; He, Weiwei; Shen, Yunheng; Zhang, Weidong

    2015-01-01

    Merrillianoid (1), a racemic neolignan possessing the characteristic benzo-2,7-dioxabicyclo[3.2.1]octane moiety, was isolated from the branches and leaves of Illicium merrillianum. Chiral separation of 1 gave two enantiomers (+)−1 and (−)−1. The structure of 1 was established by comprehensive spectroscopic analysis and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. Compound (+)−1 exhibited a better neurotrophic activity than racemate 1 by promoting nerve growth factor (NGF) induced PC12 cell neurite outgrowth, while (−)−1 showed a distinctive inhibitory effect. Furthermore, a mechanism study indicated that the two enantiomers influenced NGF-induced neurite outgrowth of PC12 cells possibly by interacting with the trkA receptor, and extracellular signal regulated kinases 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) in Ras/ERK signal cascade. But the phosphorylation level of serine/threonine kinase Akt1 and Akt2 in PI3K/Akt signal pathway showed no significant difference between (+)−1 and (−)−1. PMID:26585042

  4. Distinctive effect on nerve growth factor-induced PC12 cell neurite outgrowth by two unique neolignan enantiomers from Illicium merrillianum

    NASA Astrophysics Data System (ADS)

    Tian, Xinhui; Yue, Rongcai; Zeng, Huawu; Li, Honglin; Shan, Lei; He, Weiwei; Shen, Yunheng; Zhang, Weidong

    2015-11-01

    Merrillianoid (1), a racemic neolignan possessing the characteristic benzo-2,7-dioxabicyclo[3.2.1]octane moiety, was isolated from the branches and leaves of Illicium merrillianum. Chiral separation of 1 gave two enantiomers (+)-1 and (-)-1. The structure of 1 was established by comprehensive spectroscopic analysis and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. Compound (+)-1 exhibited a better neurotrophic activity than racemate 1 by promoting nerve growth factor (NGF) induced PC12 cell neurite outgrowth, while (-)-1 showed a distinctive inhibitory effect. Furthermore, a mechanism study indicated that the two enantiomers influenced NGF-induced neurite outgrowth of PC12 cells possibly by interacting with the trkA receptor, and extracellular signal regulated kinases 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) in Ras/ERK signal cascade. But the phosphorylation level of serine/threonine kinase Akt1 and Akt2 in PI3K/Akt signal pathway showed no significant difference between (+)-1 and (-)-1.

  5. Biomass digestibility is predominantly affected by three factors of wall polymer features distinctive in wheat accessions and rice mutants

    PubMed Central

    2013-01-01

    Background Wheat and rice are important food crops with enormous biomass residues for biofuels. However, lignocellulosic recalcitrance becomes a crucial factor on biomass process. Plant cell walls greatly determine biomass recalcitrance, thus it is essential to identify their key factors on lignocellulose saccharification. Despite it has been reported about cell wall factors on biomass digestions, little is known in wheat and rice. In this study, we analyzed nine typical pairs of wheat and rice samples that exhibited distinct cell wall compositions, and identified three major factors of wall polymer features that affected biomass digestibility. Results Based on cell wall compositions, ten wheat accessions and three rice mutants were classified into three distinct groups each with three typical pairs. In terms of group I that displayed single wall polymer alternations in wheat, we found that three wall polymer levels (cellulose, hemicelluloses and lignin) each had a negative effect on biomass digestibility at similar rates under pretreatments of NaOH and H2SO4 with three concentrations. However, analysis of six pairs of wheat and rice samples in groups II and III that each exhibited a similar cell wall composition, indicated that three wall polymer levels were not the major factors on biomass saccharification. Furthermore, in-depth detection of the wall polymer features distinctive in rice mutants, demonstrated that biomass digestibility was remarkably affected either negatively by cellulose crystallinity (CrI) of raw biomass materials, or positively by both Ara substitution degree of non-KOH-extractable hemicelluloses (reverse Xyl/Ara) and p-coumaryl alcohol relative proportion of KOH-extractable lignin (H/G). Correlation analysis indicated that Ara substitution degree and H/G ratio negatively affected cellulose crystallinity for high biomass enzymatic digestion. It was also suggested to determine whether Ara and H monomer have an interlinking with cellulose chains

  6. Defining Distinct Negative Beliefs about Uncertainty: Validating the Factor Structure of the Intolerance of Uncertainty Scale

    ERIC Educational Resources Information Center

    Sexton, Kathryn A.; Dugas, Michel J.

    2009-01-01

    This study examined the factor structure of the English version of the Intolerance of Uncertainty Scale (IUS; French version: M. H. Freeston, J. Rheaume, H. Letarte, M. J. Dugas, & R. Ladouceur, 1994; English version: K. Buhr & M. J. Dugas, 2002) using a substantially larger sample than has been used in previous studies. Nonclinical undergraduate…

  7. Distinct immunoregulatory properties of macrophage migration inhibitory factors encoded by Eimeria parasites and their chicken host

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in host defense against a variety of microorganisms including protozoan parasites. Interestingly, some microbial pathogens also express a MIF-like protein, although its role in disease pathogenesi...

  8. Higher Order Factor Convergence and Divergence of Two Distinct Personality Systems: Cattell's HSPQ and Jackson's PRF

    ERIC Educational Resources Information Center

    Nesselroade, John B.; Bates, Paul B.

    1975-01-01

    Seeks empirical evidence of convergence of concepts measured by two personality inventories--Cattell's High School Personality Questionnaire and Jackson's Personality Research Form. Implication of the levels of factor convergence obtained in relation to theory building and prediction are discussed. (RC)

  9. Factors influencing recruitment of walleye and white bass to three distinct early ontogenetic stages

    USGS Publications Warehouse

    DeBoer, Jason A.; Pope, Kevin L.

    2015-01-01

    Determining the factors that influence recruitment to sequential ontogenetic stages is critical for understanding recruitment dynamics of fish and for effective management of sportfish, particularly in dynamic and unpredictable environments. We sampled walleye (Sander vitreus) and white bass (Morone chrysops) at 3 ontogenetic stages (age 0 during spring: ‘age-0 larval’; age 0 during autumn: ‘age-0 juvenile’; and age 1 during autumn: ‘age-1 juvenile’) from 3 reservoirs. We developed multiple linear regression models to describe factors influencing age-0 larval, age-0 juvenile and age-1 juvenile walleye and white bass abundance indices. Our models explained 40–80% (68 ± 9%; mean ± SE) and 71%–97% (81 ± 6%) of the variability in catch for walleye and white bass respectively. For walleye, gizzard shad were present in the candidate model sets for all three ontogenetic stages we assessed. For white bass, there was no unifying variable in all three stage-specific candidate model sets, although walleye abundance was present in two of the three white bass candidate model sets. We were able to determine several factors affecting walleye and white bass year-class strength at multiple ontogenetic stages; comprehensive analyses of factors influencing recruitment to multiple early ontogenetic stages are seemingly rare in the literature. Our models demonstrate the interdependency among early ontogenetic stages and the complexities involved with sportfish recruitment.

  10. Identification of RNA Binding Proteins Associated with Dengue Virus RNA in Infected Cells Reveals Temporally Distinct Host Factor Requirements

    PubMed Central

    Viktorovskaya, Olga V.; Greco, Todd M.; Cristea, Ileana M.; Thompson, Sunnie R.

    2016-01-01

    Background There are currently no vaccines or antivirals available for dengue virus infection, which can cause dengue hemorrhagic fever and death. A better understanding of the host pathogen interaction is required to develop effective therapies to treat DENV. In particular, very little is known about how cellular RNA binding proteins interact with viral RNAs. RNAs within cells are not naked; rather they are coated with proteins that affect localization, stability, translation and (for viruses) replication. Methodology/Principal Findings Seventy-nine novel RNA binding proteins for dengue virus (DENV) were identified by cross-linking proteins to dengue viral RNA during a live infection in human cells. These cellular proteins were specific and distinct from those previously identified for poliovirus, suggesting a specialized role for these factors in DENV amplification. Knockdown of these proteins demonstrated their function as viral host factors, with evidence for some factors acting early, while others late in infection. Their requirement by DENV for efficient amplification is likely specific, since protein knockdown did not impair the cell fitness for viral amplification of an unrelated virus. The protein abundances of these host factors were not significantly altered during DENV infection, suggesting their interaction with DENV RNA was due to specific recruitment mechanisms. However, at the global proteome level, DENV altered the abundances of proteins in particular classes, including transporter proteins, which were down regulated, and proteins in the ubiquitin proteasome pathway, which were up regulated. Conclusions/Significance The method for identification of host factors described here is robust and broadly applicable to all RNA viruses, providing an avenue to determine the conserved or distinct mechanisms through which diverse viruses manage the viral RNA within cells. This study significantly increases the number of cellular factors known to interact with

  11. Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors.

    PubMed

    Yu, Shuyang; Li, Fengyin; Xing, Shaojun; Zhao, Tianyan; Peng, Weiqun; Xue, Hai-Hui

    2016-05-20

    Hematopoietic and leukemic stem cells (HSCs and LSCs) have self-renewal ability to maintain normal hematopoiesis and leukemia propagation, respectively. Tcf1 and Lef1 transcription factors are expressed in HSCs, and targeting both factors modestly expanded the size of the HSC pool due to diminished HSC quiescence. Functional defects of Tcf1/Lef1-deficient HSCs in multi-lineage blood reconstitution was only evident under competitive conditions or when subjected to repeated regenerative stress. These are mechanistically due to direct positive regulation of Egr and Tcf3 by Tcf1 and Lef1, and significantly, forced expression of Egr1 in Tcf1/Lef1-deficient HSCs restored HSC quiescence. In a preclinical CML model, loss of Tcf1/Lef1 did not show strong impact on leukemia initiation and progression. However, when transplanted into secondary recipients, Tcf1/Lef1-deficient LSCs failed to propagate CML. By induced deletion of Tcf1 and Lef1 in pre-established CML, we further demonstrated an intrinsic requirement for these factors in LSC self-renewal. When combined with imatinib therapy, genetic targeting of Tcf1 and Lef1 potently diminished LSCs and conferred better protection to the CML recipients. LSCs are therefore more sensitive to loss of Tcf1 and Lef1 than HSCs in their self-renewal capacity. The differential requirements in HSCs and LSCs thus identify Tcf1 and Lef1 transcription factors as novel therapeutic targets in treating hematological malignancies, and inhibition of Tcf1/Lef1-regulated transcriptional programs may thus provide a therapeutic window to eliminate LSCs with minimal side effect on normal HSC functions. PMID:27044748

  12. Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis.

    PubMed Central

    Sharma, A K; Pangburn, M K

    1996-01-01

    Human complement factor H controls spontaneous activation of complement in plasma and appears to play a role in distinguishing host cells from activators of the alternative pathway of complement. In both mice and humans, the protein is composed of 20 homologous short consensus repeat (SCR) domains. The size of the protein suggests that portions of the structure outside the known C3b binding site (SCR 1-4) possess a significant biological role. We have expressed the full-length cDNA of factor H in the baculovirus system and have shown the recombinant protein to be fully active. Mutants of this full-length protein have now been prepared, purified, and examined for cofactor activity and binding to C3b and heparin. The results demonstrate (i) that factor H has at least three sites that bind C3b, (ii) that one of these sites is located in SCR domains 1-4, as has been shown by others, (iii) that a second site exists in the domain 6-10 region, (iv) that a third site resides in the SCR 16-20 region, and (v) that two heparin binding sites exist in factor H, one near SCR 13 and another in the SCR 6-10 region. Functional assays demonstrated that only the first C3b site located in SCR 1-4 expresses factor I cofactor activity. Mutant proteins lacking any one of the three C3b binding sites exhibited 6- to 8-fold reductions in affinity for C3b on sheep erythrocytes, indicating that all three sites contribute to the control of complement activation on erythrocytes. The identification of multiple functionally distinct sites on factor H clarifies many of the heretofore unexplainable behaviors of this protein, including the heterogeneous binding of factor H to surface-bound C3b, the effects of trypsin cleavage, and the differential control of complement activation on activators and nonactivators of the alternative pathway of complement. Images Fig. 2 Fig. 3 PMID:8855297

  13. Yeast GAL11 protein is a distinctive type transcription factor that enhances basal transcription in vitro.

    PubMed Central

    Sakurai, H; Hiraoka, Y; Fukasawa, T

    1993-01-01

    The yeast auxiliary transcription factor GAL11, a candidate for the coactivator, was partially purified from yeast cells, and its function was characterized in a cell-free transcription system. The partially purified GAL11 protein stimulated basal transcription from the CYC1 core promoter by a factor of 4-5 at the step of preinitiation complex formation. GAL11 protein also enhanced transcription activated by general regulatory factor 1, GAL4-AH, or GAL4-VP16 to the same extent as the basal transcription. Therefore, the apparent potentiation of the activators by GAL11 was attributable to the stimulation of basal transcription. The wild-type GAL11 protein (but not a mutant-type protein) produced in bacteria stimulated transcription as effectively as GAL11 from yeast. These results suggest that GAL11 functions as a positive cofactor of basal and activator-induced transcription in a cell-free transcription system. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8378310

  14. Seroprevalence and risk factors for dengue infection in socioeconomically distinct areas of Recife, Brazil

    PubMed Central

    Braga, Cynthia; Luna, Carlos Feitosa; Martelli, Celina MariaTurchi; de Souza, Wayner Vieira; Cordeiro, Marli Tenório; Alexander, Neal; Militão de Albuquerque, Maria de Fátima Pessoa; Silveira Júnior, José Constantino; Marques, Ernesto T.

    2013-01-01

    Brazil currently accounts for the majority of dengue cases reported in the Americas, with co-circulation of DENV 1, 2 and 3. Striking variation in the epidemiological pattern of infection within cities has been observed. Therefore, investigation of dengue transmission in small areas is important to formulate control strategies. A population-based household survey was performed in three diverse socio-economic and environmental areas of Recife, a large urban center of Brazil, between 2005 and 2006. Dengue serostatus and individual- and household-level risk factors for infection were collected in residents aged between 5 and 64 years. A total of 2,833 individuals were examined, and their residences were geo-referenced. Anti-dengue IgG antibodies were measured using commercial ELISA. The dengue seroprevalence and the force of infection were estimated in each area. Individual and household variables associated with seropositivity were assessed by multilevel models for each area. A spatial analysis was conducted to identify risk gradients of dengue seropositivity using generalized additive models (GAM). The dengue seroprevalence was 91.1%, 87.4% 74.3%, respectively, in the deprived, intermediate and high socioeconomic areas, inversely related to their socio-economic status. In the deprived area, 59% of children had already been exposed to dengue virus by the age of 5 years and the estimated force of infection was three times higher than that in the privileged area. The risk of infection increased with age in the three areas. Working or studying outside the home area was a risk factor for seropositivity in the deprived area (OR=2.26; 95% CI: 1.18-4.30). Number of persons per room was a risk factor for seropositivity in the intermediate (OR=3.00; 95% CI: 3.21-7.37) and privileged areas (OR=1.81; 95% CI: 1.07-3.04). Living in a house, as opposed to an apartment, was a risk factor for seropositivity in the privileged area (OR=3.62; 95% CI: 2.43-5.41). The main difference

  15. Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

    PubMed Central

    Matsubara, Daisuke; Ishikawa, Shumpei; Sachiko, Oguni; Aburatani, Hiroyuki; Fukayama, Masashi; Niki, Toshiro

    2010-01-01

    Epidermal growth factor receptor (EGFR) and MET are molecular targets for lung cancer treatment. The relationships between expression, activation, and gene abnormalities of these two targets are currently unclear. Here, we demonstrate that a panel of 40 lung cancer cell lines could be classified into two groups. Group I was characterized by (1) high phosphorylations of MET and EGFR, (2) frequent mutation or amplification of EGFR, MET, and human epidermal growth factor receptor-2 (HER2), (3) high expressions of bronchial epithelial markers (thyroid transcription factor-1 (TTF-1), MUC1, and Cytokeratin 7 (CK7)); and (4) high expressions of MET, human epidermal growth factor receptor-3, E-cadherin, cyclooxygenase-2, and laminin gamma2. In contrast, Group II exhibited little or no phosphorylation of MET and EGFR; no mutation or amplification of EGFR, MET, and HER2; were triple-negative for TTF-1, MUC1, and CK7; and showed high expressions of vimentin, fibroblast growth factor receptor-1, and transcription factor 8. Importantly, Group I was more sensitive to gefitinib and more resistant to cisplatin and paclitaxel than Group II. The clinical relevance was confirmed in publicly available data on 442 primary lung adenocarcinoma patients; survival benefits by postoperative chemotherapy were seen in only patients with tumors corresponding to Group II. Overall, co-activation of EGFR and MET defines a distinct subgroup of lung carcinoma with characteristic genetic abnormalities, gene expression pattern, and response to chemotherapeutic reagents. PMID:20934974

  16. Distinct functions of elongation factor G in ribosome recycling and translocation

    PubMed Central

    Savelsbergh, Andreas; Rodnina, Marina V.; Wintermeyer, Wolfgang

    2009-01-01

    Elongation factor G (EF-G) promotes the translocation step in bacterial protein synthesis and, together with ribosome recycling factor (RRF), the disassembly of the post-termination ribosome. Unlike translocation, ribosome disassembly strictly requires GTP hydrolysis by EF-G. Here we report that ribosome disassembly is strongly inhibited by vanadate, an analog of inorganic phosphate (Pi), indicating that Pi release is required for ribosome disassembly. In contrast, the function of EF-G in single-round translocation is not affected by vanadate, while the turnover reaction is strongly inhibited. We also show that the antibiotic fusidic acid blocks ribosome disassembly by EF-G/RRF at a 1000-fold lower concentration than required for the inhibition of EF-G turnover in vitro and close to the effective inhibitory concentration in vivo, suggesting that the antimicrobial activity of fusidic acid is primarily due to the direct inhibition of ribosome recycling. Our results indicate that conformational coupling between EF-G and the ribosome is principally different in translocation and ribosome disassembly. Pi release is not required for the mechanochemical function of EF-G in translocation, whereas the interactions between RRF and EF-G introduce tight coupling between the conformational change of EF-G induced by Pi release and ribosome disassembly. PMID:19324963

  17. Distinct responses of baseline and stress-induced corticosterone levels to genetic and environmental factors.

    PubMed

    Homberger, Benjamin; Jenni-Eiermann, Susanne; Jenni, Lukas

    2015-01-01

    Glucocorticoid (GC) hormones, i.e. corticosterone (CORT) in birds, support physiological homeostasis and facilitate adaptations to stressful situations. However, maintaining high GC levels are energetically costly and interfere with other physiological processes. To keep the balance of costs and benefits of GC hormones, various mechanisms act to adapt GC levels to environmental conditions on different timescales, i.e. over generations, between parents and their offspring and within the life-time of a single individual. We elucidated whether two strains (domesticated and wild) of grey partridges (Perdix perdix) differed in the developmental trajectories of baseline and stress response CORT throughout the first 80 days of life. We also explored the potential of prenatal and postnatal factors, e.g. parental origin, predictable vs. unpredictable food treatments, individual and social factors to modify these trajectories. Baseline CORT was similar between strains and unaffected by perinatal food treatments. It was negatively related to body size and body condition. Conversely, the CORT stress response was not markedly affected by physiological condition. It was stronger in wild than in domesticated birds and it increased with age. Birds subjected to prenatal unpredictable food supply exhibited an accelerated development of the CORT stress response which could reflect an adaptive maternal effect. We conclude that the vital role of baseline CORT may allow little adaptive scope since changes can quickly become detrimental. In contrast, the CORT stress response may show considerable adaptive potential which might ultimately support homeostasis in a changing environment. PMID:25307951

  18. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

    PubMed

    Hata, Aaron N; Niederst, Matthew J; Archibald, Hannah L; Gomez-Caraballo, Maria; Siddiqui, Faria M; Mulvey, Hillary E; Maruvka, Yosef E; Ji, Fei; Bhang, Hyo-eun C; Krishnamurthy Radhakrishna, Viveksagar; Siravegna, Giulia; Hu, Haichuan; Raoof, Sana; Lockerman, Elizabeth; Kalsy, Anuj; Lee, Dana; Keating, Celina L; Ruddy, David A; Damon, Leah J; Crystal, Adam S; Costa, Carlotta; Piotrowska, Zofia; Bardelli, Alberto; Iafrate, Anthony J; Sadreyev, Ruslan I; Stegmeier, Frank; Getz, Gad; Sequist, Lecia V; Faber, Anthony C; Engelman, Jeffrey A

    2016-03-01

    Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic. PMID:26828195

  19. Distinct roles of transcription factors TFIIIB and TFIIIC in RNA polymerase III transcription reinitiation.

    PubMed

    Ferrari, Roberto; Rivetti, Claudio; Acker, Joël; Dieci, Giorgio

    2004-09-14

    Eukaryotic RNA polymerase (Pol) III is recruited to target promoters by a stable preinitiation complex containing transcription factors TFIIIC and TFIIIB. After the first transcription cycle, reinitiation proceeds through facilitated recycling, a process by which the terminating Pol III rapidly reloads onto the same transcription unit. Here, we show that Pol III is repeatedly recaptured in vitro by the first transcribed gene, even in the presence of a juxtaposed competitor promoter complex, thus suggesting that facilitated recycling is not merely due to a stochastic reassociation process favored by the small size of class III genes. The transcription factor requirements for facilitated reinitiation were investigated by taking advantage of Pol III templates that support both TFIIIC-dependent and TFIIIC-independent transcription. A TFIIIC-less transcription system, in which TFIIIB was reconstituted from recombinant TATA box-binding protein and Brf1 proteins and a crude fraction containing the Bdp1 component, was sufficient to direct efficient Pol III recycling on short ( approximately 100 bp) class III genes. Unexpectedly, however, on longer (>300 bp) transcription units, reinitiation in the presence of TFIIIB alone was compromised, and TFIIIC was further required to reestablish a high reinitiation rate. Transcription reinitiation was also severely impaired when recombinant Bdp1 protein replaced the corresponding crude fraction in reconstituted TFIIIB. The data reveal an unexpected complexity in the Pol III reinitiation mechanism and suggest the existence of a handing-back network between Pol III, TFIIIC, and TFIIIB on actively transcribed class III genes. PMID:15347814

  20. Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts.

    PubMed

    Bonanno, Anna; Albano, Giusy Daniela; Siena, Liboria; Montalbano, Angela Marina; Riccobono, Loredana; Anzalone, Giulia; Chiappara, Giuseppina; Gagliardo, Rosalia; Profita, Mirella; Sala, Angelo

    2016-03-01

    We studied the role of PGE2, its biosynthetic enzymes and its receptors, in regulating the functions of lung fibroblasts through the production of Vascular Endothelial Growth Factor (VEGF) and Interleukin-8 (IL-8) in COPD subjects. Lung fibroblasts from Control (C) (n=6), Smoker (HS) (n=6) and COPD patients (n=8) were cultured, and basal PGE2, VEGF, and IL-8 measured in supernatants by ELISA. COX-1/COX-2 and EP receptors expression were assessed by western blot and by RT-PCR. Release of VEGF and IL-8 by human fetal lung fibroblasts (HFL-1; lung, diploid, human) was evaluated under different conditions. PGE2, VEGF, and IL-8 levels, COX-2, EP2, and EP4 protein expression and mRNA were increased in COPD when compared to Controls. Low concentrations of synthetic PGE2 increased the release of VEGF in HFL-1, but higher concentrations were needed to induce the release of IL-8. This effect was mimicked by an EP2 agonist and modulated by an EP4 antagonist. In the airways of COPD subjects, fibroblast-derived PGE2 may regulate angiogenesis and inflammation through the production of VEGF and IL-8 respectively, suggesting that the increase in expression of COX-2, EP2 and EP4 observed in COPD fibroblasts may contribute to steering the role of PGE2 from homeostatic to pro-inflammatory. PMID:26926362

  1. The Daiokanzoto (TJ-84) Kampo Formulation Reduces Virulence Factor Gene Expression in Porphyromonas gingivalis and Possesses Anti-Inflammatory and Anti-Protease Activities.

    PubMed

    Fournier-Larente, Jade; Azelmat, Jabrane; Yoshioka, Masami; Hinode, Daisuke; Grenier, Daniel

    2016-01-01

    Kampo formulations used in Japan to treat a wide variety of diseases and to promote health are composed of mixtures of crude extracts from the roots, bark, leaves, and rhizomes of a number of herbs. The present study was aimed at identifying the beneficial biological properties of Daiokanzoto (TJ-84), a Kampo formulation composed of crude extracts of Rhubarb rhizomes and Glycyrrhiza roots, with a view to using it as a potential treatment for periodontal disease. Daiokanzoto dose-dependently inhibited the expression of major Porphyromonas gingivalis virulence factors involved in host colonization and tissue destruction. More specifically, Daiokanzoto reduced the expression of the fimA, hagA, rgpA, and rgpB genes, as determined by quantitative real-time PCR. The U937-3xκB-LUC monocyte cell line transfected with a luciferase reporter gene was used to evaluate the anti-inflammatory properties of Daiokanzoto. Daiokanzoto attenuated the P. gingivalis-mediated activation of the NF-κB signaling pathway. It also reduced the secretion of pro-inflammatory cytokines (IL-6 and CXCL8) by lipopolysaccharide-stimulated oral epithelial cells and gingival fibroblasts. Lastly, Daiokanzoto, dose-dependently inhibited the catalytic activity of matrix metalloproteinases (-1 and -9). In conclusion, the present study provided evidence that Daiokanzoto shows potential for treating and/or preventing periodontal disease. The ability of this Kampo formulation to act on both bacterial pathogens and the host inflammatory response, the two etiological components of periodontal disease, is of high therapeutic interest. PMID:26859747

  2. The Daiokanzoto (TJ-84) Kampo Formulation Reduces Virulence Factor Gene Expression in Porphyromonas gingivalis and Possesses Anti-Inflammatory and Anti-Protease Activities

    PubMed Central

    Fournier-Larente, Jade; Azelmat, Jabrane; Yoshioka, Masami; Hinode, Daisuke; Grenier, Daniel

    2016-01-01

    Kampo formulations used in Japan to treat a wide variety of diseases and to promote health are composed of mixtures of crude extracts from the roots, bark, leaves, and rhizomes of a number of herbs. The present study was aimed at identifying the beneficial biological properties of Daiokanzoto (TJ-84), a Kampo formulation composed of crude extracts of Rhubarb rhizomes and Glycyrrhiza roots, with a view to using it as a potential treatment for periodontal disease. Daiokanzoto dose-dependently inhibited the expression of major Porphyromonas gingivalis virulence factors involved in host colonization and tissue destruction. More specifically, Daiokanzoto reduced the expression of the fimA, hagA, rgpA, and rgpB genes, as determined by quantitative real-time PCR. The U937-3xκB-LUC monocyte cell line transfected with a luciferase reporter gene was used to evaluate the anti-inflammatory properties of Daiokanzoto. Daiokanzoto attenuated the P. gingivalis-mediated activation of the NF-κB signaling pathway. It also reduced the secretion of pro-inflammatory cytokines (IL-6 and CXCL8) by lipopolysaccharide-stimulated oral epithelial cells and gingival fibroblasts. Lastly, Daiokanzoto, dose-dependently inhibited the catalytic activity of matrix metalloproteinases (-1 and -9). In conclusion, the present study provided evidence that Daiokanzoto shows potential for treating and/or preventing periodontal disease. The ability of this Kampo formulation to act on both bacterial pathogens and the host inflammatory response, the two etiological components of periodontal disease, is of high therapeutic interest. PMID:26859747

  3. Nuclear Import of the Retrotransposon Tf1 Is Governed by a Nuclear Localization Signal That Possesses a Unique Requirement for the FXFG Nuclear Pore Factor Nup124p

    PubMed Central

    Dang, Van-Dinh; Levin, Henry L.

    2000-01-01

    Retroviruses, such as human immunodeficiency virus, that infect nondividing cells generate integration precursors that must cross the nuclear envelope to reach the host genome. As a model for retroviruses, we investigated the nuclear entry of Tf1, a long-terminal-repeat-containing retrotransposon of the fission yeast Schizosaccharomyces pombe. Because the nuclear envelope of yeasts remains intact throughout the cell cycle, components of Tf1 must be transported through the envelope before integration can occur. The nuclear localization of the Gag protein of Tf1 is different from that of other proteins tested in that it has a specific requirement for the FXFG nuclear pore factor, Nup124p. Using extensive mutagenesis, we found that Gag contained three nuclear localization signals (NLSs) which, when included individually in a heterologous protein, were sufficient to direct nuclear import. In the context of the intact transposon, mutations in the NLS that mapped to the first 10 amino acid residues of Gag significantly impaired Tf1 retrotransposition and abolished nuclear localization of Gag. Interestingly, this NLS activity in the heterologous protein was specifically dependent upon the presence of Nup124p. Deletion analysis of heterologous proteins revealed the surprising result that the residues in Gag with the NLS activity were independent from the residues that conveyed the requirement for Nup124p. In fact, a fragment of Gag that lacked NLS activity, residues 10 to 30, when fused to a heterologous protein, was sufficient to cause the classical NLS of simian virus 40 to require Nup124p for nuclear import. Within the context of the current understanding of nuclear import, these results represent the novel case of a short amino acid sequence that specifies the need for a particular nuclear pore complex protein. PMID:11003674

  4. SOX2 Co-Occupies Distal Enhancer Elements with Distinct POU Factors in ESCs and NPCs to Specify Cell State

    PubMed Central

    Lodato, Michael A.; Cheng, Albert W.; Thai, Kevin K.; Fraenkel, Ernest; Jaenisch, Rudolf; Boyer, Laurie A.

    2013-01-01

    SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs) and multipotent neural progenitor cells (NPCs); however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1) in ESCs, the related POU family member BRN2 (Pou3f2) co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors. PMID:23437007

  5. Distinct Roles for Fibroblast Growth Factor Signaling in Cerebellar Development and Medulloblastoma

    PubMed Central

    Emmenegger, Brian A.; Hwang, Eugene I.; Moore, Colin; Markant, Shirley L.; Brun, Sonja N.; Dutton, John W.; Read, Tracy-Ann; Fogarty, Marie P.; Singh, Alok R.; Durden, Donald L.; Yang, Chaofeng; McKeehan, Wallace L.; Wechsler-Reya, Robert J.

    2013-01-01

    Cerebellar granule neurons are the most abundant neurons in the brain, and a critical element of the circuitry that controls motor coordination and learning. In addition, granule neuron precursors (GNPs) are thought to represent cells of origin for medulloblastoma, the most common malignant brain tumor in children. Thus, understanding the signals that control the growth and differentiation of these cells has important implications for neurobiology and neuro-oncology. Our previous studies have shown that proliferation of GNPs is regulated by Sonic hedgehog (Shh), and that aberrant activation of the Shh pathway can lead to medulloblastoma. Moreover, we have demonstrated that Shh-dependent proliferation of GNPs and medulloblastoma cells can be blocked by basic fibroblast growth factor (bFGF). But while the mitogenic effects of Shh signaling have been confirmed in vivo, the inhibitory effects of bFGF have primarily been studied in culture. Here we demonstrate that mice lacking FGF signaling in GNPs exhibit no discernable changes in GNP proliferation or differentiation. In contrast, activation of FGF signaling has a potent effect on tumor growth: treatment of medulloblastoma cells with bFGF prevents them from forming tumors following transplantation, and inoculation of tumor-bearing mice with bFGF markedly inhibits tumor growth in vivo. These results suggest that activators of FGF signaling may be useful for targeting medulloblastoma and other Shh-dependent tumors. PMID:23045271

  6. Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations.

    PubMed

    Blaum, Bärbel S; Frank, Martin; Walker, Ross C; Neu, Ursula; Stehle, Thilo

    2016-05-01

    Mammalian cell surfaces are decorated with a variety of glycan chains that orchestrate development and defense and are exploited by pathogens for cellular attachment and entry. While glycosidic linkages are, in principle, flexible, the conformational space that a given glycan can sample is subject to spatial and electrostatic restrictions imposed by its overall chemical structure. Here, we show how the glycan moiety of the GM1 ganglioside, a branched, monosialylated pentasaccharide that serves as a ligand for various proteins, undergoes differential conformational selection in its interactions with different lectins. Using STD NMR and X-ray crystallography, we found that the innate immune regulator complement Factor H (FH) binds a previously not reported GM1 conformation that is not compatible with the GM1-binding sites of other structurally characterized GM1-binding lectins such as the Simian Virus 40 (SV40) capsid. Molecular dynamics simulations of the free glycan in explicit solvent on the 10 μs timescale reveal that the FH-bound conformation nevertheless corresponds to a minimum in the Gibbs free energy plot. In contrast to the GM1 conformation recognized by SV40, the FH-bound GM1 conformation is associated with poor NOE restraints, explaining how it escaped(1)H-(1)H NOE-restrained modeling in the past and highlighting the necessity for ensemble representations of glycan structures. PMID:26715202

  7. Adverse possession of subsurface minerals

    SciTech Connect

    Bowles, P.N.

    1983-01-01

    Concepts applicable to adverse possession of subsurface minerals are generally the same as those that apply to adverse possession of all real estate. However, special requirements must be satisfied in order to perfect title to subsurface minerals by adverse possession, particularly when there has been a severance of the true title between surface and subsurface minerals. In those jurisdictions where senior and junior grants came from the state or commonwealth covering the same or some of the same land and in those areas where descriptions of land were vague or not carefully drawn, adverse possession serves to solidify land and mineral ownership. There may be some public, social, and economic justification in rewarding, with good title, those who take possession and use real estate for its intended use, including the extraction of subsurface minerals. 96 refernces.

  8. Distinct binding and immunogenic properties of the gonococcal homologue of meningococcal factor h binding protein.

    PubMed

    Jongerius, Ilse; Lavender, Hayley; Tan, Lionel; Ruivo, Nicola; Exley, Rachel M; Caesar, Joseph J E; Lea, Susan M; Johnson, Steven; Tang, Christoph M

    2013-01-01

    Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups. PMID:23935503

  9. Shared and distinct factors driving attention and temporal processing across modalities

    PubMed Central

    Berry, Anne S.; Li, Xu; Lin, Ziyong; Lustig, Cindy

    2013-01-01

    In addition to the classic finding that “sounds are judged longer than lights,” the timing of auditory stimuli is often more precise and accurate than is the timing of visual stimuli. In cognitive models of temporal processing, these modality differences are explained by positing that auditory stimuli more automatically capture and hold attention, more efficiently closing an attentional switch that allows the accumulation of pulses marking the passage of time (Block & Zakay, 1997; Meck, 1991; Penney, 2003). However, attention is a multifaceted construct, and there has been little attempt to determine which aspects of attention may be related to modality effects. We used visual and auditory versions of the Continuous Temporal Expectancy Task (CTET; O'Connell et al., 2009) a timing task previously linked to behavioral and electrophysiological measures of mind-wandering and attention lapses, and tested participants with or without the presence of a video distractor. Performance in the auditory condition was generally superior to that in the visual condition, replicating standard results in the timing literature. The auditory modality was also less affected by declines in sustained attention indexed by declines in performance over time. In contrast, distraction had an equivalent impact on performance in the two modalities. Analysis of individual differences in performance revealed further differences between the two modalities: Poor performance in the auditory condition was primarily related to boredom whereas poor performance in the visual condition was primarily related to distractibility. These results suggest that: 1) challenges to different aspects of attention reveal both modality-specific and nonspecific effects on temporal processing, and 2) different factors drive individual differences when testing across modalities. PMID:23978664

  10. Constrained positive matrix factorization: Elemental ratios, spatial distinction, and chemical transport model source contributions

    NASA Astrophysics Data System (ADS)

    Sturtz, Timothy M.

    Source apportionment models attempt to untangle the relationship between pollution sources and the impacts at downwind receptors. Two frameworks of source apportionment models exist: source-oriented and receptor-oriented. Source based apportionment models use presumed emissions and atmospheric processes to estimate the downwind source contributions. Conversely, receptor based models leverage speciated concentration data from downwind receptors and apply statistical methods to predict source contributions. Integration of both source-oriented and receptor-oriented models could lead to a better understanding of the implications sources have on the environment and society. The research presented here investigated three different types of constraints applied to the Positive Matrix Factorization (PMF) receptor model within the framework of the Multilinear Engine (ME-2): element ratio constraints, spatial separation constraints, and chemical transport model (CTM) source attribution constraints. PM10-2.5 mass and trace element concentrations were measured in Winston-Salem, Chicago, and St. Paul at up to 60 sites per city during two different seasons in 2010. PMF was used to explore the underlying sources of variability. Information on previously reported PM10-2.5 tire and brake wear profiles were used to constrain these features in PMF by prior specification of selected species ratios. We also modified PMF to allow for combining the measurements from all three cities into a single model while preserving city-specific soil features. Relatively minor differences were observed between model predictions with and without the prior ratio constraints, increasing confidence in our ability to identify separate brake wear and tire wear features. Using separate data, source contributions to total fine particle carbon predicted by a CTM were incorporated into the PMF receptor model to form a receptor-oriented hybrid model. The level of influence of the CTM versus traditional PMF was

  11. Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

    PubMed Central

    Wohrer, Stefan; Knapp, David J.H.F.; Copley, Michael R.; Benz, Claudia; Kent, David G.; Rowe, Keegan; Babovic, Sonja; Mader, Heidi; Oostendorp, Robert A.J.; Eaves, Connie J.

    2014-01-01

    Summary Hematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion. PMID:24910437

  12. Distinct XPPX sequence motifs induce ribosome stalling, which is rescued by the translation elongation factor EF-P

    PubMed Central

    Peil, Lauri; Starosta, Agata L.; Lassak, Jürgen; Atkinson, Gemma C.; Virumäe, Kai; Spitzer, Michaela; Tenson, Tanel; Jung, Kirsten; Remme, Jaanus; Wilson, Daniel N.

    2013-01-01

    Ribosomes are the protein synthesizing factories of the cell, polymerizing polypeptide chains from their constituent amino acids. However, distinct combinations of amino acids, such as polyproline stretches, cannot be efficiently polymerized by ribosomes, leading to translational stalling. The stalled ribosomes are rescued by the translational elongation factor P (EF-P), which by stimulating peptide-bond formation allows translation to resume. Using metabolic stable isotope labeling and mass spectrometry, we demonstrate in vivo that EF-P is important for expression of not only polyproline-containing proteins, but also for specific subsets of proteins containing diprolyl motifs (XPP/PPX). Together with a systematic in vitro and in vivo analysis, we provide a distinct hierarchy of stalling triplets, ranging from strong stallers, such as PPP, DPP, and PPN to weak stallers, such as CPP, PPR, and PPH, all of which are substrates for EF-P. These findings provide mechanistic insight into how the characteristics of the specific amino acid substrates influence the fundamentals of peptide bond formation. PMID:24003132

  13. Spatial isolation and environmental factors drive distinct bacterial and archaeal communities in different types of petroleum reservoirs in China

    PubMed Central

    Gao, Peike; Tian, Huimei; Wang, Yansen; Li, Yanshu; Li, Yan; Xie, Jinxia; Zeng, Bing; Zhou, Jiefang; Li, Guoqiang; Ma, Ting

    2016-01-01

    To investigate the spatial distribution of microbial communities and their drivers in petroleum reservoir environments, we performed pyrosequencing of microbial partial 16S rRNA, derived from 20 geographically separated water-flooding reservoirs, and two reservoirs that had not been flooded, in China. The results indicated that distinct underground microbial communities inhabited the different reservoirs. Compared with the bacteria, archaeal alpha-diversity was not strongly correlated with the environmental variables. The variation of the bacterial and archaeal community compositions was affected synthetically, by the mining patterns, spatial isolation, reservoir temperature, salinity and pH of the formation brine. The environmental factors explained 64.22% and 78.26% of the total variance for the bacterial and archaeal communities, respectively. Despite the diverse community compositions, shared populations (48 bacterial and 18 archaeal genera) were found and were dominant in most of the oilfields. Potential indigenous microorganisms, including Carboxydibrachium, Thermosinus, and Neptunomonas, were only detected in a reservoir that had not been flooded with water. This study indicates that: 1) the environmental variation drives distinct microbial communities in different reservoirs; 2) compared with the archaea, the bacterial communities were highly heterogeneous within and among the reservoirs; and 3) despite the community variation, some microorganisms are dominant in multiple petroleum reservoirs. PMID:26838035

  14. Spatial isolation and environmental factors drive distinct bacterial and archaeal communities in different types of petroleum reservoirs in China

    NASA Astrophysics Data System (ADS)

    Gao, Peike; Tian, Huimei; Wang, Yansen; Li, Yanshu; Li, Yan; Xie, Jinxia; Zeng, Bing; Zhou, Jiefang; Li, Guoqiang; Ma, Ting

    2016-02-01

    To investigate the spatial distribution of microbial communities and their drivers in petroleum reservoir environments, we performed pyrosequencing of microbial partial 16S rRNA, derived from 20 geographically separated water-flooding reservoirs, and two reservoirs that had not been flooded, in China. The results indicated that distinct underground microbial communities inhabited the different reservoirs. Compared with the bacteria, archaeal alpha-diversity was not strongly correlated with the environmental variables. The variation of the bacterial and archaeal community compositions was affected synthetically, by the mining patterns, spatial isolation, reservoir temperature, salinity and pH of the formation brine. The environmental factors explained 64.22% and 78.26% of the total variance for the bacterial and archaeal communities, respectively. Despite the diverse community compositions, shared populations (48 bacterial and 18 archaeal genera) were found and were dominant in most of the oilfields. Potential indigenous microorganisms, including Carboxydibrachium, Thermosinus, and Neptunomonas, were only detected in a reservoir that had not been flooded with water. This study indicates that: 1) the environmental variation drives distinct microbial communities in different reservoirs; 2) compared with the archaea, the bacterial communities were highly heterogeneous within and among the reservoirs; and 3) despite the community variation, some microorganisms are dominant in multiple petroleum reservoirs.

  15. Purification of murine suppressive factor of allergy into distinct CD23-modulating and IgE-suppressive proteins.

    PubMed Central

    Matsushita, S; Marcelletti, J F; Katz, L R; Katz, D H

    1991-01-01

    The murine suppressive factor of allergy (SFA) has been purified from a T-cell hybridoma and found to consist of two functionally and biochemically distinct protein molecules. One protein (17 kDa) modulates the low-affinity Fc receptor for IgE on lymphocytes (i.e., CD23); it decreases the binding avidity of IgE to CD23-bearing B cells without affecting quantitative expression of CD23 and is thus designated epsilon-receptor-modulating protein. The second protein (30 kDa) suppresses IgE biosynthesis (i.e., SFA). This purified SFA suppresses interleukin 4-induced IgE and IgG1 synthesis by lipopolysaccharide-activated spleen cells but has no effect on other antibody isotypes; since the activity of SFA is not blocked by anti-interferon gamma monoclonal antibody, it is thus distinct from interferon gamma. The data presented indicate that epsilon-receptor-modulating protein and SFA are protein molecules that are involved in modulating the CD23 molecule and IgE antibody synthesis, respectively. Images PMID:1828884

  16. Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family

    PubMed Central

    Dai, Qi; Ren, Aiming; Westholm, Jakub O.; Duan, Hong; Patel, Dinshaw J.

    2015-01-01

    Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain (“BEN-solo” factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional

  17. Common and distinct DNA-binding and regulatory activities of the BEN-solo transcription factor family.

    PubMed

    Dai, Qi; Ren, Aiming; Westholm, Jakub O; Duan, Hong; Patel, Dinshaw J; Lai, Eric C

    2015-01-01

    Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain ("BEN-solo" factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional

  18. A Family of Salmonella Virulence Factors Functions as a Distinct Class of Autoregulated E3 Ubiquitin Ligases

    SciTech Connect

    Quezada, C.; Hicks, S; Galan, J; Stebbins, C

    2009-01-01

    Processes as diverse as receptor binding and signaling, cytoskeletal dynamics, and programmed cell death are manipulated by mimics of host proteins encoded by pathogenic bacteria. We show here that the Salmonella virulence factor SspH2 belongs to a growing class of bacterial effector proteins that harness and subvert the eukaryotic ubiquitination pathway. This virulence protein possesses ubiquitination activity that depends on a conserved cysteine residue. A crystal structure of SspH2 reveals a canonical leucine-rich repeat (LRR) domain that interacts with a unique E{sub 3} ligase [which we have termed NEL for Novel E{sub 3} Ligase] C-terminal fold unrelated to previously observed HECT or RING-finger E{sub 3} ligases. Moreover, the LRR domain sequesters the catalytic cysteine residue contained in the NEL domain, and we suggest a mechanism for activation of the ligase requiring a substantial conformational change to release the catalytic domain for function. We also show that the N-terminal domain targets SspH2 to the apical plasma membrane of polarized epithelial cells and propose a model whereby binding of the LRR to proteins at the target site releases the ligase domain for site-specific function.

  19. Distinct non-cerebrovascular risk factors for ischemic lacunar stroke and non-lacunar stroke: preliminary results.

    PubMed

    Chen, Y F; Luo, C H; Liu, Y J; Lu, W H; Su, B R

    2015-01-01

    Stroke is a non-communicable disease of increasing socioeconomic importance in aging populations. This study compared the risk factors implicated in two subtypes of ischemic stroke: lacunar stroke (LS) and non-lacunar stroke (NLS). A retrospective case control study was conducted on a total of 368 patients [220 cases (59.8%) of NLS and 148 cases (40.2%) of LS] with first-time onset of ischemic stroke. Multivariate logistic regression was performed to compare multiple non-cerebrovascular risk factors between the two groups. More patients with a history of diabetes were found in the NLS than the LS group (40.5 vs 26.4%), and that both fasting glucose and HbA1C levels before the onset of stroke were higher in NLS than LS patients. Multivariate analysis revealed that patients with a history of diabetes were 1.57 times more likely to have NLS than LS (OR = 1.57, 95%CI = 0.95-3.26). Moreover, male patients were more likely to develop NLS than females (OR = 1.46, 95%CI = 0.79-2.69), and patients with elevated fibrinogen levels were 1.4 times more likely to develop NLS than LS (OR = 1.40, 95%CI = 1.09-1.80). Additionally, patients who were heavy drinkers (OR = 1.39, 95%CI = 0.68-2.84) or smokers (OR = 1.62, 95%CI = 0.91-2.89) were more likely to develop NLS than LS. Other risk factors, such as hypertension, dyslipidemia, age, and average blood pressure, did not differ between the two types of stroke. Thus, distinct non-cerebrovascular risk factors (male gender, long history of diabetes, elevated fibrinogen, heavy smoking, and heavy drinking) are associated with a higher risk of developing non-lacunar stroke than lacunar stroke. PMID:25966082

  20. Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF).

    PubMed

    Yoshimura, Kimihiro; Kitagawa, Hirochika; Fujiki, Ryoji; Tanabe, Masahiko; Takezawa, Shinichiro; Takada, Ichiro; Yamaoka, Ikuko; Yonezawa, Masayoshi; Kondo, Takeshi; Furutani, Yoshiyuki; Yagi, Hisato; Yoshinaga, Shin; Masuda, Takeyoshi; Fukuda, Toru; Yamamoto, Yoko; Ebihara, Kanae; Li, Dean Y; Matsuoka, Rumiko; Takeuchi, Jun K; Matsumoto, Takahiro; Kato, Shigeaki

    2009-06-01

    A number of nuclear complexes modify chromatin structure and operate as functional units. However, the in vivo role of each component within the complexes is not known. ATP-dependent chromatin remodeling complexes form several types of protein complexes, which reorganize chromatin structure cooperatively with histone modifiers. Williams syndrome transcription factor (WSTF) was biochemically identified as a major subunit, along with 2 distinct complexes: WINAC, a SWI/SNF-type complex, and WICH, an ISWI-type complex. Here, WSTF(-/-) mice were generated to investigate its function in chromatin remodeling in vivo. Loss of WSTF expression resulted in neonatal lethality, and all WSTF(-/-) neonates and approximately 10% of WSTF(+/-) neonates suffered cardiovascular abnormalities resembling those found in autosomal-dominant Williams syndrome patients. Developmental analysis of WSTF(-/-) embryos revealed that Gja5 gene regulation is aberrant from E9.5, conceivably because of inappropriate chromatin reorganization around the promoter regions where essential cardiac transcription factors are recruited. In vitro analysis in WSTF(-/-) mouse embryonic fibroblast (MEF) cells also showed impaired transactivation functions of cardiac transcription activators on the Gja5 promoter, but the effects were reversed by overexpression of WINAC components. Likewise in WSTF(-/-) MEF cells, recruitment of Snf2h, an ISWI ATPase, to PCNA and cell survival after DNA damage were both defective, but were ameliorated by overexpression of WICH components. Thus, the present study provides evidence that WSTF is shared and is a functionally indispensable subunit of the WICH complex for DNA repair and the WINAC complex for transcriptional control. PMID:19470456

  1. BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors

    PubMed Central

    Morikawa, Masato; Koinuma, Daizo; Mizutani, Anna; Kawasaki, Natsumi; Holmborn, Katarina; Sundqvist, Anders; Tsutsumi, Shuichi; Watabe, Tetsuro; Aburatani, Hiroyuki; Heldin, Carl-Henrik; Miyazono, Kohei

    2016-01-01

    Summary Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors. PMID:26771354

  2. Modeling the Human Kinetic Adjustment Factor for Inhaled Volatile Organic Chemicals: Whole Population Approach versus Distinct Subpopulation Approach

    PubMed Central

    Valcke, M.; Nong, A.; Krishnan, K.

    2012-01-01

    The objective of this study was to evaluate the impact of whole- and sub-population-related variabilities on the determination of the human kinetic adjustment factor (HKAF) used in risk assessment of inhaled volatile organic chemicals (VOCs). Monte Carlo simulations were applied to a steady-state algorithm to generate population distributions for blood concentrations (CAss) and rates of metabolism (RAMs) for inhalation exposures to benzene (BZ) and 1,4-dioxane (1,4-D). The simulated population consisted of various proportions of adults, elderly, children, neonates and pregnant women as per the Canadian demography. Subgroup-specific input parameters were obtained from the literature and P3M software. Under the “whole population” approach, the HKAF was computed as the ratio of the entire population's upper percentile value (99th, 95th) of dose metrics to the median value in either the entire population or the adult population. Under the “distinct subpopulation” approach, the upper percentile values in each subpopulation were considered, and the greatest resulting HKAF was retained. CAss-based HKAFs that considered the Canadian demography varied between 1.2 (BZ) and 2.8 (1,4-D). The “distinct subpopulation” CAss-based HKAF varied between 1.6 (BZ) and 8.5 (1,4-D). RAM-based HKAFs always remained below 1.6. Overall, this study evaluated for the first time the impact of underlying assumptions with respect to the interindividual variability considered (whole population or each subpopulation taken separately) when determining the HKAF. PMID:22523487

  3. Three R2R3-MYB Transcription Factors Regulate Distinct Floral Pigmentation Patterning in Phalaenopsis spp.1[OPEN

    PubMed Central

    Hsu, Chia-Chi; Chen, You-Yi; Tsai, Wen-Chieh; Chen, Wen-Huei; Chen, Hong-Hwa

    2015-01-01

    Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long-lasting flowers of various colors and pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3-hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus-induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp. PMID:25739699

  4. Insulin-like growth factor binding proteins in follicular fluid from morphologically distinct healthy and atretic bovine antral follicles.

    PubMed

    Irving-Rodgers, H F; Catanzariti, K D; Master, M; Grant, P A; Owens, P C; Rodgers, R J

    2003-01-01

    In bovine follicles 2-5 mm in diameter, two morphologically distinct types of healthy follicles and two types of atretic follicles have been described recently. Healthy follicles either have columnar basal granulosa cells with follicular basal lamina composed of many layers or 'loops' or they have rounded basal cells with a conventional single-layered, aligned follicular basal lamina. In atretic follicles, cell death either commences at the basal layer and progresses to the antrum (basal atresia) with macrophage penetration of the membrana granulosa or death progresses from the antrum in a basal direction (antral atresia). Little is known about how these different phenotypes develop. To determine whether insulin-like growth factor binding protein (IGFBP) levels in follicular fluid differ between these different types of follicles, we measured IGFBP levels in fluids from these follicles. A total of 61 follicles were assessed by light microscopy and characterized by morphological analysis as either healthy, with columnar or rounded basal granulosa cells, or as undergoing antral or basal atresia. The IGFBP concentration in the follicular fluid of individual follicles from the four groups (n = 12-20 per group) was identified by Western ligand blots using (125)I-insulin-like growth factor (IGF)-II as a probe. Insulin-like growth factor binding proteins 2, 3 (44 and 40 kDa), 4 (glycosylated and non-glycosylated) and 5 were observed. The levels (per volume of fluid) of IGFBPs 2, 4 and 5 were greater in atretic follicles than in healthy follicles. However, there were no statistical differences in levels of each IGFBP between either the two types of healthy follicle or between the two types of atretic follicles. Thus, IGFBP levels are not related to the different types of healthy or atretic follicles. PMID:12921699

  5. Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis.

    PubMed

    Börner, Kenneth; Becker, Peter B

    2016-09-01

    SWR1-type nucleosome remodeling factors replace histone H2A by variants to endow chromatin locally with specialized functionality. In Drosophila melanogaster a single H2A variant, H2A.V, combines functions of mammalian H2A.Z and H2A.X in transcription regulation and the DNA damage response. A major role in H2A.V incorporation for the only SWR1-like enzyme in flies, Domino, is assumed but not well documented in vivo. It is also unclear whether the two alternatively spliced isoforms, DOM-A and DOM-B, have redundant or specialized functions. Loss of both DOM isoforms compromises oogenesis, causing female sterility. We systematically explored roles of the two DOM isoforms during oogenesis using a cell type-specific knockdown approach. Despite their ubiquitous expression, DOM-A and DOM-B have non-redundant functions in germline and soma for egg formation. We show that chromatin incorporation of H2A.V in germline and somatic cells depends on DOM-B, whereas global incorporation in endoreplicating germline nurse cells appears to be independent of DOM. By contrast, DOM-A promotes the removal of H2A.V from stage 5 nurse cells. Remarkably, therefore, the two DOM isoforms have distinct functions in cell type-specific development and H2A.V exchange. PMID:27578180

  6. Distinct roles for lymphotoxin-alpha and tumor necrosis factor in the control of Leishmania donovani infection.

    PubMed

    Engwerda, Christian R; Ato, Manabu; Stäger, Simona; Alexander, Clare E; Stanley, Amanda C; Kaye, Paul M

    2004-12-01

    Tumor necrosis factor (TNF) is critical for the control of visceral leishmaniasis caused by Leishmania donovani. However, the role of the related cytokine lymphotoxin (LT) alpha in this infection is unknown. Here we report that C57BL/6 mice deficient in TNF (B6.TNF(-/-)) or LT alpha (B6.LT alpha(-/-)) have increased susceptibility to hepatic L. donovani infection. Furthermore, the outcome of infection in bone marrow chimeric mice is dependent on donor hematopoietic cells, indicating that developmental defects in lymphoid organs were not responsible for increased susceptibility to L. donovani. Although both LT alpha and TNF regulated the migration of leukocytes into the sinusoidal area of the infected liver, their roles were distinct. LT alpha was essential for migration of leukocytes from periportal areas, an event consistent with LT alpha-dependent up-regulation of VCAM-1 on liver sinusoid lining cells, whereas TNF was essential for leukocyte recruitment to the liver. During visceral leishmaniasis, both cytokines were produced by radio-resistant cells and by CD4(+) T cells. LT alpha and TNF production by the former was required for granuloma assembly, while production of these cytokines by CD4(+) T cells was necessary to control parasite growth. The production of inducible nitric oxide synthase was also found to be deficient in TNF- and LT alpha-deficient infected mice. These results demonstrate that both LT alpha and TNF are required for control of L. donovani infection in noncompensatory ways. PMID:15579454

  7. The ternary complex factor Net contains two distinct elements that mediate different responses to MAP kinase signalling cascades.

    PubMed

    Ducret, C; Maira, S M; Lutz, Y; Wasylyk, B

    2000-10-19

    The ternary complex factors (TCFs), Elk-1, Sap-1a and Net, are key integrators of the transcriptional response to different signalling pathways. Classically, three MAP kinase pathways, involving ERK, JNK, and p38, transduce various extracellular stimuli to the nucleus. Net is a repressor that is converted into an activator by Ras/ERK signalling. Net is also exported from the nucleus in response to stress stimuli transduced through the JNK pathway, leading to relief from repression. Here we show that ERK and p38 bind to the D box and that binding is required for phosphorylation of the adjacent C-terminally located C-domain. The D box as well as the phosphorylation sites in the C-domain (the DC element) are required for transcription activation by Ras. On the other hand, JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export. In conclusion, specific targeting of Net by MAP kinase pathways involves two different docking sites and phosphorylation of two different domains. These two elements, DC and JEX, mediate two distinct functional responses. PMID:11042694

  8. A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II*S⃞

    PubMed Central

    Alvino, Clair L.; McNeil, Kerrie A.; Ong, Shee Chee; Delaine, Carlie; Booker, Grant W.; Wallace, John C.; Whittaker, Jonathan; Forbes, Briony E.

    2009-01-01

    Very little is known about the residues important for the interaction of insulin-like growth factor II (IGF-II) with the type 1 IGF receptor (IGF-1R) and the insulin receptor (IR). Insulin, to which IGF-II is homologous, is proposed to cross-link opposite halves of the IR dimer through two receptor binding surfaces, site 1 and site 2. In the present study we have analyzed the contribution of IGF-II residues equivalent to insulin's two binding surfaces toward the interaction of IGF-II with the IGF-1R and IR. Four “site 1” and six “site 2” analogues were produced and analyzed in terms of IGF-1R and IR binding and activation. The results show that Val43, Phe28, and Val14 (equivalent to site 1) are critical to IGF-1R and IR binding, whereas mutation to alanine of Gln18 affects only IGF-1R and not IR binding. Alanine substitutions at Glu12, Asp15, Phe19, Leu53, and Glu57 analogues resulted in significant (>2-fold) decreases in affinity for both the IGF-1R and IR. Furthermore, taking a novel approach using a monomeric, single-chain minimized IGF-1R we have defined a distinct second binding surface formed by Glu12, Phe19, Leu53, and Glu57 that potentially engages the IGF-1R at one or more of the FnIII domains. PMID:19139090

  9. Genetically distinct populations of northern shrimp, Pandalus borealis, in the North Atlantic: adaptation to different temperatures as an isolation factor.

    PubMed

    Jorde, Per Erik; Søvik, Guldborg; Westgaard, Jon-Ivar; Albretsen, Jon; André, Carl; Hvingel, Carsten; Johansen, Torild; Sandvik, Anne Dagrun; Kingsley, Michael; Jørstad, Knut Eirik

    2015-04-01

    The large-scale population genetic structure of northern shrimp, Pandalus borealis, was investigated over the species' range in the North Atlantic, identifying multiple genetically distinct groups. Genetic divergence among sample localities varied among 10 microsatellite loci (range: FST = -0.0002 to 0.0475) with a highly significant average (FST = 0.0149; P < 0.0001). In contrast, little or no genetic differences were observed among temporal replicates from the same localities (FST = 0.0004; P = 0.33). Spatial genetic patterns were compared to geographic distances, patterns of larval drift obtained through oceanographic modelling, and temperature differences, within a multiple linear regression framework. The best-fit model included all three factors and explained approximately 29% of all spatial genetic divergence. However, geographic distance and larval drift alone had only minor effects (2.5-4.7%) on large-scale genetic differentiation patterns, whereas bottom temperature differences explained most (26%). Larval drift was found to promote genetic homogeneity in parts of the study area with strong currents, but appeared ineffective across large temperature gradients. These findings highlight the breakdown of gene flow in a species with a long pelagic larval phase (up to 3 months) and indicate a role for local adaptation to temperature conditions in promoting evolutionary diversification and speciation in the marine environment. PMID:25782085

  10. Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency.

    PubMed

    Mathieu, Julie; Zhou, Wenyu; Xing, Yalan; Sperber, Henrik; Ferreccio, Amy; Agoston, Zsuzsa; Kuppusamy, Kavitha T; Moon, Randall T; Ruohola-Baker, Hannele

    2014-05-01

    Pluripotent stem cells have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism. Here, we show that this shift occurs early during reprogramming of human cells and requires hypoxia-inducible factors (HIFs) in a stage-specific manner. HIF1α and HIF2α are both necessary to initiate this metabolic switch and for the acquisition of pluripotency, and the stabilization of either protein during early phases of reprogramming is sufficient to induce the switch to glycolytic metabolism. In contrast, stabilization of HIF2α during later stages represses reprogramming, partly because of the upregulation of TNF-related apoptosis-inducing ligand (TRAIL). TRAIL inhibits induced pluripotent stem cell (iPSC) generation by repressing apoptotic caspase 3 activity specifically in cells undergoing reprogramming but not human embryonic stem cells (hESCs), and inhibiting TRAIL activity enhances human iPSC generation. These results shed light on the mechanisms underlying the metabolic shifts associated with the acquisition of a pluripotent identity during reprogramming. PMID:24656769

  11. The Transcription Factor NURR1 Exerts Concentration-Dependent Effects on Target Genes Mediating Distinct Biological Processes

    PubMed Central

    Johnson, Magen M.; Michelhaugh, Sharon K.; Bouhamdan, Mohamad; Schmidt, Carl J.; Bannon, Michael J.

    2011-01-01

    The transcription factor NURR1 plays a pivotal role in the development and maintenance of neurotransmitter phenotype in midbrain dopamine neurons. Conversely, decreased NURR1 expression is associated with a number of dopamine-related CNS disorders, including Parkinson’s disease and drug addiction. In order to better understand the nature of NURR1-responsive genes and their potential roles in dopamine neuron differentiation and survival, we used a human neural cellular background (SK-N-AS cells) in which to generate a number of stable clonal lines with graded NURR1 gene expression that approximated that seen in DA cell-rich human substantia nigra. Gene expression profiling data from these NURR1-expressing clonal lines were validated by quantitative RT-PCR and subjected to bioinformatic analyses. The present study identified a large number of NURR1-responsive genes and demonstrated the potential importance of concentration-dependent NURR1 effects in the differential regulation of distinct NURR1 target genes and biological pathways. These data support the promise of NURR1-based CNS therapeutics for the neuroprotection and/or functional restoration of DA neurons. PMID:22194714

  12. Paralogs of Atlantic salmon myoblast determination factor genes are distinctly regulated in proliferating and differentiating myogenic cells.

    PubMed

    Bower, Neil I; Johnston, Ian A

    2010-06-01

    The mRNA expression of myogenic regulatory factors, including myoD1 (myoblast determination factor) gene paralogs, and their regulation by amino acids and insulin-like growth factors were investigated in primary cell cultures isolated from fast myotomal muscle of Atlantic salmon (Salmo salar). The cell cycle and S phase were determined as 28.1 and 13.3 h, respectively, at 18 degrees C. Expression of myoD1b and myoD1c peaked at 8 days of culture in the initial proliferation phase and then declined more than sixfold as cells differentiated and was correlated with PCNA (proliferating cell nuclear antigen) expression (R = 0.88, P < 0.0001; R = 0.70, P < 0.0001). In contrast, myoD1a transcripts increased from 2 to 8 days and remained at elevated levels as myotubes were formed. mRNA levels of myoD1c were, on average, 3.1- and 5.7-fold higher than myoD1a and myoD1b, respectively. Depriving cells of amino acids and serum led to a rapid increase in pax7 and a decrease in myoD1c and PCNA expression, indicating a transition to a quiescent state. In contrast, amino acid replacement in starved cells produced significant increases in myoD1c (at 6 h), PCNA (at 12 h), and myoD1b (at 24 h) and decreases in pax7 expression as cells entered the cell cycle. Our results are consistent with temporally distinct patterns of myoD1c and myoD1b expression at the G(1) and S/G(2) phases of the cell cycle. Treatment of starved cells with insulin-like growth factor I or II did not alter expression of the myoD paralogs. It was concluded that, in vitro, amino acids alone are sufficient to stimulate expression of genes regulating myogenesis in myoblasts involving autocrine/paracrine pathways. The differential responses of myoD paralogs during myotube maturation and amino acid treatments suggest that myoD1b and myoD1c are primarily expressed in proliferating cells and myoD1a in differentiating cells, providing evidence for their subfunctionalization following whole genome and local duplications in

  13. Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF)

    PubMed Central

    Yoshimura, Kimihiro; Kitagawa, Hirochika; Fujiki, Ryoji; Tanabe, Masahiko; Takezawa, Shinichiro; Takada, Ichiro; Yamaoka, Ikuko; Yonezawa, Masayoshi; Kondo, Takeshi; Furutani, Yoshiyuki; Yagi, Hisato; Yoshinaga, Shin; Masuda, Takeyoshi; Fukuda, Toru; Yamamoto, Yoko; Ebihara, Kanae; Li, Dean Y.; Matsuoka, Rumiko; Takeuchi, Jun K.; Matsumoto, Takahiro; Kato, Shigeaki

    2009-01-01

    A number of nuclear complexes modify chromatin structure and operate as functional units. However, the in vivo role of each component within the complexes is not known. ATP-dependent chromatin remodeling complexes form several types of protein complexes, which reorganize chromatin structure cooperatively with histone modifiers. Williams syndrome transcription factor (WSTF) was biochemically identified as a major subunit, along with 2 distinct complexes: WINAC, a SWI/SNF-type complex, and WICH, an ISWI-type complex. Here, WSTF−/− mice were generated to investigate its function in chromatin remodeling in vivo. Loss of WSTF expression resulted in neonatal lethality, and all WSTF−/− neonates and ≈10% of WSTF+/− neonates suffered cardiovascular abnormalities resembling those found in autosomal-dominant Williams syndrome patients. Developmental analysis of WSTF−/− embryos revealed that Gja5 gene regulation is aberrant from E9.5, conceivably because of inappropriate chromatin reorganization around the promoter regions where essential cardiac transcription factors are recruited. In vitro analysis in WSTF−/− mouse embryonic fibroblast (MEF) cells also showed impaired transactivation functions of cardiac transcription activators on the Gja5 promoter, but the effects were reversed by overexpression of WINAC components. Likewise in WSTF−/− MEF cells, recruitment of Snf2h, an ISWI ATPase, to PCNA and cell survival after DNA damage were both defective, but were ameliorated by overexpression of WICH components. Thus, the present study provides evidence that WSTF is shared and is a functionally indispensable subunit of the WICH complex for DNA repair and the WINAC complex for transcriptional control. PMID:19470456

  14. Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.

    PubMed

    Rahimi, Rod A; Andrianifahanana, Mahefatiana; Wilkes, Mark C; Edens, Maryanne; Kottom, Theodore J; Blenis, John; Leof, Edward B

    2009-01-01

    Transforming growth factor-beta (TGF-beta) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-beta signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-beta has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-beta signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-beta. We show that TGF-beta activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2-dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-beta-mediated anchorage-independent growth without affecting TGF-beta transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-beta action. mTORC2 promotes TGF-beta-induced morphologic transformation and is required for TGF-beta-induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-beta-mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-beta and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia. PMID:19117990

  15. 50 CFR 20.33 - Possession limit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Possession limit. 20.33 Section 20.33... PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.33 Possession limit. No person shall possess more migratory game birds taken in the United States than the possession limit or the...

  16. Neonatal rearing conditions distinctly shape locus coeruleus neuronal activity, dendritic arborization, and sensitivity to corticotrophin-releasing factor

    PubMed Central

    Swinny, Jerome D.; O'Farrell, Eimear; Bingham, Brian C.; Piel, David A.; Valentino, Rita J.; Beck, Sheryl G.

    2010-01-01

    Early life events influence vulnerability to psychiatric illness. This has been modelled in rats and it has been demonstrated that different durations of maternal separation shape adult endocrine and behavioural stress reactivity. One system through which maternal separation may act is the locus coeruleus (LC)–norepinephrine system that regulates emotional arousal. Here we demonstrate that different durations of maternal separation have distinct effects on LC physiology and dendritic morphology. Rat pups were separated from the dam for 15 min/d (HMS-15) or 180 min/d (HMS-180) from post-natal days 2–14. Others were either undisturbed (HMS-0) or were vendor-purchased controls. LC characteristics were compared at age 22–35 d using whole-cell recordings in vitro. Cells were filled with biocytin for morphological analysis. LC neurons of HMS-180 rats were tonically activated compared to HMS-15 and control rats, with firing rates that were 2-fold higher than these groups. Corticotrophin-releasing factor (CRF) application did not further activate LC neurons of HMS-180 rats but increased LC firing rate in HMS-0 and control rats. LC neurons of HMS-15 rats were resistant to excitation by CRF. Maternal separation also affected LC dendritic morphology. LC dendrites of HMS-15 rats exhibited less branching and decreased total dendritic length, an effect that could decrease the probability of contacting limbic afferents that terminate in the pericoerulear region. This effect may provide a structural basis for an attenuated magnitude of emotional arousal. Together, these results demonstrate long-term consequences of early life events on the LC–norepinephrine system that may shape adult behaviour. PMID:19653930

  17. HTLV-1 bZIP Factor RNA and Protein Impart Distinct Functions on T-cell Proliferation and Survival.

    PubMed

    Mitobe, Yuichi; Yasunaga, Jun-ichirou; Furuta, Rie; Matsuoka, Masao

    2015-10-01

    Infection of T cells with human T-cell leukemia virus type-1 (HTLV-1) induces clonal proliferation and is closely associated with the onset of adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. Although Tax expression is frequently suppressed in HTLV-1-infected cells, the accessory gene, HTLV-1 bZIP factor (HBZ), is continuously expressed and has been implicated in HTLV-1 pathogenesis. Here, we report that transduction of mouse T cells with specific mutants of HBZ that distinguish between its RNA and protein activity results in differential effects on T-cell proliferation and survival. HBZ RNA increased cell number by attenuating apoptosis, whereas HBZ protein induced apoptosis. However, both HBZ RNA and protein promoted S-phase entry of T cells. We further identified that the first 50 bp of the HBZ coding sequence are required for RNA-mediated cell survival. Transcriptional profiling of T cells expressing wild-type HBZ, RNA, or protein revealed that HBZ RNA is associated with genes involved in cell cycle, proliferation, and survival, while HBZ protein is more closely related to immunological properties of T cells. Specifically, HBZ RNA enhances the promoter activity of survivin, an inhibitor of apoptosis, to upregulate its expression. Inhibition of survivin using YM155 resulted in impaired proliferation of several ATL cell lines as well as a T-cell line expressing HBZ RNA. The distinct functions of HBZ RNA and protein may have several implications for the development of strategies to control the proliferation and survival mechanisms associated with HTLV-1 infection and ATL. PMID:26383166

  18. Real-time monitoring of inflammation status in 3T3-L1 adipocytes possessing a secretory Gaussia luciferase gene under the control of nuclear factor-kappa B response element

    SciTech Connect

    Nagasaki, Haruka; Yoshimura, Takeshi; Aoki, Naohito

    2012-04-13

    Highlights: Black-Right-Pointing-Pointer Inflammation status in adipocytes can be monitored by the new assay system. Black-Right-Pointing-Pointer Only an aliquot of conditioned medium is required without cell lysis. Black-Right-Pointing-Pointer Inflammation-attenuating compounds can be screened more conveniently. -- Abstract: We have established 3T3-L1 cells possessing a secretory Gaussia luciferase (GLuc) gene under the control of nuclear factor-kappa B (NF-{kappa}B) response element. The 3T3-L1 cells named 3T3-L1-NF-{kappa}B-RE-GLuc could differentiate into adipocyte as comparably as parental 3T3-L1 cells. Inflammatory cytokines such as tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-1{beta} induced GLuc secretion of 3T3-L1-NF-{kappa}B-RE-GLuc adipocytes in a concentration- and time-dependent manner. GLuc secretion of 3T3-L1-NF-{kappa}B-RE-GLuc adipocytes was also induced when cultured with RAW264.7 macrophages and was dramatically enhanced by lipopolysaccharide (LPS)-activated macrophages. An NF-{kappa}B activation inhibitor BAY-11-7085 and an antioxidant N-acetyl cysteine significantly suppressed GLuc secretion induced by macrophages. Finally, we found that rosemary-derived carnosic acid strongly suppressed GLuc secretion induced by macrophages and on the contrary up-regulated adiponectin secretion. Collectively, by using 3T3-L1-NF-{kappa}B-RE-GLuc adipocytes, inflammation status can be monitored in real time and inflammation-attenuating compounds can be screened more conveniently.

  19. Involuntary mass spirit possession among the Miskitu.

    PubMed

    Wedel, Johan

    2012-01-01

    This paper seeks to understand the outbreaks and the development of grisi siknis, a form of mass spirit possession among the Miskitu of north-eastern Nicaragua. Earlier documented outbreaks typically involved a few adolescents, however, in recent years, violent large-scale epidemics have taken place, involving many people of all ages. This has coincided with recent developments in Miskitu society marked by conflicts, contradictions and tense social relations. The anthropological field technique of participant-observation was used. The research took place during 11 months from 2005 to 2008 in the port town of Puerto Cabezas. A total of 38 informants were interviewed. Group discussions, narratives and informal and semi-structured interviews were carried out, as well as participation in healing rituals. The paper shows that socio-economic, cultural, personal as well as environmental factors all contribute to outbreaks of grisi siknis. The affliction has previously been considered a 'culture-bound syndrome' only occurring among the Miskitu. However, when viewed in a more contemporary context and cross-cultural perspective, grisi siknis shows similarities with other forms of involuntary mass spirit possession, particularly in the ways it is manifested, experienced and appears to be spreading. The paper argues that the phenomenon should no longer be considered a 'culture-bound condition' but in fact a Miskitu version of involuntary mass spirit possession. Further research that seeks to understand other forms of involuntary mass spirit possession should emphasize the social, personal and environmental context as well as cross-cultural comparisons in order to encompass fully the role of culture in relation to illness and suffering. PMID:22746214

  20. 50 CFR 648.125 - Possession limit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 8 2010-10-01 2010-10-01 false Possession limit. 648.125 Section 648.125... § 648.125 Possession limit. (a) No person shall possess more than 10 scup in, or harvested from, the EEZ... moratorium permit are subject to this possession limit. The owner, operator, and crew of a charter or...

  1. 50 CFR 648.145 - Possession limit.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 8 2010-10-01 2010-10-01 false Possession limit. 648.145 Section 648.145... Fishery § 648.145 Possession limit. (a) No person shall possess more than 25 black sea bass, in, or... that is not eligible for a black sea bass moratorium permit are subject to this possession limit....

  2. Microfluidic assay of hemophilic blood clotting: Distinct deficits in platelet and fibrin deposition at low factor levels

    PubMed Central

    Colace, T.; Fogarty, Patrick F.; Panckeri, Karen A.; Li, Ruizhi; Diamond, S.L.

    2014-01-01

    Background Coagulation factor deficiencies create a range of bleeding phenotypes. Microfluidic devices offer controlled hemodynamics and defined procoagulant triggers for measurement of clotting under flow. Objectives We tested a flow assay of contact pathway-triggered clotting to quantify platelet and fibrin deposition distal of dysfunctional thrombin production. Microfluidic metrics were then compared with PTT or % factor activity assays. Methods Whole blood (WB) treated with low level corn trypsin inhibitor (4 µg/ml) from 9 healthy donors and 27 patients [deficient in: Factor VIII (19 patients); IX (1); XI (1); VWF (6)] was perfused over fibrillar collagen at wall shear rate=100 s−1. Results Using healthy WB, platelets deposited within 30 sec, while fibrin appeared within 6 min. Compared to healthy controls, WB from patients displayed a 50% reduction in platelet deposition only at <1 % factor activity. In contrast, striking defects in fibrin deposition occurred for patients with <13% factor activity (or PTT >40 sec). Full occlusion of the 60-micron high channel was completely absent over the 15 min test in patients with <1% factor activity, while an intermediate defect was present in patients with >1% factor. Conclusion Spontaneous bleeding in patients with < 1% factor activity may be linked to deficits in both platelet and fibrin deposition, a risk known to be mitigated when factor levels are raised to >1 % activity (PTT of ~40–60 sec), a level that does not necessarily rescue fibrin formation under flow. PMID:24261634

  3. The Basic Helix-Loop-Helix Transcription Factor PIF5 Acts on Ethylene Biosynthesis and Phytochrome Signaling by Distinct Mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    HYTOCHROME-INTERACTING FACTOR5 (PIF5), a basic helix-loop-helix transcription factor, interacts specifically with the photoactivated form of phytochrome B (phyB). Here, we report that dark-grown Arabidopsis thaliana seedlings overexpressing PIF5 (PIF5-OX) exhibit exaggerated apical hooks and short h...

  4. 50 CFR 648.204 - Possession restrictions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Atlantic Herring Fishery § 648.204 Possession restrictions. (a) A vessel must be issued and possess a valid limited access herring permit to fish for, possess, or land more than 6,600 lb (3 mt) of Atlantic herring from any herring management area in the EEZ, provided that the area has not been closed due to...

  5. 50 CFR 648.204 - Possession restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Atlantic Herring Fishery § 648.204 Possession restrictions. (a) A vessel must be issued and possess a valid limited access herring permit to fish for, possess, or land more than 6,600 lb (3 mt) of Atlantic herring from any herring management area in the EEZ, provided that the area has not been closed due to...

  6. 50 CFR 648.204 - Possession restrictions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Atlantic Herring Fishery § 648.204 Possession restrictions. (a) A vessel must be issued and possess a valid limited access herring permit to fish for, possess, or land more than 6,600 lb (3 mt) of Atlantic herring from any herring management area in the EEZ, provided that the area has not been closed due to...

  7. 50 CFR 648.204 - Possession restrictions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Atlantic Herring Fishery § 648.204 Possession restrictions. (a) A vessel must be issued and possess a valid limited access herring permit to fish for, possess, or land more than 6,600 lb (3 mt) of Atlantic herring from any herring management area in the EEZ, provided that the area has not been closed due to...

  8. Distinctive Expression of Bcl-2 Factors in Regulatory T Cells Determines a Pharmacological Target to Induce Immunological Tolerance

    PubMed Central

    Gabriel, Sarah Sharon; Bon, Nina; Chen, Jin; Wekerle, Thomas; Bushell, Andrew; Fehr, Thomas; Cippà, Pietro Ernesto

    2016-01-01

    Distinctive molecular characteristics of functionally diverse lymphocyte populations may represent novel pharmacological targets for immunotherapy. The intrinsic apoptosis pathway is differently regulated among conventional and regulatory T cells (Tregs). Targeted pharmacological modulation of this pathway with a small molecule Bcl-2/Bcl-xL inhibitor (ABT-737) caused a selective depletion of effector T cells and a relative enrichment of Tregs in vivo. Treatment with ABT-737 resulted in a tolerogenic milieu, which was exploited to alleviate graft-versus-host disease, to prevent allograft rejection in a stringent fully MHC-mismatched skin transplantation model and to induce immunological tolerance in combination with bone marrow transplantation. This concept has the potential to find various applications for immunotherapy, since it allows pharmacologic exploitation of the immunomodulatory properties of Tregs without the need for cell manipulation ex vivo. PMID:26973650

  9. DNA affinity labeling of adenovirus type 2 upstream promoter sequence-binding factors identifies two distinct proteins

    SciTech Connect

    Safer, B.; Cohen, R.B.; Garfinkel, S.; Thompson, J.A.

    1988-01-01

    A rapid affinity labeling procedure with enhanced specificity was developed to identify DNA-binding proteins. /sup 32/P was first introduced at unique phosphodiester bonds within the DNA recognition sequence. UV light-dependent cross-linking of pyrimidines to amino acid residues in direct contact at the binding site, followed by micrococcal nuclease digestion, resulted in the transfer of /sup 32/P to only those specific protein(s) which recognized the binding sequence. This method was applied to the detection and characterization of proteins that bound to the upstream promoter sequence (-50 to -66) of the human adenovirus type 2 major late promoter. We detected two distinct proteins with molecular weights of 45,000 and 116,000 that interacted with this promoter element. The two proteins differed significantly in their chromatographic and cross-linking behaviors.

  10. Social appearance anxiety, perfectionism, and fear of negative evaluation: distinct or shared risk factors for social anxiety and eating disorders?

    PubMed

    Levinson, Cheri A; Rodebaugh, Thomas L; White, Emily K; Menatti, Andrew R; Weeks, Justin W; Iacovino, Juliette M; Warren, Cortney S

    2013-08-01

    Social anxiety and eating disorders are highly comorbid. Social appearance anxiety (i.e., fear of negative evaluation of one's appearance), general fear of negative evaluation, and perfectionism have each been proposed as risk factors for both social anxiety disorder and the eating disorders. However, no research to date has examined all three factors simultaneously. Using structural equation modeling in two diverse samples (N=236; N=136) we tested a model in which each of these risk factors were uniquely associated with social anxiety and eating disorder symptoms. We found support for social appearance anxiety as a shared risk factor between social anxiety and eating disorder symptoms, whereas fear of negative evaluation was a risk factor only for social anxiety symptoms. Despite significant zero-order relationships, two facets of perfectionism (high standards and maladaptive perfectionism) did not emerge as a risk factor for either disorder when all constructs were considered. These results were maintained when gender, body mass index, trait negative affect, and depression were included in the model. It is possible that treating negative appearance evaluation fears may reduce both eating disorder and social anxiety symptoms. PMID:23583741

  11. Social appearance anxiety, perfectionism, and fear of negative evaluation: Distinct or shared risk factors for social anxiety and eating disorders?

    PubMed Central

    Levinson, Cheri A.; Rodebaugh, Thomas L.; White, Emily K.; Menatti, Andrew; Weeks, Justin W.; Iacovino, Juliette M.; Warren, Cortney S.

    2013-01-01

    Social anxiety and eating disorders are highly comorbid. Social appearance anxiety (i.e., fear of negative evaluation of one's appearance), general fear of negative evaluation, and perfectionism have each been proposed as risk factors for both social anxiety disorder and the eating disorders. However, no research to date has examined all three factors simultaneously. Using structural equation modeling in two diverse samples (N = 236; N = 136) we tested a model in which each of these risk factors were uniquely associated with social anxiety and eating disorder symptoms. We found support for social appearance anxiety as a shared risk factor between social anxiety and eating disorder symptoms, whereas fear of negative evaluation was a risk factor only for social anxiety symptoms. Despite significant zero-order relationships, two facets of perfectionism (high standards and maladaptive perfectionism) did not emerge as a risk factor for either disorder when all constructs were considered. These results were maintained when gender, body mass index, trait negative affect, and depression were included in the model. It is possible that treating negative appearance evaluation fears may reduce both eating disorder and social anxiety symptoms. PMID:23583741

  12. Determination of ligand-binding specificity by alternative splicing: Two distinct growth factor receptors encoded by a single gene

    SciTech Connect

    Miki, T.; Bottaro, D.P.; Fleming, T.P.; Smith, C.L.; Chan, A.M.L.; Aaronson, S.A. ); Burgess, W.H. )

    1992-01-01

    Expression cDNA cloning and structural analysis of the human keratinocyte growth factor receptor (KGFR) revealed identity with one of the fibroblast growth factor (FGF) receptors encoded by the bek gene (FGFR-2), except for a divergent stretch of 49 amino acids in their extracellular domains. Binding assays demonstrated that the KGFR was a high-affinity receptor for both KGF and acidic FGF, while FGFR-2 showed high affinity for basic and acidic FGF but no detectable binding by KGF. Genomic analysis of the bek gene revealed two alternative exons responsible for the region of divergence between the two receptors. The KGFR transcript was specific to epithelial cells, and it appeared to be differentially regulated with respect to the alternative FGFR-2 transcript. Thus, two growth factor receptors with different ligand-binding specificities and expression patterns are encoded by alternative transcripts of the same gene.

  13. Public and Private School Distinction, Regional Development Differences, and Other Factors Influencing the Success of Primary School Students in Turkey

    ERIC Educational Resources Information Center

    Sulku, Seher Nur; Abdioglu, Zehra

    2015-01-01

    This study investigates the factors influencing the success of students in primary schools in Turkey. TIMSS 2011 data for Turkey, measuring the success of eighth-grade students in the field of mathematics, were used in an econometric analysis, performed using classical linear regression models. Two hundred thirty-nine schools participated in the…

  14. A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

    NASA Astrophysics Data System (ADS)

    Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

    1995-10-01

    Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

  15. Epidemic Population Structure of Pseudomonas aeruginosa: Evidence for a Clone That Is Pathogenic to the Eye and That Has a Distinct Combination of Virulence Factors

    PubMed Central

    Lomholt, Jeanet A.; Poulsen, Knud; Kilian, Mogens

    2001-01-01

    The genetic structure of a population of Pseudomonas aeruginosa, isolated from patients with keratitis, endophthalmitis, and contact lens-associated red eye, contact lens storage cases, urine, ear, blood, lungs, wounds, feces, and the environment was determined by multilocus enzyme electrophoresis. The presence and characteristics of virulence factors were determined by restriction fragment length polymorphism analysis with DNA probes for lasA, lasB, aprA, exoS, exoT, exoU, and ctx and by zymography of staphylolysin, elastase, and alkaline protease. These analyses revealed an epidemic population structure of P. aeruginosa, characterized by frequent recombination in which a particular successful clone may increase, predominate for a time, and then disasappear as a result of recombination. Epidemic clones were found among isolates from patients with keratitis. They were characterized by high activity of a hitherto-unrecognized size variant of elastase, high alkaline protease activity, and possession of the exoU gene encoding the cytotoxic exoenzyme U. These virulence determinants are not exclusive traits in strains causing keratitis, as strains with other properties may cause keratitis in the presence of predisposing conditions. There were no uniform patterns of characteristics of isolates from other types of infection; however, all strains from urinary tract infections possessed the exoS gene, all strains from environment and feces and the major part of keratitis and wound isolates exhibited high elastase and alkaline protease activity, and all strains from feces showed high staphylolysin activity, indicating that these virulence factors may be important in the pathogenesis of these infectious diseases. PMID:11553572

  16. Two distinct factors bind to the rabbit uteroglobin TATA-box region and are required for efficient transcription.

    PubMed Central

    Klug, J; Knapp, S; Castro, I; Beato, M

    1994-01-01

    The rabbit uteroglobin gene is expressed in a variety of epithelial cell types like the lung Clara cells and the glandular and luminal epithelial cells of the endometrium. Expression in Clara cells is on a high constitutive level, whereas expression in the rabbit endometrium is under tight hormonal control. One important element of the rabbit uteroglobin gene mediating its efficient transcription in two epithelial cell lines from human endometrium (Ishikawa) and lung (NCI-H441) is its noncanonical TATA box (TACA). Here, we show that two factors (TATA core factor [TCF] and TATA palindrome factor [TPF]) different from the TATA-box binding protein bind to the DNA major groove at two adjacent sites within the uteroglobin TATA-box region and that one of them (TCF) is specifically expressed in cell lines derived from uteroglobin-expressing tissues. The binding sites for TCF and TPF, respectively, are both required for efficient transcription in Ishikawa and NCI-H441 cells. Mutation of the TACA box, which we show is a poor TATA box in functional terms, to a canonical TATA motif does not affect TCF and TPF binding. Therefore, we suggest that the function of the unusual cytosine could be to reduce rabbit uteroglobin expression in cells lacking TCF and that the interaction of TATA-box binding protein with the weak TACA site is facilitated in TCF- and TPF-positive cells. Images PMID:8065353

  17. MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages

    PubMed Central

    2014-01-01

    Background Serum response factor (SRF) is a widely expressed transcription factor involved in multiple regulatory programs. It is believed that SRF can toggle between disparate programs of gene expression through association with different cofactors. However, the direct evidence as to how these factors function on a genome-wide level is still lacking. Results In the present study, I explored the functions of SRF and its representative cofactors, megakaryoblastic leukemia 1/2 (MKL1/2) and ETS-domain protein 4 (ELK4), during fungal infection challenge in macrophages. The knockdown study, combined with gene expression array analysis, revealed that MKL1/2 regulated SRF-dependent genes were related to actin cytoskeleton organization, while ELK4 regulated SRF-dependent genes were related to external stimulus responses. Subsequent chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) suggested that many of these regulations were mediated directly in cis. Conclusions I conclude that SRF utilizes MKL1/2 to fulfill steady state cellular functions, including cytoskeletal organization, and utilizes ELK4 to facilitate acute responses to external infection. Together, these findings indicate that SRF, along with its two cofactors, are important players in both cellular homeostasis and stress responses in macrophages. PMID:24758171

  18. Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation

    PubMed Central

    Fuda, Nicholas J.; Mahat, Dig B.; Core, Leighton J.; Guertin, Michael J.

    2016-01-01

    The coordinated regulation of gene expression at the transcriptional level is fundamental to development and homeostasis. Inducible systems are invaluable when studying transcription because the regulatory process can be triggered instantaneously, allowing the tracking of ordered mechanistic events. Here, we use precision run-on sequencing (PRO-seq) to examine the genome-wide heat shock (HS) response in Drosophila and the function of two key transcription factors on the immediate transcription activation or repression of all genes regulated by HS. We identify the primary HS response genes and the rate-limiting steps in the transcription cycle that GAGA-associated factor (GAF) and HS factor (HSF) regulate. We demonstrate that GAF acts upstream of promoter-proximally paused RNA polymerase II (Pol II) formation (likely at the step of chromatin opening) and that GAF-facilitated Pol II pausing is critical for HS activation. In contrast, HSF is dispensable for establishing or maintaining Pol II pausing but is critical for the release of paused Pol II into the gene body at a subset of highly activated genes. Additionally, HSF has no detectable role in the rapid HS repression of thousands of genes. PMID:27492368

  19. Nuclear mutations that block group II RNA splicing in maize chloroplasts reveal several intron classes with distinct requirements for splicing factors.

    PubMed Central

    Jenkins, B D; Kulhanek, D J; Barkan, A

    1997-01-01

    To elucidate mechanisms that regulate chloroplast RNA splicing in multicellular plants, we sought nuclear mutations in maize that result in chloroplast splicing defects. Evidence is presented for two nuclear genes whose function is required for the splicing of group II introns in maize chloroplasts. A mutation in the crs1 (for chloroplast RNA splicing 1) gene blocks the splicing of only the atpF intron, whereas a mutation in the crs2 gene blocks the splicing of many chloroplast introns. In addition, a correlation was observed between the absence of plastid ribosomes and the failure to splice several chloroplast introns. Our results suggest that a chloroplast-encoded factor and a nuclear-encoded factor whose activity requires crs2 function facilitate the splicing of distinct sets of group II introns. These two genetically defined intron sets also differ with regard to intron structure: one set consists of only subgroup IIA introns and the other of only subgroup IIB introns. Therefore, it is likely that distinct splicing factors recognize subgroup-specific features of intron structure or facilitate subgroup-specific aspects of the splicing reaction. Of the 12 pre-mRNA introns in the maize chloroplast genome, only one is normally spliced in both crs2 mutants and in mutants lacking plastid ribosomes, indicating that few, if any, of the group II introns in the chloroplast genome undergo autocatalytic splicing in vivo. PMID:9090875

  20. The Lipid-Modifying Multiple Peptide Resistance Factor Is an Oligomer Consisting of Distinct Interacting Synthase and Flippase Subunits

    PubMed Central

    Kuhn, Sebastian; Slavetinsky, Christoph J.; Krismer, Bernhard; Heilbronner, Simon; Gekeler, Cordula; Kraus, Dirk; Wagner, Samuel; Peschel, Andreas

    2015-01-01

    -positive, Gram-negative, and even archaeal commensals or pathogens and confers resistance to CAMPs by modifying anionic phospholipids with amino acids, thereby compromising the membrane interaction of CAMPs. Here we describe how MprF does not only modify phospholipids but uses an additional, distinct domain for translocating the resulting lysinylated phospholipids to the outer leaflet of the membrane. We reveal critical details for the structure and function of MprF, the first dedicated prokaryotic phospholipid flippase, which may pave the way for targeting MprF with new antimicrobials that would not kill bacteria but sensitize them to antibiotics and innate host defense molecules. PMID:25626904

  1. Tumor Necrosis Factor Disrupts Claudin-5 Endothelial Tight Junction Barriers in Two Distinct NF-κB-Dependent Phases

    PubMed Central

    Clark, Paul R.; Kim, Richard K.; Pober, Jordan S.; Kluger, Martin S.

    2015-01-01

    Capillary leak in severe sepsis involves disruption of endothelial cell tight junctions. We modeled this process by TNF treatment of cultured human dermal microvascular endothelial cell (HDMEC) monolayers, which unlike human umbilical vein endothelial cells form claudin-5-dependent tight junctions and a high-resistance permeability barrier. Continuous monitoring with electrical cell-substrate impedance sensing revealed that TNF disrupts tight junction-dependent HDMEC barriers in discrete steps: an ~5% increase in transendothelial electrical resistance over 40 minutes; a decrease to ~10% below basal levels over 2 hours (phase 1 leak); an interphase plateau of 1 hour; and a major fall in transendothelial electrical resistance to < 70% of basal levels by 8–10 hours (phase 2 leak), with EC50 values of TNF for phase 1 and 2 leak of ~30 and ~150 pg/ml, respectively. TNF leak is reversible and independent of cell death. Leak correlates with disruption of continuous claudin-5 immunofluorescence staining, myosin light chain phosphorylation and loss of claudin-5 co-localization with cortical actin. All these responses require NF-κB signaling, shown by inhibition with Bay 11 or overexpression of IκB super-repressor, and are blocked by H-1152 or Y-27632, selective inhibitors of Rho-associated kinase that do not block other NF-κB-dependent responses. siRNA combined knockdown of Rho-associated kinase-1 and -2 also prevents myosin light chain phosphorylation, loss of claudin-5/actin co-localization, claudin-5 reorganization and reduces phase 1 leak. However, unlike H-1152 and Y-27632, combined Rho-associated kinase-1/2 siRNA knockdown does not reduce the magnitude of phase 2 leak, suggesting that H-1152 and Y-27632 have targets beyond Rho-associated kinases that regulate endothelial barrier function. We conclude that TNF disrupts TJs in HDMECs in two distinct NF-κB-dependent steps, the first involving Rho-associated kinase and the second likely to involve an as yet

  2. A genome-wide RNAi screen identifies factors required for distinct stages of C. elegans piRNA biogenesis

    PubMed Central

    Goh, Wee-Siong Sho; Seah, Jun Wen Eugene; Harrison, Emily J.; Chen, Caifu; Hammell, Christopher M.; Hannon, Gregory J.

    2014-01-01

    In animals, piRNAs and their associated Piwi proteins guard germ cell genomes against mobile genetic elements via an RNAi-like mechanism. In Caenorhabditis elegans, 21U-RNAs comprise the piRNA class, and these collaborate with 22G RNAs via unclear mechanisms to discriminate self from nonself and selectively and heritably silence the latter. Recent work indicates that 21U-RNAs are post-transcriptional processing products of individual transcription units that produce ∼26-nucleotide capped precursors. However, nothing is known of how the expression of precursors is controlled or how primary transcripts give rise to mature small RNAs. We conducted a genome-wide RNAi screen to identify components of the 21U biogenesis machinery. Screening by direct, quantitative PCR (qPCR)-based measurements of mature 21U-RNA levels, we identified 22 genes important for 21U-RNA production, termed TOFUs (Twenty-One-u Fouled Ups). We also identified seven genes that normally repress 21U production. By measuring mature 21U-RNA and precursor levels for the seven strongest hits from the screen, we assigned factors to discrete stages of 21U-RNA production. Our work identifies for the first time factors separately required for the transcription of 21U precursors and the processing of these precursors into mature 21U-RNAs, thereby providing a resource for studying the biogenesis of this important small RNA class. PMID:24696458

  3. Distinct Roles of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interferon Regulatory Factors in Inflammatory Response and Cancer

    PubMed Central

    Baresova, Petra; Pitha, Paula M.

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular interferon regulatory factors (IRFs)—viral IRF1 (vIRF1) to vIRF4—and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity. PMID:23785197

  4. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

    PubMed Central

    Kristjansdottir, G; Sandling, J K; Bonetti, A; Roos, I M; Milani, L; Wang, C; Gustafsdottir, S M; Sigurdsson, S; Lundmark, A; Tienari, P J; Koivisto, K; Elovaara, I; Pirttilä, T; Reunanen, M; Peltonen, L; Saarela, J; Hillert, J; Olsson, T; Landegren, U; Alcina, A; Fernández, O; Leyva, L; Guerrero, M; Lucas, M; Izquierdo, G; Matesanz, F; Syvänen, A-C

    2008-01-01

    Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case–control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. Conclusion: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases. PMID:18285424

  5. Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model.

    PubMed

    Molina-Portela, Maria Pilar; Samanovic, Marie; Raper, Jayne

    2008-08-01

    Humans express a unique subset of high-density lipoproteins (HDLs) called trypanosome lytic factors (TLFs) that kill many Trypanosoma parasite species. The proteins apolipoprotein (apo) A-I, apoL-I, and haptoglobin-related protein, which are involved in TLF structure and function, were expressed through the introduction of transgenes in mice to explore their physiological roles in vivo. Transgenic expression of human apolipoprotein L-I alone conferred trypanolytic activity in vivo. Coexpression of human apolipoprotein A-I and haptoglobin-related protein (Hpr) had an effect on the integration of apolipoprotein L-I into HDL, and both proteins were required to increase the specific activity of TLF, which was measurable in vitro. Unexpectedly, truncated apolipoprotein L-I devoid of the serum resistance gene interacting domain, which was previously shown to kill human infective trypanosomes, was not trypanolytic in transgenic mice despite being coexpressed with human apolipoprotein A-I and Hpr and incorporated into HDLs. We conclude that all three human apolipoproteins act cooperatively to achieve maximal killing capacity and that truncated apolipoprotein L-I does not function in transgenic animals. PMID:18606856

  6. Adjacent proline residues in the inhibitory domain of the Oct-2 transcription factor play distinct functional roles.

    PubMed Central

    Liu, Y Z; Lee, I K; Locke, I; Dawson, S J; Latchman, D S

    1998-01-01

    A 40 amino acid region of Oct-2 from amino acids 142 to 181 functions as an active repressor domain capable of inhibiting both basal activity and activation of promoters containing a TATA box, but not of those that contain an initiator element. Based on our observation that the equivalent region of the closely related Oct-1 factor does not act as an inhibitory domain, we have mutated specific residues in the Oct-2 domain in an attempt to probe their importance in repressor domain function. Although mutations of several residues have no or minimal effect, mutation of proline 175 to arginine abolishes the ability to inhibit both basal and activated transcription. In contrast, mutation of proline 174 to arginine confers upon the domain the ability to repress activation of an initiator-containing promoter by acidic activation domains, and also suppresses the effect of the proline 175 mutation. Hence, adjacent proline residues play key roles in the functioning of the inhibitory domain and in limiting its specificity to TATA-box-containing promoters. PMID:9580701

  7. Tissue-specific expression of insulin-like growth factor II mRNAs with distinct 5' untranslated regions

    SciTech Connect

    Irminger, J.C.; Rosen, K.M.; Humble, R.E.; Villa-Komaroff, L.

    1987-09-01

    The authors have used RNA from human hypothalamus as template for the production of cDNAs encoding insulin-like growth factor II (IGF-II). The prohormone coding sequence of brain IGF-II RNA is identical to that found in liver; however, the 5' untranslated sequence of the brain cDNA has no homology to the 5' untranslated sequence of the previously reported liver cDNAs. By using hybridization to specific probes as well as a method based on the properties of RNase H, they found that the human IGF-II gene has at least three exons that encode alternative 5' untranslated regions and that are expressed in a tissue-specific manner. A probe specific to the brain cDNA 5' untranslated region hybridizes to a 6.0-kilobase transcript present in placenta, hypothalamus, adrenal gland, kidney, Wilms tumor, and a pheochromocytoma. The 5' untranslated sequence of the brain cDNA does not hybridize to a 5.3-kilobase transcript found in liver or to a 5.0-kb transcript found in pheochromocytoma. By using RNase H to specifically fragment the IGF-II transcripts into 3' and 5' fragments, they found that the RNAs vary in size due to differences in the 5' end but not the 3' end.

  8. Disassembly activity of actin-depolymerizing factor (ADF) is associated with distinct cellular processes in apicomplexan parasites

    PubMed Central

    Haase, Silvia; Zimmermann, Dennis; Olshina, Maya A.; Wilkinson, Mark; Fisher, Fabio; Tan, Yan Hong; Stewart, Rebecca J.; Tonkin, Christopher J.; Wong, Wilson; Kovar, David R.; Baum, Jake

    2015-01-01

    Proteins of the actin-depolymerizing factor (ADF)/cofilin family have been shown to be crucial for the motility and survival of apicomplexan parasites. However, the mechanisms by which ADF proteins fulfill their function remain poorly understood. In this study, we investigate the comparative activities of ADF proteins from Toxoplasma gondii and Plasmodium falciparum, the human malaria parasite, using a conditional T. gondii ADF-knockout line complemented with ADF variants from either species. We show that P. falciparum ADF1 can fully restore native TgADF activity, demonstrating functional conservation between parasites. Strikingly, mutation of a key basic residue (Lys-72), previously implicated in disassembly in PfADF1, had no detectable phenotypic effect on parasite growth, motility, or development. In contrast, organelle segregation was severely impaired when complementing with a TgADF mutant lacking the corresponding residue (Lys-68). Biochemical analyses of each ADF protein confirmed the reduced ability of lysine mutants to mediate actin depolymerization via filament disassembly although not severing, in contrast to previous reports. These data suggest that actin filament disassembly is essential for apicomplexan parasite development but not for motility, as well as pointing to genus-specific coevolution between ADF proteins and their native actin. PMID:26157165

  9. Disassembly activity of actin-depolymerizing factor (ADF) is associated with distinct cellular processes in apicomplexan parasites.

    PubMed

    Haase, Silvia; Zimmermann, Dennis; Olshina, Maya A; Wilkinson, Mark; Fisher, Fabio; Tan, Yan Hong; Stewart, Rebecca J; Tonkin, Christopher J; Wong, Wilson; Kovar, David R; Baum, Jake

    2015-09-01

    Proteins of the actin-depolymerizing factor (ADF)/cofilin family have been shown to be crucial for the motility and survival of apicomplexan parasites. However, the mechanisms by which ADF proteins fulfill their function remain poorly understood. In this study, we investigate the comparative activities of ADF proteins from Toxoplasma gondii and Plasmodium falciparum, the human malaria parasite, using a conditional T. gondii ADF-knockout line complemented with ADF variants from either species. We show that P. falciparum ADF1 can fully restore native TgADF activity, demonstrating functional conservation between parasites. Strikingly, mutation of a key basic residue (Lys-72), previously implicated in disassembly in PfADF1, had no detectable phenotypic effect on parasite growth, motility, or development. In contrast, organelle segregation was severely impaired when complementing with a TgADF mutant lacking the corresponding residue (Lys-68). Biochemical analyses of each ADF protein confirmed the reduced ability of lysine mutants to mediate actin depolymerization via filament disassembly although not severing, in contrast to previous reports. These data suggest that actin filament disassembly is essential for apicomplexan parasite development but not for motility, as well as pointing to genus-specific coevolution between ADF proteins and their native actin. PMID:26157165

  10. Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.

    PubMed

    Schewe, Matthias; Franken, Patrick F; Sacchetti, Andrea; Schmitt, Mark; Joosten, Rosalie; Böttcher, René; van Royen, Martin E; Jeammet, Louise; Payré, Christine; Scott, Patricia M; Webb, Nancy R; Gelb, Michael; Cormier, Robert T; Lambeau, Gérard; Fodde, Riccardo

    2016-07-01

    The intestinal stem cell niche provides cues that actively maintain gut homeostasis. Dysregulation of these cues may compromise intestinal regeneration upon tissue insult and/or promote tumor growth. Here, we identify secreted phospholipases A2 (sPLA2s) as stem cell niche factors with context-dependent functions in the digestive tract. We show that group IIA sPLA2, a known genetic modifier of mouse intestinal tumorigenesis, is expressed by Paneth cells in the small intestine, while group X sPLA2 is expressed by Paneth/goblet-like cells in the colon. During homeostasis, group IIA/X sPLA2s inhibit Wnt signaling through intracellular activation of Yap1. However, upon inflammation they are secreted into the intestinal lumen, where they promote prostaglandin synthesis and Wnt signaling. Genetic ablation of both sPLA2s improves recovery from inflammation but increases colon cancer susceptibility due to release of their homeostatic Wnt-inhibitory role. This "trade-off" effect suggests sPLA2s have important functions as genetic modifiers of inflammation and colon cancer. PMID:27292189

  11. Possession and Morality in Early Development

    ERIC Educational Resources Information Center

    Rochat, Philippe

    2011-01-01

    From the moment children say "mine!" by two years of age, objects of possession change progressively from being experienced as primarily unalienable property (i.e., something that is absolute or nonnegotiable), to being alienable (i.e., something that is negotiable in reciprocal exchanges). As possession begins to be experienced as alienable, the…

  12. 50 CFR 648.105 - Possession restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Summer Flounder Fisheries § 648.105 Possession restrictions. (a) Unless otherwise specified pursuant to § 648.107, no person shall possess more than two summer flounder in, or harvested from, the EEZ, unless that person is the owner or operator of a fishing vessel issued a summer flounder moratorium permit,...

  13. 50 CFR 648.25 - Possession restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Atlantic Mackerel, Squid, and Butterfish Fisheries § 648.25 Possession restrictions. (a) Atlantic mackerel. During a closure of the directed Atlantic mackerel fishery that occurs prior to June 1, vessels may not fish for, possess, or land more than 20,000 lb (9.08 mt) of Atlantic mackerel per trip at any time,...

  14. 50 CFR 648.204 - Possession restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Atlantic Herring Fishery § 648.204 Possession restrictions. (a) A vessel must be issued a valid limited access herring permit to fish for, possess, or land more than 6,600 lb (3 mt) of Atlantic herring from or in the EEZ from any herring management area, provided that the area has not been closed due to...

  15. Chemical Profiles of Two Pheromone Glands Are Differentially Regulated by Distinct Mating Factors in Honey Bee Queens (Apis mellifera L.)

    PubMed Central

    Niño, Elina L.; Malka, Osnat; Hefetz, Abraham; Tarpy, David R.; Grozinger, Christina M.

    2013-01-01

    Pheromones mediate social interactions among individuals in a wide variety of species, from yeast to mammals. In social insects such as honey bees, pheromone communication systems can be extraordinarily complex and serve to coordinate behaviors among many individuals. One of the primary mediators of social behavior and organization in honey bee colonies is queen pheromone, which is produced by multiple glands. The types and quantities of chemicals produced differ significantly between virgin and mated queens, and recent studies have suggested that, in newly mated queens, insemination volume or quantity can affect pheromone production. Here, we examine the long-term impact of different factors involved during queen insemination on the chemical composition of the mandibular and Dufour's glands, two of the major sources of queen pheromone. Our results demonstrate that carbon dioxide (an anesthetic used in instrumental insemination), physical manipulation of genital tract (presumably mimicking the act of copulation), insemination substance (saline vs. semen), and insemination volume (1 vs. 8 µl) all have long-term effects on mandibular gland chemical profiles. In contrast, Dufour's gland chemical profiles were changed only upon insemination and were not influenced by exposure to carbon dioxide, manipulation, insemination substance or volume. These results suggest that the chemical contents of these two glands are regulated by different neuro-physiological mechanisms. Furthermore, workers responded differently to the different mandibular gland extracts in a choice assay. Although these studies must be validated in naturally mated queens of varying mating quality, our results suggest that while the chemical composition of Dufour's gland is associated with mating status, that of the mandibular glands is associated with both mating status and insemination success. Thus, the queen appears to be signaling both status and reproductive quality to the workers, which may impact

  16. 137Cs Inter-Plant Concentration Ratios Provide a Predictive Tool for Coral Atolls with Distinct Benefits Over Transfer Factors

    SciTech Connect

    Robison, W L; Hamilton, T F; Bogen, K; Corado, C L; Kehl, S R

    2007-07-17

    Inter-plant concentration ratios (IPCR), [Bq g{sup -1} {sup 137}Cs in coral atoll tree food-crops/Bq g{sup -1} {sup 137}Cs in leaves of native plant species whose roots share a common soil volume], can replace transfer factors (TF) to predict {sup 137}Cs concentration in tree food-crops in a contaminated area with an aged source term. The IPCR strategy has significant benefits relative to TF strategy for such purposes in the atoll ecosystem. IPCR strategy applied to specific assessments takes advantage of the fact tree roots naturally integrate 137Cs over large volumes of soil. Root absorption of {sup 137}Cs replaces large-scale, expensive soil sampling schemes to reduce variability in {sup 137}Cs concentration due to inhomogeneous radionuclide distribution. IPCR [drinking-coconut meat (DCM)/Scaevola (SCA) and Tournefortia (TOU) leaves (native trees growing on all atoll islands)] are log normally distributed (LND) with geometric standard deviation (GSD) = 1.85. TF for DCM from Enewetak, Eneu, Rongelap and Bikini Atolls are LND with GSD's of 3.5, 3.0, 2.7, and 2.1, respectively. TF GSD for Rongelap copra coconut meat is 2.5. IPCR of Pandanus fruit to SCA and TOU leaves are LND with GSD = 1.7 while TF GSD is 2.1. Because IPCR variability is much lower than TF variability, relative sampling error of an IPCR field sample mean is up 6- to 10-fold lower than that of a TF sample mean if sample sizes are small (10 to 20). Other IPCR advantages are that plant leaf samples are collected and processed in far less time with much less effort and cost than soil samples.

  17. Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action*

    PubMed Central

    Ouertatani-Sakouhi, Hajer; El-Turk, Farah; Fauvet, Bruno; Cho, Min-Kyu; Pinar Karpinar, Damla; Le Roy, Didier; Dewor, Manfred; Roger, Thierry; Bernhagen, Jürgen; Calandra, Thierry; Zweckstetter, Markus; Lashuel, Hilal A.

    2010-01-01

    Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC50 values in the range of 0.2–15.5 μm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro1; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease. PMID:20516071

  18. (137)Cs inter-plant concentration ratios provide a predictive tool for coral atolls with distinct benefits over transfer factors.

    PubMed

    Robison, William L; Hamilton, Terry F; Bogen, Kenneth T; Conrado, Cynthia L; Kehl, Steven R

    2008-01-01

    Inter-plant concentration ratios (IPCR) [Bqg(-1)(137)Cs in coral atoll tree food crops/Bqg(-1)(137)Cs in leaves of native plant species whose roots share a common soil volume] can replace transfer factors (TF) to predict (137)Cs concentration in tree food crops in a contaminated area with an aged source term. The IPCR strategy has significant benefits relative to TF strategy for such purposes in the atoll ecosystem. IPCR strategy applied to specific assessments takes advantage of the fact that tree roots naturally integrate (137)Cs over large volumes of soil. Root absorption of (137)Cs replaces large-scale, expensive soil sampling schemes to reduce variability in (137)Cs concentration due to inhomogeneous radionuclide distribution. IPCR [drinking-coconut meat (DCM)/Scaevola (SCA) and Tournefortia (TOU) leaves (native trees growing on all atoll islands)] are log-normally distributed (LND) with geometric standard deviation (GSD)=1.85. TF for DCM from Enewetak, Eneu, Rongelap and Bikini Atolls are LND with GSDs of 3.5, 3.0, 2.7, and 2.1, respectively. TF GSD for Rongelap copra coconut meat is 2.5. IPCR of Pandanus fruit to SCA and TOU leaves are LND with GSD=1.7 while TF GSD is 2.1. Because IPCR variability is much lower than TF variability, relative sampling error of an IPCR field sample mean is up 6- to 10-fold lower than that of a TF sample mean if sample sizes are small (10-20). Other IPCR advantages are that plant leaf samples are collected and processed in far less time with much less effort and cost than soil samples. PMID:17904254

  19. Chelating agents exert distinct effects on biofilm formation in Staphylococcus aureus depending on strain background: role for clumping factor B

    PubMed Central

    Abraham, Nabil M.; Lamlertthon, Supaporn; Fowler, Vance G.

    2012-01-01

    Staphylococcus aureus is a leading cause of catheter infections, and biofilm formation plays a key role in the pathogenesis. Metal ion chelators inhibit bacterial biofilm formation and viability, making them attractive candidates as components in catheter lock solutions. The goal of this study was to characterize further the effect of chelators on biofilm formation. The effect of the calcium chelators ethylene glycol tetraacetic acid (EGTA) and trisodium citrate (TSC) on biofilm formation by 30 S. aureus strains was tested. The response to subinhibitory doses of EGTA and TSC varied dramatically depending on strain variation. In some strains, the chelators prevented biofilm formation, in others they had no effect, and they actually enhanced biofilm formation in others. The molecular basis for this phenotypic variability was investigated using two related strains: Newman, in which biofilm formation was inhibited by chelators, and 10833, which formed strong biofilms in the presence of chelators. It was found that deletion of the gene encoding the surface adhesin clumping factor B (clfB) completely eliminated chelator-induced biofilm formation in strain 10833. The role of ClfB in biofilm formation activity in chelators was confirmed in additional strains. It was concluded that biofilm-forming ability varies strikingly depending on strain background, and that ClfB is involved in biofilm formation in the presence EGTA and citrate. These results suggest that subinhibitory doses of chelating agents in catheter lock solutions may actually augment biofilm formation in certain strains of S. aureus, and emphasize the importance of using these agents appropriately so that inhibitory doses are achieved consistently. PMID:22516131

  20. Misregulation of AUXIN RESPONSE FACTOR 8 underlies the developmental abnormalities caused by three distinct viral silencing suppressors in Arabidopsis.

    PubMed

    Jay, Florence; Wang, Yu; Yu, Agnès; Taconnat, Ludivine; Pelletier, Sandra; Colot, Vincent; Renou, Jean-Pierre; Voinnet, Olivier

    2011-05-01

    In Arabidopsis, micro (mi)RNAs and trans-acting (ta-si)RNAs synthesized directly or indirectly through the DICER-LIKE-1 (DCL1) ribonuclease have roles in patterning and hormonal responses, while DCL2,3,4-dependent small-interfering (si)RNAs are mainly involved in silencing of transposable elements and antiviral defense. Viral suppressors of RNA silencing (VSRs) produced by phytoviruses to counter plant defense may perturb plant developmental programs because of the collision of their inhibitory effects with the regulatory action of endogenous miRNAs and ta-siRNAs. This could explain the similar developmental aberrations displayed by Arabidopsis miRNA/ta-siRNA pathway mutants, including dcl1, and by some VSR-expressing plants. Nonetheless, the molecular bases for these morphological aberrations have remained mysterious, and their contribution to viral disease symptoms/virulence unexplored. The extent of VSR inhibitory actions to other types of endogenous small RNAs remains also unclear. Here, we present an in-depth analysis of transgenic Arabidopsis expressing constitutively HcPro, P19 and P15, three unrelated VSRs. We show that VSR expression has comparable, yet modest effects on known miRNA and ta-siRNA target RNA levels, similar to those observed using an hypomorphic dcl1 mutation. However, by combining results of transcriptome studies with deep-sequencing data from immuno-precipitated small RNAs, additional, novel endogenous targets of miRNA and ta-siRNA were identified, unraveling an unsuspected complexity in the origin and scope-of-action of these molecules. Other stringent analyses pinpointed misregulation of the miR167 target AUXIN RESPONSE FACTOR 8 (ARF8) as a major cause for the developmental aberrations exhibited by VSR transgenic plants, but also for the phenotypes induced during normal viral infection caused by the HcPro-encoding Turnip mosaic virus (TuMV). Neither RNA silencing, its suppression by VSRs, nor the virulence/accumulation of TuMV was

  1. Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence.

    PubMed

    Lohberger, Andrea; Coste, Alix T; Sanglard, Dominique

    2014-01-01

    Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion

  2. Possession and carrying of firearms among suburban youth.

    PubMed

    Sheley, J F; Brewer, V E

    1995-01-01

    Despite a growing body of anecdotal evidence suggesting the spread of firearms to suburban juvenile populations, most studies of firearm activity by juveniles focus either on urban youth or on nationally representative samples that blur urban and nonurban distinctions. This study represents the first systematic empirical investigation specifically of a suburban population of juveniles. The authors examine both ownership and carrying behaviors, distinguish types of handguns involved, and assess the influence of drug activity, violent criminality, and the perception of one's social environment as dangerous upon the possession and carrying of firearms. Among the variables linked at the bivariate level to possession and carrying of guns were sex, involvement in criminal activity, involvement in drug activity, and most indicators of a dangerous social environment. At the multivariate level, however, only sex was associated with possession of a revolver, and only sex, criminal activity (for boys only), and one indicator of dangerous environment (having been threatened with a gun, for girls only) were associated with possession of an automatic or semiautomatic handgun. Aside from sex, criminal and drug activities were associated with gun carrying. Despite its importance among urban samples, in this study the dangerous environment was not linked to firearm activity. Possible reasons for this difference are explored in the conclusion. PMID:7838938

  3. Plasma CXCL10, sCD163 and sCD14 Levels Have Distinct Associations with Antiretroviral Treatment and Cardiovascular Disease Risk Factors

    PubMed Central

    Castley, Alison; Williams, Leah; James, Ian; Guelfi, George; Berry, Cassandra; Nolan, David

    2016-01-01

    We investigate the associations of three established plasma biomarkers in the context of HIV and treatment-related variables including a comprehensive cardiovascular disease risk assessment, within a large ambulatory HIV cohort. Patients were recruited in 2010 to form the Royal Perth Hospital HIV/CVD risk cohort. Plasma sCD14, sCD163 and CXCL10 levels were measured in 475 consecutive patients with documented CVD risk (age, ethnicity, gender, smoking, blood pressure, BMI, fasting metabolic profile) and HIV treatment history including immunological/virological outcomes. The biomarkers assessed showed distinct associations with virological response: CXCL10 strongly correlated with HIV-1 RNA (p<0.001), sCD163 was significantly reduced among ‘aviraemic’ patients only (p = 0.02), while sCD14 was unaffected by virological status under 10,000 copies/mL (p>0.2). Associations between higher sCD163 and protease inhibitor therapy (p = 0.05) and lower sCD14 with integrase inhibitor therapy (p = 0.02) were observed. Levels of sCD163 were also associated with CVD risk factors (age, ethnicity, HDL, BMI), with a favourable influence of Framingham score <10% (p = 0.04). Soluble CD14 levels were higher among smokers (p = 0.002), with no effect of other CVD risk factors, except age (p = 0.045). Our findings confirm CXCL10, sCD163 and sCD14 have distinct associations with different aspects of HIV infection and treatment. Levels of CXCL10 correlated with routinely monitored variables, sCD163 levels reflect a deeper level of virological suppression and influence of CVD risk factors, while sCD14 levels were not associated with routinely monitored variables, with evidence of specific effects of smoking and integrase inhibitor therapy warranting further investigation. PMID:27355513

  4. Tobacco bZIP transcription factor TGA2.2 and related factor TGA2.1 have distinct roles in plant defense responses and plant development.

    PubMed

    Thurow, Corinna; Schiermeyer, Andreas; Krawczyk, Stefanie; Butterbrodt, Thomas; Nickolov, Kaloian; Gatz, Christiane

    2005-10-01

    Salicylic acid (SA) is a crucial internal signaling molecule needed for the induction of plant defense responses upon attack of a variety of pathogens. Basic leucine zipper transcription factors of the TGA family bind to activating sequence-1 (as-1)-like elements which are SA-responsive cis elements found in promoters of 'immediate early' and 'late' SA-inducible genes. TGA2.2 constitutes the main component of tobacco as-1-binding factor-1 (ASF-1). TGA2.1, which differs from TGA2.2 by being able to activate transcription in yeast, constitutes a minor fraction of the complex. Both proteins interact with NPR1, a protein essential for SA inducibility of 'late' genes. Here we demonstrate using dsRNAi mediated gene silencing that reducing the amount of TGA2.2 and TGA2.1 correlates with a significant decrease in ASF-1 activity and with a decreased inducibility of both 'immediate early' and 'late' genes. In contrast, reducing the amount of TGA2.1 alone had no effect on the expression of these target genes suggesting that TGA2.1 is dispensable for SA-inducible gene expression from the as-1 element. Expression of a TGA2.2 mutant unable to form heterodimers with the endogenous pool of TGA factors led to reduced SA-inducibility of 'immediate early' gene Nt103, indicating that the native leucine zipper is important for the protein to act positively on transcription. Plants with reduced amounts of TGA2.1 developed petal like stamens indicating a regulatory role of TGA2.1 in defining organ identity in tobacco flowers. A model is suggested that unifies conflicting results on the function of tobacco TGA factors with respect to activation of the 'late' PR-1a promoter. PMID:16167899

  5. 22 CFR 72.14 - Nominal possession; property not normally taken into physical possession.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and quantity that they can readily be taken into physical possession with the rest of the personal... into physical possession. 72.14 Section 72.14 Foreign Relations DEPARTMENT OF STATE PROTECTION AND... States Citizens and Nationals § 72.14 Nominal possession; property not normally taken into...

  6. 22 CFR 72.14 - Nominal possession; property not normally taken into physical possession.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and quantity that they can readily be taken into physical possession with the rest of the personal... into physical possession. 72.14 Section 72.14 Foreign Relations DEPARTMENT OF STATE PROTECTION AND... States Citizens and Nationals § 72.14 Nominal possession; property not normally taken into...

  7. Subself theory and reincarnation/possession.

    PubMed

    Lester, David

    2004-12-01

    A subself model of the mind is used to account for multiple personality, possession, the spirit controls of mediums, reincarnation, and the auditory hallucinations of schizophrenics, with suggestions for empirical research. PMID:15739836

  8. Decriminalizing Possession of All Controlled Substances.

    ERIC Educational Resources Information Center

    Kurzman, Marc G.

    1978-01-01

    Excerpts from the Minnesota Bar Association's Blue Ribbon Committee report of findings and recommendations, with regard to dealing with possession of heroin and other controlled substances, are presented here. (Author/DS)

  9. Binding of transcription factor GabR to DNA requires recognition of DNA shape at a location distinct from its cognate binding site

    PubMed Central

    Al-Zyoud, Walid A.; Hynson, Robert MG.; Ganuelas, Lorraine A.; Coster, Adelle CF.; Duff, Anthony P.; Baker, Matthew AB.; Stewart, Alastair G.; Giannoulatou, Eleni; Ho, Joshua WK.; Gaus, Katharina; Liu, Dali; Lee, Lawrence K.; Böcking, Till

    2016-01-01

    Mechanisms for transcription factor recognition of specific DNA base sequences are well characterized and recent studies demonstrate that the shape of these cognate binding sites is also important. Here, we uncover a new mechanism where the transcription factor GabR simultaneously recognizes two cognate binding sites and the shape of a 29 bp DNA sequence that bridges these sites. Small-angle X-ray scattering and multi-angle laser light scattering are consistent with a model where the DNA undergoes a conformational change to bend around GabR during binding. In silico predictions suggest that the bridging DNA sequence is likely to be bendable in one direction and kinetic analysis of mutant DNA sequences with biolayer interferometry, allowed the independent quantification of the relative contribution of DNA base and shape recognition in the GabR–DNA interaction. These indicate that the two cognate binding sites as well as the bendability of the DNA sequence in between these sites are required to form a stable complex. The mechanism of GabR–DNA interaction provides an example where the correct shape of DNA, at a clearly distinct location from the cognate binding site, is required for transcription factor binding and has implications for bioinformatics searches for novel binding sites. PMID:26681693

  10. Binding of transcription factor GabR to DNA requires recognition of DNA shape at a location distinct from its cognate binding site.

    PubMed

    Al-Zyoud, Walid A; Hynson, Robert M G; Ganuelas, Lorraine A; Coster, Adelle C F; Duff, Anthony P; Baker, Matthew A B; Stewart, Alastair G; Giannoulatou, Eleni; Ho, Joshua W K; Gaus, Katharina; Liu, Dali; Lee, Lawrence K; Böcking, Till

    2016-02-18

    Mechanisms for transcription factor recognition of specific DNA base sequences are well characterized and recent studies demonstrate that the shape of these cognate binding sites is also important. Here, we uncover a new mechanism where the transcription factor GabR simultaneously recognizes two cognate binding sites and the shape of a 29 bp DNA sequence that bridges these sites. Small-angle X-ray scattering and multi-angle laser light scattering are consistent with a model where the DNA undergoes a conformational change to bend around GabR during binding. In silico predictions suggest that the bridging DNA sequence is likely to be bendable in one direction and kinetic analysis of mutant DNA sequences with biolayer interferometry, allowed the independent quantification of the relative contribution of DNA base and shape recognition in the GabR-DNA interaction. These indicate that the two cognate binding sites as well as the bendability of the DNA sequence in between these sites are required to form a stable complex. The mechanism of GabR-DNA interaction provides an example where the correct shape of DNA, at a clearly distinct location from the cognate binding site, is required for transcription factor binding and has implications for bioinformatics searches for novel binding sites. PMID:26681693

  11. Mexico decriminalizes small-scale drug possession.

    PubMed

    2009-12-01

    On 20 August 2009, the Mexican government adopted legislation decriminalizing possession of small amounts of drugs. According to the new law, possession amounts for "personal and immediate use"--defined as up to half a gram of cocaine, five grams of marijuana, 50 milligrams of heroin, 40 milligrams of methamphetamine and 0.015 milligrams of LSD--will not lead to criminal prosecution. PMID:20225507

  12. Detailed Analysis of Clinicopathologic Factors Demonstrate Distinct Difference in Outcome and Prognostic Factors Between Surgically Treated HPV-Positive and Negative Oropharyngeal Cancer

    PubMed Central

    Iyer, N. Gopalakrishna; Dogan, Snjezana; Palmer, Frank; Rahmati, Rahmatullah; Nixon, Iain J.; Lee, Nancy; Patel, Snehal G.; Shah, Jatin P.; Ganly, Ian

    2016-01-01

    Background Oropharyngeal cancers (OPC) secondary to human papillomavirus (HPV) infections likely represent a completely different disease compared with conventional head and neck cancers. Our objective was to analyze a surgically treated cohort to determine predictors of outcome in HPV-positive versus HPV-negative patients. Methods HPV positivity was inferred based on p16-immunohistochemistry. Data was available for 201 patients with OPC treated with surgical resection with/without adjuvant radiotherapy between 1985 and 2005. Subsite distribution was: 66 (33 %) tonsil, 46 (23 %) soft palate, and 89 (44 %) tongue base. Patients were classified into low-, intermediate-, and high-risk groups based on p16 status and smoking history. Outcomes stratified by p16 status and risk groups were determined by the Kaplan–Meier method. Factors predictive of outcome were determined by univariate and multivariate analyses. Results In this cohort, 30 % had locally advanced disease (pT3/T4) and 71 % had nodal metastasis. The 5-year overall (OS), disease-specific, and recurrence-free survival rates were 60, 76, and 66 %, respectively. There were 22 % low-, 34 % intermediate-, and 44 % high-risk patients. Patients who were p16-positive had better survival compared with p16-negative (OS, 74 vs. 44 %; p < .001). Similarly, low-risk group patients had a better survival compared with intermediate- and high-risk groups (OS, 76, 68, 45 %, respectively, p < .001). Independent predictors of survival in p16-negative patients included margin status, lymphovascular invasion, pN status, and extracapsular spread. In contrast, none of these were predictive in p16-positive patients. Conclusions Surgically treated patients with p16-positive OPC have superior survival compared with p16-negative patients. Outcomes in p16-positive and p16-negative OPC are determined by different prognostic factors supporting the notion that these are very different diseases. These should be incorporated into future

  13. Induction of tenascin-C by cyclic tensile strain versus growth factors: distinct contributions by Rho/ROCK and MAPK signaling pathways.

    PubMed

    Chiquet, Matthias; Sarasa-Renedo, Ana; Tunç-Civelek, Vildan

    2004-09-17

    Expression of the extracellular matrix (ECM) protein tenascin-C is induced in fibroblasts by growth factors as well as by tensile strain. Mechanical stress can act on gene regulation directly, or indirectly via the paracrine release of soluble factors by the stimulated cells. To distinguish between these possibilities for tenascin-C, we asked whether cyclic tensile strain and soluble factors, respectively, induced its mRNA via related or separate mechanisms. When cyclic strain was applied to chick embryo fibroblasts cultured on silicone membranes, tenascin-C mRNA and protein levels were increased twofold within 6 h compared to the resting control. Medium conditioned by strained cells did not stimulate tenascin-C mRNA in resting cells. Tenascin-C mRNA in resting cells was increased by serum; however, cyclic strain still caused an additional induction. Likewise, the effect of TGF-beta1 or PDGF-BB was additive to that of cyclic strain, whereas IL-4 or H2O2 (a reactive oxygen species, ROS) did not change tenascin-C mRNA levels. Antagonists for distinct mitogen-activated protein kinases (MAPK) inhibited tenascin-C induction by TGF-beta1 and PDGF-BB, but not by cyclic strain. Conversely, a specific inhibitor of Rho-dependent kinase strongly attenuated the response of tenascin-C mRNA to cyclic strain, but had limited effect on induction by growth factors. The data suggest that regulation of tenascin-C in fibroblasts by cyclic strain occurs independently from soluble mediators and MAPK pathways; however, it requires Rho/ROCK signaling. PMID:15363633

  14. Possession Divestment by Sales in Later Life

    PubMed Central

    Ekerdt, David J.; Addington, Aislinn

    2015-01-01

    Residential relocation in later life is almost always a downsizing, with many possessions to be divested in a short period of time. This article examines older movers’ capacities for selling things, and ways that selling attenuates people's ties to those things, thus accomplishing the human dis-possession of the material convoy. In qualitative interviews in 79 households in the Midwestern United States, older adults reported their experience with possession sales associated with residential relocation. Among this group, three-quarters of the households downsized by selling some belongings. Informal sales seemed the least fraught of all strategies, estate sales had mixed reviews, and garage sales were recalled as laborious. Sellers’ efforts were eased by social relations and social networks as helpers and buyers came forward. As selling proceeded, sentiment about possessions waned as their materiality and economic value came to the fore, easing their detachment from the household. Possession selling is challenging because older adults are limited in the knowledge, skills, and efforts that they can apply to the recommodification of their belongings. Selling can nonetheless be encouraged as a divestment strategy as long as the frustrations and drawbacks are transparent, and the goal of ridding is kept in view. PMID:26162722

  15. Possession divestment by sales in later life.

    PubMed

    Ekerdt, David J; Addington, Aislinn

    2015-08-01

    Residential relocation in later life is almost always a downsizing, with many possessions to be divested in a short period of time. This article examines older movers' capacities for selling things, and ways that selling attenuates people's ties to those things, thus accomplishing the human dis-possession of the material convoy. In qualitative interviews in 79 households in the Midwestern United States, older adults reported their experience with possession sales associated with residential relocation. Among this group, three-quarters of the households downsized by selling some belongings. Informal sales seemed the least fraught of all strategies, estate sales had mixed reviews, and garage sales were recalled as laborious. Sellers' efforts were eased by social relations and social networks as helpers and buyers came forward. As selling proceeded, sentiment about possessions waned as their materiality and economic value came to the fore, easing their detachment from the household. Possession selling is challenging because older adults are limited in the knowledge, skills, and efforts that they can apply to the recommodification of their belongings. Selling can nonetheless be encouraged as a divestment strategy as long as the frustrations and drawbacks are transparent, and the goal of ridding is kept in view. PMID:26162722

  16. Distinct subcellular localization of alternative splicing variants of EFA6D, a guanine nucleotide exchange factor for Arf6, in the mouse brain.

    PubMed

    Fukaya, Masahiro; Ohta, Shingo; Hara, Yoshinobu; Tamaki, Hideaki; Sakagami, Hiroyuki

    2016-09-01

    EFA6D (guanine nucleotide exchange factor for ADP-ribosylation factor 6 [Arf6]D) is also known as EFA6R, Psd3, and HCA67. It is the fourth member of the EFA6 family with guanine nucleotide exchange activity for Arf6, a small guanosine triphosphatase (GTPase) that regulates endosomal trafficking and actin cytoskeleton remodeling. We propose a classification and nomenclature of 10 EFA6D variants deposited in the GenBank database as EFA6D1a, 1b, 1c, 1d, 1s, 2a, 2b, 2c, 2d, and 2s based on the combination of N-terminal and C-terminal insertions. Polymerase chain reaction analysis showed the expression of all EFA6D variants except for variants a and d in the adult mouse brain. Immunoblotting analysis with novel variant-specific antibodies showed the endogenous expression of EFA6D1b, EFA6D1c, and EFA6D1s at the protein level, with the highest expression being EFA6D1s, in the brain. Immunoblotting analysis of forebrain subcellular fractions showed the distinct subcellular distribution of EFA6D1b/c and EFA6D1s. The immunohistochemical analysis revealed distinct but overlapping immunoreactive patterns between EFA6D1b/c and EFA6D1s in the mouse brain. In immunoelectron microscopic analyses of the hippocampal CA3 region, EFA6D1b/c was present predominantly in the mossy fiber axons of dentate granule cells, whereas EFA6D1s was present abundantly in the cell bodies, dendritic shafts, and spines of hippocampal pyramidal cells. These results provide the first anatomical evidence suggesting the functional diversity of EFA6D variants, particularly EFA6D1b/c and EFA6D1s, in neurons. J. Comp. Neurol. 524:2531-2552, 2016. © 2016 Wiley Periodicals, Inc. PMID:27241101

  17. 50 CFR 648.25 - Possession restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Atlantic Mackerel, Squid, and Butterfish Fisheries § 648.25 Possession restrictions. Link to an amendment... Atlantic Mackerel, squid, and butterfish framework adjustments to management measures. (a) Within season... the Atlantic Mackerel, Squid, and Butterfish FMP if it finds that action is necessary to meet or...

  18. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2010-04-01 2010-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  19. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2011-04-01 2010-04-01 true Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  20. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2012-04-01 2010-04-01 true Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  1. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2013-04-01 2013-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  2. 27 CFR 479.121 - Insular possessions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 3 2014-04-01 2014-04-01 false Insular possessions. 479.121 Section 479.121 Alcohol, Tobacco Products, and Firearms BUREAU OF ALCOHOL, TOBACCO, FIREARMS, AND EXPLOSIVES, DEPARTMENT OF JUSTICE FIREARMS AND AMMUNITION MACHINE GUNS, DESTRUCTIVE DEVICES, AND...

  3. Constitutive nuclear factor-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the expression of distinct Bcl-2 family proteins.

    PubMed

    Bureau, Fabrice; Vanderplasschen, Alain; Jaspar, Fabrice; Minner, Frédéric; Pastoret, Paul-Pierre; Merville, Marie-Paule; Bours, Vincent; Lekeux, Pierre

    2002-05-15

    Constitutive nuclear factor kappaB (NF-kappaB) activity protects quiescent mature immune cells from spontaneous apoptosis. Here, we examined whether NF-kappaB exerts its antiapoptotic function in these cells through the control of Bcl-2 family proteins. Specific pharmacologic inhibitors of NF-kappaB were used to achieve total NF-kappaB inactivation in quiescent human blood lymphocytes, granulocytes, and monocytes. NF-kappaB inhibition induced drastic lymphocyte and granulocyte apoptosis, but only moderate monocyte apoptosis. T- and B-cell apoptosis was slow and associated with a gradual down-regulation of the prosurvival Bcl-2 family proteins Bcl-x(L) and Bcl-2, respectively. By contrast, granulocyte apoptosis was fast and accompanied by a rapid cellular accumulation of Bcl-x(S), the proapoptotic Bcl-x isoform that is generated from alternative splicing of the bcl-x pre-mRNA. Finally, antisense bcl-x(L) and bcl-2 knockdown in T and B cells, respectively, and induction of Bcl-x(S) expression in granulocytes through antisense oligonucleotide-mediated redirection of bcl-x pre-mRNA splicing were sufficient to induce significant apoptosis in these cells. Taken together, these results reveal that basal NF-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes through regulation of distinct members of the Bcl-2 family. This study sheds light on the constitutive mechanisms by which NF-kappaB maintains defense integrity. PMID:11986224

  4. 22 CFR 72.14 - Nominal possession; property not normally taken into physical possession.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Nominal possession; property not normally taken into physical possession. 72.14 Section 72.14 Foreign Relations DEPARTMENT OF STATE PROTECTION AND WELFARE OF AMERICANS, THEIR PROPERTY AND ESTATES DEATHS AND ESTATES Personal Estates of Deceased United States Citizens and Nationals § 72.14...

  5. Distinct epithelial growth factor receptor mutation profile in non-small-cell lung cancer patients from the Xuanwei area of China

    PubMed Central

    CHEN, YUN; YE, LIJUAN; STANFORD, REBECCA RONGRONG; ZHANG, DONGFANG; ZHANG, XINGSONG; WEI, WANLI

    2016-01-01

    The Xuanwei county in China has a high incidence of lung cancer and related mortality. Previous studies have suggested that these cases may be associated with a distinctive pattern of mutations in the epithelial growth factor receptor (EGFR) gene. In this retrospective study, we investigated the mutation profile of EGFR in non-small-cell lung cancer (NSCLC) tissues from patients in Xuanwei, and the associated clinicopathological characteristics. Specimens from 258 consecutive patients with lung cancer (90 from Xuanwei and 168 from other areas of Yunnan province) were subjected to amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) to detect EGFR mutations. In 67 specimens from Xuanwei, the results were confirmed by direct DNA sequencing for EGFR mutations. Immunohistochemistry (IHC) for the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein was performed on all specimens from Xuanwei. We observed that Xuanwei patients presented with distinctive clinicopathological characteristics, including female gender predominance, younger age, higher rate of lymph node metastasis, higher rate of adenocarcinoma histological classification and lower disease stage, and a low rate of the ‘classical’ mutations on EGFR exons 19 and 21 compared with non-Xuanwei patients (7.8 and 21.6% vs. 49.3 and 39.7%, respectively; P<0.05 for combined data). However, a significantly higher percentage of Xuanwei patients harbored co-mutation of EGFR exons 18 and 20 compared with non-Xuanwei patients (45.1 vs. 4.1%, respectively; P<0.0001). Specimens from 2 Xuanwei patients (2.2%) were positive for the EML4-ALK fusion protein; by IHC, neither harbored EGFR mutations. There was no obvious association between EGFR mutations and disease stage or lymph node involvement. Thus, NSCLC patients in Xuanwei presented with a unique EGFR profile of high rates of co-mutation of exons 18 and 20, and low rates of exon 19 or 21

  6. Possession Versus Position: Strategic Evaluation in AFL

    PubMed Central

    O’Shaughnessy, Darren M.

    2006-01-01

    In sports like Australian Rules football and soccer, teams must battle to achieve possession of the ball in sufficient space to make optimal use of it. Ultimately the teams need to score, and to do that the ball must be brought into the area in front of goal - the place where the defence usually concentrates on shutting down space and opportunity time. Coaches would like to quantify the trade-offs between contested play in good positions and uncontested play in less promising positions, in order to inform their decision-making about where to put their players, and when to gamble on sending the ball to a contest rather than simply maintain possession. To evaluate football strategies, Champion Data has collected the on-ground locations of all 350,000 possessions and stoppages in the past two seasons of AFL (2004, 2005). By following each chain of play through to the next score, we can now reliably estimate the scoreboard “equity ”of possessing the ball at any location, and measure the effect of having sufficient time to dispose of it effectively. As expected, winning the ball under physical pressure (through a “hard ball get”) is far more difficult to convert into a score than winning it via a mark. We also analyse some equity gradients to show how getting the ball 20 metres closer to goal is much more important in certain areas of the ground than in others. We conclude by looking at the choices faced by players in possession wanting to maximise their likelihood of success. Key Points Equity analysis provides a way of estimating the net value of actions on the sporting field. Combined with spatial data analysis, the relative merits of gaining position or maintaining possession can be judged. The advantage of having time and space to use the ball is measured in terms of scoreboard value, and is found to vary with field position. Each sport has identifiable areas of the field with high equity gradients, meaning that it is most important to gain territory there

  7. Tracking the actions and possessions of agents

    PubMed Central

    Gelman, Susan A.; Noles, Nicholaus S.; Stilwell, Sarah

    2014-01-01

    We propose that there is a powerful human disposition to track the actions and possessions of agents. In two experiments, 3-year-olds and adults viewed sets of objects, learned a new fact about one of the objects in each set (either that it belonged to the participant, or that it possessed a particular label), and were queried about either the taught fact or an unrelated dimension (preference) immediately after a spatiotemporal transformation, and after a delay. Adults uniformly tracked object identity under all conditions, whereas children tracked identity more when taught ownership versus labeling information, and only regarding the taught fact (not the unrelated dimension). These findings suggest that the special attention that children and adults pay to agents readily extends to include inanimate objects. That young children track an object’s history, despite their reliance on surface features on many cognitive tasks, suggests that unobservable historical features are foundational in human cognition. PMID:25111732

  8. Distinction Between Cell Proliferation and Apoptosis Signals Regulated by Brain-Derived Neurotrophic Factor in Human Periodontal Ligament Cells and Gingival Epithelial Cells.

    PubMed

    Kashiwai, Kei; Kajiya, Mikihito; Matsuda, Shinji; Ouhara, Kazuhisa; Takeda, Katsuhiro; Takata, Takashi; Kitagawa, Masae; Fujita, Tsuyoshi; Shiba, Hideki; Kurihara, Hidemi

    2016-07-01

    Previously, we reported that brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration by inducing periodontal ligament cell proliferation in vivo. In addition, the down growth of gingival epithelial cells, which comprises a major obstacle to the regeneration, was not observed. However, the underlying molecular mechanism is still unclear. Therefore, this study aimed to investigate the effect of BDNF on cell proliferation and apoptosis in human periodontal ligament (HPL) cells and human gingival epithelial cells (OBA9 cells) and to explore the molecular mechanism in vitro. HPL cells dominantly expressed a BDNF receptor, TrkB, and BDNF increased cell proliferation and ERK phosphorylation. However, its proliferative effect was diminished by a MEK1/2 inhibitor (U0126) and TrkB siRNA transfection. Otherwise, OBA9 cells showed a higher expression level of p75, which is a pan-neurotrophin receptor, than that of HPL cells. BDNF facilitated not cell proliferation but cell apoptosis and JNK phosphorylation in OBA9 cells. A JNK inhibitor (SP600125) and p75 siRNA transfection attenuated the BDNF-induced cell apoptosis. Moreover, OBA9 cells pretreated with SP600125 or p75 siRNA showed cell proliferation by BDNF stimulation, though it was reduced by U0126 and TrkB siRNA. Interestingly, overexpression of p75 in HPL cells upregulated cell apoptosis and JNK phosphorylation by BDNF treatment. These results indicated that TrkB-ERK signaling regulates BDNF-induced cell proliferation, whereas p75-JNK signaling plays roles in cell apoptotic and cytostatic effect of BDNF. Overall, BDNF activates periodontal ligament cells proliferation and inhibits the gingival epithelial cells growth via the distinct pathway. J. Cell. Biochem. 117: 1543-1555, 2016. © 2015 Wiley Periodicals, Inc. PMID:26581032

  9. β-Arrestin1 and distinct CXCR4 structures are required for stromal derived factor-1 to downregulate CXCR4 cell-surface levels in neuroblastoma.

    PubMed

    Clift, Ian C; Bamidele, Adebowale O; Rodriguez-Ramirez, Christie; Kremer, Kimberly N; Hedin, Karen E

    2014-04-01

    CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor (GPCR) located on the cell surface that signals upon binding the chemokine stromal derived factor-1 (SDF-1; also called CXCL 12). CXCR4 promotes neuroblastoma proliferation and chemotaxis. CXCR4 expression negatively correlates with prognosis and drives neuroblastoma growth and metastasis in mouse models. All functions of CXCR4 require its expression on the cell surface, yet the molecular mechanisms that regulate CXCR4 cell-surface levels in neuroblastoma are poorly understood. We characterized CXCR4 cell-surface regulation in the related SH-SY5Y and SK-N-SH human neuroblastoma cell lines. SDF-1 treatment caused rapid down-modulation of CXCR4 in SH-SY5Y cells. Pharmacologic activation of protein kinase C similarly reduced CXCR4, but via a distinct mechanism. Analysis of CXCR4 mutants delineated two CXCR4 regions required for SDF-1 treatment to decrease cell-surface CXCR4 in neuroblastoma cells: the isoleucine-leucine motif at residues 328 and 329 and residues 343-352. In contrast, and unlike CXCR4 regulation in other cell types, serines 324, 325, 338, and 339 were not required. Arrestin proteins can bind and regulate GPCR cell-surface expression, often functioning together with kinases such as G protein-coupled receptor kinase 2 (GRK2). Using SK-N-SH cells which are naturally deficient in β-arrestin1, we showed that β-arrestin1 is required for the CXCR4 343-352 region to modulate CXCR4 cell-surface expression following treatment with SDF-1. Moreover, GRK2 overexpression enhanced CXCR4 internalization, via a mechanism requiring both β-arrestin1 expression and the 343-352 region. Together, these results characterize CXCR4 structural domains and β-arrestin1 as critical regulators of CXCR4 cell-surface expression in neuroblastoma. β-Arrestin1 levels may therefore influence the CXCR4-driven metastasis of neuroblastoma as well as prognosis. PMID:24452472

  10. 50 CFR 20.38 - Possession of live birds.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 8 2011-10-01 2011-10-01 false Possession of live birds. 20.38 Section 20... WILDLIFE AND PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.38 Possession of live birds. Every migratory game bird wounded by hunting and reduced to possession by the hunter shall be immediately...

  11. 50 CFR 20.38 - Possession of live birds.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Possession of live birds. 20.38 Section 20... WILDLIFE AND PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.38 Possession of live birds. Every migratory game bird wounded by hunting and reduced to possession by the hunter shall be immediately...

  12. 50 CFR 20.38 - Possession of live birds.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 9 2012-10-01 2012-10-01 false Possession of live birds. 20.38 Section 20... WILDLIFE AND PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.38 Possession of live birds. Every migratory game bird wounded by hunting and reduced to possession by the hunter shall be immediately...

  13. 50 CFR 20.38 - Possession of live birds.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 9 2013-10-01 2013-10-01 false Possession of live birds. 20.38 Section 20... WILDLIFE AND PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.38 Possession of live birds. Every migratory game bird wounded by hunting and reduced to possession by the hunter shall be immediately...

  14. 50 CFR 20.38 - Possession of live birds.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 9 2014-10-01 2014-10-01 false Possession of live birds. 20.38 Section 20... WILDLIFE AND PLANTS (CONTINUED) MIGRATORY BIRD HUNTING Possession § 20.38 Possession of live birds. Every migratory game bird wounded by hunting and reduced to possession by the hunter shall be immediately...

  15. Planctomycetes do possess a peptidoglycan cell wall

    PubMed Central

    Jeske, Olga; Schüler, Margarete; Schumann, Peter; Schneider, Alexander; Boedeker, Christian; Jogler, Mareike; Bollschweiler, Daniel; Rohde, Manfred; Mayer, Christoph; Engelhardt, Harald; Spring, Stefan; Jogler, Christian

    2015-01-01

    Most bacteria contain a peptidoglycan (PG) cell wall, which is critical for maintenance of shape and important for cell division. In contrast, Planctomycetes have been proposed to produce a proteinaceous cell wall devoid of PG. The apparent absence of PG has been used as an argument for the putative planctomycetal ancestry of all bacterial lineages. Here we show, employing multiple bioinformatic methods, that planctomycetal genomes encode proteins required for PG synthesis. Furthermore, we biochemically demonstrate the presence of the sugar and the peptide components of PG in Planctomycetes. In addition, light and electron microscopic experiments reveal planctomycetal PG sacculi that are susceptible to lysozyme treatment. Finally, cryo-electron tomography demonstrates that Planctomycetes possess a typical PG cell wall and that their cellular architecture is thus more similar to that of other Gram-negative bacteria. Our findings shed new light on the cellular architecture and cell division of the maverick Planctomycetes. PMID:25964217

  16. Male homosexuality and spirit possession in Brazil.

    PubMed

    Fry, P

    1985-01-01

    This paper examines the relationship between male homosexuality and the Afro-Brazilian possession cults in Belém do Parà. After a discussion of the literature follows a description of the cults' beliefs, rites and social organization. Male sex roles are then discussed and the two categories, bicha and man, analyzed. It is noted that there is no term which is equivalent to the western category of "homosexual" in this taxonomic system. After putting forward folk explanations for the presence of many bichas in the cults, an analysis is put forward of the social rewards available to bichas within these cults, and the structural relationship between homosexuality and these regions in terms of their congruent marginality vis-à-vis "normal society." PMID:4093598

  17. Roots from distinct plant developmental stages are capable of rapidly selecting their own microbiome without the influence of environmental and soil edaphic factors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soil microbes live in close association with plants and are crucial for plant health and fitness. Recent literature revealed that specific microbes were cultured at distinct developmental stages of Arabidopsis. It is not clear how fast the roots, depending on their developmental stage, can alter the...

  18. [The phenomenon of possession. Conception and experiences of possession in youth].

    PubMed

    Bron, B

    1975-01-01

    In the last few years, a trend to the multiplication of experiences of possession has been observed in young people. On the basis of four typical examples, the author examines this phenomenon in the light of the psychiatric, psychoanalytic and theological understanding of possession. It involves mostly young people, who do not have hysterical fits or psychotic episodes during spiritualist practices but who specially tend to take a strong interest in occultism, who very often consume drugs and have contacts with groups in which the interest for demonology plays an important part. PMID:1192724

  19. Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster

    PubMed Central

    Valentino, Michael D.; McGuire, Abigail Manson; Rosch, Jason W.; Bispo, Paulo J. M.; Burnham, Corinna; Sanfilippo, Christine M.; Carter, Robert A.; Zegans, Michael E.; Beall, Bernard; Earl, Ashlee M.; Tuomanen, Elaine I.; Morris, Timothy W.; Haas, Wolfgang; Gilmore, Michael S.

    2014-01-01

    Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the US. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with other unencapsulated nasopharyngeal S. pneumoniae. They also possess putative adhesins that have not been described in encapsulated pneumococci. These findings suggest that the unencapsulated strains capable of causing conjunctivitis utilize a pathogenesis strategy substantially different from that described for S. pneumoniae at other infection sites. PMID:25388376

  20. 50 CFR 648.86 - NE Multispecies possession restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... common pool sub-ACL in that fishing year. (2) Possession restrictions to facilitate harvest of sub-ACLs..., a per-DAS possession limit and/or a maximum trip limit in order to facilitate harvest and enable...

  1. Lungfishes, Like Tetrapods, Possess a Vomeronasal System

    PubMed Central

    González, Agustín; Morona, Ruth; López, Jesús M.; Moreno, Nerea; Northcutt, R. Glenn

    2010-01-01

    The vomeronasal system (VNS) is an accessory olfactory system that in tetrapod vertebrates is composed of specific receptor neurons in the nasal organ and a set of centers in the forebrain that receive and relay the information consecutively towards the hypothalamus. Thus, only in tetrapods the VNS comprises a discrete vomeronasal (Jacobson's) organ, which contains receptor cells that are morphologically distinct from those of the olfactory epithelium and use different transduction mechanisms. The axons of the vomeronasal receptors in tetrapods project to the accessory olfactory bulb (AOB) in the rostral telencephalon. Secondary vomeronasal connections exist through the medial amygdala to the hypothalamus. Currently, the lungfishes are considered the closest living relatives of tetrapods. Here we show that the African lungfish, Protopterus dolloi, has epithelial crypts at the base of the lamellae of the olfactory epithelium that express markers of the vomeronasal receptors in tetrapods. The projections of these crypts allow us to identify an AOB on the lateral margin of the main olfactory bulb. The projections of this AOB reach a region that is topologically, hodologically, and immunohistochemically identical to the medial amygdala and could represent its homolog. Neurons of this putative medial amygdala were demonstrated to project to the lateral hypothalamus, as they do in tetrapods. All these features that lungfishes share with tetrapods indicate that lungfishes have the complete set of brain centers and connections involved in processing vomeronasal information and that these features were already present in the last common ancestor of lungfishes and tetrapods. PMID:20941371

  2. 50 CFR 622.408 - Bag/possession limits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Lobster Fishery of the Gulf of Mexico and South Atlantic § 622.408 Bag/possession limits. (a) EEZ off the southern Atlantic states, other than Florida. The daily bag or possession limit for spiny lobster in or... or possession limit of spiny lobster in or from the EEZ off Florida and off the Gulf states,...

  3. 50 CFR 622.408 - Bag/possession limits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Lobster Fishery of the Gulf of Mexico and South Atlantic § 622.408 Bag/possession limits. (a) EEZ off the southern Atlantic states, other than Florida. The daily bag or possession limit for spiny lobster in or... or possession limit of spiny lobster in or from the EEZ off Florida and off the Gulf states,...

  4. 50 CFR 622.277 - Bag and possession limits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... ATLANTIC Dolphin and Wahoo Fishery Off the Atlantic States § 622.277 Bag and possession limits. Section 622.11(a) provides the general applicability for bag and possession limits. (a) Atlantic dolphin and wahoo. Bag and possession limits are as follows: (1) Dolphin—10, not to exceed 60 per vessel,...

  5. 50 CFR 622.277 - Bag and possession limits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... ATLANTIC Dolphin and Wahoo Fishery Off the Atlantic States § 622.277 Bag and possession limits. Section 622.11(a) provides the general applicability for bag and possession limits. (a) Atlantic dolphin and wahoo. Bag and possession limits are as follows: (1) Dolphin—10, not to exceed 60 per vessel,...

  6. 31 CFR 0.215 - Possession of weapons and explosives.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false Possession of weapons and explosives... OF THE TREASURY EMPLOYEE RULES OF CONDUCT Rules of Conduct § 0.215 Possession of weapons and explosives. (a) Employees shall not possess firearms, explosives, or other dangerous or deadly...

  7. 31 CFR 0.215 - Possession of weapons and explosives.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false Possession of weapons and explosives... OF THE TREASURY EMPLOYEE RULES OF CONDUCT Rules of Conduct § 0.215 Possession of weapons and explosives. (a) Employees shall not possess firearms, explosives, or other dangerous or deadly...

  8. 31 CFR 0.215 - Possession of weapons and explosives.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false Possession of weapons and explosives... OF THE TREASURY EMPLOYEE RULES OF CONDUCT Rules of Conduct § 0.215 Possession of weapons and explosives. (a) Employees shall not possess firearms, explosives, or other dangerous or deadly...

  9. 31 CFR 0.215 - Possession of weapons and explosives.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Possession of weapons and explosives... OF THE TREASURY EMPLOYEE RULES OF CONDUCT Rules of Conduct § 0.215 Possession of weapons and explosives. (a) Employees shall not possess firearms, explosives, or other dangerous or deadly...

  10. 31 CFR 0.215 - Possession of weapons and explosives.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Possession of weapons and explosives... OF THE TREASURY EMPLOYEE RULES OF CONDUCT Rules of Conduct § 0.215 Possession of weapons and explosives. (a) Employees shall not possess firearms, explosives, or other dangerous or deadly...

  11. 50 CFR 648.145 - Black sea bass possession limit.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 12 2012-10-01 2012-10-01 false Black sea bass possession limit. 648.145... Measures for the Black Sea Bass Fishery § 648.145 Black sea bass possession limit. (a) From January 1 through February 28, no person shall possess more than 15 black sea bass in, or harvested from, the...

  12. 50 CFR 648.145 - Black sea bass possession limit.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 12 2013-10-01 2013-10-01 false Black sea bass possession limit. 648.145... Measures for the Black Sea Bass Fishery § 648.145 Black sea bass possession limit. (a) During the recreational fishing season specified at § 648.146, no person shall possess more than 20 black sea bass in,...

  13. 50 CFR 648.145 - Black sea bass possession limit.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 50 Wildlife and Fisheries 12 2014-10-01 2014-10-01 false Black sea bass possession limit. 648.145... Measures for the Black Sea Bass Fishery § 648.145 Black sea bass possession limit. (a) During the recreational fishing season specified at § 648.146, no person shall possess more than 15 black sea bass in,...

  14. 20 CFR 404.1093 - Possession of the United States.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Possession of the United States. 404.1093... Income § 404.1093 Possession of the United States. In using the exclusions from gross income provided under section 931 of the Code (relating to income from sources within possessions of the United...

  15. A comparative structural analysis reveals distinctive features of co-factor binding and substrate specificity in plant aldo-keto reductases.

    PubMed

    Giuseppe, Priscila Oliveira de; Santos, Marcelo Leite Dos; Sousa, Sylvia Morais de; Koch, Karen E; Yunes, José Andrés; Aparicio, Ricardo; Murakami, Mario Tyago

    2016-06-10

    Plant aldo-keto reductases of the AKR4C subfamily play key roles during stress and are attractive targets for developing stress-tolerant crops. However, these AKR4Cs show little to no activity with previously-envisioned sugar substrates. We hypothesized a structural basis for the distinctive cofactor binding and substrate specificity of these plant enzymes. To test this, we solved the crystal structure of a novel AKR4C subfamily member, the AKR4C7 from maize, in the apo form and in complex with NADP(+). The binary complex revealed an intermediate state of cofactor binding that preceded closure of Loop B, and also indicated that conformational changes upon substrate binding are required to induce a catalytically-favorable conformation of the active-site pocket. Comparative structural analyses of homologues (AKR1B1, AKR4C8 and AKR4C9) showed that evolutionary redesign of plant AKR4Cs weakened interactions that stabilize the closed conformation of Loop B. This in turn decreased cofactor affinity and altered configuration of the substrate-binding site. We propose that these structural modifications contribute to impairment of sugar reductase activity in favor of other substrates in the plant AKR4C subgroup, and that catalysis involves a three-step process relevant to other AKRs. PMID:27154221

  16. Evidence for a novel serum factor distinct from zinc alpha-2 glycoprotein that promotes body fat loss early in the development of cachexia.

    PubMed

    Byerley, Lauri O; Lee, Sang Ho; Redmann, Steve; Culberson, Cathy; Clemens, Mark; Lively, Mark O

    2010-01-01

    We provide evidence that a factor other than the previously identified lipid mobilizing factor, zinc alpha-2 glycoprotein, promotes lipolysis in the MCA-induced sarcoma-bearing cachexia model. Cachexia is characterized by progressive loss of adipose tissue and skeletal muscle without a concurrent increase in food intake to restore lost tissue stores. We compared tumor-bearing ad lib fed (TB) animals to nontumor bearing ad lib fed (NTB) animals or nontumor-bearing pair-fed (PF) animals at various time points throughout development of tumor derived cachexia. Prior to cachexia, the TB animals lost more than 10 +/- 0.7% of their body fat before losing protein mass and decreasing their food intake. Fat loss occurred because adipocyte size, not number, was reduced. Increased turnover of palmitate and significantly higher serum triglyceride levels prior to cachexia were further indicators of an early loss of lipid from the adipocytes. Yet, circulating levels of norepinephrine, epinephrine, TNF-alpha, and zinc alpha-2 glycoprotein were not increased prior to the loss of fat mass. We provide evidence for a serum factor(s), other than zinc alpha-2 glycoprotein, that stimulates release of glycerol from 3T3-L1 adipocytes and promotes the loss of stored adipose lipid prior to the loss of lean body mass in this model. PMID:20432169

  17. Regulation of energy metabolism by the extracytoplasmic function (ECF) s factors of Arcobacter butzleri

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The extracytoplasmic function (ECF) s factors are fundamental for bacterial adaptation to distinct environments and for survival under different stress conditions. The emerging pathogen Arcobacter butzleri possesses seven putative pairs of s/anti-s factors belonging to the ECF family. Here, we repor...

  18. CovS simultaneously activates and inhibits the CovR-mediated repression of distinct subsets of group A Streptococcus virulence factor-encoding genes.

    PubMed

    Treviño, Jeanette; Perez, Nataly; Ramirez-Peña, Esmeralda; Liu, Zhuyun; Shelburne, Samuel A; Musser, James M; Sumby, Paul

    2009-08-01

    To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A Streptococcus (GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS). covR and covS mutant strains arise spontaneously during invasive infections and, in in vivo models of infection, rapidly become dominant. Here, we compared wild-type GAS with covR, covS, and covRS isogenic mutant strains to investigate the heterogeneity in the types of natural mutations that occur in covR and covS and the phenotypic consequences of covR or covS mutation. We found that the response regulator CovR retains some regulatory function in the absence of CovS and that CovS modulates CovR to significantly enhance repression of one group of genes (e.g., the speA, hasA, and ska genes) while it reduces repression of a second group of genes (e.g., the speB, grab, and spd3 genes). We also found that different in vivo-induced covR mutations can lead to strikingly different transcriptomes. While covS mutant strains show increased virulence in several invasive models of infection, we determined that these mutants are significantly outcompeted by wild-type GAS during growth in human saliva, an ex vivo model of upper respiratory tract infection. We propose that CovS-mediated regulation of CovR activity plays an important role in the ability of GAS to cycle between pharyngeal and invasive infections. PMID:19451242

  19. The selective post-translational processing of transcription factor Nrf1 yields distinct isoforms that dictate its ability to differentially regulate gene expression

    PubMed Central

    Zhang, Yiguo; Li, Shaojun; Xiang, Yuancai; Qiu, Lu; Zhao, Huakan; Hayes, John D.

    2015-01-01

    Upon translation, the N-terminal homology box 1 (NHB1) signal anchor sequence of Nrf1 integrates it within the endoplasmic reticulum (ER) whilst its transactivation domains [TADs, including acidic domain 1 (AD1), the flanking Asn/Ser/Thr-rich (NST) domain and AD2] are transiently translocated into the ER lumen, whereupon the NST domain is glycosylated to yield an inactive 120-kDa glycoprotein. Subsequently, these TADs are retrotranslocated into extra-luminal subcellular compartments, where Nrf1 is deglycosylated to yield an active 95-kDa isoform. Herein, we report that AD1 and AD2 are required for the stability of the 120-kDa Nrf1 glycoprotein, but not that of the non-glycosylated/de-glycosylated 95-kDa isoform. Degrons within AD1 do not promote proteolytic degradation of the 120-kDa Nrf1 glycoprotein. However, repositioning of AD2-adjoining degrons (i.e. DSGLS-containing SDS1 and PEST2 sequences) into the cyto/nucleoplasm enables selective topovectorial processing of Nrf1 by the proteasome and/or calpains to generate a cleaved active 85-kDa Nrf1 or a dominant-negative 36-kDa Nrf1γ. Production of Nrf1γ is abolished by removal of SDS1 or PEST2 degrons, whereas production of the cleaved 85-kDa Nrf1 is blocked by deletion of the ER luminal-anchoring NHB2 sequence (aa 81–106). Importantly, Nrf1 activity is positively and/or negatively regulated by distinct doses of proteasome and calpain inhibitors. PMID:26268886

  20. CovS Simultaneously Activates and Inhibits the CovR-Mediated Repression of Distinct Subsets of Group A Streptococcus Virulence Factor-Encoding Genes▿ †

    PubMed Central

    Treviño, Jeanette; Perez, Nataly; Ramirez-Peña, Esmeralda; Liu, Zhuyun; Shelburne, Samuel A.; Musser, James M.; Sumby, Paul

    2009-01-01

    To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A Streptococcus (GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS). covR and covS mutant strains arise spontaneously during invasive infections and, in in vivo models of infection, rapidly become dominant. Here, we compared wild-type GAS with covR, covS, and covRS isogenic mutant strains to investigate the heterogeneity in the types of natural mutations that occur in covR and covS and the phenotypic consequences of covR or covS mutation. We found that the response regulator CovR retains some regulatory function in the absence of CovS and that CovS modulates CovR to significantly enhance repression of one group of genes (e.g., the speA, hasA, and ska genes) while it reduces repression of a second group of genes (e.g., the speB, grab, and spd3 genes). We also found that different in vivo-induced covR mutations can lead to strikingly different transcriptomes. While covS mutant strains show increased virulence in several invasive models of infection, we determined that these mutants are significantly outcompeted by wild-type GAS during growth in human saliva, an ex vivo model of upper respiratory tract infection. We propose that CovS-mediated regulation of CovR activity plays an important role in the ability of GAS to cycle between pharyngeal and invasive infections. PMID:19451242

  1. The selective post-translational processing of transcription factor Nrf1 yields distinct isoforms that dictate its ability to differentially regulate gene expression.

    PubMed

    Zhang, Yiguo; Li, Shaojun; Xiang, Yuancai; Qiu, Lu; Zhao, Huakan; Hayes, John D

    2015-01-01

    Upon translation, the N-terminal homology box 1 (NHB1) signal anchor sequence of Nrf1 integrates it within the endoplasmic reticulum (ER) whilst its transactivation domains [TADs, including acidic domain 1 (AD1), the flanking Asn/Ser/Thr-rich (NST) domain and AD2] are transiently translocated into the ER lumen, whereupon the NST domain is glycosylated to yield an inactive 120-kDa glycoprotein. Subsequently, these TADs are retrotranslocated into extra-luminal subcellular compartments, where Nrf1 is deglycosylated to yield an active 95-kDa isoform. Herein, we report that AD1 and AD2 are required for the stability of the 120-kDa Nrf1 glycoprotein, but not that of the non-glycosylated/de-glycosylated 95-kDa isoform. Degrons within AD1 do not promote proteolytic degradation of the 120-kDa Nrf1 glycoprotein. However, repositioning of AD2-adjoining degrons (i.e. DSGLS-containing SDS1 and PEST2 sequences) into the cyto/nucleoplasm enables selective topovectorial processing of Nrf1 by the proteasome and/or calpains to generate a cleaved active 85-kDa Nrf1 or a dominant-negative 36-kDa Nrf1γ. Production of Nrf1γ is abolished by removal of SDS1 or PEST2 degrons, whereas production of the cleaved 85-kDa Nrf1 is blocked by deletion of the ER luminal-anchoring NHB2 sequence (aa 81-106). Importantly, Nrf1 activity is positively and/or negatively regulated by distinct doses of proteasome and calpain inhibitors. PMID:26268886

  2. A case of possessive state with onset influenced by 'door-to-door' sales.

    PubMed

    Satoh, S; Obata, S; Seno, E; Okada, T; Morita, N; Saito, T; Yoshikawa, M; Yamagami, A

    1996-12-01

    Recently in Japan, 'door-to-door sales' has become of concern because it has created numerous legal and social problems. In this paper, a 47 year old dissociative trance disorder case who presented with possession by God is discussed. Specific types of door-to-door sales is known to use superstition and folk beliefs as tools to lure customers. In this particular case, these religious factors seemed to have played an important role in the precipitation of the disorder and its presentation. In addition, the brain-washing environment observed in video lectures used in door-to-door sales seemed to play an important role in the development of the possessive state. We also performed social psychiatric analysis of the occurrence of the possessive state in a city area, which has been considered to develop within traditional culture. Phenomenological classification by one of the authors was useful for diagnosing underlying disorders in the possessive state. PMID:9014228

  3. Firearm Possession Among Adolescents Presenting to an Urban Emergency Department for Assault

    PubMed Central

    Walton, Maureen A.; Newton, Manya F.; Clery, Michael; Whiteside, Lauren K.; Zimmerman, Marc A.; Cunningham, Rebecca M.

    2013-01-01

    BACKGROUND AND OBJECTIVES: Firearm violence is a leading cause of death among youth. The objectives of this study were (1) determine firearm possession rates and associated correlates among youth seeking care for assault in an emergency department (ED); (2) understand differences in risk factors for youth with firearm possession; and (3) identify firearm possession characteristics in this population: type, reason for possession, and source of firearms. METHODS: Youth (14 to 24 years old) presenting to a Level 1 ED with assault were administered a computerized screening survey. Validated instruments were administered, measuring demographics, firearm rates and characteristics, attitudes toward aggression, substance use, and previous violence history. RESULTS: Among 689 assault-injured youth, 23% reported firearm possession in the past 6 months. Only 17% of those reporting firearm possession obtained the gun from a legal source; 22% reported ownership of highly lethal automatic/semiautomatic weapons and 37.1% reported having a firearm for protection. Logistic regression analysis identified significant correlates of firearm possession, including male gender, higher socioeconomic status, illicit drug use, recent serious fight, and retaliatory attitudes. CONCLUSIONS: ED assault-injured youth had high rates of firearm possession (23.1%), most of which were not obtained from legal sources. Youth with firearm possession were more likely to have been in a recent serious fight, and to endorse aggressive attitudes that increase their risk for retaliatory violence. Future prevention efforts should focus on minimizing illegal firearm access among high-risk youth, nonviolent alternatives to retaliatory violence, and substance use prevention. PMID:23837181

  4. Different domains of the murine RNA polymerase I-specific termination factor mTTF-I serve distinct functions in transcription termination.

    PubMed Central

    Evers, R; Smid, A; Rudloff, U; Lottspeich, F; Grummt, I

    1995-01-01

    Termination of mouse ribosomal gene transcription by RNA polymerase I (Pol I) requires the specific interaction of a DNA binding protein, mTTF-I, with an 18 bp sequence element located downstream of the rRNA coding region. Here we describe the molecular cloning and functional characterization of the cDNA encoding this transcription termination factor. Recombinant mTTF-I binds specifically to the murine terminator elements and terminates Pol I transcription in a reconstituted in vitro system. Deletion analysis has defined a modular structure of mTTF-I comprising a dispensable N-terminal half, a large C-terminal DNA binding region and an internal domain which is required for transcription termination. Significantly, the C-terminal region of mTTF-I reveals striking homology to the DNA binding domains of the proto-oncogene c-Myb and the yeast transcription factor Reb1p. Site-directed mutagenesis of one of the tryptophan residues that is conserved in the homology region of c-Myb, Reb1p and mTTF-I abolishes specific DNA binding, a finding which underscores the functional relevance of these residues in DNA-protein interactions. Images PMID:7720715

  5. Peroxisome Proliferator-activated Receptor γ Regulates Genes Involved in Insulin/Insulin-like Growth Factor Signaling and Lipid Metabolism during Adipogenesis through Functionally Distinct Enhancer Classes*

    PubMed Central

    Oger, Frédérik; Dubois-Chevalier, Julie; Gheeraert, Céline; Avner, Stéphane; Durand, Emmanuelle; Froguel, Philippe; Salbert, Gilles; Staels, Bart; Lefebvre, Philippe; Eeckhoute, Jérôme

    2014-01-01

    The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPARγ induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPARγ also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPARγ utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process. PMID:24288131

  6. Russian Federation: penalties eased for possession of illegal drugs.

    PubMed

    2004-04-01

    In November 2003, after long deliberations, the Russian Parliament passed a bill amending the national Criminal Code to differentiate between the liability for possession of illegal drugs for drug users and for drug traffickers. The reforms involved redefining the terms "large" and "extra-large" with respect to the quantities for possession and trafficking of illegal substances. (There is no criminal liability for possession of less than a large amount.) On 16 December 2003, the new bill was enacted into law. PMID:15216819

  7. Recognition of distinct HLA-DQA1 promoter elements by a single nuclear factor containing Jun and Fos or antigenically related proteins.

    PubMed Central

    Neve Ombra, M; Autiero, M; DeLerma Barbaro, A; Barretta, R; Del Pozzo, G; Guardiola, J

    1993-01-01

    The activity of MHC class II promoters depends upon conserved regulatory signals one of which, the extended X-box, contains in its X2 subregion a sequence related to the cAMP response element, CRE and to the TPA response element, TRE. Accordingly, X2 is recognized by the AP-1 factor and by other c-Jun or c-Fos containing heterodimers. We report that the X-box dependent promoter activity of the HLA-DQA1 gene is down-modulated by an array of DNA elements each of which represented twice either in an invertedly or directly repeated orientation. In this frame, we describe a nuclear binding factor, namely DBF, promiscuously interacting with two of these additional signals, delta and sigma, and with a portion of the X-box, namely the X-core, devoid of X2. The presence of a single factor recognizing divergent DNA sequences was indicated by the finding that these activities were co-eluted from a heparin-Sepharose column and from DNA affinity columns carrying different DNA binding sites as ligands. Competition experiments made with oligonucleotides representing wild type and mutant DNA elements showed that each DNA element specifically inhibited the binding of the others, supporting the contention that DBF is involved in recognition of different targets. Furthermore, we found that DBF also exhibits CRE/TRE binding activity and that this activity can be competed out by addition of an excess of sigma, delta and X-core oligonucleotides. Anti-Jun peptide and anti-Fos peptide antibodies blocked not only the binding activity of DBF, but also its X-core and sigma binding; this blockade was removed by the addition of the Jun or Fos peptides against which the antibodies had been raised. In vitro synthesized Jun/Fos was able to bind to all these boxes, albeit with seemingly different affinities. The cooperativity of DBF interactions may explain the modulation of the X-box dependent promoter activity mediated by the accessory DNA elements described here. Images PMID:8493100

  8. The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding

    PubMed Central

    Andersen, Kristian G.; Hebenstreit, Daniel; Teichmann, Sarah A.; Betz, Alexander G.

    2015-01-01

    The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3’s function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression. PMID:26107960

  9. Eukaryotic Initiation Factor eIFiso4G1 and eIFiso4G2 Are Isoforms Exhibiting Distinct Functional Differences in Supporting Translation in Arabidopsis.

    PubMed

    Gallie, Daniel R

    2016-01-15

    The eukaryotic translation initiation factor (eIF) 4G is required during protein synthesis to promote the assembly of several factors involved in the recruitment of a 40S ribosomal subunit to an mRNA. Although many eukaryotes express two eIF4G isoforms that are highly similar, the eIF4G isoforms in plants, referred to as eIF4G and eIFiso4G, are highly divergent in size, sequence, and domain organization but both can interact with eIF4A, eIF4B, eIF4E isoforms, and the poly(A)-binding protein. Nevertheless, eIF4G and eIFiso4G from wheat exhibit preferences in the mRNAs they translate optimally. For example, mRNA containing the 5'-leader (called Ω) of tobacco mosaic virus preferentially uses eIF4G in wheat germ lysate. In this study, the eIF4G isoform specificity of Ω was used to examine functional differences of the eIF4G isoforms in Arabidopsis. As in wheat, Ω-mediated translation was reduced in an eif4g null mutant. Loss of the eIFiso4G1 isoform, which is similar in sequence to wheat eIFiso4G, did not substantially affect Ω-mediated translation. However, loss of the eIFiso4G2 isoform substantially reduced Ω-mediated translation. eIFiso4G2 is substantially divergent from eIFiso4G1 and is present only in the Brassicaceae, suggesting a recent evolution. eIFiso4G2 isoforms exhibit sequence-specific differences in regions representing partner protein and RNA binding sites. Loss of any eIF4G isoform also resulted in a substantial reduction in reporter transcript level. These results suggest that eIFiso4G2 appeared late in plant evolution and exhibits more functional similarity with eIF4G than with eIFiso4G1 during Ω-mediated translation. PMID:26578519

  10. The high-mobility group A-type protein CarD of the bacterium Myxococcus xanthus as a transcription factor for several distinct vegetative genes.

    PubMed Central

    Galbis-Martínez, Marisa; Fontes, Marta; Murillo, Francisco J

    2004-01-01

    CarD is the only reported prokaryotic protein showing structural and functional features typical of eukaryotic high-mobility group A transcription factors. In prokaryotes, proteins similar to CarD appear to be confined primarily to myxobacteria. In Myxococcus xanthus, CarD has been previously shown to act as a positive element in two different regulatory networks: one for light-induced synthesis of carotenoids and the other for starvation-induced fruiting body formation. We have now tested the effect of a loss-of-function mutation in the carD gene (carD1) on the expression of a random collection of lacZ-tagged genes, which are normally expressed in the dark during vegetative growth in rich medium. Our results indicate that CarD plays a significant role in the transcriptional regulation of various indicated genes. The carD1 mutation downregulates some genes and upregulates others. Also reported here is the isolation of several mutations that suppress the strong effect of carD1 on the expression of a particular vegetative gene. One of them (sud-2) also suppresses the effect of carD1 on other vegetative genes and on fruiting-body formation. Thus, CarD and the sud-2 gene product appear to participate in a single mechanism, which underlies various apparently diverse regulatory phenomena ascribed to CarD. PMID:15342500

  11. Two distinct forms of the 64,000 Mr protein of the cleavage stimulation factor are expressed in mouse male germ cells

    PubMed Central

    Wallace, A. Michelle; Dass, Brinda; Ravnik, Stuart E.; Tonk, Vijay; Jenkins, Nancy A.; Gilbert, Debra J.; Copeland, Neal G.; MacDonald, Clinton C.

    1999-01-01

    Polyadenylation in male germ cells differs from that in somatic cells. Many germ cell mRNAs do not contain the canonical AAUAAA in their 3′ ends but are efficiently polyadenylated. To determine whether the 64,000 Mr protein of the cleavage stimulation factor (CstF-64) is altered in male germ cells, we examined its expression in mouse testis. In addition to the 64,000 Mr form, we found a related ≈70,000 Mr protein that is abundant in testis, at low levels in brain, and undetectable in all other tissues examined. Expression of the ≈70,000 Mr CstF-64 was limited to meiotic spermatocytes and postmeiotic spermatids in testis. In contrast, the 64,000 Mr form was absent from spermatocytes, suggesting that the testis-specific CstF-64 might control expression of meiosis-specific genes. To determine why the 64,000 Mr CstF-64 is not expressed in spermatocytes, we mapped its chromosomal location to the X chromosome in both mouse and human. CstF-64 may, therefore, be absent in spermatocytes because the X chromosome is inactivated during male meiosis. By extension, the testis-specific CstF-64 may be expressed from an autosomal homolog of the X chromosomal gene. PMID:10359786

  12. µ-Calpain Conversion of Antiapoptotic Bfl-1 (BCL2A1) into a Prodeath Factor Reveals Two Distinct alpha-Helices Inducing Mitochondria-Mediated Apoptosis

    PubMed Central

    Jugé, Romain; Debaud, Anne-Laure; Giménez, Diana; Gillet, Germain; Bonnefoy-Bérard, Nathalie; Salgado, Jesús; Salles, Gilles; Aouacheria, Abdel; Kucharczak, Jérôme

    2012-01-01

    Anti-apoptotic Bfl-1 and pro-apoptotic Bax, two members of the Bcl-2 family sharing a similar structural fold, are classically viewed as antagonist regulators of apoptosis. However, both proteins were reported to be death inducers following cleavage by the cysteine protease µ-calpain. Here we demonstrate that calpain-mediated cleavage of full-length Bfl-1 induces the release of C-terminal membrane active α-helices that are responsible for its conversion into a pro-apoptotic factor. A careful comparison of the different membrane-active regions present in the Bfl-1 truncated fragments with homologous domains of Bax show that helix α5, but not α6, of Bfl-1 induces cell death and cytochrome c release from purified mitochondria through a Bax/Bak-dependent mechanism. In contrast, both helices α5 and α6 of Bax permeabilize mitochondria regardless of the presence of Bax or Bak. Moreover, we provide evidence that the α9 helix of Bfl-1 promotes cytochrome c release and apoptosis through a unique membrane-destabilizing action whereas Bax-α9 does not display such activities. Hence, despite a common 3D-structure, C-terminal toxic domains present on Bfl-1 and Bax function in a dissimilar manner to permeabilize mitochondria and induce apoptosis. These findings provide insights for designing therapeutic approaches that could exploit the cleavage of endogenous Bcl-2 family proteins or the use of Bfl-1/Bax-derived peptides to promote tumor cell clearance. PMID:22745672

  13. Distinct Characteristics of Small Cell Lung Cancer Correlate With Central or Peripheral Origin: Subtyping Based on Location and Expression of Transcription Factor TTF-1.

    PubMed

    Miyauchi, Eisaku; Motoi, Noriko; Ono, Hiroshi; Ninomiya, Hironori; Ohyanagi, Fumiyoshi; Nishio, Makoto; Okumura, Sakae; Ichinose, Masakazu; Ishikawa, Yuichi

    2015-12-01

    Small-cell lung carcinoma (SCLC) is a type of lung cancer with neuroendocrine differentiation and a poor prognosis that is widely believed to arise in the central lung. Thyroid transcription factor-1 (TTF-1) is a peripheral marker of lung adenocarcinoma that is also highly expressed in SCLC. In this study, we examined whether SCLC is really a central-type tumor and the relationship between tumor location, TTF-1 expression and prognosis of SCLC.Ninety six SCLCs, diagnosed from biopsies or surgical materials, for which detailed computed tomography (CT) images were available, were collected consecutively from Japanese patients between 2004 and 2011. We examined the location of the primary tumor (central or peripheral) using thin-sliced CT, a TTF-1 immunohistochemical expression, and clinicopathology including prognosis.Of the 96 SCLCs, 74% (71/96) were of the peripheral type and found to have a significantly worse prognosis than central-type tumors. TTF-1 immunoreactivity was identified in 79 tumors (82%), 78% of which (62/79) were of the peripheral type and 22% of which were central. TTF-1 expression was significantly correlated with peripheral location (P = 0.030). Multivariate analysis revealed that high TNM stages and the peripheral location were independent markers for poor survival.The majority of SCLCs were of the peripheral type. The peripheral-type SCLC expressed TTF-1 more frequently and had a poorer prognosis than central-type tumors did. Further analysis on original sites of SCLC, using molecular methodology, or based on another ethnicity, should be warranted. PMID:26705222

  14. A role for sorting nexin 2 in epidermal growth factor receptor down-regulation: evidence for distinct functions of sorting nexin 1 and 2 in protein trafficking.

    PubMed

    Gullapalli, Anuradha; Garrett, Tiana A; Paing, May M; Griffin, Courtney T; Yang, Yonghua; Trejo, JoAnn

    2004-05-01

    Sorting nexin 1 (SNX1) and SNX2, homologues of the yeast vacuolar protein-sorting (Vps)5p, contain a phospholipid-binding motif termed the phox homology (PX) domain and a carboxyl terminal coiled-coil region. A role for SNX1 in trafficking of cell surface receptors from endosomes to lysosomes has been proposed; however, the function of SNX2 remains unknown. Toward understanding the function of SNX2, we first examined the distribution of endogenous protein in HeLa cells. We show that SNX2 resides primarily in early endosomes, whereas SNX1 is found partially in early endosomes and in tubulovesicular-like structures distributed throughout the cytoplasm. We also demonstrate that SNX1 interacts with the mammalian retromer complex through its amino terminal domain, whereas SNX2 does not. Moreover, activated endogenous epidermal growth factor receptor (EGFR) colocalizes markedly with SNX2-positive endosomes, but minimally with SNX1-containing vesicles. To assess SNX2 function, we examined the effect of a PX domain-mutated SNX2 that is defective in vesicle localization on EGFR trafficking. Mutant SNX2 markedly inhibited agonist-induced EGFR degradation, whereas internalization remained intact. In contrast, SNX1 PX domain mutants failed to effect EGFR degradation, whereas a SNX1 deletion mutant significantly inhibited receptor down-regulation. Interestingly, knockdown of SNX1 and SNX2 expression by RNA interference failed to alter agonist-induced EGFR down-regulation. Together, these findings suggest that both SNX1 and SNX2 are involved in regulating lysosomal sorting of internalized EGFR, but neither protein is essential for this process. These studies are the first to demonstrate a function for SNX2 in protein trafficking. PMID:14978220

  15. Parental Contributions to Adolescents' Possessions and Educational Expenses: Gender Differences.

    ERIC Educational Resources Information Center

    Peters, John F.

    1991-01-01

    Explored adolescent gender differences in possessions and parental financial assistance. Eight common adolescent possessions were analyzed, as well as expected parental contributions to their children's postsecondary education. Findings from 448 high school students revealed that males were significantly more likely to own stereos and athletic…

  16. 50 CFR 648.235 - Possession and landing restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Measures for the Spiny Dogfish Fishery § 648.235 Possession and landing restrictions. Link to an amendment... a valid Federal spiny dogfish permit specified under § 648.4(a)(11) may: (1) Possess up to 3,000 lb (1.36 mt) of spiny dogfish per trip; and (2) Land only one trip of spiny dogfish per calendar day....

  17. 50 CFR 648.235 - Possession and landing restrictions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Measures for the Spiny Dogfish Fishery § 648.235 Possession and landing restrictions. (a) Quota Period 1. From May 1 through October 31, vessels issued a valid Federal spiny dogfish permit specified under § 648.4(a)(11) may: (1) Possess up to 3,000 lb (1.36 mt) of spiny dogfish per trip; and (2) Land...

  18. Treasured Possessions and Their Meanings in Adolescent Males and Females.

    ERIC Educational Resources Information Center

    Kamptner, N. Laura

    1995-01-01

    Analyzes treasured possessions and their meanings in adolescence, including their relation to those treasured during early life and their relation to self-identity. Subjects were 14- to 18-year-old high school students (n=249). Results showed that males' most treasured possessions embodied enjoyment and instrumental meanings, whereas females'…

  19. 50 CFR 640.23 - Bag/possession limits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ADMINISTRATION, DEPARTMENT OF COMMERCE SPINY LOBSTER FISHERY OF THE GULF OF MEXICO AND SOUTH ATLANTIC Management... daily bag or possession limit for spiny lobster in or from the EEZ off the southern Atlantic states... fishing season specified in § 640.20(b)(1), the daily bag or possession limit of spiny lobster in or...

  20. 50 CFR 640.23 - Bag/possession limits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... ADMINISTRATION, DEPARTMENT OF COMMERCE SPINY LOBSTER FISHERY OF THE GULF OF MEXICO AND SOUTH ATLANTIC Management... daily bag or possession limit for spiny lobster in or from the EEZ off the southern Atlantic states... fishing season specified in § 640.20(b)(1), the daily bag or possession limit of spiny lobster in or...

  1. 50 CFR 640.23 - Bag/possession limits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ADMINISTRATION, DEPARTMENT OF COMMERCE SPINY LOBSTER FISHERY OF THE GULF OF MEXICO AND SOUTH ATLANTIC Management... daily bag or possession limit for spiny lobster in or from the EEZ off the southern Atlantic states... fishing season specified in § 640.20(b)(1), the daily bag or possession limit of spiny lobster in or...

  2. 50 CFR 635.30 - Possession at sea and landing.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ....30 Possession at sea and landing. (a) Atlantic tunas. Persons that own or operate a fishing vessel that possesses an Atlantic tuna in the Atlantic Ocean or that lands an Atlantic tuna in an Atlantic coastal port must maintain such Atlantic tuna through offloading either in round form or eviscerated...

  3. 50 CFR 635.30 - Possession at sea and landing.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ....30 Possession at sea and landing. (a) Atlantic tunas. Persons that own or operate a fishing vessel that possesses an Atlantic tuna in the Atlantic Ocean or that lands an Atlantic tuna in an Atlantic coastal port must maintain such Atlantic tuna through offloading either in round form or eviscerated...

  4. 50 CFR 635.30 - Possession at sea and landing.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ....30 Possession at sea and landing. (a) Atlantic tunas. Persons that own or operate a fishing vessel that possesses an Atlantic tuna in the Atlantic Ocean or that lands an Atlantic tuna in an Atlantic coastal port must maintain such Atlantic tuna through offloading either in round form or eviscerated...

  5. 50 CFR 635.30 - Possession at sea and landing.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ....30 Possession at sea and landing. (a) Atlantic tunas. Persons that own or operate a fishing vessel that possesses an Atlantic tuna in the Atlantic Ocean or that lands an Atlantic tuna in an Atlantic coastal port must maintain such Atlantic tuna through offloading either in round form or eviscerated...

  6. 45 CFR 670.6 - Prior possession exception.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 3 2013-10-01 2013-10-01 false Prior possession exception. 670.6 Section 670.6 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION CONSERVATION OF ANTARCTIC ANIMALS AND PLANTS Prohibited Acts, Exceptions § 670.6 Prior possession exception. (a) Exception. Section 670.4 shall not apply...

  7. Pre-Posed Possessive Constructions in Russian and Polish

    ERIC Educational Resources Information Center

    Houle, Erik Richard

    2013-01-01

    In Contemporary Standard Russian (CSR) and Contemporary Standard Polish (CSP) nominal possession is conveyed by means of the adnominal genitive. In this construction the dependent follows the noun it modifies and is marked morphologically for possession in the genitive case. The head noun is marked morphologically for any one of the six…

  8. The Relationship between Social Capital and Weapon Possession on Campus

    ERIC Educational Resources Information Center

    Messer, Rachel H.; Bradley, Kristopher I.; Calvi, Jessica L.; Kennison, Shelia M.

    2012-01-01

    The present research focused on the problem of how college officials might be able to predict weapon possession on college campuses. We hypothesized that measures of social capital (i.e., trust and participation in society) may be useful in identifying individuals who are likely to possess weapons on campuses. Prior research has shown that those…

  9. 50 CFR 648.86 - NE Multispecies possession restrictions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... applicable provisions of this part, unless otherwise specified in § 648.90(a)(5)(i)(D)(2). (d) Small-mesh... subject to the following possession limits for small-mesh multispecies, which are based on the mesh size used by, or on board vessels fishing for, in possession of, or landing small-mesh multispecies....

  10. 27 CFR 31.202 - Possession of refilled liquor bottles.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... liquor bottles. 31.202 Section 31.202 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND... Liquor Bottles § 31.202 Possession of refilled liquor bottles. No person who sells, or offers for sale, distilled spirits, or agent or employee of such person, shall: (a) Possess any liquor bottle in which...

  11. 27 CFR 31.203 - Possession of used liquor bottles.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... bottles. 31.203 Section 31.203 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Bottles § 31.203 Possession of used liquor bottles. The possession of used liquor bottles by any person... circumstances: (a) The owner or occupant of any premises on which the used bottles have been lawfully...

  12. 27 CFR 31.203 - Possession of used liquor bottles.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... bottles. 31.203 Section 31.203 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Bottles § 31.203 Possession of used liquor bottles. The possession of used liquor bottles by any person... circumstances: (a) The owner or occupant of any premises on which the used bottles have been lawfully...

  13. 27 CFR 31.202 - Possession of refilled liquor bottles.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... liquor bottles. 31.202 Section 31.202 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND... Liquor Bottles § 31.202 Possession of refilled liquor bottles. No person who sells, or offers for sale, distilled spirits, or agent or employee of such person, shall: (a) Possess any liquor bottle in which...

  14. 50 CFR 648.40 - Prohibition on possession.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Atlantic Salmon § 648.40 Prohibition on possession. (a) Incidental catch. All Atlantic salmon caught... maximum probability of survival. (b) Presumption. The possession of Atlantic salmon is prima facie evidence that such Atlantic salmon were taken in violation of this regulation. Evidence that such fish...

  15. 50 CFR 648.40 - Prohibition on possession.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Atlantic Salmon § 648.40 Prohibition on possession. (a) Incidental catch. All Atlantic salmon caught... maximum probability of survival. (b) Presumption. The possession of Atlantic salmon is prima facie evidence that such Atlantic salmon were taken in violation of this regulation. Evidence that such fish...

  16. 50 CFR 648.40 - Prohibition on possession.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Atlantic Salmon § 648.40 Prohibition on possession. (a) Incidental catch. All Atlantic salmon caught... maximum probability of survival. (b) Presumption. The possession of Atlantic salmon is prima facie evidence that such Atlantic salmon were taken in violation of this regulation. Evidence that such fish...

  17. 50 CFR 648.40 - Prohibition on possession.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Atlantic Salmon § 648.40 Prohibition on possession. (a) Incidental catch. All Atlantic salmon caught... maximum probability of survival. (b) Presumption. The possession of Atlantic salmon is prima facie evidence that such Atlantic salmon were taken in violation of this regulation. Evidence that such fish...

  18. 50 CFR 648.40 - Prohibition on possession.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Atlantic Salmon § 648.40 Prohibition on possession. (a) Incidental catch. All Atlantic salmon caught... maximum probability of survival. (b) Presumption. The possession of Atlantic salmon is prima facie evidence that such Atlantic salmon were taken in violation of this regulation. Evidence that such fish...

  19. 50 CFR 648.94 - Monkfish possession and landing restrictions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... = 191). A vessel may not possess heads only without possessing the equivalent weight of tails allowed by... (head on and gutted), or any combination of the three provided the weight of monkfish heads on board does not exceed 1.91 times the weight of monkfish tails on board. When any combination of tails,...

  20. 19 CFR 123.62 - Baggage in possession of traveler.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Baggage in possession of traveler. 123.62 Section 123.62 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS RELATIONS WITH CANADA AND MEXICO Baggage § 123.62 Baggage in possession...

  1. 19 CFR 123.62 - Baggage in possession of traveler.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Baggage in possession of traveler. 123.62 Section 123.62 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Baggage § 123.62 Baggage in possession...

  2. 46 CFR 308.504 - Definition of territories and possessions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Definition of territories and possessions. 308.504 Section 308.504 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION EMERGENCY OPERATIONS WAR RISK INSURANCE War Risk Cargo Insurance I-Introduction § 308.504 Definition of territories and possessions. Whenever reference is made to...

  3. 9. Photocopy of 1845 manuscript (original in the possession of ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    9. Photocopy of 1845 manuscript (original in the possession of the Metropolitan Museum of Art, New York City, N.Y.; photocopy in the possession of the Onondaga Historical Association) ENTRY IN A. J. DAVIS' (ARCHITECT) ACCOUNT BOOK, SHOWING SKETCH OF WEST ELEVATION AND FIRST LEVEL PLAN, AND SCHEDULE OF TEN DRAWINGS - Sedgewick House, 742 James Street, Syracuse, Onondaga County, NY

  4. 32 CFR 552.102 - Requirements for possession and use.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 3 2013-07-01 2013-07-01 false Requirements for possession and use. 552.102 Section 552.102 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY MILITARY RESERVATIONS AND NATIONAL CEMETERIES REGULATIONS AFFECTING MILITARY RESERVATIONS Firearms and Weapons § 552.102 Requirements for possession and use....

  5. 32 CFR 552.102 - Requirements for possession and use.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 3 2014-07-01 2014-07-01 false Requirements for possession and use. 552.102 Section 552.102 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY MILITARY RESERVATIONS AND NATIONAL CEMETERIES REGULATIONS AFFECTING MILITARY RESERVATIONS Firearms and Weapons § 552.102 Requirements for possession and use....

  6. 32 CFR 552.102 - Requirements for possession and use.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 3 2011-07-01 2009-07-01 true Requirements for possession and use. 552.102 Section 552.102 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY MILITARY RESERVATIONS AND NATIONAL CEMETERIES REGULATIONS AFFECTING MILITARY RESERVATIONS Firearms and Weapons § 552.102 Requirements for possession and use....

  7. Possession experiences in dissociative identity disorder: a preliminary study.

    PubMed

    Ross, Colin A

    2011-01-01

    Dissociative trance disorder, which includes possession experiences, was introduced as a provisional diagnosis requiring further study in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Consideration is now being given to including possession experiences within dissociative identity disorder (DID) in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.), which is due to be published in 2013. In order to provide empirical data relevant to the relationship between DID and possession states, I analyzed data on the prevalence of trance, possession states, sleepwalking, and paranormal experiences in 3 large samples: patients with DID from North America; psychiatric outpatients from Shanghai, China; and a general population sample from Winnipeg, Canada. Trance, sleepwalking, paranormal, and possession experiences were much more common in the DID patients than in the 2 comparison samples. The study is preliminary and exploratory in nature because the samples were not matched in any way. PMID:21667381

  8. Dissociative trance disorder: clinical and Rorschach findings in ten persons reporting demon possession and treated by exorcism.

    PubMed

    Ferracuti, S; Sacco, R; Lazzari, R

    1996-06-01

    Although dissociative trance disorders, especially possession disorder, are probably more common than is usually though, precise clinical data are lacking. Ten persons undergoing exorcisms for devil trance possession state were studied with the Dissociative Disorders Diagnostic Schedule and the Rorschach test. These persons had many traits in common with dissociative identity disorder patients. They were overwhelmed by paranormal experiences. Despite claiming possession by a demon, most of them managed to maintain normal social functioning. Rorschach findings showed that these persons had a complex personality organization: Some of them displayed a tendency to oversimplify stimulus perception whereas others seemed more committed to psychological complexity. Most had severe impairment of reality testing, and 6 of the participants had an extratensive coping stile. In this group of persons reporting demon possession, dissociative trance disorder seems to be a distinct clinical manifestation of a dissociative continuum, sharing some features with dissociative identity disorder. PMID:8667145

  9. Does Possession of Apolipoprotein E[superscript E]4 Benefit Cognitive Function in Healthy Young Adults?

    ERIC Educational Resources Information Center

    Bunce, David; Anstey, Kaarin J.; Burns, Richard; Christensen, Helen; Easteal, Simon

    2011-01-01

    There is considerable evidence that the apolipoprotein E (APOE)[superscript E]4 allele is associated with cognitive deficits in older persons, and is a risk factor for dementia. However, it has recently been suggested that possession of the [superscript E]4 allele may benefit cognition in early adulthood. We tested this possibility in 5445…

  10. A G-string positive cis-regulatory element in the LpS1 promoter binds two distinct nuclear factors distributed non-uniformly in Lytechinus pictus embryos.

    PubMed

    Xiang, M; Lu, S Y; Musso, M; Karsenty, G; Klein, W H

    1991-12-01

    The LpS1 alpha and beta genes of Lytechinus pictus are activated at the late cleavage stage of embryogenesis, with LpS1 mRNAs accumulating only in lineages contributing to aboral ectoderm. We had shown previously that 762 bp of 5' flanking DNA from the LpS1 beta gene was sufficient for proper temporal and aboral ectoderm specific expression. In the present study, we identified a strong positive cis-regulatory element at -70 bp to -75 bp in the LpS1 beta promoter with the sequence (G)6 and a similar, more distal cis-element at -721 bp to -726 bp. The proximal 'G-string' element interacted with two nuclear factors, one specific to ectoderm and one to endoderm/mesoderm nuclear extracts, whereas the distal G-string element interacted only with the ectoderm factor. The ectoderm and endoderm/mesoderm G-string factors were distinct based on their migratory behavior in electrophoretic mobility shift assays, binding site specificities, salt optima and EDTA sensitivity. The proximal G-string element shared homology with a binding site for the mammalian transcription factor IF1, a protein that binds to negative cis-regulatory elements in the mouse alpha 1(I) and alpha 2(I) collagen gene promoters. Competition experiments using wild-type and mutant oligonucleotides indicated that the ectoderm G-string factor and IF1 have similar recognition sites. Partially purified IF1 specifically bound to an oligonucleotide containing the proximal G-string of LpS1 beta. From our results, we suggest that the ectoderm G-string factor, a member of the G-rich DNA-binding protein family, activates the LpS1 gene in aboral ectoderm cells by binding to the LpS1 promoter at the proximal G-string site. PMID:1811948