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  1. The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters.

    Science.gov (United States)

    Salinero, Alicia C; Knoll, Elisabeth R; Zhu, Z Iris; Landsman, David; Curcio, M Joan; Morse, Randall H

    2018-02-01

    The Ty1 retrotransposons present in the genome of Saccharomyces cerevisiae belong to the large class of mobile genetic elements that replicate via an RNA intermediary and constitute a significant portion of most eukaryotic genomes. The retromobility of Ty1 is regulated by numerous host factors, including several subunits of the Mediator transcriptional co-activator complex. In spite of its known function in the nucleus, previous studies have implicated Mediator in the regulation of post-translational steps in Ty1 retromobility. To resolve this paradox, we systematically examined the effects of deleting non-essential Mediator subunits on the frequency of Ty1 retromobility and levels of retromobility intermediates. Our findings reveal that loss of distinct Mediator subunits alters Ty1 retromobility positively or negatively over a >10,000-fold range by regulating the ratio of an internal transcript, Ty1i, to the genomic Ty1 transcript. Ty1i RNA encodes a dominant negative inhibitor of Ty1 retromobility that blocks virus-like particle maturation and cDNA synthesis. These results resolve the conundrum of Mediator exerting sweeping control of Ty1 retromobility with only minor effects on the levels of Ty1 genomic RNA and the capsid protein, Gag. Since the majority of characterized intrinsic and extrinsic regulators of Ty1 retromobility do not appear to effect genomic Ty1 RNA levels, Mediator could play a central role in integrating signals that influence Ty1i expression to modulate retromobility.

  2. Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP.

    Directory of Open Access Journals (Sweden)

    Julianne Elvenes

    Full Text Available The androgen receptor (AR has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.

  3. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation.

    Science.gov (United States)

    Malik, Sohail; Roeder, Robert G

    2010-11-01

    The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

  4. Unmanned Tactical Autonomous Control and Collaboration Coactive Design

    Science.gov (United States)

    2016-06-01

    process. When modeling processes with a waterfall design, the requirements are mostly understood upfront and allow developers to move on to subsequent...processes when modeling the system. As such, the focus is shifted to supplementing team capacities vice developing autonomy. The two aims of this...development method, Coactive Design. An advantage to using this method is that it includes the human and his or her internal processes when modeling the

  5. Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines

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    Kan Anne A

    2012-08-01

    Full Text Available Abstract Mesial temporal lobe epilepsy (mTLE is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25. Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25 showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7 showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7 could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I and CCL4 IR (pattern II were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti-epileptogenic immune pathways in this disease.

  6. Mediator and p300/CBP-Steroid Receptor Coactivator Complexes Have Distinct Roles, but Function Synergistically, during Estrogen Receptor α-Dependent Transcription with Chromatin Templates

    OpenAIRE

    Acevedo, Mari Luz; Kraus, W. Lee

    2003-01-01

    Ligand-dependent transcriptional activation by nuclear receptors involves the recruitment of various coactivators to the promoters of hormone-regulated genes assembled into chromatin. Nuclear receptor coactivators include histone acetyltransferase complexes, such as p300/CBP-steroid receptor coactivator (SRC), as well as the multisubunit mediator complexes (“Mediator”), which may help recruit RNA polymerase II to the promoter. We have used a biochemical approach, including an in vitro chromat...

  7. Abscisic acid promotes proteasome-mediated degradation of the transcription coactivator NPR1 in Arabidopsis thaliana.

    Science.gov (United States)

    Ding, Yezhang; Dommel, Matthew; Mou, Zhonglin

    2016-04-01

    Proteasome-mediated turnover of the transcription coactivator NPR1 is pivotal for efficient activation of the broad-spectrum plant immune responses known as localized acquired resistance (LAR) and systemic acquired resistance (SAR) in adjacent and systemic tissues, respectively, and requires the CUL3-based E3 ligase and its adaptor proteins, NPR3 and NPR4, which are receptors for the signaling molecule salicylic acid (SA). It has been shown that SA prevents NPR1 turnover under non-inducing and LAR/SAR-inducing conditions, but how cellular NPR1 homeostasis is maintained remains unclear. Here, we show that the phytohormone abscisic acid (ABA) and SA antagonistically influence cellular NPR1 protein levels. ABA promotes NPR1 degradation via the CUL3(NPR) (3/) (NPR) (4) complex-mediated proteasome pathway, whereas SA may protect NPR1 from ABA-promoted degradation through phosphorylation. Furthermore, we demonstrate that the timing and strength of SA and ABA signaling are critical in modulating NPR1 accumulation and target gene expression. Perturbing ABA or SA signaling in adjacent tissues alters the temporal dynamic pattern of NPR1 accumulation and target gene transcription. Finally, we show that sequential SA and ABA treatment leads to dynamic changes in NPR1 protein levels and target gene expression. Our results revealed a tight correlation between sequential SA and ABA signaling and dynamic changes in NPR1 protein levels and NPR1-dependent transcription in plant immune responses. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  8. Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Keiji; Oda, Kasumi; Mizuta, Shumpei; Ishino, Ruri; Urahama, Norinaga; Hasegawa, Natsumi [Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142 (Japan); Roeder, Robert G. [Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (United States); Ito, Mitsuhiro, E-mail: itomi@med.kobe-u.ac.jp [Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142 (Japan); Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (United States); Department of Family and Community Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 654-0142 (Japan); Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 159-8555 (Japan)

    2013-10-11

    Highlights: •MED1 is a bona fide T3-dependent coactivator on TSHB promoter. •Mice with LxxLL-mutant MED1 have attenuated TSHβ mRNA and thyroid hormone levels. •MED1 activates TSHB promoter T3-dependently in cultured cells. •T3-dependent MED1 action is enhanced when SRC1/SRC2 or HDAC2 is downregulated. •MED1 is also a T3-independent GATA2/Pit1 coactivator on TSHB promoter. -- Abstract: The MED1 subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor β (TRβ) on the TSHβ gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSHβ gene promoter.

  9. Role of the N-terminal activation domain of coactivator CoCoA in mediating transcriptional activation by β-catenin*

    OpenAIRE

    Yang, Catherine K.; Kim, Jeong Hoon; Stallcup, Michael R.

    2006-01-01

    The coiled-coil coactivator (CoCoA) is involved in transcriptional activation of target genes by nuclear receptors and the xenobiotic aryl hydrocarbon receptor, as well as target genes of the Wnt signaling pathway, which is mediated by the lymphocyte enhancer factor (LEF)/T cell factor transcription factors and the coactivator β-catenin. The recruitment of CoCoA by nuclear receptors is accomplished by the interaction of the central coiled-coiled domain of CoCoA with p160 coactivators; the C-t...

  10. Mediator 1 contributes to enamel mineralization as a coactivator for Notch1 signaling and stimulates transcription of the alkaline phosphatase gene.

    Science.gov (United States)

    Yoshizaki, Keigo; Hu, Lizhi; Nguyen, Thai; Sakai, Kiyoshi; Ishikawa, Masaki; Takahashi, Ichiro; Fukumoto, Satoshi; DenBesten, Pamela K; Bikle, Daniel D; Oda, Yuko; Yamada, Yoshihiko

    2017-08-18

    Tooth enamel is mineralized through the differentiation of multiple dental epithelia including ameloblasts and the stratum intermedium (SI), and this differentiation is controlled by several signaling pathways. Previously, we demonstrated that the transcriptional coactivator Mediator 1 (MED1) plays a critical role in enamel formation. For instance, conditional ablation of Med1 in dental epithelia causes functional changes in incisor-specific dental epithelial stem cells, resulting in mineralization defects in the adult incisors. However, the molecular mechanism by which Med1 deficiency causes these abnormalities is not clear. Here, we demonstrated that Med1 ablation causes early SI differentiation defects resulting in enamel hypoplasia of the Med1 -deficient molars. Med1 deletion prevented Notch1-mediated differentiation of the SI cells resulting in decreased alkaline phosphatase (ALPL), which is essential for mineralization. However, it does not affect the ability of ameloblasts to produce enamel matrix proteins. Using the dental epithelial SF2 cell line, we demonstrated that MED1 directly activates transcription of the Alpl gene through the stimulation of Notch1 signaling by forming a complex with cleaved Notch1-RBP-Jk on the Alpl promoter. These results suggest that MED1 may be essential for enamel matrix mineralization by serving as a coactivator for Notch1 signaling regulating transcription of the Alpl gene.

  11. Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

    OpenAIRE

    Gao, Lu; Rabbitt, Elizabeth H.; Condon, Jennifer C.; Renthal, Nora E.; Johnston, John M.; Mitsche, Matthew A.; Chambon, Pierre; Xu, Jianming; O’Malley, Bert W.; Mendelson, Carole R.

    2015-01-01

    The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A–deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process...

  12. Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

    International Nuclear Information System (INIS)

    Han, Ji Seung; Crowe, David L

    2010-01-01

    The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies

  13. The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation

    OpenAIRE

    Malik, Sohail; Roeder, Robert G.

    2010-01-01

    The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action ...

  14. Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition.

    Science.gov (United States)

    Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C; Renthal, Nora E; Johnston, John M; Mitsche, Matthew A; Chambon, Pierre; Xu, Jianming; O'Malley, Bert W; Mendelson, Carole R

    2015-07-01

    The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2-deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process.

  15. WORKABILITY OF A MANAGEMENT CONTROL MODEL IN SERVICE ORGANIZATIONS: A COMPARATIVE STUDY OF REACTIVE, PROACTIVE AND COACTIVE PHILOSOPHIES

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    Joshua Onome Imoniana

    2006-11-01

    Full Text Available The main objective of this study was to compare and contrast the three philosophies of management control models in the process of decision-making, namely reactive, proactive and the coactive. Research methodology was based on literature review and descriptive/exploratory approach. Additionally, a survey of 20 service organizations was carried out in order to make the analysis wider-reaching. In order to do that, the following steps were followed: firstly, fundamentals of reactive, proactive and coactive models were highlighted; secondly, management behaviors in the three approaches were compared, with concepts and their practical application being highlighted, thus retrieving managerial relationships in the organization. In so doing, we draw the hypothesis that middle and top managers who adopt control models that are distant from a more coactive one, usually spend a greater number of working hours in problem-solving, leaving little or no time for planning purposes. Finally, for study consolidation purpose, we have adopted qualitative data collection, whereby a content analysis was carried out with the assistance of six categories. Results have shown the need for a change in management paradigms so that firms are not only compared through financial perspectives, without considering the analysis of management control models which, according to this study, directly influence the operational results of the organizations.

  16. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

    International Nuclear Information System (INIS)

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun; Nishina, Hiroshi

    2014-01-01

    Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription

  17. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

    Energy Technology Data Exchange (ETDEWEB)

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp; Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp

    2014-01-17

    Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription.

  18. Antisense-mediated isoform switching of steroid receptor coactivator-1 in the central nucleus of the amygdala of the mouse brain

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    Zalachoras Ioannis

    2013-01-01

    Full Text Available Abstract Background Antisense oligonucleotide (AON-mediated exon skipping is a powerful tool to manipulate gene expression. In the present study we investigated the potential of exon skipping by local injection in the central nucleus of the amygdala (CeA of the mouse brain. As proof of principle we targeted the splicing of steroid receptor coactivator-1 (SRC-1, a protein involved in nuclear receptor function. This nuclear receptor coregulator exists in two splice variants (SRC-1a and SRC-1e which display differential distribution and opposing activities in the brain, and whose mRNAs differ in a single SRC-1e specific exon. Methods For proof of principle of feasibility, we used immunofluorescent stainings to study uptake by different cell types, translocation to the nucleus and potential immunostimulatory effects at different time points after a local injection in the CeA of the mouse brain of a control AON targeting human dystrophin with no targets in the murine brain. To evaluate efficacy we designed an AON targeting the SRC-1e-specific exon and with qPCR analysis we measured the expression ratio of the two splice variants. Results We found that AONs were taken up by corticotropin releasing hormone expressing neurons and other cells in the CeA, and translocated into the cell nucleus. Immune responses after AON injection were comparable to those after sterile saline injection. A successful shift of the naturally occurring SRC-1a:SRC-1e expression ratio in favor of SRC-1a was observed, without changes in total SRC-1 expression. Conclusions We provide a proof of concept for local neuropharmacological use of exon skipping by manipulating the expression ratio of the two splice variants of SRC-1, which may be used to study nuclear receptor function in specific brain circuits. We established that exon skipping after local injection in the brain is a versatile and useful tool for the manipulation of splice variants for numerous genes that are relevant

  19. A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.

    Science.gov (United States)

    Armour, Sean M; Bennett, Eric J; Braun, Craig R; Zhang, Xiao-Yong; McMahon, Steven B; Gygi, Steven P; Harper, J Wade; Sinclair, David A

    2013-04-01

    Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex.

  20. Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator.

    Science.gov (United States)

    Gonzalez, Deyarina; Hamidi, Nurul; Del Sol, Ricardo; Benschop, Joris J; Nancy, Thomas; Li, Chao; Francis, Lewis; Tzouros, Manuel; Krijgsveld, Jeroen; Holstege, Frank C P; Conlan, R Steven

    2014-02-18

    Mediator, an evolutionary conserved large multisubunit protein complex with a central role in regulating RNA polymerase II-transcribed genes, serves as a molecular switchboard at the interface between DNA binding transcription factors and the general transcription machinery. Mediator subunits include the Cdk8 module, which has both positive and negative effects on activator-dependent transcription through the activity of the cyclin-dependent kinase Cdk8, and the tail module, which is required for positive and negative regulation of transcription, correct preinitiation complex formation in basal and activated transcription, and Mediator recruitment. Currently, the molecular mechanisms governing Mediator function remain largely undefined. Here we demonstrate an autoregulatory mechanism used by Mediator to repress transcription through the activity of distinct components of different modules. We show that the function of the tail module component Med3, which is required for transcription activation, is suppressed by the kinase activity of the Cdk8 module. Med3 interacts with, and is phosphorylated by, Cdk8; site-specific phosphorylation triggers interaction with and degradation by the Grr1 ubiquitin ligase, thereby preventing transcription activation. This active repression mechanism involving Grr1-dependent ubiquitination of Med3 offers a rationale for the substoichiometric levels of the tail module that are found in purified Mediator and the corresponding increase in tail components seen in cdk8 mutants.

  1. Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

    Science.gov (United States)

    Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

    2017-12-01

    Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

  2. Involvement of TORC2, a CREB co-activator, in the in vivo-specific transcriptional control of HTLV-1

    Directory of Open Access Journals (Sweden)

    Furuta Rika A

    2009-08-01

    Full Text Available Abstract Background Human T-cell leukemia virus type 1 (HTLV-1 causes adult T -cell leukemia (ATL but the expression of HTLV-1 is strongly suppressed in the peripheral blood of infected people. However, such suppression, which may explain the long latency in the development of ATL, is readily reversible, and viral expression resumes quickly with ex vivo culture of infected T -cells. To investigate the mechanism of in vivo -specific transcriptional suppression, we established a mouse model in which mice were intraperitoneally administered syngeneic EL4 T -lymphoma cells transduced with a recombinant retrovirus expressing a GFP-Tax fusion protein, Gax, under the control of the HTLV-1 enhancer (EL4-Gax. Results Gax gene transcription was silenced in vivo but quickly up-regulated in ex vivo culture. Analysis of integrated Gax reporter gene demonstrated that neither CpG methylation of the promoter DNA nor histone modification was associated with the reversible suppression. ChIP-analysis of LTR under suppression revealed reduced promoter binding of TFIIB and Pol-II, but no change in the binding of CREB or CBP/p300 to the viral enhancer sequence. However, the expression of TORC2, a co-activator of CREB, decreased substantially in the EL4-Gax cells in vivo, and this returned to normal levels in ex vivo culture. The reduced expression of TORC2 was associated with translocation from the nucleus to the cytoplasm. A knock-down experiment with siRNA confirmed that TORC2 was the major functional protein of the three TORC-family proteins (TORC1, 2, 3 in EL4-Gax cells. Conclusion These results suggest that the TORC2 may play an important role in the in vivo -specific transcriptional control of HTLV-1. This study provides a new model for the reversible mechanism that suppresses HTLV-1 expression in vivo without the DNA methylation or hypoacetylated histones that is observed in the primary cells of most HTLV-1 -infected carriers and a substantial number of ATL

  3. Autophagy activation, not peroxisome proliferator-activated receptor γ coactivator 1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity.

    Science.gov (United States)

    Rosa-Caldwell, Megan E; Brown, Jacob L; Lee, David E; Blackwell, Thomas A; Turner, Kyle W; Brown, Lemuel A; Perry, Richard A; Haynie, Wesley S; Washington, Tyrone A; Greene, Nicholas P

    2017-09-01

    What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC-1α overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1α content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED

  4. Stimulation of StAR expression by cAMP is controlled by inhibition of highly inducible SIK1 via CRTC2, a co-activator of CREB.

    Science.gov (United States)

    Lee, Jinwoo; Tong, Tiegang; Takemori, Hiroshi; Jefcoate, Colin

    2015-06-15

    In mouse steroidogenic cells the activation of cholesterol metabolism is mediated by steroidogenic acute regulatory protein (StAR). Here, we visualized a coordinated regulation of StAR transcription, splicing and post-transcriptional processing, which are synchronized by salt inducible kinase (SIK1) and CREB-regulated transcription coactivator (CRTC2). To detect primary RNA (pRNA), spliced primary RNA (Sp-RNA) and mRNA in single cells, we generated probe sets by using fluorescence in situ hybridization (FISH). These methods allowed us to address the nature of StAR gene expression and to visualize protein-nucleic acid interactions through direct detection. We show that SIK1 represses StAR expression in Y1 adrenal and MA10 testis cells through inhibition of processing mediated by CRTC2. Digital image analysis matches qPCR analyses of the total cell culture. Evidence is presented for spatially separate accumulation of StAR pRNA and Sp-RNA at the gene loci in the nucleus. These findings establish that cAMP, SIK and CRTC mediate StAR expression through activation of individual StAR gene loci. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Structural and Functional Impacts of ER Coactivator Sequential Recruitment.

    Science.gov (United States)

    Yi, Ping; Wang, Zhao; Feng, Qin; Chou, Chao-Kai; Pintilie, Grigore D; Shen, Hong; Foulds, Charles E; Fan, Guizhen; Serysheva, Irina; Ludtke, Steven J; Schmid, Michael F; Hung, Mien-Chie; Chiu, Wah; O'Malley, Bert W

    2017-09-07

    Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This "ordered" recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits steroid receptor coactivator-3 (SRC-3) primary coactivator and secondary coactivators, p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-electron microscopy (cryo-EM) structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early- and late-recruited coactivators. The sequential recruitment of CARM1 not only adds a protein arginine methyltransferase activity to the ER-coactivator complex, it also alters the structural organization of the pre-existing ERE/ERα/SRC-3/p300 complex. It induces a p300 conformational change and significantly increases p300 HAT activity on histone H3K18 residues, which, in turn, promotes CARM1 methylation activity on H3R17 residues to enhance transcriptional activity. This study reveals a structural role for a coactivator sequential recruitment and biochemical process in ER-mediated transcription. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Epstein-Barr Virus Nuclear Antigen Leader Protein Coactivates EP300.

    Science.gov (United States)

    Wang, Chong; Zhou, Hufeng; Xue, Yong; Liang, Jun; Narita, Yohei; Gerdt, Catherine; Zheng, Amy Y; Jiang, Runsheng; Trudeau, Stephen; Peng, Chih-Wen; Gewurz, Benjamin E; Zhao, Bo

    2018-05-01

    Epstein-Barr virus nuclear antigen (EBNA) leader protein (EBNALP) is one of the first viral genes expressed upon B-cell infection. EBNALP is essential for EBV-mediated B-cell immortalization. EBNALP is thought to function primarily by coactivating EBNA2-mediated transcription. Chromatin immune precipitation followed by deep sequencing (ChIP-seq) studies highlight that EBNALP frequently cooccupies DNA sites with host cell transcription factors (TFs), in particular, EP300, implicating a broader role in transcription regulation. In this study, we investigated the mechanisms of EBNALP transcription coactivation through EP300. EBNALP greatly enhanced EP300 transcription activation when EP300 was tethered to a promoter. EBNALP coimmunoprecipitated endogenous EP300 from lymphoblastoid cell lines (LCLs). EBNALP W repeat serine residues 34, 36, and 63 were required for EP300 association and coactivation. Deletion of the EP300 histone acetyltransferase (HAT) domain greatly reduced EBNALP coactivation and abolished the EBNALP association. An EP300 bromodomain inhibitor also abolished EBNALP coactivation and blocked the EP300 association with EBNALP. EBNALP sites cooccupied by EP300 had significantly higher ChIP-seq signals for sequence-specific TFs, including SPI1, RelA, EBF1, IRF4, BATF, and PAX5. EBNALP- and EP300-cooccurring sites also had much higher H3K4me1 and H3K27ac signals, indicative of activated enhancers. EBNALP-only sites had much higher signals for DNA looping factors, including CTCF and RAD21. EBNALP coactivated reporters under the control of NF-κB or SPI1. EP300 inhibition abolished EBNALP coactivation of these reporters. Clustered regularly interspaced short palindromic repeat interference targeting of EBNALP enhancer sites significantly reduced target gene expression, including that of EP300 itself. These data suggest a previously unrecognized mechanism by which EBNALP coactivates transcription through subverting of EP300 and thus affects the expression of

  7. Interaction of the B cell-specific transcriptional coactivator OCA-B and galectin-1 and a possible role in regulating BCR-mediated B cell proliferation.

    Science.gov (United States)

    Yu, Xin; Siegel, Rachael; Roeder, Robert G

    2006-06-02

    OCA-B is a B cell-specific transcriptional coactivator for OCT factors during the activation of immunoglobulin genes. In addition, OCA-B is crucial for B cell activation and germinal center formation. However, the molecular mechanisms for OCA-B function in these processes are not clear. Our previous studies documented two OCA-B isoforms and suggested a novel mechanism for the function of the myristoylated, membrane-bound form of OCA-B/p35 as a signaling molecule. Here, we report the identification of galectin-1, and related galectins, as a novel OCA-B-interacting protein. The interaction of OCA-B and galectin-1 can be detected both in vivo and in vitro. The galectin-1 binding domain in OCA-B has been localized to the N terminus of OCA-B. In B cells lacking OCA-B expression, increased galectin-1 expression, secretion, and cell surface association are observed. Consistent with these observations, and a reported inhibitory interaction of galectin-1 with CD45, the phosphatase activity of CD45 is reduced modestly, but significantly, in OCA-B-deficient B cells. Finally, galectin-1 is shown to negatively regulate B cell proliferation and tyrosine phosphorylation upon BCR stimulation. Together, these results raise the possibility that OCA-B may regulate BCR signaling through an association with galectin-1.

  8. Muscle Co-activation: Definitions, Mechanisms, and Functions.

    Science.gov (United States)

    Latash, Mark L

    2018-03-28

    The phenomenon of agonist-antagonist muscle co-activation is discussed with respect to its consequences for movement mechanics (such as increasing joint apparent stiffness, facilitating faster movements, and effects on action stability), implication for movement optimization, and involvement of different neurophysiological structures. Effects of co-activation on movement stability are ambiguous and depend on the effector representing a kinematic chain with a fixed origin or free origin. Further, co-activation is discussed within the framework of the equilibrium-point hypothesis and the idea of hierarchical control with spatial referent coordinates. Relations of muscle co-activation to changes in one of the basic commands, the c-command, are discussed and illustrated. A hypothesis is suggested that agonist-antagonist co-activation reflects a deliberate neural control strategy to preserve effector-level control and avoid making it degenerate and facing the necessity to control at the level of signals to individual muscles. This strategy, in particular, allows stabilizing motor actions by co-varied adjustments in spaces of control variables. This hypothesis is able to account for higher levels of co-activation in young healthy persons performing challenging tasks and across various populations with movement impairments.

  9. IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway.

    Science.gov (United States)

    Mu, Xiaoyu; Qi, Weihong; Liu, Yunzhang; Zhou, Jianfeng; Li, Yun; Rong, Xiaozhi; Lu, Ling

    2017-08-01

    Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K-Akt-FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

  10. Dual roles for coactivator activator and its counterbalancing isoform coactivator modulator in human kidney cell tumorigenesis.

    Science.gov (United States)

    Kang, Yun Kyoung; Schiff, Rachel; Ko, Lan; Wang, Tao; Tsai, Sophia Y; Tsai, Ming-Jer; O'Malley, Bert W

    2008-10-01

    Coactivator activator (CoAA) has been reported to be a coactivator that regulates steroid receptor-mediated transcription and alternative RNA splicing. Herein, we show that CoAA is a dual-function coregulator that inhibits G(1)-S transition in human kidney cells and suppresses anchorage-independent growth and xenograft tumor formation. Suppression occurs in part by down-regulating c-myc and its downstream effectors ccnd1 and skp2 and causing accumulation of p27/Kip1 protein. In this cellular setting, CoAA directly represses the proto-oncogene c-myc by recruiting HDAC3 protein and decreasing both the acetylation of histone H3 and the presence of RNA polymerase II on the c-myc promoter. Interestingly, a splicing isoform of CoAA, coactivator modulator (CoAM), antagonizes CoAA-induced G(1)-S transition and growth inhibition by negatively regulating the mRNA levels of the endogenous CoAA isoform. In addition, we found that expression of CoAA protein is significantly decreased in human renal cell carcinoma compared with normal kidney. Our study presents evidence that CoAA is a potential tumor suppressor in renal carcinoma and that CoAM is a counterbalancing splice isoform. This is, thus far, the only example of a nuclear receptor coregulator involved in suppression of kidney cancer and suggests potentially significant new roles for coregulators in renal cancer biology.

  11. ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

    Science.gov (United States)

    Parsa, Kishore V. L.; Kain, Vasundhara; Behera, Soma; Suraj, Sashidhara Kaimal; Babu, Phanithi Prakash; Kar, Anand; Panda, Sunanda; Zhu, Yi-jun; Jia, Yuzhi; Thimmapaya, Bayar; Reddy, Janardan K.; Misra, Parimal

    2013-01-01

    PRIP-Interacting protein with methyl transferase domain (PIMT) serves as a molecular bridge between CREB-binding protein (CBP)/ E1A binding protein p300 (Ep300) -anchored histone acetyl transferase and the Mediator complex sub-unit1 (Med1) and modulates nuclear receptor transcription. Here, we report that ERK2 phosphorylates PIMT at Ser298 and enhances its ability to activate PEPCK promoter. We observed that PIMT is recruited to PEPCK promoter and adenoviral-mediated over-expression of PIMT in rat primary hepatocytes up-regulated expression of gluconeogenic genes including PEPCK. Reporter experiments with phosphomimetic PIMT mutant (PIMTS298D) suggested that conformational change may play an important role in PIMT-dependent PEPCK promoter activity. Overexpression of PIMT and Med1 together augmented hepatic glucose output in an additive manner. Importantly, expression of gluconeogenic genes and hepatic glucose output were suppressed in isolated liver specific PIMT knockout mouse hepatocytes. Furthermore, consistent with reporter experiments, PIMTS298D but not PIMTS298A augmented hepatic glucose output via up-regulating the expression of gluconeogenic genes. Pharmacological blockade of MAPK/ERK pathway using U0126, abolished PIMT/Med1-dependent gluconeogenic program leading to reduced hepatic glucose output. Further, systemic administration of T4 hormone to rats activated ERK1/2 resulting in enhanced PIMT ser298 phosphorylation. Phosphorylation of PIMT led to its increased binding to the PEPCK promoter, increased PEPCK expression and induction of gluconeogenesis in liver. Thus, ERK2-mediated phosphorylation of PIMT at Ser298 is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia. PMID:24358311

  12. The Mediator subunit SFR6/MED16 controls defence gene expression mediated by salicylic acid and jasmonate responsive pathways.

    Science.gov (United States)

    Wathugala, Deepthi L; Hemsley, Piers A; Moffat, Caroline S; Cremelie, Pieter; Knight, Marc R; Knight, Heather

    2012-07-01

    • Arabidopsis SENSITIVE TO FREEZING6 (SFR6) controls cold- and drought-inducible gene expression and freezing- and osmotic-stress tolerance. Its identification as a component of the MEDIATOR transcriptional co-activator complex led us to address its involvement in other transcriptional responses. • Gene expression responses to Pseudomonas syringae, ultraviolet-C (UV-C) irradiation, salicylic acid (SA) and jasmonic acid (JA) were investigated in three sfr6 mutant alleles by quantitative real-time PCR and susceptibility to UV-C irradiation and Pseudomonas infection were assessed. • sfr6 mutants were more susceptible to both Pseudomonas syringae infection and UV-C irradiation. They exhibited correspondingly weaker PR (pathogenesis-related) gene expression than wild-type Arabidopsis following these treatments or after direct application of SA, involved in response to both UV-C and Pseudomonas infection. Other genes, however, were induced normally in the mutants by these treatments. sfr6 mutants were severely defective in expression of plant defensin genes in response to JA; ectopic expression of defensin genes was provoked in wild-type but not sfr6 by overexpression of ERF5. • SFR6/MED16 controls both SA- and JA-mediated defence gene expression and is necessary for tolerance of Pseudomonas syringae infection and UV-C irradiation. It is not, however, a universal regulator of stress gene transcription and is likely to mediate transcriptional activation of specific regulons only. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

  13. Increased lower limb muscle coactivation reduces gait performance and increases metabolic cost in patients with hereditary spastic paraparesis.

    Science.gov (United States)

    Rinaldi, Martina; Ranavolo, Alberto; Conforto, Silvia; Martino, Giovanni; Draicchio, Francesco; Conte, Carmela; Varrecchia, Tiwana; Bini, Fabiano; Casali, Carlo; Pierelli, Francesco; Serrao, Mariano

    2017-10-01

    The aim of this study was to investigate the lower limb muscle coactivation and its relationship with muscles spasticity, gait performance, and metabolic cost in patients with hereditary spastic paraparesis. Kinematic, kinetic, electromyographic and energetic parameters of 23 patients and 23 controls were evaluated by computerized gait analysis system. We computed ankle and knee antagonist muscle coactivation indexes throughout the gait cycle and during the subphases of gait. Energy consumption and energy recovery were measured as well. In addition to the correlation analysis between coactivation indexes and clinical variables, correlations between coactivation indexes and time-distance, kinematic, kinetic, and energetic parameters were estimated. Increased coactivity indexes of both knee and ankle muscles throughout the gait cycle and during the subphases of gait were observed in patients compared with controls. Energetic parameters were significantly higher in patients than in controls. Both knee and ankle muscle coactivation indexes were positively correlated with knee and ankle spasticity (Ashworth score), respectively. Knee and ankle muscle coactivation indexes were both positively correlated with energy consumption and both negatively correlated with energy recovery. Positive correlations between the Ashworth score and lower limb muscle coactivation suggest that abnormal lower limb muscle coactivation in patients with hereditary spastic paraparesis reflects a primary deficit linked to lower limb spasticity. Furthermore, these abnormalities influence the energetic mechanisms during walking. Identifying excessive muscle coactivation may be helpful in individuating the rehabilitative treatments and designing specific orthosis to restrain spasticity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Effect of higher muscle coactivation on standing postural response to perturbation in older adults.

    Science.gov (United States)

    Nagai, Koutatsu; Okita, Yusuke; Ogaya, Shinya; Tsuboyama, Tadao

    2017-04-01

    Although several studies have reported that muscle coactivation during postural control increases with age, the effect of higher muscle coactivation on standing postural response to perturbation is unknown. To investigate whether higher muscle coactivation affects standing postural response to perturbation in older adults. Thirty-four community-dwelling older participants were randomly assigned either to the coactivation group (CG), where muscle coactivation was increased intentionally, or to the non-coactivation group (NCG). The participants were instructed to stand on a force plate that moved forward or backward. Electromyography data were collected from the lower leg muscles. We requested the participants in the CG to increase the activity of their tibialis anterior, and to maintain this posture during the tasks. We moved the force plate with a constant amplitude and velocity, and measured kinematic data with a camera during the tasks. During forward transfer, the knee extension and hip flexion decreased in the CG after perturbation compared to NCG, and the trunk extension angle increased. The center of pressure (COP) displacement decreased around the peak of the movement in the CG compared to NCG. During backward transfer, ankle dorsal and knee flexion changed after perturbation in the CG compared to NCG. Our study found that higher muscle coactivation inhibits lower limb and COP movement as well as increases trunk tilt and the risk for falls during forward perturbations. Postural control with higher coactivation appears to be inefficient for maintaining balance during the backward sway of posture.

  15. Co-activation: its association with weakness and specific neurological pathology

    Directory of Open Access Journals (Sweden)

    Wiles Charles M

    2006-11-01

    Full Text Available Abstract Background Net agonist muscle strength is in part determined by the degree of antagonist co-activation. The level of co-activation might vary in different neurological disorders causing weakness or might vary with agonist strength. Aim This study investigated whether antagonist co-activation changed a with the degree of muscle weakness and b with the nature of the neurological lesion causing weakness. Methods Measures of isometric quadriceps and hamstrings strength were obtained. Antagonist (hamstring co-activation during knee extension was calculated as a ratio of hamstrings over quadriceps activity both during an isometric and during a functional sit to stand (STS task (using kinematics in groups of patients with extrapyramidal (n = 15, upper motor neuron (UMN (n = 12, lower motor neuron (LMN with (n = 18 or without (n = 12 sensory loss, primary muscle or neuromuscular junction disorder (n = 17 and in healthy matched controls (n = 32. Independent t-tests or Mann Witney U tests were used to compare between the groups. Correlations between variables were also investigated. Results In healthy subjects mean (SD co-activation of hamstrings during isometric knee extension was 11.8 (6.2% and during STS was 20.5 (12.9%. In patients, co-activation ranged from 7 to 17% during isometric knee extension and 15 to 25% during STS. Only the extrapyramidal group had lower co-activation levels than healthy matched controls (p Conclusion It is concluded that antagonist co-activation does not systematically vary with the site of neurological pathology when compared to healthy matched controls or, in most patient groups, with strength. The lower co-activation levels found in the extrapyramidal group require confirmation and further investigation. Co-activation may be relevant to individuals with muscle weakness. Within patient serial studies in the presence of changing muscle strength may help to understand these relationships more clearly.

  16. Multiple functions and essential roles of nuclear receptor coactivators of bHLH-PAS family.

    Science.gov (United States)

    Pecenova, L; Farkas, Robert

    2016-07-01

    Classical non-peptide hormones, such as steroids, retinoids, thyroid hormones, vitamin D3 and their derivatives including prostaglandins, benzoates, oxysterols, and bile acids, are collectively designated as small lipophilic ligands, acting via binding to the nuclear receptors (NRs). The NRs form a large superfamily of transcription factors that participate virtually in every key biological process. They control various aspects of animal development, fertility, gametogenesis, and numerous metabolic pathways, and can be misregulated in many types of cancers. Their enormous functional plasticity, as transcription factors, relates in part to NR-mediated interactions with plethora of coregulatory proteins upon ligand binding to their ligand binding domains (LBD), or following covalent modification. Here, we review some general views of a specific group of NR coregulators, so-called nuclear receptor coactivators (NRCs) or steroid receptor coactivators (SRCs) and highlight some of their unique functions/roles, which are less extensively mentioned and discussed in other reviews. We also try to pinpoint few neglected moments in the cooperative action of SRCs, which may also indicate their variable roles in the hormone-independent signaling pathways.

  17. [Coactivators in energy metabolism: peroxisome proliferator-activated receptor-gamma coactivator 1 family].

    Science.gov (United States)

    Wang, Rui; Chang, Yong-sheng; Fang, Fu-de

    2009-12-01

    Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family is highly expressed in tissues with high energy metabolism. They coactivate transcription factors in regulating genes engaged in processes such as gluconeogenesis, adipose beta-oxydation, lipoprotein synthesis and secretion, mitochondrial biogenesis, and oxidative metabolism. Protein conformation studies demonstrated that they lack DNA binding domains and act as coactivators through physical interaction with transcription factors. PGC1 activity is regulated at transcription level or by multiple covalent chemical modifications such as phosphorylation, methylation and acetylation/deacetylation. Abnormal expression of PGC1 coactivators usually is closely correlated with diseases such as diabetes, obesity, hyperglycemia, hyperlipemia, and arterial and brain neuron necrosis diseases.

  18. Processes mediating expertise in air traffic control

    NARCIS (Netherlands)

    Van Meeuwen, Ludo; Jarodzka, Halszka; Brand-Gruwel, Saskia; Van Merriënboer, Jeroen; De Bock, Jeano; Kirschner, Paul A.

    2010-01-01

    Van Meeuwen, L., Jarodzka, H., Brand-Gruwel, S., Van Merriënboer, J. J. G., De Bock, J. J. P. R., & Kirschner, P. A. (2010, August). Processes mediating expertise in air traffic control. Meeting of the EARLI SIG6/7 Instructional Design and Learning and Instruction with Computers, Ulm, Germany.

  19. Processes mediating expertise in air traffic control

    NARCIS (Netherlands)

    Van Meeuwen, Ludo; Jarodzka, Halszka; Brand-Gruwel, Saskia; Van Merriënboer, Jeroen; De Bock, Jeano; Kirschner, Paul A.

    2011-01-01

    Van Meeuwen, L. W., Jarodzka, H., Brand-Gruwel, S., Van Merriënboer, J. J. G., De Bock, J. J. P. R., & Kirschner, P. A. (2010, September). Processes mediating expertise in air traffic control. Poster presented at the European Association for Aviation Psychology Conference, Budapest.

  20. Effect of Knee Joint Angle and Contraction Intensity on Hamstrings Coactivation.

    Science.gov (United States)

    Wu, Rui; Delahunt, Eamonn; Ditroilo, Massimiliano; Lowery, Madeleine M; DE Vito, Giuseppe

    2017-08-01

    This study investigated the effect of knee joint angle and contraction intensity on the coactivation of the hamstring muscles (when acting as antagonists to the quadriceps) in young and older individuals of both sexes. A total of 25 young (24 ± 2.6 yr) and 26 older (70 ± 2.5 yr) healthy men and women participated. Maximal voluntary isometric contraction of the knee extensors and flexors was assessed at two knee joint angles (90° and 60°, 0° = full extension). At each angle, participants performed submaximal contractions of the knee extensors (20%, 50%, and 80% maximal voluntary isometric contraction), whereas surface EMG was simultaneously acquired from the vastus lateralis and biceps femoris muscles to assess the level (EMG root-mean-square) of agonist activation and antagonist coactivation. Subcutaneous adipose tissue in the areas corresponding to surface EMG electrode placements was measured via ultrasonography. The contractions performed at 90° knee flexion demonstrated higher levels of antagonist coactivation (all P < 0.01) and agonist activation (all P < 0.01) as a function of contraction intensity compared with the 60° knee flexion. Furthermore, after controlling for subcutaneous adipose tissue, older participants exhibited a higher level of antagonist coactivation at 60° knee flexion compared with young participants (P < 0.05). The results of the present study suggest that 1) the antagonist coactivation is dependent on knee joint angle and contraction intensity and 2) subcutaneous adipose tissue may affect the measured coactivation level likely because of a cross-talk effect. Antagonist coactivation may play a protective role in stabilizing the knee joint and maintaining constant motor output.

  1. Mediator and Cohesin Connect Gene Expression and Chromatin Architecture

    Science.gov (United States)

    Kagey, Michael H.; Newman, Jamie J.; Bilodeau, Steve; Zhan, Ye; Orlando, David A.; van Berkum, Nynke L.; Ebmeier, Christopher C.; Goossens, Jesse; Rahl, Peter B.; Levine, Stuart S.; Taatjes, Dylan J.; Dekker, Job; Young, Richard A.

    2010-01-01

    Summary Transcription factors control cell specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. We report here that Mediator and Cohesin physically and functionally connect the enhancers and core promoters of active genes in embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with Cohesin, which can form rings that connect two DNA segments. The Cohesin loading factor Nipbl is associated with Mediator/Cohesin complexes, providing a means to load Cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and Cohesin. Mediator and Cohesin occupy different promoters in different cells, thus generating cell-type specific DNA loops linked to the gene expression program of each cell. PMID:20720539

  2. Co-activated yet disconnected-Neural correlates of eye closures when trying to stay awake.

    Science.gov (United States)

    Ong, Ju Lynn; Kong, Danyang; Chia, Tiffany T Y; Tandi, Jesisca; Thomas Yeo, B T; Chee, Michael W L

    2015-09-01

    Spontaneous eye-closures that herald sleep onset become more frequent when we are sleep deprived. Although these are typically associated with decreased responsiveness to external stimuli, it is less clear what occurs in the brain at these transitions to drowsiness and light sleep. To investigate this, task-free fMRI of sleep-deprived participants was acquired. BOLD activity associated with periods of spontaneously occurring eye closures were marked and analyzed. We observed concurrent and extensive hypnagogic co-activation of the extrastriate visual, auditory, and somatosensory cortices as well as the default mode network, consistent with internal sensory activity without external stimulation. Co-activation of fronto-parietal areas known to mediate attentional control could correspond with participants resisting sleep or additional engagement of mental imagery. This constellation of signal changes differed from those elicited by cued eye closures of similar duration and distribution in the same, rested participants. They also differ from signal changes associated with mind-wandering and consolidated light sleep. Concurrent with the observed event-related changes, eye closures elicited additional reduction in functional connectivity within nodes of the DMN and DAN, superposed on already reduced connectivity associated with sleep deprivation. There was concurrent deactivation of the thalamus during eye-closure during the sleep-deprived state but almost similar changes occurred in the well-rested state that may also be relevant. These findings highlight the dynamic shifts in brain activity and connectivity at border between wakefulness and sleep. Copyright © 2015. Published by Elsevier Inc.

  3. Nuclear localization of the transcriptional coactivator YAP is associated with invasive lobular breast cancer

    NARCIS (Netherlands)

    Vlug, E.J.; Ven, R.A. van de; Vermeulen, J.F.; Bult, P.; Diest, P.J. van; Derksen, P.W.B.

    2013-01-01

    BACKGROUND: Yes Associated Protein (YAP) has been implicated in the control of organ size by regulating cell proliferation and survival. YAP is a transcriptional coactivator that controls cellular responses through interaction with TEAD transcription factors in the nucleus, while its transcriptional

  4. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

    International Nuclear Information System (INIS)

    Kanno, Yuichiro; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

    2015-01-01

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR

  5. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

    Energy Technology Data Exchange (ETDEWEB)

    Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

    2015-03-27

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.

  6. Nuclear localization of the transcriptional coactivator YAP is associated with invasive lobular breast cancer.

    Science.gov (United States)

    Vlug, Eva J; van de Ven, Robert A H; Vermeulen, Jeroen F; Bult, Peter; van Diest, Paul J; Derksen, Patrick W B

    2013-10-01

    Yes Associated Protein (YAP) has been implicated in the control of organ size by regulating cell proliferation and survival. YAP is a transcriptional coactivator that controls cellular responses through interaction with TEAD transcription factors in the nucleus, while its transcriptional functions are inhibited by phosphorylation-dependent translocation to the cytosol. YAP overexpression has been associated with different types of cancer, such as lung, skin, prostate, ovary and liver cancer. Recently, YAP was linked to E-cadherin-dependent regulation of contact inhibition in breast cancer cells. In this study we examined YAP protein expression and cellular localization in 237 cases of human invasive breast cancer by immunohistochemistry and related its expression to clinicopathological features and E-cadherin expression. We observed that invasive lobular carcinoma is characterized by higher expression levels of both nuclear and cytosolic YAP (p invasive breast cancer. We observed that high nuclear and cytosolic YAP expression are associated with the E-cadherin deficient breast cancer subtype ILC (p cancers and conditional mouse models of human lobular breast cancer. Since our data indicate that nuclear YAP localization is more common in breast cancers lacking functional adherens junctions, it suggests that YAP-mediated transcription may be involved in the development and progression of invasive lobular breast cancer.

  7. Real-time Control Mediation in Agile Distributed Software Development

    DEFF Research Database (Denmark)

    Persson, John Stouby; Aaen, Ivan; Mathiassen, Lars

    2008-01-01

    Agile distributed environments pose particular challenges related to control of quality and collaboration in software development. Moreover, while face-to-face interaction is fundamental in agile development, distributed environments must rely extensively on mediated interactions. On this backdrop...... control was mediated over distance by technology through real-time exchanges. Contrary to previous research, the analysis suggests that both formal and informal elements of real-time mediated control were used; that evolving goals and adjustment of expectations were two of the main issues in real......-time mediated control exchanges; and, that the actors, despite distances in space and culture, developed a clan-like pattern mediated by technology to help control quality and collaboration in software development....

  8. Expression and function of androgen receptor coactivator p44/Mep50/WDR77 in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Martin Ligr

    Full Text Available Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR and estrogen receptor (ER in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis.

  9. The Dark Side of Computer-Mediated Control

    DEFF Research Database (Denmark)

    Cunha, J. V.; Carugati, Andrea; Leclercq, A.

    2015-01-01

    of computer-mediated control when work and its electronic representation are loosely coupled, because it is employees who report their work in IT systems. Data from a 15-month ethnographic study of the appropriation of a customer relationship management system in the sales department of a large organization......Research on the dark side of computer-mediated control has explained the consequences of computer-mediated control when work is tightly coupled with its electronic representation because information systems record work automatically. Our study complements prior research by addressing the dark side...

  10. Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor

    International Nuclear Information System (INIS)

    Fan Shuli; Goto, Kiminobu; Chen Guangchun; Morinaga, Hidetaka; Nomura, Masatoshi; Okabe, Taijiro; Nawata, Hajime; Yanase, Toshihiko

    2006-01-01

    Previously, we identified a transcriptional coactivator for the activation function-1 (AF-1) domain of the human androgen receptor (AR) and designated it androgen receptor N-terminal domain transactivating protein-1 (ANT-1). This coactivator, which contains multiple tetratricopeptide repeat (TPR) motifs from amino acid (aa) 294, is identical to a component of U5 small nuclear ribonucleoprotein particles and binds specifically to the AR or glucocorticoid receptor. Here, we identified four distinct functional domains. The AR-AF-1-binding domain, which bound to either aa 180-360 or 360-532 in AR-AF-1, clearly overlapped with TAU-1 and TAU-5. This domain and the subnuclear speckle formation domain in ANT-1 were assigned within the TPR motifs, while the transactivating and nuclear localization signal domains resided within the N-terminal sequence. The existence of these functional domains may further support the idea that ANT-1 can function as an AR-AF-1-specific coactivator while mediating a transcription-splicing coupling

  11. An Extension of SIC Predictions to the Wiener Coactive Model.

    Science.gov (United States)

    Houpt, Joseph W; Townsend, James T

    2011-06-01

    The survivor interaction contrasts (SIC) is a powerful measure for distinguishing among candidate models of human information processing. One class of models to which SIC analysis can apply are the coactive, or channel summation, models of human information processing. In general, parametric forms of coactive models assume that responses are made based on the first passage time across a fixed threshold of a sum of stochastic processes. Previous work has shown that that the SIC for a coactive model based on the sum of Poisson processes has a distinctive down-up-down form, with an early negative region that is smaller than the later positive region. In this note, we demonstrate that a coactive process based on the sum of two Wiener processes has the same SIC form.

  12. Multi-scale complexity analysis of muscle coactivation during gait in children with cerebral palsy

    Directory of Open Access Journals (Sweden)

    Wen eTao

    2015-07-01

    Full Text Available The objective of this study is to characterize complexity of lower-extremity muscle coactivation and coordination during gait in children with cerebral palsy (CP, children with typical development (TD and healthy adults, by applying recently developed multivariate multi-scale entropy (MMSE analysis to surface EMG signals. Eleven CP children (CP group, eight TD children and seven healthy adults (consider as an entire control group were asked to walk while surface EMG signals were collected from 5 thigh muscles and 3 lower leg muscles on each leg (16 EMG channels in total. The 16-channel surface EMG data, recorded during a series of consecutive gait cycles, were simultaneously processed by multivariate empirical mode decomposition (MEMD, to generate fully aligned data scales for subsequent MMSE analysis. In order to conduct extensive examination of muscle coactivation complexity using the MEMD-enhanced MMSE, 14 data analysis schemes were designed by varying partial muscle combinations and time durations of data segments. Both TD children and healthy adults showed almost consistent MMSE curves over multiple scales for all the 14 schemes, without any significant difference (p > 0.09. However, quite diversity in MMSE curve was observed in the CP group when compared with those in the control group. There appears to be diverse neuropathological processes in CP that may affect dynamical complexity of muscle coactivation and coordination during gait. The abnormal complexity patterns emerging in CP group can be attributed to different factors such as motor control impairments, loss of muscle couplings, and spasticity or paralysis in individual muscles. All these findings expand our knowledge of neuropathology of CP from a novel point of view of muscle co-activation complexity, also indicating the potential to derive a quantitative index for assessing muscle activation characteristics as well as motor function in CP.

  13. Cdc42-mediated tubulogenesis controls cell specification

    DEFF Research Database (Denmark)

    Kesavan, Gokul; Sand, Fredrik Wolfhagen; Greiner, Thomas Uwe

    2009-01-01

    Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled......, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later...... for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data...

  14. Boundary mediated position control of traveling waves

    Science.gov (United States)

    Martens, Steffen; Ziepke, Alexander; Engel, Harald

    Reaction control is an essential task in biological systems and chemical process industry. Often, the excitable medium supporting wave propagation exhibits an irregular shape and/or is limited in size. In particular, the analytic treatment of wave phenomena is notoriously difficult due to the spatial modulation of the domain's. Recently, we have provided a first systematic treatment by applying asymptotic perturbation analysis leading to an approximate description that involves a reduction of dimensionality; the 3D RD equation with spatially dependent NFBCs on the reactants reduces to a 1D reaction-diffusion-advection equation. Here, we present a novel method to control the position ϕ (t) of traveling waves in modulated domains according to a prespecified protocol of motion. Given this protocol, the ``optimal'' geometry of reactive domains Q (x) is found as the solution of the perturbatively derived equation of motion. Noteworthy, such a boundary control can be expressed in terms of the uncontrolled wave profile and its propagation velocity, rendering detailed knowledge of the reaction kinetics unnecessary. German Science Foundation DFG through the SFB 910 ''Control of Self-Organizing Nonlinear Systems''.

  15. Nitroxide-mediated controlled radical polymerisation: towards control of molar mass Controlled Radical Polymerisation

    NARCIS (Netherlands)

    Bon, S.A.F.; Bergman, F.A.C.; Es, van J.J.G.S.; Klumperman, B.; German, A.L.; Matyjaszewski, K.

    1998-01-01

    The mechanism of the TEMPO-mediated controlled radical polymerization of styrene in bulk is discussed. It is shown that the isotropic correlation time (tc) of a nitroxide can be used as a measure of the diffusive rate coefficient of trapping (ketD). A general empirical relationship for the density

  16. The mediating effect of sustainability control system on reverse ...

    African Journals Online (AJOL)

    This paper analyses part of the viability of green supply chain management practices created for fisheries industry to implement sustainability control system adoption as mediating on reverse logistics innovation and customer environmental collaboration towards sustainability performance. It examines reverse logistics ...

  17. Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes

    Science.gov (United States)

    Kim, Eunha; Tyagi, Richa; Lee, Joo-Young; Park, Jina; Kim, Young-ran; Beon, Jiyoon; Chen, Po Yu; Cha, Jiyoung Y.; Snyder, Solomon H.; Kim, Seyun

    2013-01-01

    Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes. Stimulation by serum of many immediate early genes is greatly reduced by IPMK deletion. IPMK stimulates expression of these genes, an influence also displayed by catalytically inactive IPMK. IPMK acts by binding directly to SRF and thereby enhancing interactions of SRF with the serum response element of diverse genes. PMID:24248338

  18. Coactive Design : Designing Support for Interdependence in Joint Activity

    NARCIS (Netherlands)

    Johnson, M.; Bradshaw, J.M.; Feltovich, P.J.; Jonker, C.M.; Van Riemsdijk, M.B.; Sierhuis, M.

    2014-01-01

    Coactive Design is a new approach to address the increasingly sophisticated roles that people and robots play as the use of robots expands into new, complex domains. The approach is motivated by the desire for robots to perform less like teleoperated tools or independent automatons and more like

  19. Evidence of an association between genetic variation of the coactivator PGC-1beta and obesity

    DEFF Research Database (Denmark)

    Andersen, G; Wegner, L; Yanagisawa, K

    2005-01-01

    Peroxisome proliferator activated receptor-gamma coactivator-1beta (PGC-1beta) is a recently identified homologue of the tissue specific coactivator PGC-1alpha, a coactivator of transcription factors such as the peroxisome proliferators activated receptors and nuclear respiratory factors. PGC-1...

  20. Asymmetry and Thigh Muscle Coactivity in Fatigued Anterior Cruciate Ligament-Reconstructed Elite Skiers

    DEFF Research Database (Denmark)

    Jordan, Matthew J; Aagaard, Per; Herzog, Walter

    2017-01-01

    PURPOSE: The acute effects of fatigue on functional interlimb asymmetry and quadriceps/hamstring muscle activity levels, including preparatory coactivation during squat jump takeoff and landing, were evaluated in elite alpine ski racers with/without anterior cruciate ligament reconstruction (ACLR......). METHODS: Twenty-two elite ski racers (ACLR, n = 11; control, n = 11) performed an 80-s repeated squat jump test (jump test) on a dual force plate system with simultaneous EMG recordings in vastus lateralis, vastus medialis, semitendinosus, and biceps femoris. Asymmetry index (AI) and jump height of body...

  1. Tennis players show a lower coactivation of the elbow antagonist muscles during isokinetic exercises.

    Science.gov (United States)

    Bazzucchi, Ilenia; Riccio, Maria Elena; Felici, Francesco

    2008-10-01

    Previous studies have suggested that muscle coactivation could be reduced by a recurrent activity (training, daily activities). If this was correct, skilled athletes should show a specific muscle activation pattern with a low level of coactivation of muscles which are typically involved in their discipline. In particular, the aim of this study was to verify the hypothesis that the amount of antagonist activation of biceps brachii (BB) and triceps brachii (TB) is different between tennis players and non-players individuals during maximal isokinetic contractions. Ten young healthy men and eight male tennis players participated in the study. The surface electromyographic signals (sEMG) were recorded from the BB and TB muscles during three maximal voluntary isometric contractions (MVC) of elbow flexors and extensors and a set of three maximal elbow flexions and extensions at 15 degrees , 30 degrees , 60 degrees , 120 degrees , 180 degrees and 240 degrees /s. Normalized root mean square (RMS) of sEMG was calculated as an index of sEMG amplitude. Antagonist activation (%RMSmax) of TB was significantly lower in tennis players (from 14.0+/-7.9% at MVC to 16.3+/-8.9% at 240 degrees /s) with respect to non-players (from 27.7+/-19.7% at MVC to 38.7+/-17.6% at 240 degrees /s) at all angular velocities. Contrary to non-players, tennis players did not show any difference in antagonist activation between BB and TB muscles. Tennis players, with a constant practice in controlling forces around the elbow joint, learn how to reduce coactivation of muscles involved in the control of this joint. This has been shown by the lower antagonist muscular activity of triceps brachii muscle during isokinetic elbow flexion found in tennis players with respect to non-players.

  2. Cell cycle-dependent expression of Dub3, Nanog and the p160 family of nuclear receptor coactivators (NCoAs in mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Siem van der Laan

    Full Text Available Pluripotency of embryonic stem cells (ESC is tightly regulated by a network of transcription factors among which the estrogen-related receptor β (Esrrb. Esrrb contributes to the relaxation of the G1 to S-phase (G1/S checkpoint in mouse ESCs by transcriptional control of the deubiquitylase Dub3 gene, contributing to Cdc25A persistence after DNA damage. We show that in mESCs, Dub3 gene expression is cell cycle regulated and is maximal prior G1/S transition. In addition, following UV-induced DNA damage in G1, Dub3 expression markedly increases in S-phase also suggesting a role in checkpoint recovery. Unexpectedly, we also observed cell cycle-regulation of Nanog expression, and not Oct4, reaching high levels prior to G1/S transition, finely mirroring Cyclin E1 fluctuations. Curiously, while Esrrb showed only limited cell-cycle oscillations, transcript levels of the p160 family of nuclear receptor coactivators (NCoAs displayed strong cell cycle-dependent fluctuations. Since NCoAs function in concert with Esrrb in transcriptional activation, we focussed on NCoA1 whose levels specifically increase prior onset of Dub3 transcription. Using a reporter assay, we show that NCoA1 potentiates Esrrb-mediated transcription of Dub3 and we present evidence of protein interaction between the SRC1 splice variant NCoA1 and Esrrb. Finally, we show a differential developmental regulation of all members of the p160 family during neural conversion of mESCs. These findings suggest that in mouse ESCs, changes in the relative concentration of a coactivator at a given cell cycle phase, may contribute to modulation of the transcriptional activity of the core transcription factors of the pluripotent network and be implicated in cell fate decisions upon onset of differentiation.

  3. Cell cycle-dependent expression of Dub3, Nanog and the p160 family of nuclear receptor coactivators (NCoAs) in mouse embryonic stem cells.

    Science.gov (United States)

    van der Laan, Siem; Golfetto, Eleonora; Vanacker, Jean-Marc; Maiorano, Domenico

    2014-01-01

    Pluripotency of embryonic stem cells (ESC) is tightly regulated by a network of transcription factors among which the estrogen-related receptor β (Esrrb). Esrrb contributes to the relaxation of the G1 to S-phase (G1/S) checkpoint in mouse ESCs by transcriptional control of the deubiquitylase Dub3 gene, contributing to Cdc25A persistence after DNA damage. We show that in mESCs, Dub3 gene expression is cell cycle regulated and is maximal prior G1/S transition. In addition, following UV-induced DNA damage in G1, Dub3 expression markedly increases in S-phase also suggesting a role in checkpoint recovery. Unexpectedly, we also observed cell cycle-regulation of Nanog expression, and not Oct4, reaching high levels prior to G1/S transition, finely mirroring Cyclin E1 fluctuations. Curiously, while Esrrb showed only limited cell-cycle oscillations, transcript levels of the p160 family of nuclear receptor coactivators (NCoAs) displayed strong cell cycle-dependent fluctuations. Since NCoAs function in concert with Esrrb in transcriptional activation, we focussed on NCoA1 whose levels specifically increase prior onset of Dub3 transcription. Using a reporter assay, we show that NCoA1 potentiates Esrrb-mediated transcription of Dub3 and we present evidence of protein interaction between the SRC1 splice variant NCoA1 and Esrrb. Finally, we show a differential developmental regulation of all members of the p160 family during neural conversion of mESCs. These findings suggest that in mouse ESCs, changes in the relative concentration of a coactivator at a given cell cycle phase, may contribute to modulation of the transcriptional activity of the core transcription factors of the pluripotent network and be implicated in cell fate decisions upon onset of differentiation.

  4. The impact of language co-activation on L1 and L2 speech fluency.

    Science.gov (United States)

    Bergmann, Christopher; Sprenger, Simone A; Schmid, Monika S

    2015-10-01

    Fluent speech depends on the availability of well-established linguistic knowledge and routines for speech planning and articulation. A lack of speech fluency in late second-language (L2) learners may point to a deficiency of these representations, due to incomplete acquisition. Experiments on bilingual language processing have shown, however, that there are strong reasons to believe that multilingual speakers experience co-activation of the languages they speak. We have studied to what degree language co-activation affects fluency in the speech of bilinguals, comparing a monolingual German control group with two bilingual groups: 1) first-language (L1) attriters, who have fully acquired German before emigrating to an L2 English environment, and 2) immersed L2 learners of German (L1: English). We have analysed the temporal fluency and the incidence of disfluency markers (pauses, repetitions and self-corrections) in spontaneous film retellings. Our findings show that learners to speak more slowly than controls and attriters. Also, on each count, the speech of at least one of the bilingual groups contains more disfluency markers than the retellings of the control group. Generally speaking, both bilingual groups-learners and attriters-are equally (dis)fluent and significantly more disfluent than the monolingual speakers. Given that the L1 attriters are unaffected by incomplete acquisition, we interpret these findings as evidence for language competition during speech production. Copyright © 2015. Published by Elsevier B.V.

  5. Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible factor 1α.

    Science.gov (United States)

    Zhao, Wei; Chang, Cunjie; Cui, Yangyan; Zhao, Xiaozhi; Yang, Jun; Shen, Lan; Zhou, Ji; Hou, Zhibo; Zhang, Zhen; Ye, Changxiao; Hasenmayer, Donald; Perkins, Robert; Huang, Xiaojing; Yao, Xin; Yu, Like; Huang, Ruimin; Zhang, Dianzheng; Guo, Hongqian; Yan, Jun

    2014-04-18

    Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as "Warburg effect," to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

  6. Interactome analysis of transcriptional coactivator multiprotein bridging factor 1 unveils a yeast AP-1-like transcription factor involved in oxidation tolerance of mycopathogen Beauveria bassiana.

    Science.gov (United States)

    Chu, Xin-Ling; Dong, Wei-Xia; Ding, Jin-Li; Feng, Ming-Guang; Ying, Sheng-Hua

    2018-02-01

    Oxidation tolerance is an important determinant to predict the virulence and biocontrol potential of Beauveria bassiana, a well-known entomopathogenic fungus. As a transcriptional coactivator, multiprotein bridging factor 1 mediates the activity of transcription factor in diverse physiological processes, and its homolog in B. bassiana (BbMBF1) contributes to fungal oxidation tolerance. In this study, the BbMBF1-interactomes under oxidative stress and normal growth condition were deciphered by mass spectrometry integrated with the immunoprecipitation. BbMBF1p factor has a broad interaction with proteins that are involved in various cellular processes, and this interaction is dynamically regulated by oxidative stress. Importantly, a B. bassiana homolog of yeast AP-1-like transcription factor (BbAP-1) was specifically associated with the BbMBF1-interactome under oxidation and significantly contributed to fungal oxidation tolerance. In addition, qPCR analysis revealed that several antioxidant genes are jointly controlled by BbAP-1 and BbMBF1. Conclusively, it is proposed that BbMBF1p protein mediates BbAP-1p factor to transcribe the downstream antioxidant genes in B. bassiana under oxidative stress. This study demonstrates for the first time a proteomic view of the MBF1-interactome in fungi, and presents an initial framework to probe the transcriptional mechanism involved in fungal response to oxidation, which will provide a new strategy to improve the biocontrol efficacy of B. bassiana.

  7. Chloride (Cl−) ion-mediated shape control of palladium nanoparticles

    International Nuclear Information System (INIS)

    Nalajala, Naresh; Chakraborty, Arup; Bera, Bapi; Neergat, Manoj

    2016-01-01

    The shape control of Pd nanoparticles is investigated using chloride (Cl − ) ions as capping agents in an aqueous medium in the temperature range of 60–100 °C. With weakly adsorbing and strongly etching Cl − ions, oxygen plays a crucial role in shape control. The experimental factors considered are the concentration of the capping agents, reaction time and reaction atmosphere. Thus, Pd nanoparticles of various shapes with high selectivity can be synthesized. Moreover, the removal of Cl − ions from the nanoparticle surface is easier than that of Br − ions (moderately adsorbing and etching) and I − ions (strongly adsorbing and weakly etching). The cleaned Cl − ion-mediated shape-controlled Pd nanoparticles are electrochemically characterized and the order of the half-wave potential of the oxygen reduction reaction in oxygen-saturated 0.1 M HClO 4 solution is of the same order as that observed with single-crystal Pd surfaces. (paper)

  8. Sertad1 encodes a novel transcriptional co-activator of SMAD1 in mouse embryonic hearts

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Yin [Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Zhao, Shaomin [Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294 (United States); School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069 (China); Song, Langying [Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Wang, Manyuan [School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069 (China); Jiao, Kai, E-mail: kjiao@uab.edu [Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

    2013-11-29

    Highlights: •SERTAD1 interacts with SMAD1. •Sertad1 is expressed in mouse embryonic hearts. •SERTAD1 is localized in both cytoplasm and nucleus of cardiomyocytes. •SERTAD1 enhances expression of BMP target cardiogenic genes as a SMAD1 co-activator. -- Abstract: Despite considerable advances in surgical repairing procedures, congenital heart diseases (CHDs) remain the leading noninfectious cause of infant morbidity and mortality. Understanding the molecular/genetic mechanisms underlying normal cardiogenesis will provide essential information for the development of novel diagnostic and therapeutic strategies against CHDs. BMP signaling plays complex roles in multiple cardiogenic processes in mammals. SMAD1 is a canonical nuclear mediator of BMP signaling, the activity of which is critically regulated through its interaction partners. We screened a mouse embryonic heart yeast two-hybrid library using Smad1 as bait and identified SERTAD1 as a novel interaction partner of SMAD1. SERTAD1 contains multiple potential functional domains, including two partially overlapping transactivation domains at the C terminus. The SERTAD1-SMAD1 interaction in vitro and in mammalian cells was further confirmed through biochemical assays. The expression of Sertad1 in developing hearts was demonstrated using RT-PCR, western blotting and in situ hybridization analyses. We also showed that SERTAD1 was localized in both the cytoplasm and nucleus of immortalized cardiomyocytes and primary embryonic cardiomyocyte cultures. The overexpression of SERTAD1 in cardiomyocytes not only enhanced the activity of two BMP reporters in a dose-dependent manner but also increased the expression of several known BMP/SMAD regulatory targets. Therefore, these data suggest that SERTAD1 acts as a SMAD1 transcriptional co-activator to promote the expression of BMP target genes during mouse cardiogenesis.

  9. Mediatization

    DEFF Research Database (Denmark)

    Hjarvard, Stig

    2017-01-01

    Mediatization research shares media effects studies' ambition of answering the difficult questions with regard to whether and how media matter and influence contemporary culture and society. The two approaches nevertheless differ fundamentally in that mediatization research seeks answers...... to these general questions by distinguishing between two concepts: mediation and mediatization. The media effects tradition generally considers the effects of the media to be a result of individuals being exposed to media content, i.e. effects are seen as an outcome of mediated communication. Mediatization...... research is concerned with long-term structural changes involving media, culture, and society, i.e. the influences of the media are understood in relation to how media are implicated in social and cultural changes and how these processes come to create new conditions for human communication and interaction...

  10. Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma.

    LENUS (Irish Health Repository)

    Jennings, Cormac J

    2012-02-01

    INTRODUCTION: Estrogen receptor beta (ERbeta) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance. METHODS: Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERbeta. Allred scores for expression of ERbeta and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival. RESULTS: ERbeta and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test). CONCLUSIONS: Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.

  11. PRMT1-mediated arginine methylation controls ATXN2L localization

    Energy Technology Data Exchange (ETDEWEB)

    Kaehler, Christian; Guenther, Anika; Uhlich, Anja; Krobitsch, Sylvia, E-mail: krobitsc@molgen.mpg.de

    2015-05-15

    Arginine methylation is a posttranslational modification that is of importance in diverse cellular processes. Recent proteomic mass spectrometry studies reported arginine methylation of ataxin-2-like (ATXN2L), the paralog of ataxin-2, a protein that is implicated in the neurodegenerative disorder spinocerebellar ataxia type 2. Here, we investigated the methylation state of ATXN2L and its significance for ATXN2L localization. We first confirmed that ATXN2L is asymmetrically dimethylated in vivo, and observed that the nuclear localization of ATXN2L is altered under methylation inhibition. We further discovered that ATXN2L associates with the protein arginine-N-methyltransferase 1 (PRMT1). Finally, we showed that neither mutation of the arginine–glycine-rich motifs of ATXN2L nor methylation inhibition alters ATXN2L localization to stress granules, suggesting that methylation of ATXN2L is probably not mandatory. - Highlights: • ATXN2L is asymmetrically dimethylated in vivo. • ATXN2L interacts with PRMT1 under normal and stress conditions. • PRMT1-mediated dimethylation of ATXN2L controls its nuclear localization. • ATXN2L localization to stress granules appears independent of its methylation state.

  12. Thermoluminescent coactivated rare earth oxyhalide phosphors and x-ray image converters utilizing said phosphors

    International Nuclear Information System (INIS)

    Rabatin, J.G.

    1984-01-01

    Oxyhalides of lanthanum, gadolinium and lutetium coactivated with a first activator selected from bismuth and samarium to provide the color of light emission and a second coactivator (e.g. terbium or praseodymium) which increases the amount of stored energy in a stored radiographic latent image are found to be superior in their conversion efficiency of x-rays to visible light. (author)

  13. Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction

    NARCIS (Netherlands)

    Fuchs, S.; Nguyen, H.D.; Phan, T.T.T.; Burton, M.F.; Nieto, L.; Vries-van Leeuwen, I.J. de; Schmidt, A.; Goodarzifard, M.; Agten, S.M.; Rose, R.; Ottmann, C.; Milroy, L.G.; Brunsveld, L.

    2013-01-01

    Nuclear receptor binding to coactivator proteins is an obligate first step in the regulation of gene transcription. Nuclear receptors preferentially bind to an LXXLL peptide motif which is highly conserved throughout the 300 or so natural coactivator proteins. This knowledge has shaped current

  14. CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis.

    Science.gov (United States)

    Hill, Micah J; Suzuki, Shigeru; Segars, James H; Kino, Tomoshige

    2016-01-01

    Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP-signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561-693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenolpyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.

  15. Governance and control as mediating instruments in an inter-firm relationship : Towards collaboration or transactions?

    NARCIS (Netherlands)

    Zahir-Ul-Hassan, Muhammad Kaleem; Minnaar, Reinald A.; Vosselman, E.G.J.

    2016-01-01

    This paper explores the mediation of governance and control structures in an inter-firm relationship between a semiconductor producer and its contractor. As mediating instruments the contract and the control structures are not just pre-given results of distanced managerial decision-making, but are

  16. Governance and control as mediating instruments in an inter-firm relationship: towards collaboration or transactions?

    NARCIS (Netherlands)

    Zahir-ul-Hassan, M.K.; Minnaar, R.A.; Vosselman, E.G.J.

    2016-01-01

    This paper explores the mediation of governance and control structures in an inter-firm relationship between a semiconductor producer and its contractor. As mediating instruments the contract and the control structures are not just pre-given results of distanced managerial decision-making, but are

  17. Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

    International Nuclear Information System (INIS)

    Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki; Viitala, Pirkko; Lang, Matti A.; Pelkonen, Olavi; Hakkola, Jukka

    2008-01-01

    The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor γ coactivator (PGC)-1α triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1α and CYP2A5 mRNAs in murine primary hepatocytes. Furthermore, the elevation of the PGC-1α expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1α expression vector demonstrated that PGC-1α is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4α response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1α binds, together with HNF-4α, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1α mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4α. This strongly suggests that PGC-1α is the major factor mediating the fasting response of CYP2A5

  18. Cervical Muscle Strength and Muscle Coactivation During Isometric Contractions in Patients With Migraine: A Cross-Sectional Study.

    Science.gov (United States)

    Florencio, Lidiane Lima; de Oliveira, Anamaria Siriani; Carvalho, Gabriela Ferreira; Tolentino, Gabriella de Almeida; Dach, Fabiola; Bigal, Marcelo Eduardo; Fernández-de-las-Peñas, César; Bevilaqua Grossi, Débora

    2015-01-01

    This cross-sectional study investigated potential differences in cervical musculature in groups of migraine headaches vs. non-headache controls. Differences in cervical muscle strength and antagonist coactivation during maximal isometric voluntary contraction (MIVC) were analyzed between individuals with migraine and non-headache subjects and relationships between force with migraine and neck pain clinical aspects. A customized hand-held dynamometer was used to assess cervical flexion, extension, and bilateral lateral flexion strength in subjects with episodic migraine (n=31), chronic migraine (n = 21) and healthy controls (n = 31). Surface electromyography (EMG) from sternocleidomastoid, anterior scalene, and splenius capitis muscles were recorded during MIVC to evaluate antagonist coactivation. Comparison of main outcomes among groups was conducted with one-way analysis of covariance with the presence of neck pain as covariable. Correlations between peak force and clinical variables were demonstrated by Spearman's coefficient. Chronic migraine subjects exhibited lower cervical extension force (mean diff. from controls: 4.4 N/kg; mean diff from episodic migraine: 3.7 N/kg; P = .006) and spent significantly more time to generate peak force during cervical flexion (mean diff. from controls: 0.5 seconds; P = .025) and left lateral-flexion (mean diff. from controls: 0.4 seconds; mean diff. from episodic migraine: 0.5 seconds; P = .007). Both migraine groups showed significantly higher antagonist muscle coactivity of the splenius capitis muscle (mean diff. from controls: 20%MIVC, P = .03) during cervical flexion relative to healthy controls. Cervical extension peak force was moderately associated with the migraine frequency (rs: -0.30, P = .034), neck pain frequency (rs: -0.26, P = .020), and neck pain intensity (rs: -0.27, P = .012). Patients with chronic migraine exhibit altered muscle performance, took longer to reach peak of

  19. p53-Mediated Molecular Control of Autophagy in Tumor Cells

    Directory of Open Access Journals (Sweden)

    Maria Mrakovcic

    2018-03-01

    Full Text Available Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

  20. The association between antagonist hamstring coactivation and episodes of knee joint shifting and buckling.

    Science.gov (United States)

    Segal, N A; Nevitt, M C; Welborn, R D; Nguyen, U-S D T; Niu, J; Lewis, C E; Felson, D T; Frey-Law, L

    2015-07-01

    Hamstring coactivation during quadriceps activation is necessary to counteract the quadriceps pull on the tibia, but coactivation can be elevated with symptomatic knee osteoarthritis (OA). To guide rehabilitation to attenuate risk for mobility limitations and falls, this study evaluated whether higher antagonistic open kinetic chain hamstring coactivation is associated with knee joint buckling (sudden loss of support) and shifting (a sensation that the knee might give way). At baseline, median hamstring coactivation was assessed during maximal isokinetic knee extensor strength testing and at baseline and 24-month follow-up, knee buckling and shifting was self-reported. Associations between tertiles of co-activation and knee (1) buckling, (2) shifting and (3) either buckling or shifting were assessed using logistic regression, adjusted for age, sex, knee OA and pain. 1826 participants (1089 women) were included. Mean ± SD age was 61.7 ± 7.7 years, BMI was 30.3 ± 5.5 kg/m(2) and 38.2% of knees had OA. There were no consistent statistically significant associations between hamstring coactivation and ipsilateral prevalent or incident buckling or the combination of buckling and shifting. The odds ratios for incident shifting in the highest in comparison with the lowest tertile of coactivation had similar magnitudes in the combined and medial hamstrings, but only reached statistical significance for lateral hamstring coactivation, OR(95%CI) 1.53 (0.99, 2.36). Hamstring coactivation during an open kinetic chain quadriceps exercise was not consistently associated with prevalent or incident self-reported knee buckling or shifting in older adults with or at risk for knee OA. Copyright © 2015. Published by Elsevier Ltd.

  1. Ankle torque steadiness is related to muscle activation variability and co-activation in children with cerebral palsy

    DEFF Research Database (Denmark)

    Bandholm, Thomas; Rose, Martin; Sløk, Rikke

    2009-01-01

    The aims of this study were to: (1) investigate the significance of muscle activation variability and coactivation for the ability to perform steady submaximal ankle torque (torque steadiness) in healthy children and those with cerebral palsy (CP), and (2) assess ankle function during isometric...... contractions in those children. Fourteen children with CP who walked with equinus foot deformity and 14 healthy (control) children performed maximal and steady submaximal ankle dorsi- and plantarflexions. Dorsiflexion torque steadiness was related to agonist and antagonist muscle activation variability as well...

  2. PIC Activation through Functional Interplay between Mediator and TFIIH.

    Science.gov (United States)

    Malik, Sohail; Molina, Henrik; Xue, Zhu

    2017-01-06

    The multiprotein Mediator coactivator complex functions in large part by controlling the formation and function of the promoter-bound preinitiation complex (PIC), which consists of RNA polymerase II and general transcription factors. However, precisely how Mediator impacts the PIC, especially post-recruitment, has remained unclear. Here, we have studied Mediator effects on basal transcription in an in vitro transcription system reconstituted from purified components. Our results reveal a close functional interplay between Mediator and TFIIH in the early stages of PIC development. We find that under conditions when TFIIH is not normally required for transcription, Mediator actually represses transcription. TFIIH, whose recruitment to the PIC is known to be facilitated by the Mediator, then acts to relieve Mediator-induced repression to generate an active form of the PIC. Gel mobility shift analyses of PICs and characterization of TFIIH preparations carrying mutant XPB translocase subunit further indicate that this relief of repression is achieved through expending energy via ATP hydrolysis, suggesting that it is coupled to TFIIH's established promoter melting activity. Our interpretation of these results is that Mediator functions as an assembly factor that facilitates PIC maturation through its various stages. Whereas the overall effect of the Mediator is to stimulate basal transcription, its initial engagement with the PIC generates a transcriptionally inert PIC intermediate, which necessitates energy expenditure to complete the process. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer’s Disease?

    Directory of Open Access Journals (Sweden)

    Kelsey E. Murphy

    2017-05-01

    Full Text Available Alzheimer’s disease (AD is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD.

  4. Mediator subunit18 controls flowering time and floral organ identity in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Zhengui Zheng

    Full Text Available Mediator is a conserved multi-protein complex that plays an important role in regulating transcription by mediating interactions between transcriptional activator proteins and RNA polymerase II. Much evidence exists that Mediator plays a constitutive role in the transcription of all genes transcribed by RNA polymerase II. However, evidence is mounting that specific Mediator subunits may control the developmental regulation of specific subsets of RNA polymerase II-dependent genes. Although the Mediator complex has been extensively studied in yeast and mammals, only a few reports on Mediator function in flowering time control of plants, little is known about Mediator function in floral organ identity. Here we show that in Arabidopsis thaliana, MEDIATOR SUBUNIT 18 (MED18 affects flowering time and floral organ formation through FLOWERING LOCUS C (FLC and AGAMOUS (AG. A MED18 loss-of-function mutant showed a remarkable syndrome of later flowering and altered floral organ number. We show that FLC and AG mRNA levels and AG expression patterns are altered in the mutant. Our results support parallels between the regulation of FLC and AG and demonstrate a developmental role for Mediator in plants.

  5. Trajectories of late-life change in God-mediated control.

    Science.gov (United States)

    Hayward, R David; Krause, Neal

    2013-01-01

    To track within-individual change during late life in the sense of personal control and God-mediated control (the belief that one can work collaboratively with God to achieve one's goals and exercise control over life events) and to evaluate the hypothesis that this element of religion is related to declining personal control. A longitudinal survey representative of older White and Black adults in the United States tracked changes in personal and God-mediated control in four waves over the course of 7 years. Growth curve analysis found that the pattern of change differed by race. White adults had less sense of God-mediated control at younger ages, which increased among those who were highly religious but decreased among those who were less religious. Black adults had higher God-mediated control, which increased over time among those with low personal control. These results indicate that God-mediated control generally increases during older adulthood, but that its relationships with personal control and religious commitment are complex and differ between Black and White adults.

  6. Enhancing the smoothness of joint motion induced by functional electrical stimulation using co-activation strategies

    Directory of Open Access Journals (Sweden)

    Ruppel Mirjana

    2017-09-01

    Full Text Available The motor precision of today’s neuroprosthetic devices that use artificial generation of limb motion using Functional Electrical Stimulation (FES is generally low. We investigate the adoption of natural co-activation strategies as present in antagonistic muscle pairs aiming to improve motor precision produced by FES. In a test in which artificial knee-joint movements were generated, we could improve the smoothness of FES-induced motion by 513% when applying co-activation during the phases in which torque production is switched between muscles – compared to no co-activation. We further demonstrated how the co-activation level influences the joint stiffness in a pendulum test.

  7. Attentional control mediates the effect of social anxiety on positive affect☆

    Science.gov (United States)

    Morrison, Amanda S.; Heimberg, Richard G.

    2015-01-01

    The goal of the present studies was to examine whether attentional control, a self-regulatory attentional mechanism, mediates the effect of social anxiety on positive affect. We tested this mediation in two studies using undergraduate students selected to represent a broad range of severity of social anxiety. Self-report assessments of social anxiety, attentional control, and positive affect were collected in a cross-sectional design (Study 1) and in a longitudinal design with three assessment points (Study 2). Results of both studies supported the hypothesized mediational model. Specifically, social anxiety was inversely related to attentional control, which itself positively predicted positive affect. This mediation remained significant even when statistically controlling for the effects of depression. Additionally, the hypothesized model provided superior model fit to theoretically-grounded equivalent models in both studies. Implications of these findings for understanding diminished positive affect in social anxiety are discussed. PMID:23254261

  8. Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta.

    Directory of Open Access Journals (Sweden)

    Marc Liesa

    Full Text Available There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression.Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2 expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1beta increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha.Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.

  9. Regulated degradation of the APC coactivator Cdc20

    Directory of Open Access Journals (Sweden)

    Robbins Jonathan A

    2010-09-01

    Full Text Available Abstract Background Cdc20 is a highly conserved activator of the anaphase-promoting complex (APC, promoting cell-cycle-regulated ubiquitination and proteolysis of a number of critical cell-cycle-regulatory targets including securin and mitotic cyclins. APC-Cdc20 activity is tightly regulated, and this regulation is likely important for accurate cell cycle control. One significant component of Cdc20 regulation is thought to be Cdc20 proteolysis. However, published literature suggests different mechanisms and requirements for Cdc20 proteolysis. The degree to which Cdc20 proteolysis is cell-cycle regulated, the dependence of Cdc20 proteolysis on Cdc20 destruction boxes (recognition sequences for APC-mediated ubiqutination, either by Cdc20 or by the related Cdh1 APC activator, and the need for APC itself for Cdc20 proteolysis all have been disputed to varying extents. In animals, Cdc20 proteolysis is thought to be mediated by Cdh1, contributing an intrinsic order of APC activation by Cdc20 and then by Cdh1. One report suggests a Cdh1 requirement for Cdc20 proteolysis in budding yeast; this idea has not been tested further. Results We characterized Cdc20 proteolysis using Cdc20 expressed from its endogenous locus; previous studies generally employed strongly overexpressed Cdc20, which can cause significant artifacts. We analyzed Cdc20 proteolysis with or without mutations in previously identified destruction box sequences, using varying methods of cell cycle synchronization, and in the presence or absence of Cdh1. Cdc20 instability is only partially dependent on destruction boxes. A much stronger dependence on Cdh1 for Cdc20 proteolysis was observed, but Cdh1-independent proteolysis was also clearly observed. Cdc20 proteolysis independent of both destruction boxes and Cdh1 was especially detectable around the G1/S transition; Cdh1-dependent proteolysis was most notable in late mitosis and G1. Conclusions Cdc20 proteolysis is under complex control

  10. God-Mediated Control and Change in Self-Rated Health.

    Science.gov (United States)

    Krause, Neal

    2010-10-01

    The purpose of this study was to see if feelings of God-mediated control are associated with change in self-rated health over time. In the process, an effort was made to see if a sense of meaning in life and optimism mediated the relationship between God-mediated control and change in health. The following hypothesized relationships were contained in the conceptual model that was developed to evaluate these issues: (1) people who go to church more often tend to have stronger God-mediated control beliefs than individuals who do not attend worship services as often; (2) people with a strong sense of God-mediated control are more likely to find a sense of meaning in life and be more optimistic than individuals who do not have a strong sense of God-mediated control; (3) people who are optimistic and who have a strong sense of meaning in life will rate their health more favorably over time than individuals who are not optimistic, as well as individuals who have not found a sense of meaning in life. Data from a longitudinal nationwide survey of older adults provided support for each of these hypotheses.

  11. The Schizosaccharomyces pombe Mediator

    DEFF Research Database (Denmark)

    Venturi, Michela

    , Schizosaccharomyces pombe and mammalian Mediator. In our study, we have taken the S. pombe Mediator into consideration and characterized genetically and biochemically two subunits already know in S. cerevisiae, Med9 and Med11, but still not identified in the S. pombe Mediator. Genetic analysis has shown that med9......In the past several years great attention has been dedicated to the characterization of the Mediator complex in a different range of model organisms. Mediator is a conserved co-activator complex involved in transcriptional regulation and it conveys signals from regulatory transcription factors...... to the basal transcription machinery. Mediator was initially isolated from Saccharomyces cerevisiae based on its ability to render a RNA polymerase II in vitro transcription system responsive to activators. Additionally, structural studies have revealed striking structural similarities between S. cerevisiae...

  12. Lateral presynaptic inhibition mediates gain control in an olfactory circuit.

    Science.gov (United States)

    Olsen, Shawn R; Wilson, Rachel I

    2008-04-24

    Olfactory signals are transduced by a large family of odorant receptor proteins, each of which corresponds to a unique glomerulus in the first olfactory relay of the brain. Crosstalk between glomeruli has been proposed to be important in olfactory processing, but it is not clear how these interactions shape the odour responses of second-order neurons. In the Drosophila antennal lobe (a region analogous to the vertebrate olfactory bulb), we selectively removed most interglomerular input to genetically identified second-order olfactory neurons. Here we show that this broadens the odour tuning of these neurons, implying that interglomerular inhibition dominates over interglomerular excitation. The strength of this inhibitory signal scales with total feedforward input to the entire antennal lobe, and has similar tuning in different glomeruli. A substantial portion of this interglomerular inhibition acts at a presynaptic locus, and our results imply that this is mediated by both ionotropic and metabotropic receptors on the same nerve terminal.

  13. Social Control of Hypothalamus-Mediated Male Aggression.

    Science.gov (United States)

    Yang, Taehong; Yang, Cindy F; Chizari, M Delara; Maheswaranathan, Niru; Burke, Kenneth J; Borius, Maxim; Inoue, Sayaka; Chiang, Michael C; Bender, Kevin J; Ganguli, Surya; Shah, Nirao M

    2017-08-16

    How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. RACK1-mediated translation control promotes liver fibrogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Min; Peng, Peike; Wang, Jiajun [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Wang, Lan; Duan, Fangfang [Institute of Biomedical Science, Fudan University, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Ruan, Yuanyuan, E-mail: yuanyuanruan@fudan.edu.cn [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032 (China); Institute of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2015-07-31

    Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis. - Highlights: • RACK1 induces the assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. • RACK1 stimulates the translation of collagen 1α1, snail and cyclin E1 in HSCs. • RACK1 promotes HSCs activation via cap-mediated translation. • Depletion of eIF4E suppresses liver fibrogenesis in vivo.

  15. RACK1-mediated translation control promotes liver fibrogenesis

    International Nuclear Information System (INIS)

    Liu, Min; Peng, Peike; Wang, Jiajun; Wang, Lan; Duan, Fangfang; Jia, Dongwei; Ruan, Yuanyuan; Gu, Jianxin

    2015-01-01

    Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis. - Highlights: • RACK1 induces the assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. • RACK1 stimulates the translation of collagen 1α1, snail and cyclin E1 in HSCs. • RACK1 promotes HSCs activation via cap-mediated translation. • Depletion of eIF4E suppresses liver fibrogenesis in vivo

  16. Passion, Trait Self-Control, and Wellbeing: Comparing Two Mediation Models Predicting Wellbeing.

    Science.gov (United States)

    Briki, Walid

    2017-01-01

    Research has found that passion and trait self-control represented key determinants of wellbeing. Yet, no study to date has attempted to investigate the mediating influences of trait self-control and passion for accounting for the relationships between passion, trait self-control, and wellbeing (dependent variable). Using different frameworks, such as the dualistic model of passion and the neo-socioanalytic theory, the present study proposed two mediation models, considering either trait self-control (model 1) or passion (model 2) as the mediating variable. Five hundred nine volunteers from the United States (326 females and 183 males; M age = 31.74, SD age = 11.05, from 18 to 70 years old), who reported being passionate about a specific activity (e.g., fishing, swimming, blogging; M passion = 5.94, SD passion = 0.89), answered questionnaires assessing harmonious and obsessive passion, trait self-control, and wellbeing (measured through hedonic and eudaimonic wellbeing scales). Preliminary analyses revealed that both models were significant ( model 1: absolute GoF = 0.366, relative GoF = 0.971, outer model GoF = 0.997, inner model GoF = 0.973, R 2 = 18.300%, p passion, trait self-control, and wellbeing, and no relationships of obsessive passion with trait self-control and wellbeing. Mediation analyses revealed that trait self-control significantly mediated the relationship between harmonious passion and wellbeing (i.e., partial mediation, VAF = 33.136%). Harmonious passion appeared to significantly mediate the positive effect of trait self-control on wellbeing; however, the size of the mediating effect indicated that (almost) no mediation would take place (i.e., VAF = 11.144%). The present study is the first to examine the relationships between passion, trait self-control, and wellbeing, and supports the view that trait self-control and harmonious passion represent not only adaptive and powerful constructs, but also key determinants of wellbeing. Implications for

  17. Proactive sustainability strategy and corporate sustainability performance: The mediating effect of sustainability control systems.

    Science.gov (United States)

    Wijethilake, Chaminda

    2017-07-01

    This study examines to what extent corporations use sustainability control systems (SCS) to translate proactive sustainability strategy into corporate sustainability performance. The study investigates the mediating effect of SCS on the relationship between proactive sustainability strategy and corporate sustainability performance. Survey data were collected from top managers in 175 multinational and local corporations operating in Sri Lanka and analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). SCS were observed to only partially mediate the relationship between proactive sustainability strategy and corporate sustainability performance. The mediating effect of SCS is further examined under three sustainability strategies; environmental and social strategies reveal a partial mediation, while the economic strategy exhibits no mediation. The study also finds that (i) a proactive sustainability strategy is positively associated with SCS and corporate sustainability performance and (ii) SCS are positively associated with corporate sustainability performance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. CRISPR-mediated control of the bacterial initiation of replication

    NARCIS (Netherlands)

    Wiktor, J.M.; Lesterlin, Christian; Sherratt, David J.; Dekker, C.

    2016-01-01

    Programmable control of the cell cycle has been shown to be a powerful tool in cell-biology studies. Here, we develop a novel system for controlling the bacterial cell cycle, based on binding of CRISPR/dCas9 to the origin-of-replication locus. Initiation of replication of bacterial chromosomes is

  19. Discerning measures of conscious brain processes associated with superior early motor performance: Capacity, coactivation, and character.

    Science.gov (United States)

    van Duijn, Tina; Buszard, Tim; Hoskens, Merel C J; Masters, Rich S W

    2017-01-01

    This study explored the relationship between working memory (WM) capacity, corticocortical communication (EEG coherence), and propensity for conscious control of movement during the performance of a complex far-aiming task. We were specifically interested in the role of these variables in predicting motor performance by novices. Forty-eight participants completed (a) an assessment of WM capacity (an adapted Rotation Span task), (b) a questionnaire that assessed the propensity to consciously control movement (the Movement Specific Reinvestment Scale), and (c) a hockey push-pass task. The hockey push-pass task was performed in a single task (movement only) condition and a combined task (movement plus decision) condition. Electroencephalography (EEG) was used to examine brain activity during the single task. WM capacity best predicted single task performance. WM capacity in combination with T8-Fz coherence (between the visuospatial and motor regions of the brain) best predicted combined task performance. We discuss the implied roles of visuospatial information processing capacity, neural coactivation, and propensity for conscious processing during performance of complex motor tasks. © 2017 Elsevier B.V. All rights reserved.

  20. The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo

    International Nuclear Information System (INIS)

    Eisele, Petra Sabine; Furrer, Regula; Beer, Markus; Handschin, Christoph

    2015-01-01

    The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed a PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12). In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation. - Highlights: • Muscle PGC-1s are insufficient to prevent acute systemic inflammation. • The muscle PGC-1s however promote a local anti-inflammatory environment. • This anti-inflammatory environment could contribute to the therapeutic effect of the PGC-1s

  1. The PGC-1 coactivators promote an anti-inflammatory environment in skeletal muscle in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Eisele, Petra Sabine [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, CH-4056 Basel (Switzerland); Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich (Switzerland); Furrer, Regula; Beer, Markus [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, CH-4056 Basel (Switzerland); Handschin, Christoph, E-mail: christoph.handschin@unibas.ch [Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, CH-4056 Basel (Switzerland); Zurich Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich (Switzerland)

    2015-08-28

    The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed a PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12). In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation. - Highlights: • Muscle PGC-1s are insufficient to prevent acute systemic inflammation. • The muscle PGC-1s however promote a local anti-inflammatory environment. • This anti-inflammatory environment could contribute to the therapeutic effect of the PGC-1s.

  2. Achievement goals and emotions: The mediational roles of perceived progress, control, and value.

    Science.gov (United States)

    Hall, Nathan C; Sampasivam, Lavanya; Muis, Krista R; Ranellucci, John

    2016-06-01

    The link between achievement goals and achievement emotions is well established; however, research exploring potential mediators of this relationship is lacking. The control-value theory of achievement emotions (Pekrun, 2006, Educational Psychology Review, 18, 315) posits that perceptions of control and value mediate the relationship between achievement goals and achievement emotions, whereas the bidirectional theory of affect (Linnenbrink & Pintrich, 2002, Educational Psychologist, 37, 69) proposes that perceived progress mediates this relationship. The present study empirically evaluated three hypothesized mediators of the effects of achievement goals on learning-related emotions as proposed in the control-value theory and the bidirectional theory of affect. Undergraduate students (N = 273) from humanities, social science, and STEM disciplines participated. Participants completed web-based questionnaires evaluating academic achievement goals, perceptions of control, perceived task value, and achievement emotions. Results provided empirical support primarily for perceived progress as a mediator of mastery-approach goal effects on positive emotions (enjoyment, hope), showing indirect effects of mastery- and performance-approach goals on outcome-related emotions (hope, anxiety) via perceived control. Indirect effects of mastery- and performance-approach goals were further observed on anxiety via perceived value, with higher value levels predicting greater anxiety. Study findings partially support Linnenbrink and Pintrich's (2002, Educational Psychologist, 37, 69) bidirectional theory of affect while underscoring the potential for indirect effects of goals on emotions through perceived control as proposed by Pekrun (2006, Educational Psychology Review, 18, 315). © 2016 The British Psychological Society.

  3. Incremental change in the set of coactive cortical assemblies enables mental continuity.

    Science.gov (United States)

    Reser, Jared Edward

    2016-12-01

    This opinion article explores how sustained neural firing in association areas allows high-order mental representations to be coactivated over multiple perception-action cycles, permitting sequential mental states to share overlapping content and thus be recursively interrelated. The term "state-spanning coactivity" (SSC) is introduced to refer to neural nodes that remain coactive as a group over a given period of time. SSC ensures that contextual groupings of goal or motor-relevant representations will demonstrate continuous activity over a delay period. It also allows potentially related representations to accumulate and coactivate despite delays between their initial appearances. The nodes that demonstrate SSC are a subset of the active representations from the previous state, and can act as referents to which newly introduced representations of succeeding states relate. Coactive nodes pool their spreading activity, converging on and activating new nodes, adding these to the remaining nodes from the previous state. Thus, the overall distribution of coactive nodes in cortical networks evolves gradually during contextual updating. The term "incremental change in state-spanning coactivity" (icSSC) is introduced to refer to this gradual evolution. Because a number of associated representations can be sustained continuously, each brain state is embedded recursively in the previous state, amounting to an iterative process that can implement learned algorithms to progress toward a complex result. The longer representations are sustained, the more successive mental states can share related content, exhibit progressive qualities, implement complex algorithms, and carry thematic or narrative continuity. Included is a discussion of the implications that SSC and icSSC may have for understanding working memory, defining consciousness, and constructing AI architectures. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

  4. Imidazoline and imidazolidine nitroxides as controlling agents in nitroxide-mediated pseudoliving radical polymerization

    Science.gov (United States)

    Edeleva, M. V.; Marque, S. R. A.; Bagryanskaya, E. G.

    2018-04-01

    Controlled, or pseudoliving, radical polymerization provides unique opportunities for the synthesis of structurally diverse polymers with a narrow molecular-weight distribution. These reactions occur under relatively mild conditions with broad tolerance to functional groups in the monomers. The nitroxide-mediated pseudoliving radical polymerization is of particular interest for the synthesis of polymers for biomedical applications. This review briefly describes one of the mechanisms of controlled radical polymerization. The studies dealing with the use of imidazoline and imidazolidine nitroxides as controlling agents for nitroxide-mediated pseudoliving radical polymerization of various monomers are summarized and analyzed. The publications addressing the key steps of the controlled radical polymerization in the presence of imidazoline and imidazolidine nitroxides and new approaches to nitroxide-mediated polymerization based on protonation of both nitroxides and monomers are considered. The bibliography includes 154 references.

  5. Stress and adult smartphone addiction: Mediation by self-control, neuroticism, and extraversion.

    Science.gov (United States)

    Cho, Hea-Young; Kim, Dai Jin; Park, Jae Woo

    2017-12-01

    This study employed descriptive statistics and correlation analysis to examine the influence of stress on smartphone addiction as well as the mediating effects of self-control, neuroticism, and extraversion using 400 men and women in their 20s to 40s followed by structural equation analysis. Our findings indicate that stress had a significant influence on smartphone addiction, and self-control mediates the influence of stress on smartphone addiction. As stress increases, self-control decreases, which subsequently leads to increased smartphone addiction. Self-control was confirmed as an important factor in the prevention of smartphone addiction. Finally, among personality factors, neuroticism, and extraversion mediate the influence of stress on smartphone addiction. Copyright © 2017 John Wiley & Sons, Ltd.

  6. Effortless inhibition: habit mediates the relation between self-control and unhealthy snack consumption

    OpenAIRE

    Adriaanse, Marieke A.; Kroese, Floor M.; Gillebaart, Marleen; De Ridder, Denise T. D.

    2014-01-01

    In contrast to prevailing beliefs, recent research suggests that trait self-control promotes health behavior not because those high in self-control are more successful at resisting single temptations, but rather because they develop adaptive habits. The present paper presents a first empirical test of this novel suggestion by investigating the mediating role of habit in explaining the relation between self-control and unhealthy snacking behavior. Results showed that self-control was negativel...

  7. A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.

    Science.gov (United States)

    Chen, Wei; Zhang, Xiaoting; Birsoy, Kivanc; Roeder, Robert G

    2010-06-01

    As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.

  8. Mediator-dependent Nuclear Receptor Functions

    Science.gov (United States)

    Chen, Wei; Roeder, Robert

    2011-01-01

    As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

  9. Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA

    OpenAIRE

    Kim, Jeong Hoon; Yang, Catherine K.; Stallcup, Michael R.

    2006-01-01

    The coiled-coil coactivator (CoCoA) is a transcriptional coactivator for nuclear receptors and enhances nuclear receptor function by the interaction with the bHLH-PAS domain (AD3) of p160 coactivators. The C-terminal activation domain (AD) of CoCoA possesses strong transactivation activity and is required for the coactivator function of CoCoA with nuclear receptors. To understand how CoCoA AD transmits its activating signal to the transcription machinery, we defined specific subregions, amino...

  10. GR and ER co-activation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

    Science.gov (United States)

    West, Diana C.; Pan, Deng; Tonsing-Carter, Eva Y.; Hernandez, Kyle M.; Pierce, Charles F.; Styke, Sarah C.; Bowie, Kathleen R.; Garcia, Tzintzuni I.; Kocherginsky, Masha; Conzen, Suzanne D.

    2016-01-01

    In estrogen receptor (ER)-negative breast cancer (BC), high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS) (independently of progesterone receptor (PR) expression). To understand the mechanism by which GR expression is associated with a better ER+ BC outcome, the global effect of GR-mediated transcriptional activation in ER+ BC cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in ER+/GR+ MCF-7 cells revealed that upon co-activation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased GR chromatin association was observed at ER, FOXO, and AP1 response elements. In addition, ER associated with GR response elements, suggesting that ER and GR interact in a complex. Co-activation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g. KDM4B, VDR) and inhibiting the Wnt-signaling pathway (IGFBP4). Finally, expression of these individual pro-differentiation genes was associated with significantly improved RFS in ER+ BC patients. Together, these data suggest that the co-expression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage BC by coordinating the altered expression of genes favoring differentiation. Implications The interaction between estrogen and glucocorticoid receptor activity highlights the importance of context-dependent nuclear receptor function in cancer. PMID:27141101

  11. Signatures of memory: brain coactivations during retrieval distinguish correct from incorrect recollection

    Directory of Open Access Journals (Sweden)

    Avi Mendelsohn

    2010-04-01

    Full Text Available Are specific distributed coactivations in the brain during memory retrieval a signature of retrieval outcome? Here we show that this is indeed the case. Widespread brain networks were reported to be involved in the retrieval of long-term episodic memories. Although functional coactivation among particular regions occurs during episodic memory retrieval, it is unknown to what extent it contributes to the accuracy and confidence of recollection. In this study we set out to explore this question. Participants saw a narrative documentary movie. A week later they underwent an fMRI scan during which they either accepted or rejected factual or fictitious verbal statements concerning the movie. Correct vs. incorrect responses to factual statements were more common and were provided with higher confidence than those made to fictitious statements. Whereas activity in the retrieval network correlated mostly with confidence, coactivations primarily correlated with memory accuracy. Specifically, coactivations of left medial temporal lobe regions with temporal and parietal cortices were greater during correct responses to factual statements, but did not differ between responses to fictitious statements. We propose that network coactivations play a role in recovering memory traces that are relevant to online retrieval cues, culminating in distinct retrieval outcomes.

  12. The multitalented Mediator complex.

    Science.gov (United States)

    Carlsten, Jonas O P; Zhu, Xuefeng; Gustafsson, Claes M

    2013-11-01

    The Mediator complex is needed for regulated transcription of RNA polymerase II (Pol II)-dependent genes. Initially, Mediator was only seen as a protein bridge that conveyed regulatory information from enhancers to the promoter. Later studies have added many other functions to the Mediator repertoire. Indeed, recent findings show that Mediator influences nearly all stages of transcription and coordinates these events with concomitant changes in chromatin organization. We review the multitude of activities associated with Mediator and discuss how this complex coordinates transcription with other cellular events. We also discuss the inherent difficulties associated with in vivo characterization of a coactivator complex that can indirectly affect diverse cellular processes via changes in gene transcription. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Maladaptive perfectionism as mediator among psychological control, eating disorders, and exercise dependence symptoms in habitual exerciser.

    Science.gov (United States)

    Costa, Sebastiano; Hausenblas, Heather A; Oliva, Patrizia; Cuzzocrea, Francesca; Larcan, Rosalba

    2016-03-01

    Background and aims The current study examined the mediating role of maladaptive perfectionism among parental psychological control, eating disorder symptoms, and exercise dependence symptoms by gender in habitual exercisers. Methods Participants were 348 Italian exercisers (n = 178 men and n = 170 women; M age = 20.57, SD = 1.13) who completed self-report questionnaires assessing their parental psychological control, maladaptive perfectionism, eating disorder symptoms, and exercise dependence symptoms. Results Results of the present study confirmed the mediating role of maladaptive perfectionism for eating disorder and exercise dependence symptoms for the male and female exercisers in the maternal data. In the paternal data, maladaptive perfectionism mediated the relationships between paternal psychological control and eating disorder and exercise dependence symptoms as full mediator for female participants and as partial mediator for male participants. Discussion Findings of the present study suggest that it may be beneficial to consider dimensions of maladaptive perfectionism and parental psychological control when studying eating disorder and exercise dependence symptoms in habitual exerciser.

  14. CRISPR-mediated control of the bacterial initiation of replication.

    Science.gov (United States)

    Wiktor, Jakub; Lesterlin, Christian; Sherratt, David J; Dekker, Cees

    2016-05-05

    Programmable control of the cell cycle has been shown to be a powerful tool in cell-biology studies. Here, we develop a novel system for controlling the bacterial cell cycle, based on binding of CRISPR/dCas9 to the origin-of-replication locus. Initiation of replication of bacterial chromosomes is accurately regulated by the DnaA protein, which promotes the unwinding of DNA at oriC We demonstrate that the binding of CRISPR/dCas9 to any position within origin or replication blocks the initiation of replication. Serial-dilution plating, single-cell fluorescence microscopy, and flow-cytometry experiments show that ongoing rounds of chromosome replication are finished upon CRISPR/dCas9 binding, but no new rounds are initiated. Upon arrest, cells stay metabolically active and accumulate cell mass. We find that elevating the temperature from 37 to 42°C releases the CRISR/dCas9 replication inhibition, and we use this feature to recover cells from the arrest. Our simple and robust method of controlling the bacterial cell cycle is a useful asset for synthetic biology and DNA-replication studies in particular. The inactivation of CRISPR/dCas9 binding at elevated temperatures may furthermore be of wide interest for CRISPR/Cas9 applications in genomic engineering. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. College drinking behaviors: mediational links between parenting styles, impulse control, and alcohol-related outcomes.

    Science.gov (United States)

    Patock-Peckham, Julie A; Morgan-Lopez, Antonio A

    2006-06-01

    Mediational links between parenting styles (authoritative, authoritarian, permissive), impulsiveness (general control), drinking control (specific control), and alcohol use and abuse were tested. A pattern-mixture approach (for modeling non-ignorable missing data) with multiple-group structural equation models with 421 (206 female, 215 male) college students was used. Gender was examined as a potential moderator of parenting styles on control processes related to drinking. Specifically, the parent-child gender match was found to have implications for increased levels of impulsiveness (a significant mediator of parenting effects on drinking control). These findings suggest that a parent with a permissive parenting style who is the same gender as the respondent can directly influence control processes and indirectly influence alcohol use and abuse.

  16. Estrogen-mediated Height Control in Girls with Marfan Syndrome.

    Science.gov (United States)

    Lee, Dong-Yun; Hyun, Hye Sun; Huh, Rimm; Jin, Dong-Kyu; Kim, Duk-Kyung; Yoon, Byung-Koo; Choi, DooSeok

    2016-02-01

    This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old.

  17. Spin-orbit mediated control of spin qubits

    DEFF Research Database (Denmark)

    Flindt, Christian; Sørensen, A.S; Flensberg, Karsten

    2006-01-01

    We propose to use the spin-orbit interaction as a means to control electron spins in quantum dots, enabling both single-qubit and two-qubit operations. Very fast single-qubit operations may be achieved by temporarily displacing the electrons. For two-qubit operations the coupling mechanism is bas...... on a combination of the spin-orbit coupling and the mutual long-ranged Coulomb interaction. Compared to existing schemes using the exchange coupling, the spin-orbit induced coupling is less sensitive to random electrical fluctuations in the electrodes defining the quantum dots....

  18. Safety aid use and social anxiety symptoms: The mediating role of perceived control.

    Science.gov (United States)

    Korte, Kristina J; Unruh, Amanda S; Oglesby, Mary E; Schmidt, Norman B

    2015-08-30

    The use of safety aids, cognitive or behavioral strategies used to reduce or cope with anxiety, has emerged as a key construct of interest in anxiety disorders due to their role in the development and maintenance of anxiety symptoms. It has been suggested that individuals with anxiety engage in safety aid use to reduce their anxiety and feel more in control of a situation; however, no studies to date have examined the association between perceived control, that is, perceived level of control over internal events in anxiety provoking situations, and the use of safety aids. The purpose of the present study was to examine the association of perceived control, the use of safety aids, and symptoms of social anxiety. It was predicted that the association between safety aid use and social anxiety symptoms would be mediated by perceived control. This prediction was examined in a large sample of 281 participants. As predicted, perceived control was a significant mediator of the association between the use of safety aids and social anxiety symptoms. This effect remained significant after running a multiple mediation model with distress tolerance added as a competing mediator. Implications for future research are discussed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Parental behavioral and psychological control and problematic internet use among Chinese adolescents: the mediating role of self-control.

    Science.gov (United States)

    Li, Xian; Li, Dongping; Newman, Joan

    2013-06-01

    Previous research has reported contradictory effects of parental control on adolescents' problematic Internet use (PIU). To reconcile the discrepant findings, the current study examined the differential effects of parental behavioral control (solicitation and restriction) and psychological control (guilt induction, love withdrawal, and authority assertion) on adolescents' PIU. The mediating effect of self-control on the relationships between parental control and PIU was also examined. A total of 694 Chinese adolescents (M=13.67 years) completed questionnaire measures of parental behavioral control, psychological control, self-control, and PIU. After adjusting for age, gender, and family financial status, it was found that parental restriction (a form of behavioral control) was negatively associated with PIU, whereas love withdrawal (a form of psychological control) was positively associated with PIU. Increased self-control was associated with decreased PIU, and changes in self-control at least partially mediated the differential effects of parental behavioral and psychological control on PIU. Theoretical and practical implications of these findings are discussed.

  20. Improved Metabolic Control in Diabetes, HSP60, and Proinflammatory Mediators

    Directory of Open Access Journals (Sweden)

    Claudio Blasi

    2012-01-01

    Full Text Available The diabetes-atherosclerosis relationship remains to be fully defined. Repeated prolonged hyperglycemia, increased ROS production and endothelial dysfunction are important factors. One theory is that increased blood levels of heat shock protein (HSP60 are proinflammatory, through activation of innate immunity, and contribute to the progression of vascular disease. It was hypothesized that improvement of diabetes control in patients presenting with metabolic syndrome would lower HSP60, and anti-HSP60 antibody levels and decrease inflammatory markers. Paired sera of 17 Italian patients, before and after intensive treatment, were assayed for cytokines, HSP60 and anti-HSP60 antibodies. As expected, intensive treatment was associated with a decrease in HgbA1C (P<0.001 and BMI (P<0.001. After treatment, there was a significant decrease in IL-6 (P<0.05. HSP60 levels were before treatment −6.9+1.9, after treatment −7.1+2.0 ng/mL (P=ns. Overall HSP60 concentrations were lower than published reports. Anti-HSP60 antibody titers were high and did not decrease with treatment. In conclusion, improvement of diabetic control did not alter HSP60 concentrations or antiHSP60 antibody titers, but led to a reduction of IL-6 levels.

  1. Activation of Akt is essential for the propagation of mitochondrial respiratory stress signaling and activation of the transcriptional coactivator heterogeneous ribonucleoprotein A2.

    Science.gov (United States)

    Guha, Manti; Fang, Ji-Kang; Monks, Robert; Birnbaum, Morris J; Avadhani, Narayan G

    2010-10-15

    Mitochondrial respiratory stress (also called mitochondrial retrograde signaling) activates a Ca(2+)/calcineurin-mediated signal that culminates in transcription activation/repression of a large number of nuclear genes. This signal is propagated through activation of the regulatory proteins NFκB c-Rel/p50, C/EBPδ, CREB, and NFAT. Additionally, the heterogeneous ribonucleoprotein A2 (hnRNPA2) functions as a coactivator in up-regulating the transcription of Cathepsin L, RyR1, and Glut-4, the target genes of stress signaling. Activation of IGF1R, which causes a metabolic switch to glycolysis, cell invasiveness, and resistance to apoptosis, is a phenotypic hallmark of C2C12 myoblasts subjected to mitochondrial stress. In this study, we report that mitochondrial stress leads to increased expression, activation, and nuclear localization of Akt1. Mitochondrial respiratory stress also activates Akt1-gene expression, which involves hnRNPA2 as a coactivator, indicating a complex interdependency of these two factors. Using Akt1(-/-) mouse embryonic fibroblasts and Akt1 mRNA-silenced C2C12 cells, we show that Akt1-mediated phosphorylation is crucial for the activation and recruitment of hnRNPA2 to the enhanceosome complex. Akt1 mRNA silencing in mtDNA-depleted cells resulted in reversal of the invasive phenotype, accompanied by sensitivity to apoptotic stimuli. These results show that Akt1 is an important regulator of the nuclear transcriptional response to mitochondrial stress.

  2. FTZ-Factor1 and Fushi tarazu interact via conserved nuclear receptor and coactivator motifs

    Science.gov (United States)

    Schwartz, Carol J.E.; Sampson, Heidi M.; Hlousek, Daniela; Percival-Smith, Anthony; Copeland, John W.R.; Simmonds, Andrew J.; Krause, Henry M.

    2001-01-01

    To activate transcription, most nuclear receptor proteins require coactivators that bind to their ligand-binding domains (LBDs). The Drosophila FTZ-Factor1 (FTZ-F1) protein is a conserved member of the nuclear receptor superfamily, but was previously thought to lack an AF2 motif, a motif that is required for ligand and coactivator binding. Here we show that FTZ-F1 does have an AF2 motif and that it is required to bind a coactivator, the homeodomain-containing protein Fushi tarazu (FTZ). We also show that FTZ contains an AF2-interacting nuclear receptor box, the first to be found in a homeodomain protein. Both interaction motifs are shown to be necessary for physical interactions in vitro and for functional interactions in developing embryos. These unexpected findings have important implications for the conserved homologs of the two proteins. PMID:11157757

  3. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Rui; Zhang, Haiyang; Zhang, Yan; Li, Shuang; Wang, Xinyi; Wang, Xia; Wang, Cheng; Liu, Bin; Zen, Ke; Zhang, Chen-Yu; Zhang, Chunni; Ba, Yi

    2017-04-01

    Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor

  4. Laser pulse control of bridge mediated heterogeneous electron transfer

    International Nuclear Information System (INIS)

    Wang Luxia; May, Volkhard

    2009-01-01

    Ultrafast heterogeneous electron transfer from surface attached dye molecules into semiconductor band states is analyzed. The focus is on systems where the dye is separated from the surface by different bridge anchor groups. To simulate the full quantum dynamics of the transfer process a model of reduced dimensionality is used. It comprises the electronic levels of the dye, the bridge anchor group electronic levels and the continuum of semiconductor band states, all defined versus a single intramolecular vibrational coordinate. The effect of the bridge states is demonstrated, firstly, in studying the injection dynamics following an impulsive excitation of the dye. Then, by discussing different control tasks it is demonstrate in which way the charge injection process can be influenced by tailored laser pulses. To highlight the importance of electron wave function interference emphasis is put on asymmetric two-bridge molecule systems which are also characterized by different and complex valued electronic transfer matrix elements.

  5. Radiation-pressure-mediated control of an optomechanical cavity

    Science.gov (United States)

    Cripe, Jonathan; Aggarwal, Nancy; Singh, Robinjeet; Lanza, Robert; Libson, Adam; Yap, Min Jet; Cole, Garrett D.; McClelland, David E.; Mavalvala, Nergis; Corbitt, Thomas

    2018-01-01

    We describe and demonstrate a method to control a detuned movable-mirror Fabry-Pérot cavity using radiation pressure in the presence of a strong optical spring. At frequencies below the optical spring resonance, self-locking of the cavity is achieved intrinsically by the optomechanical (OM) interaction between the cavity field and the movable end mirror. The OM interaction results in a high rigidity and reduced susceptibility of the mirror to external forces. However, due to a finite delay time in the cavity, this enhanced rigidity is accompanied by an antidamping force, which destabilizes the cavity. The cavity is stabilized by applying external feedback in a frequency band around the optical spring resonance. The error signal is sensed in the amplitude quadrature of the transmitted beam with a photodetector. An amplitude modulator in the input path to the cavity modulates the light intensity to provide the stabilizing radiation pressure force.

  6. Phytochrome-mediated responses: Implications for controlled environment research facilities

    Science.gov (United States)

    Smith, Harry

    1994-01-01

    Light is undoubtedly the most important environmental variable for plant growth and development; plants not only use radiant energy in photosynthesis, they also respond to the quantity, quality, direction and timing of incident radiation through photomorphogenic response that can have huge effects on the rate of growth and the pattern of development. It is surprising, therefore, that the manufacturers and suppliers of controlled environment facilities have been singularly uninventive in the design of the lighting assemblies they provide. The consumer has one choice only - a lighting assembly that provides irradiance levels usually only a fraction of sunlight, and a control system that is limited to regulating the timing of the on-off switch. The reasons for these limitations are partly technological, but in the main they result from ignorance on the part of both the consumer and the manufacturer. A specific and powerful example of this ignorance relates to the importance of the so-called far-red wavelengths (FR = 700-800 nm). Because the human eye can hardly detect wavelengths above 700 nm, and photosynthesis also cuts off at about 700 nm, the majority of plant and crop physiologists are still almost completely unaware that FR radiation can have massive effects on growth rate and development. In consequence, most growth cabinets have light sources based on fluorescent tubes, and provide very little FR apart from that emitted by a token number of small incandescent bulbs. Larger growth facilities often use broader spectrum light sources, but growth facilities that provide the capability to vary the FR incident upon the plants are about as abundant as seals in the Sahara. This article sets the background of the significance of FR radiation in the natural environment and its importance for plant growth and development in the hope that it might inform intelligently those concerned with improving the design of plant growth facilities.

  7. Phytochrome-mediated responses implications for controlled environment research facilities

    Energy Technology Data Exchange (ETDEWEB)

    Smith, H. [Univ. of Leicester (United Kingdom)

    1994-12-31

    Light is undoubtedly the most important environmental variable for plant growth and development; plants not only use radiant energy in photosynthesis, they also respond to the quantity, quality, direction and timing of incident radiation through photomorphogenic responses that can have huge effects on the rate of growth and the pattern of development. It is surprising, therefore, that the manufacturers and suppliers of controlled environment facilities have been singularly uninventive in the design of the lighting assemblies they provide. The consumer has one choice only - a lighting assembly that provides irradiance levels usually only a fraction of sunlight, and a control system that is limited to regulating the timing of the on-off switch. The reasons for these limitations are partly technological, but in the main they result from ignorance on the part of both the consumer and the manufacturer. A specific and powerful example of this ignorance relates to the importance of the so-called far-red wavelengths (FR = 700-800 nm). Because the human eye can hardly detect wavelengths above 700 nm, and photosynthesis also cuts off at ca. 700 mn, the majority of plant and crop physiologists are still almost completely unaware that FR radiation can have massive effects on growth rate and development. In consequence, most growth cabinets have light sources based on fluorescent tubes, and provide very little FR apart from that emitted by a token number of small incandescent bulbs. Larger growth facilities often use broader spectrum light sources, but growth facilities that provide the capability to vary the FR incident upon the plants are about as abundant as seals in the Sahara. This article sets the background of the significance of FR radiation in the natural environment and its importance for plant growth and development in the hope that it might inform intelligently those concerned with improving the design of plant growth facilities.

  8. Motivation toward Physical Exercise and Subjective Wellbeing: The Mediating Role of Trait Self-Control

    Directory of Open Access Journals (Sweden)

    Walid Briki

    2016-10-01

    Full Text Available Motivation toward physical exercise (MPE and trait self-control (TSC were identified as key predictors of subjective wellbeing (SWB. However, there has not been any research designed to examine the mediating role of TSC in the relationship between MPE and SWB. The present study utilizes self-determination theory, control-process theory of self-regulation, and theory of multiple pathways of TSC in order to examine whether TSC mediates the relationships of autonomous MPE (A-MPE, controlled MPE (C-MPE, and impersonal MPE (NO-MPE with SWB using structural equation modeling (XLSTAT PLS. Three hundred seventeen adult American individuals (Mage = 32.97, SDage = 11.30, who reported to be regular exercisers, voluntarily answered questionnaires assessing MPE, TSC, and SWB. Correlational analyses revealed positive relationships between A-MPE, TSC, and SWB, and negative relationships of C-MPE and NO-MPE with TSC and SWB. Mediation analyses revealed that TSC mediated the relationships of A-MPE (partial mediation and C-MPE (full mediation with SWB, but did not mediate the relationship between NO-MPE and SWB. The estimates of the quality of the hypothesized model were acceptable (outer model GoF = .935; absolute GoF = .330; relative GoF = .942; inner model GoF = 1.008; R2 = 36.947%. Finally, this study supports the view that MPE can influence SWB through TSC, and incites to pursue the examination of the relationships between self-determined motivation, self-regulation mechanisms, and health-related outcomes.

  9. Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

    Science.gov (United States)

    Magani, Fiorella; Peacock, Stephanie O; Rice, Meghan A; Martinez, Maria J; Greene, Ann M; Magani, Pablo S; Lyles, Rolando; Weitz, Jonathan R; Burnstein, Kerry L

    2017-11-01

    Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels. Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Differential coactivation in a redundant signals task with weak and strong go/no-go stimuli

    DEFF Research Database (Denmark)

    Minakata, Katsumi; Gondan, Matthias

    2018-01-01

    When participants respond to stimuli of two sources, response times (RT) are often faster when both stimuli are presented together relative to the RTs obtained when presented separately (redundant signals effect, RSE). Race models and coactivation models can explain the RSE. In race models......, separate channels process the two stimulus components, and the faster processing time determines the overall RT. In audiovisual experiments, the RSE is often higher than predicted by race models, and coactivation models have been proposed that assume integrated processing of the two stimuli. Where does...

  11. Global efficiency of structural networks mediates cognitive control in Mild Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Rok Berlot

    2016-12-01

    Full Text Available Background: Cognitive control has been linked to both the microstructure of individual tracts and the structure of whole-brain networks, but their relative contributions in health and disease remain unclear. Objective: To determine the contribution of both localised white matter tract damage and disruption of global network architecture to cognitive control, in older age and Mild Cognitive Impairment (MCI.Methods: 25 patients with MCI and 20 age, sex and intelligence-matched healthy volunteers were investigated with 3 Tesla structural magnetic resonance imaging (MRI. Cognitive control and episodic memory were evaluated with established tests. Structural network graphs were constructed from diffusion MRI-based whole-brain tractography. Their global measures were calculated using graph theory. Regression models utilized both global network metrics and microstructure of specific connections, known to be critical for each domain, to predict cognitive scores. Results: Global efficiency and the mean clustering coefficient of networks were reduced in MCI. Cognitive control was associated with global network topology. Episodic memory, in contrast, correlated with individual temporal tracts only. Relationships between cognitive control and network topology were attenuated by addition of single tract measures to regression models, consistent with a partial mediation effect. The mediation effect was stronger in MCI than healthy volunteers, explaining 23-36% of the effect of cingulum microstructure on cognitive control performance. Network clustering was a significant mediator in the relationship between tract microstructure and cognitive control in both groups. Conclusions: The status of critical connections and large-scale network topology are both important for maintenance of cognitive control in MCI. Mediation via large-scale networks is more important in patients with MCI than healthy volunteers. This effect is domain-specific, and true for cognitive

  12. Thermodynamic control of small RNA-mediated gene silencing

    Directory of Open Access Journals (Sweden)

    Kumiko eUi-Tei

    2012-06-01

    Full Text Available Small interfering RNAs (siRNAs and microRNAs (miRNAs are crucial regulators of posttranscriptional gene silencing, which is referred to as RNA interference (RNAi or RNA silencing. In RNAi, siRNA loaded onto the RNA-induced silencing complex (RISC downregulates target gene expression by cleaving mRNA whose sequence is perfectly complementary to the siRNA guide strand. We previously showed that highly functional siRNAs possessed the following characteristics: A or U residues at nucleotide position 1 measured from the 5’ terminal, four to seven A/Us in positions 1–7, and G or C residues at position 19. This finding indicated that an RNA strand with a thermodynamically unstable 5’ terminal is easily retained in the RISC and functions as a guide strand. In addition, it is clear that unintended genes with complementarities only in the seed region (positions 2–8 are also downregulated by off-target effects. siRNA efficiency is mainly determined by the Watson-Crick base-pairing stability formed between the siRNA seed region and target mRNA. siRNAs with a low seed-target duplex melting temperature (Tm have little or no seed-dependent off-target activity. Thus, important parts of the RNA silencing machinery may be regulated by nucleotide base-pairing thermodynamic stability. A mechanistic understanding of thermodynamic control may enable an efficient target gene-specific RNAi for functional genomics and safe therapeutic applications.

  13. Parenting Styles and Bullying at School: The Mediating Role of Locus of Control

    Science.gov (United States)

    Georgiou, Stelios N.; Ioannou, Myria; Stavrinides, Panayiotis

    2017-01-01

    The current study examined the mediating role of children's locus of control in the relation between parenting styles and bully-victim experiences at school. Participants were 447 students aged 10 and 11 years old from 13 different elementary, urban, and rural schools in Cyprus. Analyses using structural equation modeling showed that parenting…

  14. Inhibitory Control Mediates the Relationship between Depressed Mood and Overgeneral Memory Recall in Children

    Science.gov (United States)

    Raes, Filip; Verstraeten, Katrien; Bijttebier, Patricia; Vasey, Michael W.; Dalgleish, Tim

    2010-01-01

    It has been well established that depressed mood is related to overgeneral memory recall (OGM), which refers to a relative difficulty in retrieving specific information from one's autobiographical memory (AM). The present study examined whether OGM is also related to depressed mood in children and whether lack of inhibitory control mediates this…

  15. Perceived Academic Control: Mediating the Effects of Optimism and Social Support on College Students' Psychological Health

    Science.gov (United States)

    Ruthig, Joelle C.; Haynes, Tara L.; Stupnisky, Robert H.; Perry, Raymond P.

    2009-01-01

    The first year of college presents numerous challenges experienced as overwhelming by some freshmen who may become overly stressed and depressed. This longitudinal study examined perceived academic control (PAC) as a mediator of optimism and social support's buffering effects on freshman students' psychological health. Multiple regressions…

  16. Mother-adolescent conflict as a mediator between adolescent problem behaviors and maternal psychological control.

    Science.gov (United States)

    Steeger, Christine M; Gondoli, Dawn M

    2013-04-01

    This study examined mother-adolescent conflict as a mediator of longitudinal reciprocal relations between adolescent aggression and depressive symptoms and maternal psychological control. Motivated by family systems theory and the transactions that occur between individual and dyadic levels of the family system, we examined the connections among these variables during a developmental period when children and parents experience significant psychosocial changes. Three years of self-report data were collected from 168 mother-adolescent dyads, beginning when the adolescents (55.4% girls) were in 6th grade. Models were tested using longitudinal path analysis. Results indicated that the connection between adolescent aggression (and depressive symptoms) and maternal psychological control was best characterized as adolescent-driven, indirect, and mediated by mother-adolescent conflict; there were no indications of parent-driven indirect effects. That is, prior adolescent aggression and depressive symptoms were associated with increased conflict. In turn, conflict was associated with increased psychological control. Within our mediation models, reciprocal direct effects between both problem behaviors and conflict and between conflict and psychological control were also found. Additionally, exploratory analyses regarding the role of adolescent gender as a moderator of variable relations were conducted. These analyses revealed no gender-related patterns of moderation, whether moderated mediation or specific path tests for moderation were considered. This study corroborates prior research finding support for child effects on parenting behaviors during early adolescence. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

  17. Computer-mediated communication in adults with high-functioning autism spectrum disorders and controls

    NARCIS (Netherlands)

    van der Aa, Christine; Pollmann, Monique; Plaat, Aske; van der Gaag, Rutger Jan

    2016-01-01

    It has been suggested that people with Autism Spectrum Disorders (ASD) are attracted to computer-mediated communication (CMC). In this study, we compare CMC use in adults with high-functioning ASD (N = 113) and a control group (N = 72). We find that people with ASD spend more time on CMC than

  18. Polarization control of intermediate state absorption in resonance-mediated multi-photon absorption process

    International Nuclear Information System (INIS)

    Xu, Shuwu; Yao, Yunhua; Jia, Tianqing; Ding, Jingxin; Zhang, Shian; Sun, Zhenrong; Huang, Yunxia

    2015-01-01

    We theoretically and experimentally demonstrate the control of the intermediate state absorption in an (n + m) resonance-mediated multi-photon absorption process by the polarization-modulated femtosecond laser pulse. An analytical solution of the intermediate state absorption in a resonance-mediated multi-photon absorption process is obtained based on the time-dependent perturbation theory. Our theoretical results show that the control efficiency of the intermediate state absorption by the polarization modulation is independent of the laser intensity when the transition from the intermediate state to the final state is coupled by the single-photon absorption, but will be affected by the laser intensity when this transition is coupled by the non-resonant multi-photon absorption. These theoretical results are experimentally confirmed via a two-photon fluorescence control in (2 + 1) resonance-mediated three-photon absorption of Coumarin 480 dye and a single-photon fluorescence control in (1 + 2) resonance-mediated three-photon absorption of IR 125 dye. (paper)

  19. The LEGO toolbox: Supramolecular building blocks by nitroxide-mediated controlled radical polymerization

    NARCIS (Netherlands)

    Lohmeijer, B.G.G.; Schubert, U.S.

    2005-01-01

    A terpyridine-functionalized alkoxyamine unimolecular initiator was used for the nitroxide-mediated controlled living radical polymerization of n-butylacrylate, N,N-dimethylacrylamide, 4-vinylpyridine, 2-vinylpyridine, and isoprene. For the former three monomers, the kinetics were studied. All

  20. Job autonomy in relation to work engagement and workaholism: Mediation of autonomous and controlled work motivation.

    Science.gov (United States)

    Malinowska, Diana; Tokarz, Aleksandra; Wardzichowska, Anna

    2018-02-07

    This study integrates the Self Determination Theory and the Job Demands-Resource model in explaining motivational antecedents of 2 forms of excessive work: work engagement and workaholism. It specifically examines the relationship between job autonomy, situational work motivation, work engagement, and workaholism. The sample comprised 318 full-time employees of an international outsourcing company located in Poland. The mediation analysis was used for testing hypotheses about the mediation of autonomous and controlled motivation in the relationship between job autonomy, work engagement, and workaholism. The results have confirmed that autonomous motivation mediates the relationship between job autonomy and work engagement. The assumption about the mediation role of controlled motivation in the relationship between job autonomy and workaholism has not been confirmed; however, external regulation (i.e., controlled motivation) is a significant predictor of workaholism. Giving employees more job autonomy might increase their intrinsic and identified regulation and may therefore lead to more energetic, enthusiastic, and dedicated engagement with their jobs. Workaholism may be predicted by external regulation, and work characteristics other than job autonomy may play an important role in enhancing this controlled type of motivation. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

  1. Inhibitory Control Mediates the Association between Perceived Stress and Secure Relationship Quality.

    Science.gov (United States)

    Herd, Toria; Li, Mengjiao; Maciejewski, Dominique; Lee, Jacob; Deater-Deckard, Kirby; King-Casas, Brooks; Kim-Spoon, Jungmeen

    2018-01-01

    Past research has demonstrated negative associations between exposure to stressors and quality of interpersonal relationships among children and adolescents. Nevertheless, underlying mechanisms of this association remain unclear. Chronic stress has been shown to disrupt prefrontal functioning in the brain, including inhibitory control abilities, and evidence is accumulating that inhibitory control may play an important role in secure interpersonal relationship quality, including peer problems and social competence. In this prospective longitudinal study, we examine whether changes in inhibitory control, measured at both behavioral and neural levels, mediate the association between stress and changes in secure relationship quality with parents and peers. The sample included 167 adolescents (53% males) who were first recruited at age 13 or 14 years and assessed annually three times. Adolescents' inhibitory control was measured by their behavioral performance and brain activities, and adolescents self-reported perceived stress levels and relationship quality with mothers, fathers, and peers. Results suggest that behavioral inhibitory control mediates the association between perceived stress and adolescent's secure relationship quality with their mothers and fathers, but not their peers. In contrast, given that stress was not significantly correlated with neural inhibitory control, we did not further test the mediation path. Our results highlight the role of inhibitory control as a process through which stressful life experiences are related to impaired secure relationship quality between adolescents and their mothers and fathers.

  2. Work stress and emotional exhaustion in nurses: the mediating role of internal locus of control.

    Science.gov (United States)

    Partlak Günüşen, Neslihan; Ustün, Besti; Erdem, Sabri

    2014-01-01

    Burnout is a major problem for nursing. There is a strong relationship between work stress and emotional exhaustion. Although studies report a negative correlation between the internal locus of control and emotional exhaustion and work stress, the number of studies available on the subject is limited. This study intends to examine the extent to which the relationship between work stress and emotional exhaustion is mediated by nurses' internal locus of control. The study adopted a cross-sectional survey design. The data were analyzed using structural equation modeling techniques. The study sample consisted of 347 nurses who worked in a university hospital in Izmir, Turkey and who agreed to participate in the study. The Work-Related Strain Inventory was used to evaluate the nurses' work stress level, Maslach Burnout Inventory was used to evaluate their emotional exhaustion levels, and the Locus of Control Scale was used to evaluate the internal locus of control. The variables of the study were based on the Neuman Systems Model. Work stress was positively related to internal locus of control (β3 = .21, p 0.1). Internal locus of control was negatively related to emotional exhaustion (β = -.14, p Work stress is directly (β = .87, p Work stress is directly (β = .87, p work stress was mediated, the impact of internal locus of control was limited. It is recommended that different variables be included in future studies so that they can mediate the relationship between work stress and emotional exhaustion.

  3. Inhibitory Control Mediates the Association between Perceived Stress and Secure Relationship Quality

    Directory of Open Access Journals (Sweden)

    Toria Herd

    2018-02-01

    Full Text Available Past research has demonstrated negative associations between exposure to stressors and quality of interpersonal relationships among children and adolescents. Nevertheless, underlying mechanisms of this association remain unclear. Chronic stress has been shown to disrupt prefrontal functioning in the brain, including inhibitory control abilities, and evidence is accumulating that inhibitory control may play an important role in secure interpersonal relationship quality, including peer problems and social competence. In this prospective longitudinal study, we examine whether changes in inhibitory control, measured at both behavioral and neural levels, mediate the association between stress and changes in secure relationship quality with parents and peers. The sample included 167 adolescents (53% males who were first recruited at age 13 or 14 years and assessed annually three times. Adolescents’ inhibitory control was measured by their behavioral performance and brain activities, and adolescents self-reported perceived stress levels and relationship quality with mothers, fathers, and peers. Results suggest that behavioral inhibitory control mediates the association between perceived stress and adolescent’s secure relationship quality with their mothers and fathers, but not their peers. In contrast, given that stress was not significantly correlated with neural inhibitory control, we did not further test the mediation path. Our results highlight the role of inhibitory control as a process through which stressful life experiences are related to impaired secure relationship quality between adolescents and their mothers and fathers.

  4. Human GW182 Paralogs Are the Central Organizers for RNA-Mediated Control of Transcription.

    Science.gov (United States)

    Hicks, Jessica A; Li, Liande; Matsui, Masayuki; Chu, Yongjun; Volkov, Oleg; Johnson, Krystal C; Corey, David R

    2017-08-15

    In the cytoplasm, small RNAs can control mammalian translation by regulating the stability of mRNA. In the nucleus, small RNAs can also control transcription and splicing. The mechanisms for RNA-mediated nuclear regulation are not understood and remain controversial, hindering the effective application of nuclear RNAi and investigation of its natural regulatory roles. Here, we reveal that the human GW182 paralogs TNRC6A/B/C are central organizing factors critical to RNA-mediated transcriptional activation. Mass spectrometry of purified nuclear lysates followed by experimental validation demonstrates that TNRC6A interacts with proteins involved in protein degradation, RNAi, the CCR4-NOT complex, the mediator complex, and histone-modifying complexes. Functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation. These findings describe protein complexes capable of bridging RNA-mediated sequence-specific recognition of noncoding RNA transcripts with the regulation of gene transcription. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Different ankle muscle coordination patterns and co-activation during quiet stance between young adults and seniors do not change after a bout of high intensity training.

    Science.gov (United States)

    Donath, Lars; Kurz, Eduard; Roth, Ralf; Zahner, Lukas; Faude, Oliver

    2015-03-04

    Available evidence suggests that young adults and seniors use different strategies to adjust for increasing body sway during quiet standing. Altered antagonist muscle co-activation and different ankle muscle coordination patterns may account for this finding. Consequently, we aimed at addressing whether aging leads to changes in neuromuscular coordination patterns as well as co-activation during quiet stance. We additionally investigated whether a bout of high intensity interval training additionally alters these patterns. Twenty healthy seniors (age: 70 ± 4 y) and twenty young adults (age: 27 ± 3 y) were enrolled in the present study. In between the testing procedures, four consecutive high-intensity intervals of 4 min duration at a target exercise intensity of 90 to 95% HRmax were completed on a treadmill. The total center of pressure (COP) path length displacement served as standing balance performance outcome. In order to assess ankle muscle coordination patterns, amplitude ratios (AR) were calculated for each muscle (e.g. tibialis anterior (TA) [%] = (TA × 100)/(gastrocnemius medialis (GM) + soleus (SOL) + peroneus longus (PL) + TA). The co-activation was calculated for the SOL and TA muscles computing the co-activation index (CAI = 2 × TA/TA + SOL). Seniors showed an inverted ankle muscle coordination pattern during single limb stance with eyes open (SLEO), compared to young adults (rest: GM, S: 15 ± 8% vs Y: 24 ± 9%; p = 0.03; SOL, S: 27 ± 14% vs Y: 37 ± 18%; p = 0.009; TA, S: 31 ± 13% vs Y: 13 ± 7%; p = 0.003). These patterns did not change after a high-intensity training session. A moderate correlation between amplitude ratios of the TA-contribution and postural sway was observed for seniors during SLEO (r = 0.61). Ankle co-activation was twofold elevated in seniors compared to young adults during SLEO (p Seniors with decreased postural control showed higher TA

  6. Maternal Parenting as a Mediator of the Relationship between Intimate Partner Violence and Effortful Control

    OpenAIRE

    Gustafsson, Hanna C.; Cox, Martha J.; Blair, Clancy

    2011-01-01

    The current study examined the relationship between intimate partner violence (IPV), maternal parenting behaviors, and child effortful control in a diverse sample of 705 families living in predominantly low-income, rural communities. Using structural equation modeling, the authors simultaneously tested whether observed sensitive parenting and/or harsh-intrusive parenting over the toddler years mediated the relationship between early IPV and later effortful control. Results suggest that parent...

  7. Self-control mediates the relationship between time perspective and BMI.

    Science.gov (United States)

    Price, Menna; Higgs, Suzanne; Lee, Michelle

    2017-01-01

    Trait future time perspective measures the extent to which behaviour is dominated by a striving for future goals and rewards. Trait present time perspective measures orientation towards immediate pleasure. Previous research has explored the relationship between future and present time perspective and BMI with mixed findings. In addition, the psychological mechanism underlying this relationship is unclear. Self-control is a likely candidate, as it has been related to both BMI and time perspective, but the relationship between all of these concepts has not been examined in a single study. Therefore, the aim of this study was to examine if trait self-control mediates the relationship between time perspective (future and present) and BMI. Self-report time perspective (ZTPI), self-control (SCS) and height/weight data were collected using an online survey from a mixed student and community sample (N = 218) with wide ranging age (mean 29, SD 11, range 18-73 years) and BMI (mean 24, SD 4, range 15-43). The results of a structural equation model including both facets of time perspective suggested that the traits are related yet distinct measures that independently predict BMI through changes in self-control. Bootstrap mediation analysis showed that self-control mediated the relationship between both future time perspective (95% CI, -0.10 to -0.02) and present time perspective (95% CI, 0.03 to 0.17), and BMI in opposite directions. Participants with higher future time perspective scores (higher present time perspective scores) had higher (lower) self-control, which predicted lower (higher) BMI. These results are consistent with previous research suggesting an important role for time perspective in health outcomes. Self-control likely mediates the relationship between temporal perspectives and BMI, suggesting that time perspective may be a target for individualised interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Hamstrings co-activation in ACL-deficient subjects during isometric whole-leg extensions

    NARCIS (Netherlands)

    Aalbersberg, S.; Kingma, I.; van Dieen, J.H.

    2009-01-01

    It has been reported that anterior cruciate ligament (ACL)-deficient subjects increase the level of hamstrings activation and this has been interpreted as a means to cope with increased anterior tibial laxity in the knee. This study aimed to establish to what extent co-activation strategies in

  9. Ankle torque steadiness is related to muscle activation variability and coactivation in children with cerebral palsy

    DEFF Research Database (Denmark)

    Bandholm, Thomas; Rose, Martin Høyer; Sløk, Rikke

    2009-01-01

    The aims of this study were to: (1) investigate the significance of muscle activation variability and coactivation for the ability to perform steady submaximal ankle torque (torque steadiness) in healthy children and those with cerebral palsy (CP), and (2) assess ankle function during isometric...

  10. The Race that Precedes Coactivation: Development of Multisensory Facilitation in Children

    Science.gov (United States)

    Barutchu, Ayla; Crewther, David P.; Crewther, Sheila G.

    2009-01-01

    Rationale: The facilitating effect of multisensory integration on motor responses in adults is much larger than predicted by race-models and is in accordance with the idea of coactivation. However, the development of multisensory facilitation of endogenously driven motor processes and its relationship to the development of complex cognitive skills…

  11. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1

    NARCIS (Netherlands)

    Zwijsen, R.M.L.; Buckle, R.S.; Hijmans, E.M.; Loomans, C.J.M.; Bernards, R.A.

    1998-01-01

    The estrogen receptor (ER) is an important regulator of growth and differentiation of breast epithelium. Transactivation by ER depends on a leucine-rich motif, which constitutes a ligand-regulated binding site for steroid receptor coactivators (SRCs). Cyclin D1 is frequently amplified in breast

  12. SRC-2 is an essential coactivator for orchastrating metabolism and circadian rhythm

    Science.gov (United States)

    Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:C...

  13. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity

    DEFF Research Database (Denmark)

    Wang, Yiguo; Inoue, Hiroshi; Ravnskjær, Kim

    2010-01-01

    Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to at...

  14. Religiousness and aggression in adolescents: The mediating roles of self-control and compassion.

    Science.gov (United States)

    Shepperd, James A; Miller, Wendi A; Smith, Colin Tucker

    2015-01-01

    Although people have used religion to justify aggression, evidence suggests that greater religiousness corresponds with less aggression. We explored two explanations for the religion-aggression link. First, most major religions teach self-control (e.g., delaying gratification, resisting temptation), which diminishes aggression. Second, most major religions emphasize compassionate beliefs and behavior (i.e., perspective taking, forgiveness, a broader love of humanity) that are incompatible with aggression. We tested whether self-control and compassion mediated the relationship between religion and aggression (direct and indirect) in a longitudinal study of 1,040 adolescents in the United States. Structural equation analyses revealed that self-control and compassion together completely mediated the religion-aggression relationship for both types of aggression. © 2015 Wiley Periodicals, Inc.

  15. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex

    Directory of Open Access Journals (Sweden)

    Lisa M. Tuttle

    2018-03-01

    Full Text Available Summary: Transcription activation domains (ADs are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements. : Tuttle et al. report a “fuzzy free-for-all” interaction mechanism that explains how seemingly unrelated transcription activators converge on a limited number of coactivator targets. The mechanism provides a rationale for the observation that individually weak and low-specificity interactions can combine to produce biologically critical function without requiring highly ordered structure. Keywords: transcription activation, intrinsically disordered proteins, fuzzy binding

  16. Autoimmune regulator is acetylated by transcription coactivator CBP/p300

    Energy Technology Data Exchange (ETDEWEB)

    Saare, Mario, E-mail: mario.saare@ut.ee [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, 19th Ravila Str, Tartu (Estonia); Rebane, Ana [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, 19th Ravila Str, Tartu (Estonia); SIAF, Swiss Institute of Allergy and Asthma Research, University of Zuerich, Davos (Switzerland); Rajashekar, Balaji; Vilo, Jaak [BIIT, Bioinformatics, Algorithmics and Data Mining group, Institute of Computer Science, University of Tartu, Tartu (Estonia); Peterson, Paert [Molecular Pathology, Institute of General and Molecular Pathology, University of Tartu, 19th Ravila Str, Tartu (Estonia)

    2012-08-15

    The Autoimmune Regulator (AIRE) is a regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes. -- Highlights: Black-Right-Pointing-Pointer AIRE is acetylated by the acetyltransferases p300 and CBP. Black-Right-Pointing-Pointer Acetylation occurs between CARD and SAND domains and within the SAND domain. Black-Right-Pointing-Pointer Acetylation increases the size of AIRE nuclear dots. Black-Right-Pointing-Pointer Acetylation increases AIRE protein stability. Black-Right-Pointing-Pointer AIRE acetylation mimic regulates a different set of AIRE

  17. Callous-Unemotional Traits and Effortful Control Mediate the Effect of Parenting Intervention on Preschool Conduct Problems.

    Science.gov (United States)

    Elizur, Yoel; Somech, Lior Y

    2018-02-24

    Parenting intervention (PI) is an effective treatment for children's conduct problems (CP) that has been shown to be mediated by improved parenting practices and parenting self-efficacy. Recently, Hitkashrut's randomized controlled trial demonstrated that ineffective parenting (IP) mediated effects on callous-unemotional (CU) traits and effortful control (EC), while controlling for more general treatment effects on CP. These temperament and personality-based features predict the formation of early-onset antisocial trajectories with poor long-term prognosis. The objective of this study was to use Hitkashrut's 3-wave dataset to test posttreatment EC and CU mediation of treatment effect on 1-year follow-up CP, and to determine whether mediation by each child-level potential mediator remains significant when tested concurrently with the parenting mediator. Parents of 209 3-5 year-old preschoolers (163 boys; 46 girls), with subclinical-clinical range CP were assigned to 14-session co-parent training groups (n = 140 couples), or to minimal intervention control groups (n = 69 couples). Assessments were based on both parents' questionnaires. An intent-to-treat analysis showed that EC and CU traits simultaneously mediated treatment effects on CP in one EC/CU mediational model. The concurrent testing of child- and parent-level mediators showed mediation by IP and CU traits in the CU/IP model, and IP mediation in the EC/IP model. Similar results were obtained in mediational analyses that controlled for the shared variance between the mediators and CP at T2. Overall, the findings support an intervention model of coaching parents of high-CP children to promote moral self-regulatory competencies while concurrently applying behavioral methods that directly target CP.

  18. Transcriptional coactivator NT-PGC-1α promotes gluconeogenic gene expression and enhances hepatic gluconeogenesis.

    Science.gov (United States)

    Chang, Ji Suk; Jun, Hee-Jin; Park, Minsung

    2016-10-01

    The transcriptional coactivator PGC-1α plays a central role in hepatic gluconeogenesis. We previously reported that alternative splicing of the PGC-1α gene produces an additional transcript encoding the truncated protein NT-PGC-1α NT-PGC-1α is co-expressed with PGC-1α and highly induced by fasting in the liver. NT-PGC-1α regulates tissue-specific metabolism, but its role in the liver has not been investigated. Thus, the objective of this study was to determine the role of hepatic NT-PGC-1α in the regulation of gluconeogenesis. Adenovirus-mediated expression of NT-PGC-1α in primary hepatocytes strongly stimulated the expression of key gluconeogenic enzyme genes (PEPCK and G6Pase), leading to increased glucose production. To further understand NT-PGC-1α function in hepatic gluconeogenesis in vivo, we took advantage of a previously reported FL-PGC-1α -/- mouse line that lacks full-length PGC-1α (FL-PGC-1α) but retains a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α 254 ). In FL-PGC-1α -/- mice, NT-PGC-1α 254 was induced by fasting in the liver and recruited to the promoters of PEPCK and G6Pase genes. The enrichment of NT-PGC-1α 254 at the promoters was closely associated with fasting-induced increase in PEPCK and G6Pase gene expression and efficient production of glucose from pyruvate during a pyruvate tolerance test in FL-PGC-1α -/- mice. Moreover, FL-PGC-1α -/- primary hepatocytes showed a significant increase in gluconeogenic gene expression and glucose production after treatment with dexamethasone and forskolin, suggesting that NT-PGC-1α 254 is sufficient to stimulate the gluconeogenic program in the absence of FL-PGC-1α Collectively, our findings highlight the role of hepatic NT-PGC-1α in stimulating gluconeogenic gene expression and glucose production. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  19. Effortless Inhibition: Habit Mediates the Relation Between Self-Control and Unhealthy Snack Consumption

    Directory of Open Access Journals (Sweden)

    Marieke eAdriaanse

    2014-05-01

    Full Text Available In contrast to prevailing beliefs, recent research suggests that trait self-control promotes health behavior not because those high in self-control are more successful at resisting single temptations, but rather because they develop adaptive habits. The present paper presents a first empirical test of this novel suggestion by investigating the mediating role of habit in explaining the relation between self-control and unhealthy snacking behavior. Results showed that self-control was negatively associated with unhealthy snack consumption and unhealthy snacking habits. As hypothesized, the relation between self-control and unhealthy snack intake was mediated by habit strength. Self-control was not associated with fruit consumption or fruit consumption habits. These results provide the first evidence for the notion that high self-control may influence the formation of habits and in turn affect behavior. Moreover, results imply that self-control may be particularly influential in case of inhibiting unhealthy food intake rather than promoting healthy food intake.

  20. Hepatitis C virus core protein regulates p300/CBP co-activation function. Possible role in the regulation of NF-AT1 transcriptional activity

    International Nuclear Information System (INIS)

    Gomez-Gonzalo, Marta; Benedicto, Ignacio; Carretero, Marta; Lara-Pezzi, Enrique; Maldonado-Rodriguez, Alejandra; Moreno-Otero, Ricardo; Lai, Michael M.C.; Lopez-Cabrera, Manuel

    2004-01-01

    Hepatitis C virus (HCV) core is a viral structural protein; it also participates in some cellular processes, including transcriptional regulation. However, the mechanisms of core-mediated transcriptional regulation remain poorly understood. Oncogenic virus proteins often target p300/CBP, a known co-activator of a wide variety of transcription factors, to regulate the expression of cellular and viral genes. Here we demonstrate, for the first time, that HCV core protein interacts with p300/CBP and enhances both its acetyl-transferase and transcriptional activities. In addition, we demonstrate that nuclear core protein activates the NH 2 -terminal transcription activation domain (TAD) of NF-AT1 in a p300/CBP-dependent manner. We propose a model in which core protein regulates the co-activation function of p300/CBP and activates NF-AT1, and probably other p300/CBP-regulated transcription factors, by a novel mechanism involving the regulation of the acetylation state of histones and/or components of the transcriptional machinery

  1. A liver X receptor (LXR)-β alternative splicing variant (LXRBSV) acts as an RNA co-activator of LXR-β

    International Nuclear Information System (INIS)

    Hashimoto, Koshi; Ishida, Emi; Matsumoto, Shunichi; Shibusawa, Nobuyuki; Okada, Shuichi; Monden, Tsuyoshi; Satoh, Tetsurou; Yamada, Masanobu; Mori, Masatomo

    2009-01-01

    We report the isolation and functional characterization of a novel transcriptional co-activator, termed LXRBSV. LXRBSV is an alternative splicing variant of liver X receptor (LXR)-β LXRBSV has an intronic sequence between exons 2 and 3 in the mouse LXR-β gene. The LXRBSV gene is expressed in various tissues including the liver and brain. We sub-cloned LXRBSV into pSG5, a mammalian expression vector, and LXRBSV in pSG5 augmented human Sterol Response Element Binding Protein (SREBP)-1c promoter activity in HepG2 cells in a ligand (TO901317) dependent manner. The transactivation mediated by LXRBSV is selective for LXR-β. The LXRBSV protein was deduced to be 64 amino acids in length; however, a GAL4-LXRBSV fusion protein was not able to induce transactivation. Serial deletion constructs of LXRBSV demonstrated that the intronic sequence inserted in LXRBSV is required for its transactivation activity. An ATG mutant of LXRBSV was able to induce transactivation as wild type. Furthermore, LXRBSV functions in the presence of cycloheximide. Taken together, we have concluded that LXRBSV acts as an RNA transcript not as a protein. In the current study, we have demonstrated for the first time that an alternative splicing variant of a nuclear receptor acts as an RNA co-activator.

  2. Exploring the relationship between socioeconomic status, control beliefs and exercise behavior: a multiple mediator model.

    Science.gov (United States)

    Murray, Terra C; Rodgers, Wendy M; Fraser, Shawn N

    2012-02-01

    The purpose of this study was to examine the relationship between control beliefs, socioeconomic status and exercise intentions and behavior. Specifically, we examined whether distal and proximal control beliefs mediated the association between socioeconomic status and exercise intentions and behavior. A one time, cross sectional mail out survey (N = 350) was conducted in a large urban Canadian city. Distal (i.e., personal constraints) and proximal (i.e., scheduling self-efficacy) control beliefs mediated the association between socioeconomic status and exercise, explaining approximately 30% of the variance. Proximal control beliefs (i.e., scheduling self-efficacy) partially mediated the association between socioeconomic status and intentions, with the models explaining approximately 50% of the variance. Compared to individuals with lower socioeconomic status, individuals with higher socioeconomic status reported more exercise and stronger intentions to exercise. This was at least partly because higher socioeconomic status respondents reported fewer barriers in their lives, and were more confident to cope with the scheduling demands of exercise.

  3. LDB1-mediated enhancer looping can be established independent of mediator and cohesin.

    Science.gov (United States)

    Krivega, Ivan; Dean, Ann

    2017-08-21

    Mechanistic studies in erythroid cells indicate that LDB1, as part of a GATA1/TAL1/LMO2 complex, brings erythroid-expressed genes into proximity with enhancers for transcription activation. The role of co-activators in establishing this long-range interaction is poorly understood. Here we tested the contributions of the RNA Pol II pre-initiation complex (PIC), mediator and cohesin to establishment of locus control region (LCR)/β-globin proximity. CRISPR/Cas9 editing of the β-globin promoter to eliminate the RNA Pol II PIC by deleting the TATA-box resulted in loss of transcription, but enhancer-promoter interaction was unaffected. Additional deletion of the promoter GATA1 site eliminated LDB1 complex and mediator occupancy and resulted in loss of LCR/β-globin proximity. To separate the roles of LDB1 and mediator in LCR looping, we expressed a looping-competent but transcription-activation deficient form of LDB1 in LDB1 knock down cells: LCR/β-globin proximity was restored without mediator core occupancy. Further, Cas9-directed tethering of mutant LDB1 to the β-globin promoter forced LCR loop formation in the absence of mediator or cohesin occupancy. Moreover, ENCODE data and our chromatin immunoprecipitation results indicate that cohesin is almost completely absent from validated and predicted LDB1-regulated erythroid enhancer-gene pairs. Thus, lineage specific factors largely mediate enhancer-promoter looping in erythroid cells independent of mediator and cohesin. Published by Oxford University Press on behalf of Nucleic Acids Research 2017.

  4. Diverse coactivator recruitment through differential PPARγ nuclear receptor agonism

    Directory of Open Access Journals (Sweden)

    Fernando Lizcano

    2013-01-01

    Full Text Available The PPARγ nuclear receptor regulates the expression of genes involved in lipid and carbohydrate metabolism, and it has protective effects in some patients with type 2 diabetes. Nevertheless, the therapeutic value of the PPARγ nuclear receptor protein is limited due to the secondary effects of some PPARγ ligands. Because the downstream effects of PPARγ are determined by the binding of specific cofactors that are mediated by ligand-induced conformational changes, we evaluated the differential effects of various ligands on the binding of certain cofactors associated with PPARγ. The ligands used were rosiglitazone for treating type 2 diabetes and telmisartan for treating arterial hypertension. Functional, phenotypic, and molecular studies were conducted on pre-adipocyte 3T3-L1 and functional studies in U2OS cells. The moderating influence of various cofactor families was evaluated using transient transfection assays. Our findings confirm that telmisartan has a partial modulating effect on PPARγ activity compared to rosiglitazone. The cofactors SRC1 and GRIP1 mediate the activity of telmisartan and rosiglitazone and partially determine the difference in their effects. Studying the modulating activity of these cofactors can provide interesting insights for developing new therapeutic approaches for certain metabolic diseases.

  5. Mother–Adolescent Conflict as a Mediator Between Adolescent Problem Behaviors and Maternal Psychological Control

    OpenAIRE

    Steeger, Christine M.; Gondoli, Dawn M.

    2012-01-01

    This study examined mother–adolescent conflict as a mediator of longitudinal reciprocal relations between adolescent aggression and depressive symptoms and maternal psychological control. Motivated by family systems theory and the transactions that occur between individual and dyadic levels of the family system, we examined the connections among these variables during a developmental period when children and parents experience significant psychosocial changes. Three years of self-report data ...

  6. Control of Dog Mediated Human Rabies in Haiti: No Time to Spare.

    Directory of Open Access Journals (Sweden)

    Max F Millien

    Full Text Available The American region has pledged to eliminate dog-mediated human rabies by 2015. As part of these efforts, we describe the findings of a desk and field mission review of Haiti's rabies situation by the end of 2013. While government officials recognize the importance of dog-mediated rabies control, and the national rabies plan adequately contemplates the basic capacities to that effect, regular and sufficient implementation, for example, of dog vaccination, is hampered by limited funding. Compounding insufficient funding and human resources, official surveillance figures do not accurately reflect the risk to the population, as evidenced by the large number of rabid dogs detected by focalized and enhanced surveillance activities conducted by the Ministry of Agriculture, Natural Resources and Rural Development (MARNDR and the Health and Population Ministry (MSPP with the technical assistance of the United States Centers for Disease Control and Prevention. Although international support is common, either in the form of on-the-ground technical support or donations of immunobiologicals, it is not comprehensive. In addition, there is limited coordination with MARNDR/MSPP and with other actors at the strategic or operational level due to human resources limitations. Given these findings, the 2015 elimination goal in the region is compromised by the situation in Haiti where control of the disease is not yet in sight despite the best efforts of the resolute national officials. More importantly, dog-mediated rabies is still a threat to the Haitian population.

  7. MiR130b-Regulation of PPARγ Coactivator- 1α Suppresses Fat Metabolism in Goat Mammary Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Zhi Chen

    Full Text Available Fat metabolism is a complicated process regulated by a series of factors. microRNAs (miRNAs are a class of negative regulator of proteins and play crucial roles in many biological processes; including fat metabolism. Although there have been some researches indicating that miRNAs could influence the milk fat metabolism through targeting some factors, little is known about the effect of miRNAs on goat milk fat metabolism. Here we utilized an improved miRNA detection assay, S-Poly-(T, to profile the expression of miRNAs in the goat mammary gland in different periods, and found that miR-130b was abundantly and differentially expressed in goat mammary gland. Additionally, overexpressing miR-130b impaired adipogenesis while inhibiting miR-130b enhanced adipogenesis in goat mammary epithelial cells. Utilizing 3'-UTR assay and Western Blot analusis, the protein peroxisome proliferator-activated receptor coactivator-1α (PGC1α, a major regulator of fat metabolism, was demonstrated to be a potential target of miR-130b. Interestingly, miR-130b potently repressed PGC1α expression by targeting both the PGC1α mRNA coding and 3' untranslated regions. These findings have some insight of miR-130b in mediating adipocyte differentiation by repressing PGC1α expression and this contributes to further understanding about the functional significance of miRNAs in milk fat synthesis.

  8. Perceived discrimination and psychological well-being: the mediating and moderating role of sense of control.

    Science.gov (United States)

    Jang, Yuri; Chiriboga, David A; Small, Brent J

    2008-01-01

    Being discriminated against is an unpleasant and stressful experience, and its connection to reduced psychological well-being is well-documented. The present study hypothesized that a sense of control would serve as both mediator and moderator in the dynamics of perceived discrimination and psychological well-being. In addition, variations by age, gender, and race in the effects of perceived discrimination were explored. Data from the Midlife Development in the United States (MIDUS) survey (N=1554; age range = 45 to 74) provided supportive evidence for the hypotheses. The relationships between perceived discrimination and positive and negative affect were reduced when sense of control was controlled, demonstrating the role of sense of control as a mediator. The moderating role of sense of control was also supported, but only in the analysis for negative affect: the combination of a discriminatory experience and low sense of control markedly increased negative affect. In addition, age and gender variations were observed: the negative impact of perceived discrimination on psychological well-being was more pronounced among younger adults and females compared to their counterparts. The findings elucidated the mechanisms by which perceived discrimination manifested its psychological outcomes, and suggest ways to reduce adverse consequences associated with discriminatory experiences.

  9. Alcohol-specific parenting, adolescents' self-control, and alcohol use: a moderated mediation model.

    Science.gov (United States)

    Koning, Ina M; van den Eijnden, Regina J J M; Vollebergh, Wilma A M

    2014-01-01

    There is convincing evidence that parental rules about alcohol are important in curbing adolescents' alcohol use. However, little is known about the mechanisms through which the direct link between alcohol-specific parenting and alcohol use is obtained. In this study, we investigated the mediating effect of adolescent self-control on the relationship between alcohol-specific rules and adolescents' drinking behavior and whether this mediation effect depends on the level of quality of communication. A total of 883 adolescents participated in this longitudinal study at ages 13, 14, and 15 years. Strict rules predicted lower rates of drinking, but no direct effect of the quality of communication on adolescents' alcohol use was found. A higher level of self-control was related to lower rates of drinking in adolescents. The indirect effect of rules about alcohol through adolescents' self-control was statistically significant, yet only in adolescents with high qualitative parent-child communication about alcohol. In adolescents with low quality of parent-child communication, self-control was not related to drinking. These findings imply that strict rule setting in combination with qualitative parent-child communication is an important target for prevention. In addition, findings point at the importance of high qualitative parent-child communication for adolescents' motivation to engage in self-control to avoid drinking.

  10. Mediating effects of emotional exhaustion on the relationship between job demand–control model and mental health.

    Science.gov (United States)

    Huang, Yu-Hwa; Du, Pey-Ian; Chen, Chin-Hui; Yang, Chin-Ann; Huang, Ing-Chung

    2011-04-01

    This study attempted to investigate the role of emotional exhaustion as a mediator on the relationship between job demands-control (JDC) model and mental health. Three-wave data from 297 employees were collected. The results showed that job demands were positively related to emotional exhaustion, and increasing job demands will increase the level of emotional exhaustion. Job control was negatively associated with emotional exhaustion; therefore, increasing job control will decrease the level of emotional exhaustion. Emotional exhaustion was negatively related to mental health. Emotional exhaustion fully mediated the relationship between job demands and mental health, and partially mediated the positive relationship between job control and mental health. In addition, job control was positively associated with mental health directly. The remarkable finding of the present study was that emotional exhaustion served as the key mediator between the JDC model and mental health. Theoretical and managerial implications and limitations were discussed.

  11. Conformational selection in the molten globule state of the nuclear coactivator binding domain of CBP

    DEFF Research Database (Denmark)

    Kjærgaard, Magnus; Teilum, Kaare; Poulsen, Flemming M

    2010-01-01

    Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about the mechanism by which native molten globules bind to their cognate ligands to form fully folded complexes. The nuclear coactivator binding domain (NCBD) of CREB binding protein is particul......Native molten globules are the most folded kind of intrinsically disordered proteins. Little is known about the mechanism by which native molten globules bind to their cognate ligands to form fully folded complexes. The nuclear coactivator binding domain (NCBD) of CREB binding protein....... Biophysical studies show that despite the molten globule nature of the domain, it contains a small cooperatively folded core. By NMR spectroscopy, we have demonstrated that the folded core of NCBD has a well ordered conformer with specific side chain packing. This conformer resembles the structure of the NCBD...

  12. Listening to Puns Elicits the Co-Activation of Alternative Homophone Meanings during Language Production.

    Directory of Open Access Journals (Sweden)

    Sebastian Benjamin Rose

    Full Text Available Recent evidence suggests that lexical-semantic activation spread during language production can be dynamically shaped by contextual factors. In this study we investigated whether semantic processing modes can also affect lexical-semantic activation during word production. Specifically, we tested whether the processing of linguistic ambiguities, presented in the form of puns, has an influence on the co-activation of unrelated meanings of homophones in a subsequent language production task. In a picture-word interference paradigm with word distractors that were semantically related or unrelated to the non-depicted meanings of homophones we found facilitation induced by related words only when participants listened to puns before object naming, but not when they heard jokes with unambiguous linguistic stimuli. This finding suggests that a semantic processing mode of ambiguity perception can induce the co-activation of alternative homophone meanings during speech planning.

  13. Aggregation control of quantum dots through ion-mediated hydrogen bonding shielding.

    Science.gov (United States)

    Liu, Jianbo; Yang, Xiaohai; Wang, Kemin; He, Xiaoxiao; Wang, Qing; Huang, Jin; Liu, Yan

    2012-06-26

    Nanoparticle stabilization against detrimental aggregation is a critical parameter that needs to be well controlled. Herein, we present a facile and rapid ion-mediated dispersing technique that leads to hydrophilic aggregate-free quantum dots (QDs). Because of the shielding of the hydrogen bonds between cysteamine-capped QDs, the presence of F(-) ions disassembled the aggregates of QDs and afforded their high colloidal stability. The F(-) ions also greatly eliminated the nonspecific adsorption of the QDs on glass slides and cells. Unlike the conventional colloidal stabilized method that requires the use of any organic ligand and/or polymer for the passivation of the nanoparticle surface, the proposed approach adopts the small size and large diffusion coefficient of inorganic ions as dispersant, which offers the disaggregation a fast reaction dynamics and negligible influence on their intrinsic surface functional properties. Therefore, the ion-mediated dispersing strategy showed great potential in chemosensing and biomedical applications.

  14. Ablation of Steroid Receptor Coactivator-3 resembles the human CACT metabolic myopathy

    OpenAIRE

    York, Brian; Reineke, Erin L.; Sagen, Jørn V.; Nikolai, Bryan C.; Zhou, Suoling; Louet, Jean-Francois; Chopra, Atul R.; Chen, Xian; Reed, Graham; Noebels, Jeffrey; Adesina, Adekunle M.; Yu, Hui; Wong, Lee-Jun C.; Tsimelzon, Anna; Hilsenbeck, Susan

    2012-01-01

    Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypog...

  15. Development of Coactivator-Dependent, First-in-Class Therapies for Breast Cancer

    Science.gov (United States)

    2014-09-01

    y. ME65CH18-Dasgupta ARI 14 December 2013 18:9 amplified in chronic lymphocytic leukemia ( CLL ). Gain of 2p chromosomal region func- tion...inCLLpatients is detected at an early stage of the disease and correlates with poor prog- nosis, indicating SRC-1 may contribute to the pathological state of CLL ...70), recent evidence points to a require- ment for coactivators in chemoresistance (71) as well as in stem cell self-renewal and pluripo- tency

  16. A transcriptional coregulator, SPIN·DOC, attenuates the coactivator activity of Spindlin1.

    Science.gov (United States)

    Bae, Narkhyun; Gao, Min; Li, Xu; Premkumar, Tolkappiyan; Sbardella, Gianluca; Chen, Junjie; Bedford, Mark T

    2017-12-22

    Spindlin1 (SPIN1) is a transcriptional coactivator with critical functions in embryonic development and emerging roles in cancer. SPIN1 harbors three Tudor domains, two of which engage the tail of histone H3 by reading the H3-Lys-4 trimethylation and H3-Arg-8 asymmetric dimethylation marks. To gain mechanistic insight into how SPIN1 functions as a transcriptional coactivator, here we purified its interacting proteins. We identified an uncharacterized protein (C11orf84), which we renamed SPIN1 docking protein (SPIN·DOC), that directly binds SPIN1 and strongly disrupts its histone methylation reading ability, causing it to disassociate from chromatin. The Spindlin family of coactivators has five related members (SPIN1, 2A, 2B, 3, and 4), and we found that all of them bind SPIN·DOC. It has been reported previously that SPIN1 regulates gene expression in the Wnt signaling pathway by directly interacting with transcription factor 4 (TCF4). We observed here that SPIN·DOC associates with TCF4 in a SPIN1-dependent manner and dampens SPIN1 coactivator activity in TOPflash reporter assays. Furthermore, knockdown and overexpression experiments indicated that SPIN·DOC represses the expression of a number of SPIN1-regulated genes, including those encoding ribosomal RNA and the cytokine IL1B. In conclusion, we have identified SPIN·DOC as a transcriptional repressor that binds SPIN1 and masks its ability to engage the H3-Lys-4 trimethylation activation mark. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Transcription factor YY1 can control AID-mediated mutagenesis in mice.

    Science.gov (United States)

    Zaprazna, Kristina; Basu, Arindam; Tom, Nikola; Jha, Vibha; Hodawadekar, Suchita; Radova, Lenka; Malcikova, Jitka; Tichy, Boris; Pospisilova, Sarka; Atchison, Michael L

    2018-02-01

    Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1 f/f ) or that express normal AID levels (yy1 f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Phase-dependence of elbow muscle coactivation in front crawl swimming.

    Science.gov (United States)

    Lauer, Jessy; Figueiredo, Pedro; Vilas-Boas, João Paulo; Fernandes, Ricardo J; Rouard, Annie Hélène

    2013-08-01

    Propulsion in swimming is achieved by complex sculling movements with elbow quasi-fixed on the antero-posterior axis to transmit forces from the hand and the forearm to the body. The purpose of this study was to investigate how elbow muscle coactivation was influenced by the front crawl stroke phases. Ten international level male swimmers performed a 200-m front crawl race-pace bout. Sagittal views were digitized frame by frame to determine the stroke phases (aquatic elbow flexion and extension, aerial elbow flexion and extension). Surface electromyograms (EMG) of the right biceps brachii and triceps brachii were recorded and processed using the integrated EMG to calculate a coactivation index (CI) for each phase. A significant effect of the phases on the CI was revealed with highest levels of coactivation during the aquatic elbow flexion and the aerial elbow extension. Swimmers stabilize the elbow joint to overcome drag during the aquatic phase, and act as a brake at the end of the recovery to replace the arm for the next stroke. The CI can provide insight into the magnitude of mechanical constraints supported by a given joint, in particular during a complex movement. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Cryptocephal, the Drosophila melanogaster ATF4, is a specific coactivator for ecdysone receptor isoform B2.

    Directory of Open Access Journals (Sweden)

    Sebastien A Gauthier

    Full Text Available The ecdysone receptor is a heterodimer of two nuclear receptors, the Ecdysone receptor (EcR and Ultraspiracle (USP. In Drosophila melanogaster, three EcR isoforms share common DNA and ligand-binding domains, but these proteins differ in their most N-terminal regions and, consequently, in the activation domains (AF1s contained therein. The transcriptional coactivators for these domains, which impart unique transcriptional regulatory properties to the EcR isoforms, are unknown. Activating transcription factor 4 (ATF4 is a basic-leucine zipper transcription factor that plays a central role in the stress response of mammals. Here we show that Cryptocephal (CRC, the Drosophila homolog of ATF4, is an ecdysone receptor coactivator that is specific for isoform B2. CRC interacts with EcR-B2 to promote ecdysone-dependent expression of ecdysis-triggering hormone (ETH, an essential regulator of insect molting behavior. We propose that this interaction explains some of the differences in transcriptional properties that are displayed by the EcR isoforms, and similar interactions may underlie the differential activities of other nuclear receptors with distinct AF1-coactivators.

  20. The Arabidopsis mediator complex subunits MED16, MED14, and MED2 regulate mediator and RNA polymerase II recruitment to CBF-responsive cold-regulated genes.

    Science.gov (United States)

    Hemsley, Piers A; Hurst, Charlotte H; Kaliyadasa, Ewon; Lamb, Rebecca; Knight, Marc R; De Cothi, Elizabeth A; Steele, John F; Knight, Heather

    2014-01-01

    The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation-induced freezing tolerance. In addition, these three subunits are required for low temperature-induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced.

  1. Corepressive function of nuclear receptor coactivator 2 in androgen receptor of prostate cancer cells treated with antiandrogen

    International Nuclear Information System (INIS)

    Takeda, Keisuke; Hara, Noboru; Nishiyama, Tsutomu; Tasaki, Masayuki; Ishizaki, Fumio; Tomita, Yoshihiko

    2016-01-01

    Recruitment of cofactors in the interaction of the androgen receptor (AR) and AR ligands plays a critical role in determining androgenic/antiandrogenic effects of the AR ligand on signaling, but the functions of key cofactors, including nuclear receptor coactivator (NCOA), remain poorly understood in prostate cancer cells treated with AR ligands. We examined prostate cancer cell lines LNCaP and VCaP expressing mutated and wild-type ARs, respectively, to clarify the significance of NCOAs in the effect of antiandrogens. Hydroxyflutamide showed antagonistic activity against VCaP and an agonistic effect on LNCaP. Bicalutamide served as an antagonist for both. We analyzed mRNA transcription and protein expression of NCOAs in these cells pretreated with dihydrotestosterone and thereafter treated with the mentioned antiandrogens. Transcriptional silencing of candidate NCOAs and AR was performed using small interfering RNA (siRNA). Cell proliferation was evaluated with MTT assay. LNCaP treated with bicalutamide showed an about four-fold increase in the expression of NCOA2 mRNA compared to those pretreated with dihydrotestosterone alone (P <0.01). In VCaP pretreated with dihydrotestosterone, transcriptions of NCOA2 and NCOA7 were slightly increased with bicalutamide (1.96- and 2.42-fold, respectively) and hydroxyflutamide (1.33-fold in both). With Western blotting, the expression of NCOA2 protein also increased in LNCaP cells treated with bicalutamide compared with that in control cells pretreated with dihydrotestosterone alone. Following silencing with siRNA for NCOA2, PSA levels in media with LNCaP receiving bicalutamide were elevated compared with those in non-silencing controls (101.6 ± 4.2 vs. 87.8 ± 1.4 ng/mL, respectively, P =0.0495). In LNCaP cells treated with dihydrotestosterone and bicalutamide, NCOA2-silencing was associated with a higher proliferation activity compared with non-silencing control and AR-silencing. NCOA2, which has been thought to be recruited

  2. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

    International Nuclear Information System (INIS)

    Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

    2012-01-01

    Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs and HER-2 and -3 is stimulated

  3. The relationship between self-control and health: The mediating effect of avoidant coping.

    Science.gov (United States)

    Boals, Adriel; Vandellen, Michelle R; Banks, Jonathan B

    2011-08-01

    Trait self-control is related to a number of positive outcomes, including mental health, interpersonal success, academic success and health-related behaviours. This study sought to explore the relationships between self-control, reports of mental and physical health symptoms and coping styles. The results revealed that higher self-control was related to fewer mental and physical health symptoms and less avoidance coping. There was not a significant relationship between self-control and problem-focused or emotion-focused coping styles. Further, the relationships between self-control and mental and physical health outcomes were partially mediated by avoidance coping style. Specifically, the data suggest lower self-control is associated with unhealthy coping strategies (avoidance coping), which in turn are associated with worse mental health outcomes and greater reports of physical health symptoms. Thus lower trait self-control can serve as an indicator, suggesting circumstances in which individuals' tendencies to engage in unhealthy coping strategies are increased. These findings add to a growing body of literature underscoring the importance of trait self-control.

  4. Gait variability and motor control in people with knee osteoarthritis

    DEFF Research Database (Denmark)

    Alkjaer, Tine; Raffalt, Peter C; Dalsgaard, Helle

    2015-01-01

    fluctuation analysis. The motor control was assessed by the soleus (SO) Hoffmann (H)-reflex modulation and muscle co-activation during walking. The results showed no statistically significant mean group differences in any of the gait variability measures or muscle co-activation levels. The SO H...

  5. Mediators of the association between narcissism and compulsive buying: the roles of materialism and impulse control.

    Science.gov (United States)

    Rose, Paul

    2007-12-01

    Building upon past research about the guiding values and self-regulation difficulties of people with narcissistic personalities, this study tested a model of the association between narcissism and compulsive consumption. In data obtained from a sample of undergraduate consumers (N=238) with varying degrees of spending problems, positive associations emerged between narcissism, materialism, and compulsive buying. Impulse control was negatively correlated with each of these variables. Mediation tests revealed that both impulse control and materialism accounted for significant portions of the shared variance between narcissism and compulsive consumption. These findings highlight the importance of both personal values and impulse control as correlates of addictive buying. They also add to growing evidence that people who are relatively narcissistic are poor self-regulators who may be at risk of developing a variety of addictive behaviors.

  6. Nutrient Control of Yeast Gametogenesis Is Mediated by TORC1, PKA and Energy Availability.

    Directory of Open Access Journals (Sweden)

    Hilla Weidberg

    2016-06-01

    Full Text Available Cell fate choices are tightly controlled by the interplay between intrinsic and extrinsic signals, and gene regulatory networks. In Saccharomyces cerevisiae, the decision to enter into gametogenesis or sporulation is dictated by mating type and nutrient availability. These signals regulate the expression of the master regulator of gametogenesis, IME1. Here we describe how nutrients control IME1 expression. We find that protein kinase A (PKA and target of rapamycin complex I (TORC1 signalling mediate nutrient regulation of IME1 expression. Inhibiting both pathways is sufficient to induce IME1 expression and complete sporulation in nutrient-rich conditions. Our ability to induce sporulation under nutrient rich conditions allowed us to show that respiration and fermentation are interchangeable energy sources for IME1 transcription. Furthermore, we find that TORC1 can both promote and inhibit gametogenesis. Down-regulation of TORC1 is required to activate IME1. However, complete inactivation of TORC1 inhibits IME1 induction, indicating that an intermediate level of TORC1 signalling is required for entry into sporulation. Finally, we show that the transcriptional repressor Tup1 binds and represses the IME1 promoter when nutrients are ample, but is released from the IME1 promoter when both PKA and TORC1 are inhibited. Collectively our data demonstrate that nutrient control of entry into sporulation is mediated by a combination of energy availability, TORC1 and PKA activities that converge on the IME1 promoter.

  7. Electrochemiluminescent DNA sensor based on controlled Zn-mediated grafting of diazonium precursors.

    Science.gov (United States)

    Torréns, Mabel; Ortiz, Mayreli; Bejarano-Nosas, Diego; O'Sullivan, Ciara K

    2015-07-01

    Controlled Zn-mediated grafting of a thin layer of a diazonium salt was used to functionalise a carbon electrode with ruthenium(II)-tris-bipyridine (Ru)-labelled DNA for use as a capture probe in an electrochemiluminescent genosensor. A secondary reporter probe was labelled with a ferrocene (Fc) molecule, and in the presence of the single-stranded DNA target a genocomplex formed, where the Fc-label effectively quenched the electrochemiluminescence of the signal emitted from the Ru-label. The spacing of the labels for maximum sensitivity and minimum detection limit was optimised, and the signal reproducibility and stability of the method was established.

  8. A collapsin response mediator protein 2 isoform controls myosin II-mediated cell migration and matrix assembly by trapping ROCK II

    DEFF Research Database (Denmark)

    Yoneda, Atsuko; Morgan-Fisher, Marie; Wait, Robin

    2012-01-01

    Collapsin response mediator protein 2 (CRMP-2) is known as a regulator of neuronal polarity and differentiation through microtubule assembly and trafficking. Here, we show that CRMP-2 is ubiquitously expressed and a splice variant (CRMP-2L), which is expressed mainly in epithelial cells among...... nonneuronal cells, regulates myosin II-mediated cellular functions, including cell migration. While the CRMP-2 short form (CRMP-2S) is recognized as a substrate of the Rho-GTP downstream kinase ROCK in neuronal cells, a CRMP-2 complex containing 2L not only bound the catalytic domain of ROCK II through two......-2L but not -2S inhibited fibronectin matrix assembly in fibroblasts. Underlying these responses, CRMP-2L regulated the kinase activity of ROCK II but not ROCK I, independent of GTP-RhoA levels. This study provides a new insight into CRMP-2 as a controller of myosin II-mediated cellular functions...

  9. Right ventrolateral prefrontal cortex mediates individual differences in conflict-driven cognitive control

    Science.gov (United States)

    Egner, Tobias

    2013-01-01

    Conflict adaptation – a conflict-triggered improvement in the resolution of conflicting stimulus or response representations – has become a widely used probe of cognitive control processes in both healthy and clinical populations. Previous functional magnetic resonance imaging (fMRI) studies have localized activation foci associated with conflict resolution to dorsolateral prefrontal cortex (dlPFC). The traditional group-analysis approach employed in these studies highlights regions that are, on average, activated during conflict resolution, but does not necessarily reveal areas mediating individual differences in conflict resolution, because between-subject variance is treated as noise. Here, we employed a complementary approach in order to elucidate the neural bases of variability in the proficiency of conflict-driven cognitive control. We analyzed two independent fMRI data sets of face-word Stroop tasks by using individual variability in the behavioral expression of conflict adaptation as the metric against which brain activation was regressed, while controlling for individual differences in mean reaction time and Stroop interference. Across the two experiments, a replicable neural substrate of individual variation in conflict adaptation was found in ventrolateral prefrontal cortex (vlPFC), specifically, in the right inferior frontal gyrus, pars orbitalis (BA 47). Unbiased regression estimates showed that variability in activity in this region accounted for ~40% of the variance in behavioral expression of conflict adaptation across subjects, thus documenting a heretofore unsuspected key role for vlPFC in mediating conflict-driven adjustments in cognitive control. We speculate that vlPFC plays a primary role in conflict control that is supplemented by dlPFC recruitment under conditions of suboptimal performance. PMID:21568631

  10. Photoperiod- and temperature-mediated control of growth cessation and dormancy in trees: a molecular perspective.

    Science.gov (United States)

    Maurya, Jay P; Bhalerao, Rishikesh P

    2017-09-01

    How plants adapt their developmental patterns to regular seasonal changes is an important question in biology. The annual growth cycle in perennial long-lived trees is yet another example of how plants can adapt to seasonal changes. The two main signals that plants rely on to respond to seasonal changes are photoperiod and temperature, and these signals have critical roles in the temporal regulation of the annual growth cycle of trees. This review presents the latest findings to provide insight into the molecular mechanisms that underlie how photoperiodic and temperature signals regulate seasonal growth in trees. The results point to a high level of conservation in the signalling pathways that mediate photoperiodic control of seasonal growth in trees and flowering in annual plants such as arabidopsis. Furthermore, the data indicate that symplastic communication may mediate certain aspects of seasonal growth. Although considerable insight into the control of phenology in model plants such as poplar and spruce has been obtained, the future challenge is extending these studies to other, non-model trees. © The Author 2017. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  11. Safety climate and self-reported injury: assessing the mediating role of employee safety control.

    Science.gov (United States)

    Huang, Yueng-Hsiang; Ho, Michael; Smith, Gordon S; Chen, Peter Y

    2006-05-01

    To further reduce injuries in the workplace, companies have begun focusing on organizational factors which may contribute to workplace safety. Safety climate is an organizational factor commonly cited as a predictor of injury occurrence. Characterized by the shared perceptions of employees, safety climate can be viewed as a snapshot of the prevailing state of safety in the organization at a discrete point in time. However, few studies have elaborated plausible mechanisms through which safety climate likely influences injury occurrence. A mediating model is proposed to link safety climate (i.e., management commitment to safety, return-to-work policies, post-injury administration, and safety training) with self-reported injury through employees' perceived control on safety. Factorial evidence substantiated that management commitment to safety, return-to-work policies, post-injury administration, and safety training are important dimensions of safety climate. In addition, the data support that safety climate is a critical factor predicting the history of a self-reported occupational injury, and that employee safety control mediates the relationship between safety climate and occupational injury. These findings highlight the importance of incorporating organizational factors and workers' characteristics in efforts to improve organizational safety performance.

  12. The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility

    KAUST Repository

    Jégu, Teddy

    2017-06-15

    Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored.In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome-free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms.These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions.

  13. The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility

    KAUST Repository

    Jé gu, Teddy; Veluchamy, Alaguraj; Ramirez Prado, Juan Sebastian; Rizzi-Paillet, Charley; Perez, Magalie; Lhomme, Anaï s; Latrasse, David; Coleno, Emeline; Vicaire, Serge; Legras, Sté phanie; Jost, Bernard; Rougé e, Martin; Barneche, Fredy; Bergounioux, Catherine; Crespi, Martin; Mahfouz, Magdy M.; Hirt, Heribert; Raynaud, Cé cile; Benhamed, Moussa

    2017-01-01

    Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored.In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome-free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms.These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions.

  14. Controlled/living photopolymerization of methyl methacrylate in miniemulsion mediated by HTEMPO

    Institute of Scientific and Technical Information of China (English)

    Xiaoxuan LIU; Yanni JING; Yingkun BAI

    2008-01-01

    Controlled/living photopolymerization of methyl methacrylate (MMA) in miniemulsion mediated by 4-hydroxy-2,2,6,6-tetramethyl-piperidinyloxy (HTEMPO) was carried out at ambient temperatures. MMA miniemulsion was prepared by using an anionic surfactant with cetylalcohol as a co-stabilizer. The photopolymerization led to stable lattices and they were obtained with no coagulation during synthesis and no destabilization over time. It was found that the obtained MMA homopolymers exhibited relatively narrow mole-cular weight distribution (PDI = 1.27- 1.36) which was characterized by GPC. The plots of number-average molecular weight in (Mn) vs. Conversion and ln([MO]/[M]) vs. Time both were linear indicating that the reaction was a controlled/living free radical polymerization.

  15. Vascular risk factor burden correlates with cerebrovascular reactivity but not resting state coactivation in the default mode network.

    Science.gov (United States)

    Tchistiakova, Ekaterina; Crane, David E; Mikulis, David J; Anderson, Nicole D; Greenwood, Carol E; Black, Sandra E; MacIntosh, Bradley J

    2015-11-01

    White matter hyperintensities (WMH) are prevalent among older adults and are often associated with cognitive decline and increased risk of stroke and dementia. Vascular risk factors (VRFs) are linked to WMH, yet the impact of multiple VRFs on gray matter function is still unclear. The goal of this study was to test for associations between the number of VRFs and cerebrovascular reactivity (CVR) and resting state (RS) coactivation among individuals with WMH. Twenty-nine participants with suspected WMH were grouped based on the number of VRFs (subgroups: 0, 1, or ≥2). CVR and RS coactivation were measured with blood oxygenation level-dependent (BOLD) imaging on a 3T magnetic resonance imaging (MRI) system during hypercapnia and rest, respectively. Default-mode (DMN), sensory-motor, and medial-visual networks, generated using independent component analysis of RS-BOLD, were selected as networks of interest (NOIs). CVR-BOLD was analyzed using two methods: 1) a model-based approach using CO2 traces, and 2) a dual-regression (DR) approach using NOIs as spatial inputs. Average CVR and RS coactivations within NOIs were compared between VRF subgroups. A secondary analysis investigated the correlation between CVR and RS coactivation. VRF subgroup differences were detected using DR-based CVR in the DMN (F20,2  = 5.17, P = 0.015) but not the model-based CVR nor RS coactivation. DR-based CVR was correlated with RS coactivation in the DMN (r(2)  = 0.28, P = 0.006) but not the sensory-motor nor medial-visual NOIs. In individuals with WMH, CVR in the DMN was inversely associated with the number of VRFs and correlated with RS coactivation. © 2015 Wiley Periodicals, Inc.

  16. A randomised controlled trial evaluating family mediated exercise (FAME therapy following stroke

    Directory of Open Access Journals (Sweden)

    Stokes Emma

    2008-06-01

    Full Text Available Abstract Background Stroke is a leading cause of disability among adults worldwide. Evidence suggests that increased duration of exercise therapy following stroke has a positive impact on functional outcome following stroke. The main objective of this randomised controlled trial is to evaluate the impact of additional family assisted exercise therapy in people with acute stroke. Methods/Design A prospective multi-centre single blind randomised controlled trial will be conducted. Forty patients with acute stroke will be randomised into either an experimental or control group. The experimental group will receive routine therapy and additional lower limb exercise therapy in the form of family assisted exercises. The control group will receive routine therapy with no additional formal input from their family members. Participants will be assessed at baseline, post intervention and followed up at three months using a series of standardised outcome measures. A secondary aim of the project is to evaluate the impact of the family mediated exercise programme on the person with stroke and the individual(s assisting in the delivery of exercises using a qualitative methodology. The study has gained ethical approval from the Research Ethics Committees of each of the clinical sites involved in the study. Discussion This study will evaluate a structured programme of exercises that can be delivered to people with stroke by their 'family members/friends'. Given that the progressive increase in the population of older people is likely to lead to an increased prevalence of stroke in the future, it is important to reduce the burden of this illness on the individual, the family and society. Family mediated exercises can maximise the carry over outside formal physiotherapy sessions, giving patients the opportunity for informal practice. Trial Registration The protocol for this study is registered with the US NIH Clinical trials registry (NCT00666744

  17. Gratitude mediates quality of life differences between fibromyalgia patients and healthy controls.

    Science.gov (United States)

    Toussaint, Loren; Sirois, Fuschia; Hirsch, Jameson; Weber, Annemarie; Vajda, Christian; Schelling, Jorg; Kohls, Niko; Offenbacher, Martin

    2017-09-01

    Despite a growing literature on the benefits of gratitude for adjustment to chronic illness, little is known about gratitude in medical populations compared to healthy populations, or the degree to which potential deficits in gratitude might impact quality of life. The purpose of the present study was to (1) examine levels of gratitude and quality of life in fibromyalgia patients and healthy controls and (2) consider the role of gratitude in explaining quality of life differences between fibromyalgia patients and healthy controls. Participants were 173 fibromyalgia patients and 81 healthy controls. All participants completed measures of gratitude, quality of life, and socio-demographics. Although gratitude was positively associated with quality of life, levels of gratitude and quality of life were lower in the fibromyalgia sample relative to the healthy controls. This difference in gratitude partially mediated differences in quality of life between the two groups after controlling for socio-demographic variables. Our findings suggest that gratitude is a valuable positive psychological trait for quality of life in people with fibromyalgia. Interventions to improve gratitude in this patient population may also bring enhancement in quality of life.

  18. Characteristics of the home food environment that mediate immediate and sustained increases in child fruit and vegetable consumption: mediation analysis from the Healthy Habits cluster randomised controlled trial.

    Science.gov (United States)

    Wyse, Rebecca; Wolfenden, Luke; Bisquera, Alessandra

    2015-09-17

    The home food environment can influence the development of dietary behaviours in children, and interventions that modify characteristics of the home food environment have been shown to increase children's fruit and vegetable consumption. However to date, interventions to increase children's fruit and vegetable consumption have generally produced only modest effects. Mediation analysis can help in the design of more efficient and effective interventions by identifying the mechanisms through which interventions have an effect. This study aimed to identify characteristics of the home food environment that mediated immediate and sustained increases in children's fruit and vegetable consumption following the 4-week Healthy Habits telephone-based parent intervention. Analysis was conducted using 2-month (immediate) and 12-month (sustained) follow-up data from a cluster randomised control trial of a home food environment intervention to increase the fruit and vegetable consumption of preschool children. Using recursive path analysis, a series of mediation models were created to investigate the direct and indirect effects of immediate and sustained changes to characteristics of the home food environment (fruit and vegetable availability, accessibility, parent intake, parent providing behaviour, role-modelling, mealtime eating practices, child feeding strategies, and pressure to eat), on the change in children's fruit and vegetable consumption. Of the 394 participants in the randomised trial, 357 and 329 completed the 2- and 12-month follow-up respectively. The final mediation model suggests that the effect of the intervention on the children's fruit and vegetable consumption was mediated by parent fruit and vegetable intake and parent provision of these foods at both 2- and 12-month follow-up. Analysis of data from the Healthy Habits trial suggests that two environmental variables (parental intake and parent providing) mediate the immediate and sustained effect of the

  19. A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.

    Science.gov (United States)

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-06-22

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.

  20. A Novel Acetylation Cycle of Transcription Co-activator Yes-associated Protein That Is Downstream of Hippo Pathway Is Triggered in Response to SN2 Alkylating Agents*

    Science.gov (United States)

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-01-01

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to SN2 alkylating agents. We show that after treatment of cells with the SN2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by SN2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID:22544757

  1. Can Job Control Ameliorate Work-family Conflict and Enhance Job Satisfaction among Chinese Registered Nurses? A Mediation Model

    Directory of Open Access Journals (Sweden)

    Xiaotong Ding

    2018-04-01

    Full Text Available Background: Low job satisfaction is the most common cause of nurses' turnover and influences the quality of nursing service. Moreover, we have no idea regarding whether job control, as an individual factor, can play a role in the relationship. Objective: To explore the relationship between work-family conflict and job satisfaction among Chinese registered nurses and the mediating role of job control in this relationship. Methods: From August 2015 to November 2016, 487 Chinese registered nurses completed a survey. The study used work-family conflict scale, job control scale, job satisfaction scale, as well as general information. Multiple regression analysis was used to explore the independent factors of job satisfaction. Structural equation model was used to explore the mediating role of job control. Results: Work-family conflict was negatively correlated with job satisfaction (r ‑0.432, p<0.01. In addition, job control was positively related to job satisfaction (r 0.567, p<0.01. Work-family conflict and job control had significant predictive effects on job satisfaction. Job control partially mediated the relationship between work-family conflict and job satisfaction. Conclusion: Work-family conflict affected job satisfaction and job control was a mediator in this relationship among Chinese registered nurses. Job control could potentially improve nurses' job satisfaction.

  2. Can Job Control Ameliorate Work-family Conflict and Enhance Job Satisfaction among Chinese Registered Nurses? A Mediation Model.

    Science.gov (United States)

    Ding, Xiaotong; Yang, Yajuan; Su, Dan; Zhang, Ting; Li, Lunlan; Li, Huiping

    2018-04-01

    Low job satisfaction is the most common cause of nurses' turnover and influences the quality of nursing service. Moreover, we have no idea regarding whether job control, as an individual factor, can play a role in the relationship. To explore the relationship between work-family conflict and job satisfaction among Chinese registered nurses and the mediating role of job control in this relationship. From August 2015 to November 2016, 487 Chinese registered nurses completed a survey. The study used work-family conflict scale, job control scale, job satisfaction scale, as well as general information. Multiple regression analysis was used to explore the independent factors of job satisfaction. Structural equation model was used to explore the mediating role of job control. Work-family conflict was negatively correlated with job satisfaction (r ‑0.432, pjob control was positively related to job satisfaction (r 0.567, pjob control had significant predictive effects on job satisfaction. Job control partially mediated the relationship between work-family conflict and job satisfaction. Work-family conflict affected job satisfaction and job control was a mediator in this relationship among Chinese registered nurses. Job control could potentially improve nurses' job satisfaction.

  3. DNA methylation mediated control of gene expression is critical for development of crown gall tumors.

    Directory of Open Access Journals (Sweden)

    Jochen Gohlke

    Full Text Available Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA-encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA-mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes

  4. PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity

    Energy Technology Data Exchange (ETDEWEB)

    Chengye, Zhan; Daixing, Zhou, E-mail: dxzhou7246@hotmail.com; Qiang, Zhong; Shusheng, Li

    2013-09-13

    Highlights: •First time to display that LPS downregulate the expression of PRC. •First time to show that PRC inhibits the induction of VCAM-1 and E-selectin. •First time to show that PRC inhibit monocytes attachment to endothelial cells. •First time to display that PRC inhibits transcriptional activity of NF-κB. •PRC protects the respiration rate and suppresses the glycolysis rate against LPS. -- Abstract: PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor known to activate many of the nuclear genes specifying mitochondrial respiratory function. Endothelial dysfunction is a prominent feature found in many inflammatory diseases. Adhesion molecules, such as VCAM-1, mediate the attachment of monocytes to endothelial cells, thereby playing an important role in endothelial inflammation. The effects of PRC in regards to endothelial inflammation remain unknown. In this study, our findings show that PRC can be inhibited by the inflammatory cytokine LPS in cultured human umbilical vein endothelial cells (HUVECs). In the presence of LPS, the expression of endothelial cell adhesion molecular, such as VCAM1 and E-selectin, is found to be increased. These effects can be negated by overexpression of PRC. Importantly, monocyte adhesion to endothelial cells caused by LPS is significantly attenuated by PRC. In addition, overexpression of PRC protects mitochondrial metabolic function and suppresses the rate of glycolysis against LPS. It is also found that overexpression of PRC decreases the transcriptional activity of NF-κB. These findings suggest that PRC is a negative regulator of endothelial inflammation.

  5. SPBP is a sulforaphane induced transcriptional coactivator of NRF2 regulating expression of the autophagy receptor p62/SQSTM1.

    Directory of Open Access Journals (Sweden)

    Sagar Ramesh Darvekar

    Full Text Available Organisms exposed to oxidative stress respond by orchestrating a stress response to prevent further damage. Intracellular levels of antioxidant agents increase, and damaged components are removed by autophagy induction. The KEAP1-NRF2 signaling pathway is the main pathway responsible for cell defense against oxidative stress and for maintaining the cellular redox balance at physiological levels. Sulforaphane, an isothiocyanate derived from cruciferous vegetables, is a potent inducer of KEAP1-NRF2 signaling and antioxidant response element driven gene expression. In this study, we show that sulforaphane enhances the expression of the transcriptional coregulator SPBP. The expression curve peaks 6-8 hours post stimulation, and parallels the sulforaphane-induced expression of NRF2 and the autophagy receptor protein p62/SQSTM1. Reporter gene assays show that SPBP stimulates the expression of p62/SQSTM1 via ARE elements in the promoter region, and siRNA mediated knock down of SPBP significantly decreases the expression of p62/SQSTM1 and the formation of p62/SQSTM1 bodies in HeLa cells. Furthermore, SPBP siRNA reduces the sulforaphane induced expression of NRF2, and the expression of the autophagy marker protein LC3B. Both these proteins contain ARE-like elements in their promoter regions. Over-expressed SPBP and NRF2 acts synergistically on the p62/SQSTM1 promoter and colocalize in nuclear speckles in HeLa cells. Collectively, these results suggest that SPBP is a coactivator of NRF2, and hence may be important for securing enhanced and sustained expression of NRF2 induced genes such as proteins involved in selective autophagy.

  6. The effects of redox controls mediated by glutathione peroxidases on root architecture in Arabidopsis thaliana.

    Science.gov (United States)

    Passaia, Gisele; Queval, Guillaume; Bai, Juan; Margis-Pinheiro, Marcia; Foyer, Christine H

    2014-03-01

    Glutathione peroxidases (GPXs) fulfil important functions in oxidative signalling and protect against the adverse effects of excessive oxidation. However, there has been no systematic characterization of the functions of the different GPX isoforms in plants. The roles of the different members of the Arabidopsis thaliana GPX gene (AtGPX) family were therefore investigated using gpx1, gpx2, gpx3, gpx4, gpx6, gpx7, and gpx8 T-DNA insertion mutant lines. The shoot phenotypes were largely similar in all genotypes, with small differences from the wild type observed only in the gpx2, gpx3, gpx7, and gpx8 mutants. In contrast, all the mutants showed altered root phenotypes compared with the wild type. The gpx1, gpx4, gpx6, gpx7, and gpx8 mutants had a significantly greater lateral root density (LRD) than the wild type. Conversely, the gpx2 and gpx3 mutants had significantly lower LRD values than the wild type. Auxin increased the LRD in all genotypes, but the effect of auxin was significantly greater in the gpx1, gpx4, and gpx7 mutants than in the wild type. The application of auxin increased GPX4 and GPX7 transcripts, but not GPX1 mRNAs in the roots of wild-type plants. The synthetic strigolactone GR24 and abscisic acid (ABA) decreased LRD to a similar extent in all genotypes, except gpx6, which showed increased sensitivity to ABA. These data not only demonstrate the importance of redox controls mediated by AtGPXs in the control of root architecture but they also show that the plastid-localized GPX1 and GPX7 isoforms are required for the hormone-mediated control of lateral root development.

  7. A Mediation Analysis of Mothers' Dietary Intake: The Entre Familia: Reflejos de Salud Randomized Controlled Trial.

    Science.gov (United States)

    Horton, Lucy A; Ayala, Guadalupe X; Slymen, Donald J; Ibarra, Leticia; Hernandez, Erika; Parada, Humberto; Rock, Cheryl L; Arredondo, Elva M; Elder, John P

    2017-12-01

    Examine intervention effects among mothers involved in a healthy eating randomized controlled trial. Furthermore, examine the mediating roles of individual and familial influences on observed outcomes. Between 2009 and 2011, 361 families were recruited; half were assigned to an 11-session community health worker-delivered family-based intervention targeting Spanish-speaking Latino families in Imperial County, California. The intervention was delivered over a 4-month period. Home visits and telephone calls were delivered approximately weekly, with tapering near the end of the intervention to promote independence from the promotora. In this article, mothers' self-reported dietary intake was the primary outcome. Evaluation measures were taken at baseline, 4 months, and 10 months. Daily servings of fruits were higher among intervention versus control mothers (mean = 1.86 vs. mean = 1.47; effect size [ES] = 0.22) at 10 months post-baseline. Mothers in the intervention versus control condition also reported consuming a lower percent energy from fat (mean = 30.0% vs. 31.0%; ES = 0.30) and a higher diet quality (mean = 2.93 vs. mean = 2.67; ES = 0.29). Mediators of improvements were behavioral strategies to increase fiber and lower fat intake, family support for vegetable purchasing, and decreased unhealthy eating behaviors and perceived family barriers to healthy eating. Family-based behavioral interventions are effective for changing the skills and family system needed to improve diet among Latina mothers. Health care providers and other practitioners are encouraged to target skill development and fostering a socially supportive environment.

  8. Regulation of Nampt expression by transcriptional coactivator NCOA6 in pancreatic β-cells

    International Nuclear Information System (INIS)

    Yoon, Jin; Lee, Kyung Jin; Oh, Gyun-Sik; Kim, Geun Hyang; Kim, Seung-Whan

    2017-01-01

    Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator and crucial for insulin secretion and glucose metabolism in pancreatic β-cells. However, the regulatory mechanism of β-cell function by NCOA6 is largely unknown. In this study, we found that the transcript levels of nicotinamide phosphoribosyltransferase (Nampt) were decreased in islets of NCOA6 +/− mice compared with NCOA6 +/+ mice. Moreover, NCOA6 overexpression increased the levels of Nampt transcripts in the mouse pancreatic β-cell line NIT-1. Promoter analyses showed that transcriptional activity of the Nampt promoter was stimulated by cooperation of sterol regulatory element binding protein-1c (SREBP-1c) and NCOA6. Additional studies using mutant promoters demonstrated that SREBP-1c activates Nampt promoter through the sterol regulatory element (SRE), but not through the E-box. Using chromatin immunoprecipitation assay, NCOA6 was also shown to be directly recruited to the SRE region of the Nampt promoter. Furthermore, treatment with nicotinamide mononucleotide (NMN), a product of the Nampt reaction and a key NAD + intermediate, ameliorates glucose-stimulated insulin secretion from NCOA6 +/− islets. These results suggest that NCOA6 stimulates insulin secretion, at least partially, by modulating Nampt expression in pancreatic β-cells. - Highlights: • Nampt transcription in β-cells is activated by SREBP-1c through the SRE element. • NCOA6 enhances the transcriptional activity of SREBP-1c in the Nampt promoter. • Defective insulin secretion of NCOA6 +/− islets is recovered by NMN treatment. • NCOA6 is reportedly the first coactivator involved in Nampt expression.

  9. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.

    Science.gov (United States)

    Tuttle, Lisa M; Pacheco, Derek; Warfield, Linda; Luo, Jie; Ranish, Jeff; Hahn, Steven; Klevit, Rachel E

    2018-03-20

    Transcription activation domains (ADs) are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs) on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Task vs. rest-different network configurations between the coactivation and the resting-state brain networks.

    Science.gov (United States)

    Di, Xin; Gohel, Suril; Kim, Eun H; Biswal, Bharat B

    2013-01-01

    There is a growing interest in studies of human brain networks using resting-state functional magnetic resonance imaging (fMRI). However, it is unclear whether and how brain networks measured during the resting-state exhibit comparable properties to brain networks during task performance. In the present study, we investigated meta-analytic coactivation patterns among brain regions based upon published neuroimaging studies, and compared the coactivation network configurations with those in the resting-state network. The strength of resting-state functional connectivity between two regions were strongly correlated with the coactivation strength. However, the coactivation network showed greater global efficiency, smaller mean clustering coefficient, and lower modularity compared with the resting-state network, which suggest a more efficient global information transmission and between system integrations during task performing. Hub shifts were also observed within the thalamus and the left inferior temporal cortex. The thalamus and the left inferior temporal cortex exhibited higher and lower degrees, respectively in the coactivation network compared with the resting-state network. These results shed light regarding the reconfiguration of the brain networks between task and resting-state conditions, and highlight the role of the thalamus in change of network configurations in task vs. rest.

  11. Task vs. rest—different network configurations between the coactivation and the resting-state brain networks

    Science.gov (United States)

    Di, Xin; Gohel, Suril; Kim, Eun H.; Biswal, Bharat B.

    2013-01-01

    There is a growing interest in studies of human brain networks using resting-state functional magnetic resonance imaging (fMRI). However, it is unclear whether and how brain networks measured during the resting-state exhibit comparable properties to brain networks during task performance. In the present study, we investigated meta-analytic coactivation patterns among brain regions based upon published neuroimaging studies, and compared the coactivation network configurations with those in the resting-state network. The strength of resting-state functional connectivity between two regions were strongly correlated with the coactivation strength. However, the coactivation network showed greater global efficiency, smaller mean clustering coefficient, and lower modularity compared with the resting-state network, which suggest a more efficient global information transmission and between system integrations during task performing. Hub shifts were also observed within the thalamus and the left inferior temporal cortex. The thalamus and the left inferior temporal cortex exhibited higher and lower degrees, respectively in the coactivation network compared with the resting-state network. These results shed light regarding the reconfiguration of the brain networks between task and resting-state conditions, and highlight the role of the thalamus in change of network configurations in task vs. rest. PMID:24062654

  12. Phosphorylation of carbonic anhydrase IX controls its ability to mediate extracellular acidification in hypoxic tumors.

    Science.gov (United States)

    Ditte, Peter; Dequiedt, Franck; Svastova, Eliska; Hulikova, Alzbeta; Ohradanova-Repic, Anna; Zatovicova, Miriam; Csaderova, Lucia; Kopacek, Juraj; Supuran, Claudiu T; Pastorekova, Silvia; Pastorek, Jaromir

    2011-12-15

    In the hypoxic regions of a tumor, carbonic anhydrase IX (CA IX) is an important transmembrane component of the pH regulatory machinery that participates in bicarbonate transport. Because tumor pH has implications for growth, invasion, and therapy, determining the basis for the contributions of CA IX to the hypoxic tumor microenvironment could lead to new fundamental and practical insights. Here, we report that Thr443 phosphorylation at the intracellular domain of CA IX by protein kinase A (PKA) is critical for its activation in hypoxic cells, with the fullest activity of CA IX also requiring dephosphorylation of Ser448. PKA is activated by cAMP, which is elevated by hypoxia, and we found that attenuating PKA in cells disrupted CA IX-mediated extracellular acidification. Moreover, following hypoxia induction, CA IX colocalized with the sodium-bicarbonate cotransporter and other PKA substrates in the leading edge membranes of migrating tumor cells, in support of the concept that bicarbonate metabolism is spatially regulated at cell surface sites with high local ion transport and pH control. Using chimeric CA IX proteins containing heterologous catalytic domains derived from related CA enzymes, we showed that CA IX activity was modulated chiefly by the intracellular domain where Thr443 is located. Our findings indicate that CA IX is a pivotal mediator of the hypoxia-cAMP-PKA axis, which regulates pH in the hypoxic tumor microenvironment.

  13. GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules

    Science.gov (United States)

    Hur, Eun-Mi; Saijilafu; Lee, Byoung Dae; Kim, Seong-Jin; Xu, Wen-Lin; Zhou, Feng-Quan

    2011-01-01

    Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs. PMID:21937714

  14. Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta

    International Nuclear Information System (INIS)

    Hirai, Yohei; Radisky, Derek; Boudreau, Rosanne; Simian, Marina; Stevens, Mary E.; Oka, Yumiko; Takebe, Kyoko; Niwa, Shinichiro; Bissell, Mina J.

    2002-01-01

    We have previously shown that epimorphin, a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which epimorphin mediates luminal morphogenesis. Treatment of cells with epimorphin to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, as constitutive expression of LIP was sufficient to produce lumen formation, while constitutive expression of LAP blocked epimorphin-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which epimorphin expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPbeta, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for epimorphin in luminal morphogenesis through control of C/EBPbeta expression

  15. A genetically mediated bias in decision making driven by failure of amygdala control.

    Science.gov (United States)

    Roiser, Jonathan P; de Martino, Benedetto; Tan, Geoffrey C Y; Kumaran, Dharshan; Seymour, Ben; Wood, Nicholas W; Dolan, Raymond J

    2009-05-06

    Genetic variation at the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with altered amygdala reactivity and lack of prefrontal regulatory control. Similar regions mediate decision-making biases driven by contextual cues and ambiguity, for example the "framing effect." We hypothesized that individuals hemozygous for the short (s) allele at the 5-HTTLPR would be more susceptible to framing. Participants, selected as homozygous for either the long (la) or s allele, performed a decision-making task where they made choices between receiving an amount of money for certain and taking a gamble. A strong bias was evident toward choosing the certain option when the option was phrased in terms of gains and toward gambling when the decision was phrased in terms of losses (the frame effect). Critically, this bias was significantly greater in the ss group compared with the lala group. In simultaneously acquired functional magnetic resonance imaging data, the ss group showed greater amygdala during choices made in accord, compared with those made counter to the frame, an effect not seen in the lala group. These differences were also mirrored by differences in anterior cingulate-amygdala coupling between the genotype groups during decision making. Specifically, lala participants showed increased coupling during choices made counter to, relative to those made in accord with, the frame, with no such effect evident in ss participants. These data suggest that genetically mediated differences in prefrontal-amygdala interactions underpin interindividual differences in economic decision making.

  16. Coordination of KSHV Latent and Lytic Gene Control by CTCF-Cohesin Mediated Chromosome Conformation

    Science.gov (United States)

    Kang, Hyojeung; Wiedmer, Andreas; Yuan, Yan; Robertson, Erle; Lieberman, Paul M.

    2011-01-01

    Herpesvirus persistence requires a dynamic balance between latent and lytic cycle gene expression, but how this balance is maintained remains enigmatic. We have previously shown that the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) major latency transcripts encoding LANA, vCyclin, vFLIP, v-miRNAs, and Kaposin are regulated, in part, by a chromatin organizing element that binds CTCF and cohesins. Using viral genome-wide chromatin conformation capture (3C) methods, we now show that KSHV latency control region is physically linked to the promoter regulatory region for ORF50, which encodes the KSHV immediate early protein RTA. Other linkages were also observed, including an interaction between the 5′ and 3′ end of the latency transcription cluster. Mutation of the CTCF-cohesin binding site reduced or eliminated the chromatin conformation linkages, and deregulated viral transcription and genome copy number control. siRNA depletion of CTCF or cohesin subunits also disrupted chromosomal linkages and deregulated viral latent and lytic gene transcription. Furthermore, the linkage between the latent and lytic control region was subject to cell cycle fluctuation and disrupted during lytic cycle reactivation, suggesting that these interactions are dynamic and regulatory. Our findings indicate that KSHV genomes are organized into chromatin loops mediated by CTCF and cohesin interactions, and that these inter-chromosomal linkages coordinate latent and lytic gene control. PMID:21876668

  17. Mediating Parent Learning to Promote Social Communication for Toddlers with Autism: Effects from a Randomized Controlled Trial

    Science.gov (United States)

    Schertz, Hannah H.; Odom, Samuel L.; Baggett, Kathleen M.; Sideris, John H.

    2018-01-01

    A randomized controlled trial was conducted to evaluate effects of the Joint Attention Mediated Learning (JAML) intervention. Toddlers with autism spectrum disorders (ASD) aged 16-30 months (n = 144) were randomized to intervention and community control conditions. Parents, who participated in 32 weekly home-based sessions, followed a mediated…

  18. DMPD: Protein kinase C epsilon: a new target to control inflammation andimmune-mediated disorders. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14643884 Protein kinase C epsilon: a new target to control inflammation andimmune-m...g) (.html) (.csml) Show Protein kinase C epsilon: a new target to control inflammation andimmune-mediated di...sorders. PubmedID 14643884 Title Protein kinase C epsilon: a new target to contro

  19. Self-reported impulsivity, but not behavioral approach or inhibition, mediates the relationship between stress and self-control.

    Science.gov (United States)

    Hamilton, Kristen R; Sinha, Rajita; Potenza, Marc N

    2014-11-01

    Stress has been associated with poor self-control. Individual differences in impulsivity and other behavioral tendencies may influence the relationship of stress with self-control, although this possibility has not been examined to date. The present research investigated whether cumulative stress is associated with poor self-control, and whether this relationship is mediated by impulsivity, behavioral approach, and behavioral inhibition in men and women. A community sample of 566 adults (319 women and 247 men) was assessed on the Cumulative Adversity Interview, Brief Self-control Scale, Barratt Impulsivity Scale, and Behavioral Activation System and Behavioral Inhibition System Scale (BIS/BAS). Data were analyzed using regression and bootstrapping techniques. In the total sample, the effects of cumulative stress on self-control were mediated by impulsivity. Neither behavioral inhibition nor behavioral approach mediated the association between cumulative stress and self-control in the total sample. Results were similar when men and women were considered separately, with impulsivity, but not behavioral inhibition or approach, mediating the association between cumulative stress and self-control. Impulsive individuals might benefit preferentially from interventions focusing on stress management and strategies for improving self-control. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. More than Resisting Temptation: Beneficial Habits Mediate the Relationship between Self-Control and Positive Life Outcomes

    Science.gov (United States)

    Galla, Brian M.; Duckworth, Angela L.

    2015-01-01

    Why does self-control predict such a wide array of positive life outcomes? Conventional wisdom holds that self-control is used to effortfully inhibit maladaptive impulses, yet this view conflicts with emerging evidence that self-control is associated with less inhibition in daily life. We propose that one of the reasons individuals with better self-control use less effortful inhibition, yet make better progress on their goals is that they rely on beneficial habits. Across six studies (total N = 2,274), we found support for this hypothesis. In Study 1, habits for eating healthy snacks, exercising, and getting consistent sleep mediated the effect of self-control on both increased automaticity and lower reported effortful inhibition in enacting those behaviors. In Studies 2 and 3, study habits mediated the effect of self-control on reduced motivational interference during a work-leisure conflict and on greater ability to study even under difficult circumstances. In Study 4, homework habits mediated the effect of self-control on classroom engagement and homework completion. Study 5 was a prospective longitudinal study of teenage youth who participated in a five-day meditation retreat. Better self-control before the retreat predicted stronger meditation habits three months after the retreat, and habits mediated the effect of self-control on successfully accomplishing meditation practice goals. Finally, in Study 6, study habits mediated the effect of self-control on homework completion and two objectively measured long-term academic outcomes: grade point average and first-year college persistence. Collectively, these results suggest that beneficial habits--perhaps more so than effortful inhibition--are an important factor linking self-control with positive life outcomes. PMID:25643222

  1. More than resisting temptation: Beneficial habits mediate the relationship between self-control and positive life outcomes.

    Science.gov (United States)

    Galla, Brian M; Duckworth, Angela L

    2015-09-01

    Why does self-control predict such a wide array of positive life outcomes? Conventional wisdom holds that self-control is used to effortfully inhibit maladaptive impulses, yet this view conflicts with emerging evidence that self-control is associated with less inhibition in daily life. We propose that one of the reasons individuals with better self-control use less effortful inhibition, yet make better progress on their goals is that they rely on beneficial habits. Across 6 studies (total N = 2,274), we found support for this hypothesis. In Study 1, habits for eating healthy snacks, exercising, and getting consistent sleep mediated the effect of self-control on both increased automaticity and lower reported effortful inhibition in enacting those behaviors. In Studies 2 and 3, study habits mediated the effect of self-control on reduced motivational interference during a work-leisure conflict and on greater ability to study even under difficult circumstances. In Study 4, homework habits mediated the effect of self-control on classroom engagement and homework completion. Study 5 was a prospective longitudinal study of teenage youth who participated in a 5-day meditation retreat. Better self-control before the retreat predicted stronger meditation habits 3 months after the retreat, and habits mediated the effect of self-control on successfully accomplishing meditation practice goals. Finally, in Study 6, study habits mediated the effect of self-control on homework completion and 2 objectively measured long-term academic outcomes: grade point average and first-year college persistence. Collectively, these results suggest that beneficial habits-perhaps more so than effortful inhibition-are an important factor linking self-control with positive life outcomes. (c) 2015 APA, all rights reserved).

  2. RNA- and protein-mediated control of Listeria monocytogenes virulence gene expression

    Science.gov (United States)

    Lebreton, Alice; Cossart, Pascale

    2017-01-01

    ABSTRACT The model opportunistic pathogen Listeria monocytogenes has been the object of extensive research, aiming at understanding its ability to colonize diverse environmental niches and animal hosts. Bacterial transcriptomes in various conditions reflect this efficient adaptability. We review here our current knowledge of the mechanisms allowing L. monocytogenes to respond to environmental changes and trigger pathogenicity, with a special focus on RNA-mediated control of gene expression. We highlight how these studies have brought novel concepts in prokaryotic gene regulation, such as the ‘excludon’ where the 5′-UTR of a messenger also acts as an antisense regulator of an operon transcribed in opposite orientation, or the notion that riboswitches can regulate non-coding RNAs to integrate complex metabolic stimuli into regulatory networks. Overall, the Listeria model exemplifies that fine RNA tuners act together with master regulatory proteins to orchestrate appropriate transcriptional programmes. PMID:27217337

  3. Streptophage-mediated control of off-flavour taint producing streptomycetes isolated from barramundi ponds

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    Jodi Anne Jonns

    2017-06-01

    Following the determination of the streptophage susceptibility of the isolates one of the most odourous streptomycete species (USC-14510 was selected to be tested further using different pond simulations resembling real-life applications. Geosmin was tested as the indicator of off-flavour taint production and as it has been previously reported that the cyanobacteria-actinomycete interactions occurring in ponds result in even greater levels of geosmin and 2-methylisoborneol, the geosmin levels for the isolate in the presence of cyanobacteria and streptophages were also tested. Findings indicated that the highly odourous Streptomyces species (USC-14510 once infected with streptophages, can lose its capacity to produce off-flavour taints. Pond simulation studies also revealed geosmin production was significantly reduced when streptophages were introduced into the pond water where streptomycete species were grown. The bacteriophage control method developed in the presented study might again confirm significant potential for the bacteriophage-mediated remediation strategy to be adapted by the aquaculture industry.

  4. Hyperglycemic conditions inhibit C3-mediated immunologic control of Staphylococcus aureus

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    Hair Pamela S

    2012-03-01

    Full Text Available Abstract Background Diabetic patients are at increased risk for bacterial infections; these studies provide new insight into the role of the host defense complement system in controlling bacterial pathogens in hyperglycemic environments. Methods The interactions of complement C3 with bacteria in elevated glucose were assayed for complement activation to opsonic forms, phagocytosis and bacterial killing. C3 was analyzed in euglycemic and hyperglycemic conditions by mass spectrometry to measure glycation and structural differences. Results Elevated glucose inhibited S. aureus activation of C3 and deposition of C3b and iC3b on the bacterial surface. S. aureus-generated C5a and serum-mediated phagocytosis by neutrophils were both decreased in elevated glucose conditions. Interestingly, elevated glucose increased the binding of unactivated C3 to S. aureus, which was reversible on return to normal glucose concentrations. In a model of polymicrobial infection, S. aureus in elevated glucose conditions depleted C3 from serum resulting in decreased complement-mediated killing of E. coli. To investigate the effect of differing glucose concentration on C3 structure and glycation, purified C3 incubated with varying glucose concentrations was analyzed by mass spectrometry. Glycation was limited to the same three lysine residues in both euglycemic and hyperglycemic conditions over one hour, thus glycation could not account for observed changes between glucose conditions. However, surface labeling of C3 with sulfo-NHS-biotin showed significant changes in the surface availability of seven lysine residues in response to increasing glucose concentrations. These results suggest that the tertiary structure of C3 changes in response to hyperglycemic conditions leading to an altered interaction of C3 with bacterial pathogens. Conclusions These results demonstrate that hyperglycemic conditions inhibit C3-mediated complement effectors important in the immunological

  5. ERECTA signaling controls Arabidopsis inflorescence architecture through chromatin-mediated activation of PRE1 expression.

    Science.gov (United States)

    Cai, Hanyang; Zhao, Lihua; Wang, Lulu; Zhang, Man; Su, Zhenxia; Cheng, Yan; Zhao, Heming; Qin, Yuan

    2017-06-01

    Flowering plants display a remarkable diversity in inflorescence architecture, and pedicel length is one of the key contributors to this diversity. In Arabidopsis thaliana, the receptor-like kinase ERECTA (ER) mediated signaling pathway plays important roles in regulating inflorescence architecture by promoting cell proliferation. However, the regulating mechanism remains elusive in the pedicel. Genetic interactions between ERECTA signaling and the chromatin remodeling complex SWR1 in the control of inflorescence architecture were studied. Comparative transcriptome analysis was applied to identify downstream components. Chromatin immunoprecipitation and nucleosome occupancy was further investigated. The results indicated that the chromatin remodeler SWR1 coordinates with ERECTA signaling in regulating inflorescence architecture by activating the expression of PRE1 family genes and promoting pedicel elongation. It was found that SWR1 is required for the incorporation of the H2A.Z histone variant into nucleosomes of the whole PRE1 gene family and the ERECTA controlled expression of PRE1 gene family through regulating nucleosome dynamics. We propose that utilization of a chromatin remodeling complex to regulate gene expression is a common theme in developmental control across kingdoms. These findings shed light on the mechanisms through which chromatin remodelers orchestrate complex transcriptional regulation of gene expression in coordination with a developmental cue. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  6. Fluid Intelligence as a Mediator of the Relationship between Executive Control and Balanced Time Perspective.

    Science.gov (United States)

    Zajenkowski, Marcin; Stolarski, Maciej; Witowska, Joanna; Maciantowicz, Oliwia; Łowicki, Paweł

    2016-01-01

    This study examined the cognitive foundations of the balanced time perspective (BTP) proposed by Zimbardo and Boyd (1999). Although BTP is defined as the mental ability to switch effectively between different temporal perspectives, its connection with cognitive functioning has not yet been established. We addressed this by exploring the relationships between time perspectives and both fluid intelligence (measured with Raven's and Cattell's tests) and executive control (Go/No-go and anti-saccade tasks). An investigation conducted among Polish adults ( N = 233) revealed that more balanced TP profile was associated with higher fluid intelligence, and higher executive control. Moreover, we found that the relationship between executive control and BTP was completely mediated by fluid intelligence with the effect size (the ratio of the indirect effect to the total effect) of 0.75, which suggests that cognitive abilities play an important role in adoption of temporal balance. The findings have relevance to time perspective theory as they provide valuable insight into the mechanisms involved in assigning human experience to certain time frames.

  7. Electroacupuncture Potentiates Cannabinoid Receptor-Mediated Descending Inhibitory Control in a Mouse Model of Knee Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Xiao-Cui Yuan

    2018-04-01

    Full Text Available Knee osteoarthritis (KOA is a highly prevalent, chronic joint disorder, which can lead to chronic pain. Although electroacupuncture (EA is effective in relieving chronic pain in the clinic, the involved mechanisms remain unclear. Reduced diffuse noxius inhibitory controls (DNIC function is associated with chronic pain and may be related to the action of endocannabinoids. In the present study, we determined whether EA may potentiate cannabinoid receptor-mediated descending inhibitory control and inhibit chronic pain in a mouse model of KOA. We found that the optimized parameters of EA inhibiting chronic pain were the low frequency and high intensity (2 Hz + 1 mA. EA reversed the reduced expression of CB1 receptors and the 2-arachidonoylglycerol (2-AG level in the midbrain in chronic pain. Microinjection of the CB1 receptor antagonist AM251 into the ventrolateral periaqueductal gray (vlPAG can reversed the EA effect on pain hypersensitivity and DNIC function. In addition, CB1 receptors on GABAergic but not glutamatergic neurons are involved in the EA effect on DNIC function and descending inhibitory control of 5-HT in the medulla, thus inhibiting chronic pain. Our data suggest that endocannabinoid (2-AG-CB1R-GABA-5-HT may be a novel signaling pathway involved in the effect of EA improving DNIC function and inhibiting chronic pain.

  8. Hydrogen Peroxide- and Nitric Oxide-mediated Disease Control of Bacterial Wilt in Tomato Plants

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    Jeum Kyu Hong

    2013-12-01

    Full Text Available Reactive oxygen species (ROS generation in tomato plants by Ralstonia solanacearum infection and the role of hydrogen peroxide (H₂O₂ and nitric oxide in tomato bacterial wilt control were demonstrated. During disease development of tomato bacterial wilt, accumulation of superoxide anion (O₂− and H₂O₂ was observed and lipid peroxidation also occurred in the tomato leaf tissues. High doses of H₂O₂and sodium nitroprusside (SNP nitric oxide donor showed phytotoxicity to detached tomato leaves 1 day after petiole feeding showing reduced fresh weight. Both H₂O₂and SNP have in vitro antibacterial activities against R. solanacearum in a dose-dependent manner, as well as plant protection in detached tomato leaves against bacterial wilt by 10⁶ and 10⁷ cfu/ml of R. solanacearum. H₂O₂- and SNP-mediated protection was also evaluated in pots using soil-drench treatment with the bacterial inoculation, and relative ‘area under the disease progressive curve (AUDPC’ was calculated to compare disease protection by H₂O₂ and/or SNP with untreated control. Neither H₂O₂ nor SNP protect the tomato seedlings from the bacterial wilt, but H₂O₂+ SNP mixture significantly decreased disease severity with reduced relative AUDPC. These results suggest that H₂O₂ and SNP could be used together to control bacterial wilt in tomato plants as bactericidal agents.

  9. Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy.

    Science.gov (United States)

    York, Brian; Reineke, Erin L; Sagen, Jørn V; Nikolai, Bryan C; Zhou, Suoling; Louet, Jean-Francois; Chopra, Atul R; Chen, Xian; Reed, Graham; Noebels, Jeffrey; Adesina, Adekunle M; Yu, Hui; Wong, Lee-Jun C; Tsimelzon, Anna; Hilsenbeck, Susan; Stevens, Robert D; Wenner, Brett R; Ilkayeva, Olga; Xu, Jianming; Newgard, Christopher B; O'Malley, Bert W

    2012-05-02

    Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypoglycemia, hyperammonemia, and impaired neurologic, cardiac and skeletal muscle performance, each of which is apparent in mice lacking SRC-3 expression. Consistent with human cases of CACT deficiency, dietary rescue with short chain fatty acids drastically attenuates the clinical hallmarks of the disease in mice devoid of SRC-3. Collectively, our results position SRC-3 as a key regulator of β-oxidation. Moreover, these findings allow us to consider platform coactivators such as the SRCs as potential contributors to syndromes such as CACT deficiency, previously considered as monogenic. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Implicit co-activation of American Sign Language in deaf readers: An ERP study.

    Science.gov (United States)

    Meade, Gabriela; Midgley, Katherine J; Sevcikova Sehyr, Zed; Holcomb, Phillip J; Emmorey, Karen

    2017-07-01

    In an implicit phonological priming paradigm, deaf bimodal bilinguals made semantic relatedness decisions for pairs of English words. Half of the semantically unrelated pairs had phonologically related translations in American Sign Language (ASL). As in previous studies with unimodal bilinguals, targets in pairs with phonologically related translations elicited smaller negativities than targets in pairs with phonologically unrelated translations within the N400 window. This suggests that the same lexicosemantic mechanism underlies implicit co-activation of a non-target language, irrespective of language modality. In contrast to unimodal bilingual studies that find no behavioral effects, we observed phonological interference, indicating that bimodal bilinguals may not suppress the non-target language as robustly. Further, there was a subset of bilinguals who were aware of the ASL manipulation (determined by debrief), and they exhibited an effect of ASL phonology in a later time window (700-900ms). Overall, these results indicate modality-independent language co-activation that persists longer for bimodal bilinguals. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Transcriptional activity of Pax3 is co-activated by TAZ

    International Nuclear Information System (INIS)

    Murakami, Masao; Tominaga, Junji; Makita, Ryosuke; Uchijima, Yasunobu; Kurihara, Yukiko; Nakagawa, Osamu; Asano, Tomoichiro; Kurihara, Hiroki

    2006-01-01

    Pax3 is a transcription factor which functions in embryonic development and human diseases. In a yeast two-hybrid screen with full-length Pax3 as bait, we isolated a clone encoding transcriptional co-activator with PDZ-binding motif (TAZ) from an E10.5 mouse embryo cDNA library. Co-immunoprecipitation and nuclear co-localization of TAZ with Pax3 suggest that their association is functionally relevant. In situ hybridization revealed TAZ and Pax3 expression to partially overlap in the paraxial mesoderm, limb buds, and the neural tube. In C2C12 myoblast cells and NIH3T3 cells, TAZ enhanced the transcriptional activity of Pax3 on artificial and microphthalmia-associated transcription factor promoter-luciferase constructs, suggesting that TAZ can function as a co-activator of Pax3. Functional interaction between Pax3 and TAZ may provide a clue to clarifying the mechanism by which Pax3 serves as a transcriptional activator during embryogenesis

  12. Reverting doxorubicin resistance in colon cancer by targeting a key signaling protein, steroid receptor coactivator.

    Science.gov (United States)

    Xiong, Sang; Xiao, Gong-Wei

    2018-04-01

    Although there have been notable improvements in treatments against cancer, further research is required. In colon cancer, nearly all patients eventually experience drug resistance and stop responding to the approved drugs, making treatment difficult. Steroid receptor coactivator (SRC) is an oncogenic nuclear receptor coactivator that serves an important role in drug resistance. The present study generated a doxorubicin-resistant colon cancer cell line, in which the upregulation/activation of SRC was responsible for drug resistance, which in turn activated AKT. Overexpression of receptor tyrosine kinase-like epidermal growth factor receptor and insulin-like growth factor 1 receptor also induced SRC expression. It was observed that doxorubicin resistance in colon cancer also induced epithelial to mesenchymal transition, a decrease in expression of epithelial marker E-cadherin and an increase in the expression of mesenchymal markers, including N-cadherin and vimentin. Additionally, the present study indicated that SRC acts as a common signaling node, and inhibiting SRC in combination with doxorubicin treatment in doxorubicin-resistant cells aids in reversing the resistance. Thus, the present study suggests that activation of SRC is responsible for doxorubicin resistance in colon cancer. However, further research is required to understand the complete mechanism of how drug resistance occurs and how it may be tackled to treat patients.

  13. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.

    Science.gov (United States)

    Lin, Jiandie; Wu, Hai; Tarr, Paul T; Zhang, Chen-Yu; Wu, Zhidan; Boss, Olivier; Michael, Laura F; Puigserver, Pere; Isotani, Eiji; Olson, Eric N; Lowell, Bradford B; Bassel-Duby, Rhonda; Spiegelman, Bruce M

    2002-08-15

    The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1 alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1 alpha is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type II muscles from PGC-1 alpha transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1 alpha is a principal factor regulating muscle fibre type determination.

  14. Fate control and well-being in Chinese rural people living with HIV: mediation effect of resilience.

    Science.gov (United States)

    Yu, Nancy Xiaonan; Zhang, Jianxin; Chow, Amy Y M; Chan, Celia H Y; Chan, Cecilia L W

    2017-01-01

    Fate control has been often misconceptualized as a superstitious belief and overlooked in health psychology. It is not known how this cultural belief might impact the well-being of Chinese people living with HIV. This study examined the protective role of fate control for well-being and the potential mediation effect of resilience. Participants in this study were rural patients who contracted HIV via commercial blood donation. In this cross-sectional survey, 250 participants completed measures of fate control, well-being, and resilience. The results showed that fate control and resilience were positively associated with well-being. Resilience mediated the association between fate control and well-being. Our findings provide insight into the adaptive function of fate control as a cognitive defensive mechanism and highlight the need to incorporate this cultural belief in developing culturally sensitive intervention programs for resilience enhancement tailored for this understudied population infected with HIV living in rural China.

  15. Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes

    Directory of Open Access Journals (Sweden)

    Shih-Han Kao

    2016-02-01

    Full Text Available Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT, metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA demethylation mediated by the Ten-eleven translocation (TET proteins induces major epigenetic changes and controls key steps of cancer development. TET enzymes serve as 5mC (5-methylcytosine-specific dioxygenases and cause DNA demethylation. Hypoxia activates the expression of TET1, which also serves as a co-activator of HIF-1α transcriptional regulation to modulate HIF-1α downstream target genes and promote epithelial-mesenchymal transition. As HIF is a negative prognostic factor for tumor progression, hypoxia-activated prodrugs (HAPs may provide a favorable therapeutic approach to lessen hypoxia-induced malignancy.

  16. Reduced Inhibitory Control Mediates the Relationship Between Cortical Thickness in the Right Superior Frontal Gyrus and Body Mass Index.

    Science.gov (United States)

    Lavagnino, Luca; Mwangi, Benson; Bauer, Isabelle E; Cao, Bo; Selvaraj, Sudhakar; Prossin, Alan; Soares, Jair C

    2016-08-01

    Unhealthy eating behaviors often develop in the setting of inadequate inhibitory control, a function broadly ascribed to the prefrontal cortex (PFC). Regulation of inhibitory control by the PFC and its anatomical components and their contribution to increasing body mass index (BMI) are poorly understood. To study the role of PFC in the regulation of inhibitory control and body weight, we examined measures of cortical thickness in PFC sub-regions, inhibitory control (color-word interference task (CWIT)), and BMI in 91 healthy volunteers. We tested the predictive effect of PFC sub-regional cortical thickness on BMI and mediation by inhibitory control measured with CWIT. Measures of depression (BDI-II), anxiety (STAI-T) and trauma-related symptoms (TSC-40) were collected; the disinhibition scale of the three-factor eating questionnaire (TFEQ) was used to assess disinhibited eating. We then tested the relationship between BD-II, STAI-T, TSC-40, TFEQ, CWIT, and BMI with correlation analyses. Right superior frontal gyrus cortical thickness significantly predicted BMI (β=-0.91; t=-3.2; p=0.002). Mediation analysis showed a significant indirect effect of cortical thickness on BMI mediated by inhibitory control (95% CI=-6.1, -0.67). BMI was unrelated to BDI-II, STAI-T, TSC-40, or TFEQ scores. We found an inverse relationship between cortical thickness in the right-superior frontal gyrus and BMI, which was fully mediated by inhibitory control neurocognitive performance. Our results suggest possible targets for neuromodulation in obesity (ie superior frontal gyrus) and a quantifiable mediator of their effects (ie inhibitory control).

  17. The Arabidopsis Mediator Complex Subunits MED16, MED14, and MED2 Regulate Mediator and RNA Polymerase II Recruitment to CBF-Responsive Cold-Regulated Genes[C][W][OPEN

    Science.gov (United States)

    Hemsley, Piers A.; Hurst, Charlotte H.; Kaliyadasa, Ewon; Lamb, Rebecca; Knight, Marc R.; De Cothi, Elizabeth A.; Steele, John F.; Knight, Heather

    2014-01-01

    The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation–induced freezing tolerance. In addition, these three subunits are required for low temperature–induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced. PMID:24415770

  18. Crop domestication, global human-mediated migration, and the unresolved role of geography in pest control

    Directory of Open Access Journals (Sweden)

    Yolanda H. Chen

    2016-05-01

    Full Text Available Abstract Ecological pest management seeks to improve pest control through the manipulation of ecological processes that promote natural enemies and suppress pests. These approaches can involve cultural practices such as reduced tillage, increased use of non-crop plants that provide food and shelter for natural enemies, and intercropping to enhance the abundance and diversity of natural enemies. A major assumption of ecological pest management is that these activities can be equally effective for all insect herbivores. Here, I propose that these strategies may only be effective for a subset of pests and geographic regions because most insect pests have complex evolutionary histories that make them difficult to manage. I discuss how crop domestication and human-mediated migration are major evolutionary events that shape the geography of interactions between plants, herbivores, and natural enemies. Insect herbivores can evolve to be pests through three major modes: 1 herbivores associated with the crop wild ancestor may shift onto the domesticated crop, 2 herbivores may host-shift from native host plants onto an introduced crop, or 3 human-mediated migration can introduce insect pests into new cropping regions. The resulting geographic structure can influence the success of pest management by altering ecological factors such as: species distributions, patterns of biodiversity, community structure, and natural enemy attack rates. I discuss how the different modes of insect pest evolution structure a set of relevant questions and approaches for ecological pest management. By acknowledging how agricultural history and geography shape the ecology and evolution of insect pests, we may collectively develop a better capacity to identify where and how ecological pest management approaches can be most broadly effective.

  19. Phosphorylation-mediated control of histone chaperone ASF1 levels by Tousled-like kinases.

    Directory of Open Access Journals (Sweden)

    Maxim Pilyugin

    Full Text Available Histone chaperones are at the hub of a diverse interaction networks integrating a plethora of chromatin modifying activities. Histone H3/H4 chaperone ASF1 is a target for cell-cycle regulated Tousled-like kinases (TLKs and both proteins cooperate during chromatin replication. However, the precise role of post-translational modification of ASF1 remained unclear. Here, we identify the TLK phosphorylation sites for both Drosophila and human ASF1 proteins. Loss of TLK-mediated phosphorylation triggers hASF1a and dASF1 degradation by proteasome-dependent and independent mechanisms respectively. Consistent with this notion, introduction of phosphorylation-mimicking mutants inhibits hASF1a and dASF1 degradation. Human hASF1b is also targeted for proteasome-dependent degradation, but its stability is not affected by phosphorylation indicating that other mechanisms are likely to be involved in control of hASF1b levels. Together, these results suggest that ASF1 cellular levels are tightly controlled by distinct pathways and provide a molecular mechanism for post-translational regulation of dASF1 and hASF1a by TLK kinases.

  20. Surface receptor Toso controls B cell-mediated regulation of T cell immunity.

    Science.gov (United States)

    Yu, Jinbo; Duong, Vu Huy Hoang; Westphal, Katrin; Westphal, Andreas; Suwandi, Abdulhadi; Grassl, Guntram A; Brand, Korbinian; Chan, Andrew C; Föger, Niko; Lee, Kyeong-Hee

    2018-05-01

    The immune system is tightly controlled by regulatory processes that allow for the elimination of invading pathogens, while limiting immunopathological damage to the host. In the present study, we found that conditional deletion of the cell surface receptor Toso on B cells unexpectedly resulted in impaired proinflammatory T cell responses, which led to impaired immune protection in an acute viral infection model and was associated with reduced immunopathological tissue damage in a chronic inflammatory context. Toso exhibited its B cell-inherent immunoregulatory function by negatively controlling the pool of IL-10-competent B1 and B2 B cells, which were characterized by a high degree of self-reactivity and were shown to mediate immunosuppressive activity on inflammatory T cell responses in vivo. Our results indicate that Toso is involved in the differentiation/maintenance of regulatory B cells by fine-tuning B cell receptor activation thresholds. Furthermore, we showed that during influenza A-induced pulmonary inflammation, the application of Toso-specific antibodies selectively induced IL-10-competent B cells at the site of inflammation and resulted in decreased proinflammatory cytokine production by lung T cells. These findings suggest that Toso may serve as a novel therapeutic target to dampen pathogenic T cell responses via the modulation of IL-10-competent regulatory B cells.

  1. Differentiating neural systems mediating the acquisition versus expression of goal-directed and habitual behavioral control

    Science.gov (United States)

    Liljeholm, Mimi; Dunne, Simon; O'Doherty, John P.

    2015-01-01

    Considerable behavioral data indicates that operant actions can become habitual, as evidenced by insensitivity to changes in the action-outcome contingency and in subjective outcome values. Notably, although several studies have investigated the neural substrates of habits, none has clearly differentiated the areas of the human brain that support habit formation from those that implement habitual control. We scanned participants with fMRI as they learned and performed an operant task in which the conditional structure of the environment encouraged either goal-directed encoding of the consequences of actions, or a habit-like mapping of actions to antecedent cues. Participants were also scanned during a subsequent assessment of insensitivity to outcome devaluation. We identified dissociable roles of the cerebellum and ventral striatum, across learning and test performance, in behavioral insensitivity to outcome devaluation. We also show that the inferior parietal lobule – an area previously implicated in several aspects of goal-directed action selection, including the attribution of intent and awareness of agency – predicts sensitivity to outcome devaluation. Finally, we reveal a potential functional homology between the human subgenual cortex and rodent infralimbic cortex in the implementation of habitual control. In summary, our findings suggest a broad systems division, at the cortical and subcortical levels, between brain areas mediating the encoding and expression of action-outcome and stimulus-response associations. PMID:25892332

  2. CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis.

    Science.gov (United States)

    Stromberg, Paul E; Woolsey, Cheryl A; Clark, Andrew T; Clark, Jessica A; Turnbull, Isaiah R; McConnell, Kevin W; Chang, Katherine C; Chung, Chun-Shiang; Ayala, Alfred; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

    2009-06-01

    Lymphocytes help determine whether gut epithelial cells proliferate or differentiate but are not known to affect whether they live or die. Here, we report that lymphocytes play a controlling role in mediating gut epithelial apoptosis in sepsis but not under basal conditions. Gut epithelial apoptosis is similar in unmanipulated Rag-1(-/-) and wild-type (WT) mice. However, Rag-1(-/-) animals have a 5-fold augmentation in gut epithelial apoptosis following cecal ligation and puncture (CLP) compared to septic WT mice. Reconstitution of lymphocytes in Rag-1(-/-) mice via adoptive transfer decreases intestinal apoptosis to levels seen in WT animals. Subset analysis indicates that CD4(+) but not CD8(+), gammadelta, or B cells are responsible for the antiapoptotic effect of lymphocytes on the gut epithelium. Gut-specific overexpression of Bcl-2 in transgenic mice decreases mortality following CLP. This survival benefit is lymphocyte dependent since gut-specific overexpression of Bcl-2 fails to alter survival when the transgene is overexpressed in Rag-1(-/-) mice. Further, adoptively transferring lymphocytes to Rag-1(-/-) mice that simultaneously overexpress gut-specific Bcl-2 results in improved mortality following sepsis. Thus, sepsis unmasks CD4(+) lymphocyte control of gut apoptosis that is not present under homeostatic conditions, which acts as a key determinant of both cellular survival and host mortality.

  3. Litter Controls Earthworm-Mediated Carbon and Nitrogen Transformations in Soil from Temperate Riparian Buffers

    Directory of Open Access Journals (Sweden)

    Maria Kernecker

    2014-01-01

    Full Text Available Nutrient cycling in riparian buffers is partly influenced by decomposition of crop, grass, and native tree species litter. Nonnative earthworms in riparian soils in southern Quebec are expected to speed the processes of litter decomposition and nitrogen (N mineralization, increasing carbon (C and N losses in gaseous forms or via leachate. A 5-month microcosm experiment evaluated the effect of Aporrectodea turgida on the decomposition of 3 litter types (deciduous leaves, reed canarygrass, and soybean stem residue. Earthworms increased CO2 and N2O losses from microcosms with soybean residue, by 112% and 670%, respectively, but reduced CO2 and N2O fluxes from microcosms with reed canarygrass by 120% and 220%, respectively. Litter type controlled the CO2 flux (soybean ≥ deciduous-mix litter = reed canarygrass > no litter and the N2O flux (soybean ≥ no litter ≥ reed canarygrass > deciduous-mix litter. However, in the presence of earthworms, there was a slight increase in C and N gaseous losses of C and N relative to their losses via leachate, across litter treatments. We conclude that litter type determines the earthworm-mediated decomposition effect, highlighting the importance of vegetation management in controlling C and N losses from riparian buffers to the environment.

  4. A Collapsin Response Mediator Protein 2 Isoform Controls Myosin II-Mediated Cell Migration and Matrix Assembly by Trapping ROCK II

    Science.gov (United States)

    Morgan-Fisher, Marie; Wait, Robin; Couchman, John R.; Wewer, Ulla M.

    2012-01-01

    Collapsin response mediator protein 2 (CRMP-2) is known as a regulator of neuronal polarity and differentiation through microtubule assembly and trafficking. Here, we show that CRMP-2 is ubiquitously expressed and a splice variant (CRMP-2L), which is expressed mainly in epithelial cells among nonneuronal cells, regulates myosin II-mediated cellular functions, including cell migration. While the CRMP-2 short form (CRMP-2S) is recognized as a substrate of the Rho-GTP downstream kinase ROCK in neuronal cells, a CRMP-2 complex containing 2L not only bound the catalytic domain of ROCK II through two binding domains but also trapped and inhibited the kinase. CRMP-2L protein levels profoundly affected haptotactic migration and the actin-myosin cytoskeleton of carcinoma cells as well as nontransformed epithelial cell migration in a ROCK activity-dependent manner. Moreover, the ectopic expression of CRMP-2L but not -2S inhibited fibronectin matrix assembly in fibroblasts. Underlying these responses, CRMP-2L regulated the kinase activity of ROCK II but not ROCK I, independent of GTP-RhoA levels. This study provides a new insight into CRMP-2 as a controller of myosin II-mediated cellular functions through the inhibition of ROCK II in nonneuronal cells. PMID:22431514

  5. On the origin of muscle synergies: invariant balance in the co-activation of agonist and antagonist muscle pairs

    Directory of Open Access Journals (Sweden)

    Hiroaki eHirai

    2015-11-01

    Full Text Available Investigation of neural representation of movement planning has attracted the attention of neuroscientists, as it may reveal the sensorimotor transformation essential to motor control. The analysis of muscle synergies based on the activity of agonist-antagonist (AA muscle pairs may provide insight into such transformations, especially for a reference frame in the muscle space. In this study, we examined the AA concept using the following explanatory variables: the AA ratio, which is related to the equilibrium-joint angle, and the AA sum, which is associated with joint stiffness. We formulated muscle synergies as a function of AA sums, positing that muscle synergies are composite units of mechanical impedance. The AA concept can be regarded as another form of the equilibrium-point (EP hypothesis, and it can be extended to the concept of EP-based synergies. We introduce here a novel tool for analyzing the neurological and motor functions underlying human movements and review some initial insights from our results about the relationships between muscle synergies, endpoint stiffness, and virtual trajectories (time series of EP. Our results suggest that (1 muscle synergies reflect an invariant balance in the co-activation of AA muscle pairs; (2 each synergy represents the basis for the radial, tangential, and null movements of the virtual trajectory in the polar coordinates centered on the specific joint at the base of the body; and (3 the alteration of muscle synergies (for example, due to spasticity or rigidity following neurological injury results in significant distortion of endpoint stiffness and concomitant virtual trajectories. These results indicate that muscle synergies (i.e., the balance of muscle mechanical impedance are essential for motor control.

  6. On the Origin of Muscle Synergies: Invariant Balance in the Co-activation of Agonist and Antagonist Muscle Pairs.

    Science.gov (United States)

    Hirai, Hiroaki; Miyazaki, Fumio; Naritomi, Hiroaki; Koba, Keitaro; Oku, Takanori; Uno, Kanna; Uemura, Mitsunori; Nishi, Tomoki; Kageyama, Masayuki; Krebs, Hermano Igo

    2015-01-01

    Investigation of neural representation of movement planning has attracted the attention of neuroscientists, as it may reveal the sensorimotor transformation essential to motor control. The analysis of muscle synergies based on the activity of agonist-antagonist (AA) muscle pairs may provide insight into such transformations, especially for a reference frame in the muscle space. In this study, we examined the AA concept using the following explanatory variables: the AA ratio, which is related to the equilibrium-joint angle, and the AA sum, which is associated with joint stiffness. We formulated muscle synergies as a function of AA sums, positing that muscle synergies are composite units of mechanical impedance. The AA concept can be regarded as another form of the equilibrium-point (EP) hypothesis, and it can be extended to the concept of EP-based synergies. We introduce, here, a novel tool for analyzing the neurological and motor functions underlying human movements and review some initial insights from our results about the relationships between muscle synergies, endpoint stiffness, and virtual trajectories (time series of EP). Our results suggest that (1) muscle synergies reflect an invariant balance in the co-activation of AA muscle pairs; (2) each synergy represents the basis for the radial, tangential, and null movements of the virtual trajectory in the polar coordinates centered on the specific joint at the base of the body; and (3) the alteration of muscle synergies (for example, due to spasticity or rigidity following neurological injury) results in significant distortion of endpoint stiffness and concomitant virtual trajectories. These results indicate that muscle synergies (i.e., the balance of muscle mechanical impedance) are essential for motor control.

  7. Parental supervision for their children's toothbrushing: Mediating effects of planning, self-efficacy, and action control.

    Science.gov (United States)

    Hamilton, Kyra; Cornish, Stephen; Kirkpatrick, Aaron; Kroon, Jeroen; Schwarzer, Ralf

    2018-05-01

    With 60-90% of children worldwide reportedly experiencing dental caries, poor oral health in the younger years is a major public health issue. As parents are important to children's oral hygiene practices, we examined the key self-regulatory behaviours of parents for supervising their children's toothbrushing using the health action process approach. Participants (N = 281, 197 mothers) comprised Australian parents of 2- to 5-year-olds. A longitudinal design was used to investigate the sequential mediation chain for the effect of intention (Time 1) on parental supervision for their youngest child's toothbrushing (Time 3), via self-efficacy and planning (Time 2), and action control (Time 3). A latent-variable structural equation model, controlling for baseline behaviour and habit, revealed significant indirect effects from intention via self-efficacy and action control and intention via planning and action control, on parental supervision behaviour. The model was a good fit to the data, explaining 74% of the variance in parents' supervising behaviour for their children's toothbrushing. While national recommendations are provided to guide parents in promoting good oral hygiene practices with their children, current results show the importance of going beyond simple knowledge transmission to support parents' intentions to supervise their children's toothbrushing actually materialize. Current findings make a significant contribution to the cumulative empirical evidence regarding self-regulatory components in health behaviour change and can inform intervention development to increase parents' participation in childhood oral hygiene practices, thus helping to curb rising oral health conditions and diseases. Statement of contribution What is already known on this subject? Self-regulatory skills are important to translate intentions into behaviour. Self-efficacy, planning, and action control are key self-regulatory skills for behaviour change. What does this study add

  8. O-GlcNAcylation mediates the control of cytosolic phosphoenolpyruvate carboxykinase activity via Pgc1α.

    Directory of Open Access Journals (Sweden)

    Pedro Latorre

    Full Text Available PGC1α is a coactivator of many transcription factors and cytosolic phosphoenolpyruvate carboxykinase (PCK1 is a key enzyme for gluconeogenesis. PGC1α interacts with the transcription factor PPARγ to stimulate PCK1 expression and thus de novo glucose synthesis. These proteins are not only important for central energy metabolism but also for supplying intermediates for other metabolic pathways, including lipidogenesis and protein synthesis and might therefore be important factors in the ethiopathogenesis of metabolic disorders like diabetes but also in other pathologies like cancer. Since polymorphisms in these proteins have been related to some phenotypic traits in animals like pigs and PGC1α G482S polymorphism increases fat deposition in humans, we have investigated the molecular basis of such effects focusing on a commonly studied polymorphism in pig Pgc1α, which changes a cysteine at position 430 (WT of the protein to a serine (C430S. Biochemical analyses show that Pgc1α WT stimulates higher expression of human PCK1 in HEK293T and HepG2 cells. Paradoxically, Pgc1α WT is less stable than Pgc1α p.C430S in HEK293T cells. However, the study of different post-translational modifications shows a higher O-GlcNAcylation level of Pgc1α p.C430S. This higher O-GlcNAcylation level significantly decreases the interaction between Pgc1α and PPARγ demonstrating the importance of post-translational glycosylation of PGC1α in the regulation of PCK1 activity. This, furthermore, could explain at least in part the observed epistatic effects between PGC1α and PCK1 in pigs.

  9. Mediators of cognitive behavioral therapy for anxiety-disordered children and adolescents : cognition, perceived control, and coping

    NARCIS (Netherlands)

    Hogendoorn, Sanne M; Prins, Pier J M; Boer, Frits; Vervoort, Leentje; Wolters, Lidewij H; Moorlag, Harma; Nauta, Maaike H; Garst, Harry; Hartman, Catharina A; de Haan, Else

    2014-01-01

    The purpose is to investigate whether a change in putative mediators (negative and positive thoughts, coping strategies, and perceived control over anxious situations) precedes a change in anxiety symptoms in anxiety-disordered children and adolescents receiving cognitive behavioral therapy (CBT).

  10. Therapist-Aided Exposure for Women with Lifelong Vaginismus: Mediators of Treatment Outcome: A Randomized Waiting List Control Trial.

    Science.gov (United States)

    Ter Kuile, Moniek M; Melles, Reinhilde J; Tuijnman-Raasveld, Charlotte C; de Groot, Helen E; van Lankveld, Jacques J D M

    2015-08-01

    Therapist-aided exposure seems an effective treatment for lifelong vaginismus, but mechanisms of action have not yet been established. The purpose of the present study was to investigate whether treatment outcome of a therapist-aided exposure treatment was mediated by changes in positive and negative penetration beliefs or feelings of sexual disgust. Participants with lifelong vaginismus were allocated at random to a 3-month exposure (n = 35) or a waiting list control condition (n = 35). Full intercourse was assessed daily during 12 weeks. Secondary outcome measures (complaints about vaginismus and coital pain) were assessed at baseline and after 12 weeks. Possible mediators: penetration beliefs (catastrophic pain beliefs, genital incompatibility beliefs, perceived control beliefs) and feelings of sexual disgust were assessed at baseline and 6 weeks. Treatment outcome (coital frequency, symptoms of vaginismus, and coital pain) at 12 weeks was mediated by changes in negative and positive penetration beliefs at 6 weeks, in particular by more pronounced reduction of catastrophic pain penetration beliefs. No evidence was found that changes in feelings of sexual disgust mediated treatment outcome. The results strongly suggest that therapist-aided exposure affects negative penetration beliefs and that these changes in negative penetration beliefs mediate treatment outcome in women with lifelong vaginismus. Implications for treatment are discussed. © 2015 International Society for Sexual Medicine.

  11. Locus of control fails to mediate between stress and anxiety and depression in parents of children with a developmental disorder.

    Science.gov (United States)

    Hamlyn-Wright, Sarah; Draghi-Lorenz, Riccardo; Ellis, Jason

    2007-11-01

    Stress, anxiety and depression are raised amongst parents of children with a developmental disorder. However, the processes by which stress leads to depression and anxiety are poorly understood. In a cross-sectional survey, levels of parental stress, depression and anxiety were compared between parents of children with an autistic disorder, children with Down's syndrome and children with no disorder (N = 619) and the mediational role of locus of control was examined. Anxiety and depression were higher in parents of children with a disorder, and highest in parents of children with autism. Locus of control was more external in parents of children with autism. Locus of control failed to mediate the relationship between stress and both anxiety and depression in parents of children with a disorder. This suggests that help for parents of a child with a disorder may be effective if focused on the sources of stress rather than perceived control over events.

  12. Reconstitution of active human core Mediator complex reveals a pivotal role of the MED14 subunit

    Science.gov (United States)

    Cevher, Murat A.; Shi, Yi; Li, Dan; Chait, Brian T.; Malik, Sohail; Roeder, Robert G.

    2014-01-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here, we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to mass spectrometry (CX-MS). Whereas the reconstituted head and middle modules can stably associate, only with incorporation of MED14 into the bi-modular complex does it acquire basal and coactivator functions. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematically dissecting the multiple layers of functionalities associated with the Mediator complex. PMID:25383669

  13. Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit.

    Science.gov (United States)

    Cevher, Murat A; Shi, Yi; Li, Dan; Chait, Brian T; Malik, Sohail; Roeder, Robert G

    2014-12-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.

  14. Perturbation of estrogen receptor α localization with synthetic nona-arginine LXXLL-peptide coactivator binding inhibitors

    NARCIS (Netherlands)

    Carraz, M.; Zwart, W.; Phan, T.; Michalides, R.; Brunsveld, L.

    2009-01-01

    The interaction of estrogen receptor a (ERa) with the consensus LXXLL motifs of transcriptional coactivators provides an entry for functional ERa inhibition. Here, synthetic cell-permeable LXXLL peptide probes are brought forward that allow evaluation of the interaction of specific recognition

  15. Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata.

    Science.gov (United States)

    Balan, Kannan V; Kc, Prabha; Hoxha, Zana; Mayer, Catherine A; Wilson, Christopher G; Martin, Richard J

    2011-09-30

    Perinatal sepsis and inflammation trigger lung and brain injury in preterm infants, and associated apnea of prematurity. We hypothesized that endotoxin exposure in the immature lung would upregulate proinflammatory cytokine mRNA expression in the medulla oblongata and be associated with impaired respiratory control. Lipopolysaccharide (LPS, 0.1mg/kg) or saline was administered intratracheally to rat pups and medulla oblongatas were harvested for quantifying expression of mRNA for proinflammatory cytokines. LPS-exposure significantly increased medullary mRNA for IL-1β and IL-6, and vagotomy blunted this increase in IL-1β, but not IL-6. Whole-body flow plethysmography revealed that LPS-exposed pups had an attenuated ventilatory response to hypoxia both before and after carotid sinus nerve transection. Immunochemical expression of IL-1β within the nucleus of the solitary tract and area postrema was increased after LPS-exposure. In summary, intratracheal endotoxin-exposure in rat pups is associated with upregulation of proinflammatory cytokines in the medulla oblongata that is vagally mediated for IL-1β and associated with an impaired hypoxic ventilatory response. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling.

    Science.gov (United States)

    Queval, Christophe J; Song, Ok-Ryul; Carralot, Jean-Philippe; Saliou, Jean-Michel; Bongiovanni, Antonino; Deloison, Gaspard; Deboosère, Nathalie; Jouny, Samuel; Iantomasi, Raffaella; Delorme, Vincent; Debrie, Anne-Sophie; Park, Sei-Jin; Gouveia, Joana Costa; Tomavo, Stanislas; Brosch, Roland; Yoshimura, Akihiko; Yeramian, Edouard; Brodin, Priscille

    2017-09-26

    Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS) protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH), which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling

    Directory of Open Access Journals (Sweden)

    Christophe J. Queval

    2017-09-01

    Full Text Available Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH, which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive.

  18. Long-range spin wave mediated control of defect qubits in nanodiamonds

    Energy Technology Data Exchange (ETDEWEB)

    Andrich, Paolo; de las Casas, Charles F.; Liu, Xiaoying; Bretscher, Hope L.; Berman, Jonson R.; Heremans, F. Joseph; Nealey, Paul F.; Awschalom, David D.

    2017-07-17

    Hybrid architectures that combine nitrogen-vacancy (NV) centers in diamond with other materials and physical systems have been proposed to enhance the NV center’s capabilities in many quantum sensing and information applications. In particular, spin waves (SWs) in ferromagnetic materials are a promising candidate to implement these platforms due to their strong magnetic fields, which could be used to efficiently interact with the NV centers. Here we develop an yttrium iron garnet-nanodiamond hybrid architecture constructed with the help of directed assembly and transfer printing techniques. Operating at ambient conditions, we demonstrate that surface confined SWs excited in the ferromagnet (FM) can strongly amplify the interactions between a microwave source and the NV centers by enhancing the local microwave magnetic field by several orders of magnitude. Crucially, we show the existence of a regime in which coherent interactions between SWs and NV centers dominate over incoherent mechanisms associated with the broadband magnetic field noise generated by the FM. These accomplishments enable the SW mediated coherent control of spin qubits over distances larger than 200 um, and allow low power operations for future spintronic technologies.

  19. How Structure-Directing Agents Control Nanocrystal Shape: Polyvinylpyrrolidone-Mediated Growth of Ag Nanocubes.

    Science.gov (United States)

    Qi, Xin; Balankura, Tonnam; Zhou, Ya; Fichthorn, Kristen A

    2015-11-11

    The importance of structure-directing agents (SDAs) in the shape-selective synthesis of colloidal nanostructures has been well documented. However, the mechanisms by which SDAs actuate shape control are poorly understood. In the polyvinylpyrrolidone (PVP)-mediated growth of {100}-faceted Ag nanocrystals, this capability has been attributed to preferential binding of PVP to Ag(100). We use molecular dynamics simulations to probe the mechanisms by which Ag atoms add to Ag(100) and Ag(111) in ethylene glycol solution with PVP. We find that PVP induces kinetic Ag nanocrystal shapes by regulating the relative Ag fluxes to these facets. Stronger PVP binding to Ag(100) leads to a larger Ag flux to Ag(111) and cubic nanostructures through two mechanisms: enhanced Ag trapping by more extended PVP films on Ag(111) and a reduced free-energy barrier for Ag to cross lower-density films on Ag(111). These flux-regulating capabilities depend on PVP concentration and chain length, consistent with experiment.

  20. Hemi-fused structure mediates and controls fusion and fission in live cells.

    Science.gov (United States)

    Zhao, Wei-Dong; Hamid, Edaeni; Shin, Wonchul; Wen, Peter J; Krystofiak, Evan S; Villarreal, Seth A; Chiang, Hsueh-Cheng; Kachar, Bechara; Wu, Ling-Gang

    2016-06-23

    Membrane fusion and fission are vital for eukaryotic life. For three decades, it has been proposed that fusion is mediated by fusion between the proximal leaflets of two bilayers (hemi-fusion) to produce a hemi-fused structure, followed by fusion between the distal leaflets, whereas fission is via hemi-fission, which also produces a hemi-fused structure, followed by full fission. This hypothesis remained unsupported owing to the lack of observation of hemi-fusion or hemi-fission in live cells. A competing fusion hypothesis involving protein-lined pore formation has also been proposed. Here we report the observation of a hemi-fused Ω-shaped structure in live neuroendocrine chromaffin cells and pancreatic β-cells, visualized using confocal and super-resolution stimulated emission depletion microscopy. This structure is generated from fusion pore opening or closure (fission) at the plasma membrane. Unexpectedly, the transition to full fusion or fission is determined by competition between fusion and calcium/dynamin-dependent fission mechanisms, and is notably slow (seconds to tens of seconds) in a substantial fraction of the events. These results provide key missing evidence in support of the hemi-fusion and hemi-fission hypothesis in live cells, and reveal the hemi-fused intermediate as a key structure controlling fusion and fission, as fusion and fission mechanisms compete to determine the transition to fusion or fission.

  1. RUNX2 Mediates Plasmacytoid Dendritic Cell Egress from the Bone Marrow and Controls Viral Immunity

    Directory of Open Access Journals (Sweden)

    Michaël Chopin

    2016-04-01

    Full Text Available Plasmacytoid dendritic cells (pDCs represent a unique immune cell type that responds to viral nucleic acids through the rapid production of type I interferons. Within the hematopoietic system, the transcription factor RUNX2 is exclusively expressed in pDCs and is required for their peripheral homeostasis. Here, we show that RUNX2 plays an essential role in promoting pDC localization and function. RUNX2 is required for the appropriate expression of the integrin-mediated adhesion machinery, as well as for the down-modulation of the chemokine receptor CXCR4, which allows pDC egress into the circulation. RUNX2 also facilitates the robust response to viral infection through the control of IRF7, the major regulator of type I interferon production. Mice lacking one copy of Runx2 have reduced numbers of peripheral pDCs and IFN-α expression, which might contribute to the reported difficulties of individuals with cleidocranial dysplasia, who are haploinsufficient for RUNX2, to clear viral infections.

  2. Physical control of carrier-mediated ion-transporters by entrainment of their turnover rate

    Science.gov (United States)

    Chen, Wei; Mathis, Clausell; Fang, Zhihui; Mast, Jason; Hamidi, Karim; Kelly, Patrick; Eve, Max

    2012-02-01

    In the past, tremendous efforts have been made to physically activate carrier-mediated ion-transporters, such as Na/K pumps. However, the outcome is not significant. Recently, we developed a new technique which can effectively and efficiently control the pumping rate by introducing a concept of an electronic synchrotron accelerator to the biological system. The approach consists of two steps. First, a specially designed oscillating electric field is used to force or synchronize individual pump molecules to run at the same turnover rate and phase as the field oscillation frequency. Then, by gradually changing the field frequency and carefully keeping the pump synchronization we can entrain the pump molecules so that their pumping rate can be progressively modulated, either decelerated or accelerated, following the field frequency to a defined value. Based on theoretical analysis of the underlying mechanisms involved in the technique, computer simulation of the entrainment process, and intensive experimental studies we have realized significant activation of the Na/K pumping rate up to ten-folds quickly in less than ten seconds.

  3. Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.

    Science.gov (United States)

    Mailloux, Ryan J; Xuan, Jian Ying; McBride, Skye; Maharsy, Wael; Thorn, Stephanie; Holterman, Chet E; Kennedy, Christopher R J; Rippstein, Peter; deKemp, Robert; da Silva, Jean; Nemer, Mona; Lou, Marjorie; Harper, Mary-Ellen

    2014-05-23

    Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Singlet oxygen explicit dosimetry to predict local tumor control for HPPH-mediated photodynamic therapy

    Science.gov (United States)

    Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    This preclinical study examines four dosimetric quantities (light fluence, photosensitizer photobleaching ratio, PDT dose, and reacted singlet oxygen ([1O2]rx)) to predict local control rate (LCR) for 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated photodynamic therapy (PDT). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (135, 250 and 350 J/cm2) and in-air fluence rates (50, 75 and 150 mW/cm2) at 0.25 mg/kg HPPH and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 665 nm wavelength. A macroscopic model was used to calculate ([1O2]rx)) based on in vivo explicit dosimetry of the initial tissue oxygenation, photosensitizer concentration, and tissue optical properties. PDT dose was defined as a temporal integral of drug concentration and fluence rate (φ) at a 3 mm tumor depth. Light fluence rate was calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. The tumor volume of each mouse was tracked for 30 days after PDT and Kaplan-Meier analyses for LCR were performed based on a tumor volume <=100 mm3, for four dose metrics: fluence, HPPH photobleaching rate, PDT dose, and ([1O2]rx)). The results of this study showed that ([1O2]rx)) is the best dosimetric quantity that can predict tumor response and correlate with LCR.

  5. Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor.

    Science.gov (United States)

    LaFrate, Andrew L; Gunther, Jillian R; Carlson, Kathryn E; Katzenellenbogen, John A

    2008-12-01

    Most patients with hormone-responsive breast cancer eventually develop resistance to traditional antiestrogens such as tamoxifen, and this has become a major obstacle in their treatment. We prepared and characterized the activity of a series of 16 guanylhydrazone small molecules that are designed to block estrogen receptor (ER) activity through a non-traditional mechanism, by directly interfering with coactivator binding to agonist-liganded ER. The inhibitory activity of these compounds was determined in cell-based transcription assays using ER-responsive reporter gene and mammalian two-hybrid assays. Several of the compounds gave IC(50) values in the low micromolar range. Two secondary assays were used to confirm that these compounds were acting through the proposed non-traditional mode of estrogen inhibitory action and not as conventional antagonists at the ligand binding site.

  6. Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

    DEFF Research Database (Denmark)

    Hogan, Meghan F; Ravnskjaer, Kim; Matsumura, Shigenobu

    2015-01-01

    and dephosphorylation of the cAMP regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where...... increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S171,275A expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite...... accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice demonstrating that chronic increases in CRTC2 activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis....

  7. Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos

    Directory of Open Access Journals (Sweden)

    Brook T Chernet

    2015-01-01

    Full Text Available In addition to the immediate microenvironment, long-range signaling may be an important component of cancer. Molecular-genetic analyses have implicated gap junctions – key mediators of cell-cell communication – in carcinogenesis. We recently showed that the resting voltage potential of distant cell groups is a key determinant of metastatic transformation and tumor induction. Here, we show in the Xenopus laevis model that gap junctional communication (GJC is a modulator of the long-range bioelectric signaling that regulates tumor formation. Genetic disruption of GJC taking place within tumors, within remote host tissues, or between the host and tumors – significantly lowers the incidence of tumors induced by KRAS mutations. The most pronounced suppression of tumor incidence was observed upon GJC disruption taking place farther away from oncogene-expressing cells, revealing a role for GJC in distant cells in the control of tumor growth. In contrast, enhanced GJC communication through the overexpression of wild-type connexin Cx26 increased tumor incidence. Our data confirm a role for GJC in tumorigenesis, and reveal that this effect is non-local. Based on these results and on published data on movement of ions through GJs, we present a quantitative model linking the GJC coupling and bioelectrical state of cells to the ability of oncogenes to initiate tumorigenesis. When integrated with data on endogenous bioelectric signaling during left-right patterning, the model predicts differential tumor incidence outcomes depending on the spatial configurations of gap junction paths relative to tumor location and major anatomical body axes. Testing these predictions, we found that the strongest influence of GJ modulation on tumor suppression by hyperpolarization occurred along the embryonic left-right axis. Together, these data reveal new, long-range aspects of cancer control by the host’s physiological parameters.

  8. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity.

    Directory of Open Access Journals (Sweden)

    Isao Kurihara

    2007-06-01

    Full Text Available Progesterone and estrogen are critical regulators of uterine receptivity. To facilitate uterine remodeling for embryo attachment, estrogen activity in the uterine epithelia is attenuated by progesterone; however, the molecular mechanism by which this occurs is poorly defined. COUP-TFII (chicken ovalbumin upstream promoter transcription factor II; also known as NR2F2, a member of the nuclear receptor superfamily, is highly expressed in the uterine stroma and its expression is regulated by the progesterone-Indian hedgehog-Patched signaling axis that emanates from the epithelium. To further assess COUP-TFII uterine function, a conditional COUP-TFII knockout mouse was generated. This mutant mouse is infertile due to implantation failure, in which both embryo attachment and uterine decidualization are impaired. Using this animal model, we have identified a novel genetic pathway in which BMP2 lies downstream of COUP-TFII. Epithelial progesterone-induced Indian hedgehog regulates stromal COUP-TFII, which in turn controls BMP2 to allow decidualization to manifest in vivo. Interestingly, enhanced epithelial estrogen activity, which impedes maturation of the receptive uterus, was clearly observed in the absence of stromal-derived COUP-TFII. This finding is consistent with the notion that progesterone exerts its control of implantation through uterine epithelial-stromal cross-talk and reveals that stromal-derived COUP-TFII is an essential mediator of this complex cross-communication pathway. This finding also provides a new signaling paradigm for steroid hormone regulation in female reproductive biology, with attendant implications for furthering our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in such human reproductive disorders as endometriosis and endometrial cancer.

  9. Effect of posterior cruciate ligament creep on muscular co-activation around knee: a pilot study.

    Science.gov (United States)

    Cheng, Xiangrong; Zhang, Tailai; Shan, Xinhai; Wang, Jingyuan

    2014-04-01

    The effect of posterior cruciate ligament (PCL) on muscle co-activation (MCO) is not known though MCO has been extensively studied. The purpose of the study was to investigate the effect of PCL creep on MCO and on joint moment around the knee. Twelve males and twelve females volunteered for this study. PCL creep was estimated via tibial posterior displacement which was elicited by a 20kg dumbbell hanged on horizontal shank near patella for 10min. Electromyography activity from both rectus femoris and biceps femoris as well as muscle strength on the right thigh was recorded synchronically during knee isokinetic flexion-extension performance in speed of 60deg/s as well as 120deg/s on a dynamometer before and after PCL creep. A one-way ANOVA with repeated measures was used to evaluate the effect of creep, gender and speed. The results showed that significant tibial posterior displacement was found (p=0.01) in both male and female groups. No significant increase of joint moment was found in flexion as well as in extension phase in both female and male groups. There was a significant effect of speed (p=0.036) on joint moment in extension phase. Co-activation index (CI) decreased significantly (p=0.049) in extension phase with a significant effect of gender (p⩽0.001). It was concluded that creep developed in PCL due to static posterior load on the proximal tibia could significantly elicit the increase of the activation of agonist muscles but with no compensation from the antagonist in flexion as well as in extension phase. The creep significantly elicited the decrease of the antagonist-agonist CI in extension phase. MCO in females was reduced significantly in extension phase. It was suggested that PCL creep might be one of risk factors to the knee injury in sports activity. Copyright © 2014. Published by Elsevier Ltd.

  10. Job attitudes and well-being among public vs. private physicians: organizational justice and job control as mediators.

    Science.gov (United States)

    Heponiemi, Tarja; Kuusio, Hannamaria; Sinervo, Timo; Elovainio, Marko

    2011-08-01

    The present study examined whether there are differences in job-related attitudes and well-being among physicians working in private sector and public sector. In addition, we examined whether psychosocial factors (organizational justice and job control) could mediate these possible differences in different sectors. Cross-sectional survey data from the Finnish Health Professional Study was used. A random sample of Finnish physicians included 1522 women and 1047 men aged 25-65 years. Outcome variables were job satisfaction, organizational commitment, psychological distress, work ability and sleeping problems. Job control and organizational justice were measured using established questionnaires. Series of regression analyses were performed and the mediational effects were tested following the procedures outlined by Baron and Kenny. Physicians working in private sector had higher levels of job satisfaction and organizational commitment and lower levels of psychological distress and sleeping problems when compared with physicians working in public sector. Private physicians also had higher levels of organizational justice, which acted as a mediator behind more positive attitudes and better well-being in private sector. Private physicians had higher levels of job control but it did not act as a mediator. Private physicians feel better than public physicians and this is partly due to higher organizational justice in private sector. Public health care organizations should invest effort to increase the fairness in their organizations and management and pay more attention in improving the well-being of their employees, which could possibly increase the attractiveness of public sector as a career option.

  11. Enforced expression of the transcriptional coactivator OBF1 impairs B cell differentiation at the earliest stage of development.

    Directory of Open Access Journals (Sweden)

    Alain Bordon

    Full Text Available OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation.

  12. Delay Discounting Mediates Parent-Adolescent Relationship Quality and Risky Sexual Behavior for Low Self-Control Adolescents

    Science.gov (United States)

    Kahn, Rachel E.; Holmes, Christopher; Farley, Julee P.; Kim-Spoon, Jungmeen

    2015-01-01

    Parent-adolescent relationship quality and delay discounting may play important roles in adolescents’ sexual decision making processes, and levels of self-control during adolescence could act as a buffer within these factors. This longitudinal study included 219 adolescent (55% male; mean age = 12.66 years at Wave 1; mean age = 15.10 years at Wave 2) and primary caregiver dyads. Structural equation modeling was utilized to determine whether delay discounting mediated the association between parent-adolescent relationship quality and adolescents’ risky sexual behavior and how this mediated association may differ between those with high versus low self-control. The results revealed parent-adolescent relationship quality plays a role in the development of risky sexual behavior indirectly through levels of delay discounting, but only for adolescents with low self-control. These findings could inform sex education policies and health prevention programs that address adolescent risky sexual behavior. PMID:26202153

  13. HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703

    DEFF Research Database (Denmark)

    Matthews, Philippa C; Adland, Emily; Listgarten, Jennifer

    2011-01-01

    -clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1...... epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated...... with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which...

  14. Smartphone Addiction and School Life Adjustment Among High School Students: The Mediating Effect of Self-Control.

    Science.gov (United States)

    Heo, YoungJin; Lee, Kyunghee

    2018-05-08

    Previous studies have reported associations among smartphone addiction, school adjustment, and self-control. However, the causal relationship between smartphone addiction and school adjustment has not been clearly demonstrated. The current study examined the association between smartphone addiction and school adjustment and investigated the mediating effect of self-control in this association. A total of 790 students from five high schools in Daegu City, South Korea, were asked to provide demographic information and complete a self-diagnostic smartphone addiction scale and validated Korean version of a self-control scale. Among at-risk students, self-control did not mediate the relation between smartphone addiction and school adjustment; among those not at risk, there was a partial mediating effect. To improve school adjustment among high school students, prevention of smartphone addiction seems important. Smartphone addiction could be managed by strengthening self-control to promote healthy use of smartphones. The current results can serve as groundwork for the development of programs to improve school adjustment among high school students. [Journal of Psychosocial Nursing and Mental Health Services, xx(x), xx-xx.]. Copyright 2018, SLACK Incorporated.

  15. Harsh parenting and academic achievement in Chinese adolescents: Potential mediating roles of effortful control and classroom engagement.

    Science.gov (United States)

    Wang, Mingzhong; Deng, Xueli; Du, Xiuxiu

    2018-04-01

    This study examined (a) the potential mediating roles of effortful control and classroom engagement in the association between harsh parenting and adolescent academic achievement, and (b) the potential moderating role of gender. Sixth through eighth graders in rural China (n=815, mean age=12.55years) reported on harsh parenting, effortful control, and classroom engagement. Parents also reported on each other's harsh parenting. Academic achievement was assessed by students' test scores and teacher-rated academic performance. Results of structural equation modeling revealed gender differences in patterns of association among the model variables. Harsh parenting was negatively and directly associated with academic achievement for both boys and girls. It was also negatively and indirectly associated with academic achievement via effortful control and classroom engagement sequentially, forming a common indirect "path" for boys and girls. The indirect negative effect of harsh parenting on boys' academic achievement was mainly realized through the mediator of effortful control, whereas this same indirect effect for girls was mainly realized through the mediator of classroom engagement. Jointly, effortful control and classroom engagement precipitates more indirect effects for boys than for girls in the association between harsh parenting and academic achievement. The discussion analyzes the potential "paths" from harsh parenting to adolescent academic achievement, as well as gender differences in these "paths." The current study has implications for teachers and parents eager to improve students' classroom engagement and academic achievement. Copyright © 2017. Published by Elsevier Ltd.

  16. Mechanism of Integrim-Mediated Growth Control in Normal, Transformed, and Neoplastic Breast Cells

    National Research Council Canada - National Science Library

    Wayner, Elizabeth

    1999-01-01

    .... The primary cell adhesion receptors that mediate binding to extracellular matrix proteins are integrins Our data suggest that alpha 3 beta 1 and alpha 6 beta 4 are the primary integrins responsible...

  17. Assessing the relationships among stress, god-mediated control, and psychological distress/well-being: Does the level of education matter?

    Science.gov (United States)

    Krause, Neal

    2018-01-24

    One of the primary functions of religion is to help people cope with stressful life events. The purpose of the current study is to see if God-mediated control beliefs perform this stress-buffering function. God-mediated control refers to the belief that people work together with God to reduce the effects of unwanted stressors in their lives. An effort is made to probe this relationship more deeply by seeing whether the stress moderating function of God-mediated control beliefs varies across levels of educational attainment. Findings from a recent nationwide survey suggest that strong God-mediated control beliefs reduce the magnitude of the relationship between stress and depressive symptoms, anxiety, happiness, and hope, but only among more highly educated study participants. In contrast, God-mediated control beliefs do not appear to influence the relationship between stress and distress/well-being among study participants with lower levels of educational attainment.

  18. Cytosolic chaperones mediate quality control of higher-order septin assembly in budding yeast.

    Science.gov (United States)

    Johnson, Courtney R; Weems, Andrew D; Brewer, Jennifer M; Thorner, Jeremy; McMurray, Michael A

    2015-04-01

    Septin hetero-oligomers polymerize into cytoskeletal filaments with essential functions in many eukaryotic cell types. Mutations within the oligomerization interface that encompasses the GTP-binding pocket of a septin (its "G interface") cause thermoinstability of yeast septin hetero-oligomer assembly, and human disease. When coexpressed with its wild-type counterpart, a G interface mutant is excluded from septin filaments, even at moderate temperatures. We show that this quality control mechanism is specific to G interface mutants, operates during de novo septin hetero-oligomer assembly, and requires specific cytosolic chaperones. Chaperone overexpression lowers the temperature permissive for proliferation of cells expressing a G interface mutant as the sole source of a given septin. Mutations that perturb the septin G interface retard release from these chaperones, imposing a kinetic delay on the availability of nascent septin molecules for higher-order assembly. Un-expectedly, the disaggregase Hsp104 contributes to this delay in a manner that does not require its "unfoldase" activity, indicating a latent "holdase" activity toward mutant septins. These findings provide new roles for chaperone-mediated kinetic partitioning of non-native proteins and may help explain the etiology of septin-linked human diseases. © 2015 Johnson et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  19. Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.

    Science.gov (United States)

    Hsieh, Jui-Cheng; Estess, Rudolf C; Kaneko, Ichiro; Whitfield, G Kerr; Jurutka, Peter W; Haussler, Mark R

    2014-02-01

    The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine whether their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49-72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at -9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41-59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at -6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56- to 2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by three nucleotides (DR3) was identified at -7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred tri-iodothyronine (T3)-independent transcriptional activation. Because the thyroid hormone receptor controls HR expression in the CNS, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1, resulting in integration of bone morphogenic protein and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.

  20. How information about overdetection changes breast cancer screening decisions: a mediation analysis within a randomised controlled trial.

    Science.gov (United States)

    Hersch, Jolyn; McGeechan, Kevin; Barratt, Alexandra; Jansen, Jesse; Irwig, Les; Jacklyn, Gemma; Houssami, Nehmat; Dhillon, Haryana; McCaffery, Kirsten

    2017-10-06

    In a randomised controlled trial, we found that informing women about overdetection changed their breast screening decisions. We now present a mediation analysis exploring the psychological pathways through which study participants who received the intervention processed information about overdetection and how this influenced their decision-making. We examined a series of potential mediators in the causal chain between exposure to overdetection information and women's subsequently reported breast screening intentions. Serial multiple mediation analysis within a randomised controlled trial. New South Wales, Australia. 811 women aged 48-50 years with no personal history of breast cancer. Two versions of a decision aid giving women information about breast cancer deaths averted and false positives from mammography screening, either with (intervention) or without (control) information on overdetection. Intentions to undergo breast cancer screening in the next 2-3 years. Knowledge about overdetection, worry about breast cancer, attitudes towards breast screening and anticipated regret. The effect of information about overdetection on women's breast screening intentions was mediated through multiple cognitive and affective processes. In particular, the information led to substantial improvements in women's understanding of overdetection, and it influenced-both directly and indirectly via its effect on knowledge-their attitudes towards having screening. Mediation analysis showed that the mechanisms involving knowledge and attitudes were particularly important in determining women's intentions about screening participation. Even in this emotive context, new information influenced women's decision-making by changing their understanding of possible consequences of screening and their attitudes towards undergoing it. These findings emphasise the need to provide good-quality information on screening outcomes and to communicate this information effectively, so that women can

  1. The dampening effect of employees' future orientation on cyberloafing behaviors: the mediating role of self-control.

    Science.gov (United States)

    Zhang, Heyun; Zhao, Huanhuan; Liu, Jingxuan; Xu, Yan; Lu, Hui

    2015-01-01

    Previous studies on reducing employees' cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one's current behavior. To explore further whether and how employees' future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees' future orientation and cyberloafing behaviors. The mediation effect of employees' objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees' future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2) to examine the causal relationship and psychological mechanism between employees' future orientation and cyberloafing behaviors. The results demonstrated that employees' future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self-control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed.

  2. The dampening effect of employees’ future orientation on cyberloafing behaviors: the mediating role of self-control

    Science.gov (United States)

    Zhang, Heyun; Zhao, Huanhuan; Liu, Jingxuan; Xu, Yan; Lu, Hui

    2015-01-01

    Previous studies on reducing employees’ cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one’s current behavior. To explore further whether and how employees’ future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees’ future orientation and cyberloafing behaviors. The mediation effect of employees’ objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees’ future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2) to examine the causal relationship and psychological mechanism between employees’ future orientation and cyberloafing behaviors. The results demonstrated that employees’ future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self-control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed. PMID:26483735

  3. The dampening effect of employees’ future orientation on cyberloafing behaviors: The mediating role of self-control

    Directory of Open Access Journals (Sweden)

    Heyun eZhang

    2015-09-01

    Full Text Available Previous studies on reducing employees’ cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one’s current behavior. To explore further whether and how employees’ future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees’ future orientation and cyberloafing behaviors. The mediation effect of employees’ objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees’ future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2 to examine the causal relationship and psychological mechanism between employees’ future orientation and cyberloafing behaviors. The results demonstrated that employees’ future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self-control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed.

  4. Locus of control, self-efficacy, and the mediating effect of outcome control: predicting course-level and global outcomes in an academic context.

    Science.gov (United States)

    Au, Evelyn W M

    2015-01-01

    The current study utilizes Skinner's framework to examine the unique contributions of internal locus of control, self-efficacy, and perceived outcome control over course performance on students' academic experiences. Undergraduate students (N = 225) took part in a longitudinal study and completed two surveys (Time 1: just before their mid-term exams; Time 2: just before their final exam in the same semester). Both locus of control and self-efficacy at Time 1 predicted course-level perceived control over course performance at Time 2. Student-level perceived control over course performance at Time 2 mediated the relationship between self-efficacy at Time 1 and course-level perseverance, course-specific stress, and course enjoyment at Time 2. For global perceived stress and life satisfaction measured at Time 2, both locus of control and self-efficacy at Time 1 had only a direct effect on global perceived stress at Time 2, but only self-efficacy at Time 1 predicted life satisfaction at Time 2. Both locus of control and self-efficacy uniquely contribute to students' academic experiences. Student-level perceived control plays an important mediating role between locus of control and self-efficacy at Time 1, and course-level perseverance, course-specific stress, and course enjoyment at Time 2.

  5. The Mediating Effect of Self-Control on Parenting and Delinquency: A Gendered Approach With a Multinational Sample.

    Science.gov (United States)

    Muftić, Lisa R; Updegrove, Alexander H

    2017-08-01

    This study aims to clarify the relationships between parenting techniques, low self-control, and juvenile delinquency in Gottfredson and Hirschi's general theory of crime while controlling for alternative explanations of delinquency. We relied on a sample of 35,511 adolescent students from 31 countries from the International Self-Report Delinquency 2 Study. Results indicate that parenting exhibits a direct effect on adolescents' violence perpetration and property offending, and that while self-control weakens the strength of this relationship, it fails to fully mediate it. Males reported lower levels of self-control, exposure to poorer parenting techniques, and higher rates of violence perpetration and property offending. The relationship between parenting, self-control, and juvenile delinquency was similar for females and males. These results provide evidence that parenting has important implications for adolescents' involvement in delinquency above and beyond its influence on their level of self-control.

  6. Impaired cognitive control mediates the relationship between cortical thickness of the superior frontal gyrus and role functioning in schizophrenia.

    Science.gov (United States)

    Tully, Laura M; Lincoln, Sarah Hope; Liyanage-Don, Nadia; Hooker, Christine I

    2014-02-01

    Structural abnormalities in the lateral prefrontal cortex (LPFC) are well-documented in schizophrenia and recent evidence suggests that these abnormalities relate to functional outcome. Cognitive control mechanisms, reliant on the LPFC, are impaired in schizophrenia and predict functional outcome, thus impaired cognitive control could mediate the relationship between neuroanatomical abnormalities in the LPFC and functional outcome. We used surface-based morphometry to investigate relationships between cortical surface characteristics, cognitive control, and measures of social and role functioning in 26 individuals with schizophrenia and 29 healthy controls. Results demonstrate that schizophrenia participants had thinner cortex in a region of the superior frontal gyrus (BA10). Across all participants, decreased cortical thickness in this region related to decreased cognitive control and decreased role functioning. Moreover, cognitive control fully mediated the relationship between cortical thickness in the superior frontal gyrus and role functioning, indicating that neuroanatomical abnormalities in the LPFC adversely impact role functioning via impaired cognitive control processes. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Compromised virus control and augmented perforin-mediated immunopathology in IFN-gamma-deficient mice infected with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Nansen, A; Jensen, Teis; Christensen, Jan Pravsgaard

    1999-01-01

    To define the role of IFN-gamma in the control of acute infection with a noncytopathogenic virus, mice with targeted defects of the genes encoding IFN-gamma, perforin, or both were infected i.v. with two strains of lymphocytic choriomeningitis virus differing markedly in their capacity to spread...... in wild-type mice. Our results reveal that IFN-gamma is pivotal to T cell-mediated control of a rapidly invasive stain, whereas it is less important in the acute elimination of a slowly invasive strain. Moreover, the majority of mice infected with the rapidly invasive strain succumb to a wasting syndrome...... mediated by CD8+ effector cells. The primary effector mechanism underlying this disease is perforin-dependent lysis, but other mechanisms are also involved. Wasting disease can be prevented if naive CD8+ cells from mice transgenic for an MHC class I-restricted lymphocytic choriomeningitis virus...

  8. Effect of sports participation on Internet addiction mediated by self-control: A case of Korean adolescents

    Directory of Open Access Journals (Sweden)

    Jae-Ahm Park

    2016-09-01

    SEM indicated a significant effect of sports participation on Internet addiction mediated by self-control. The results suggest the effectiveness of and need for sport and physical activity in Internet addiction treatment programs and for other addictions as well. Moreover, sports participation has a wider variety of psychological and physical benefits unlike intervention strategies or pharmacological treatments. Thus, the adoption of sports needs to be broadened from physical development to treating diverse psychological problems among adolescents.

  9. Mediators of cognitive behavioral therapy for anxiety-disordered children and adolescents: cognition, perceived control, and coping.

    Science.gov (United States)

    Hogendoorn, Sanne M; Prins, Pier J M; Boer, Frits; Vervoort, Leentje; Wolters, Lidewij H; Moorlag, Harma; Nauta, Maaike H; Garst, Harry; Hartman, Catharina A; de Haan, Else

    2014-01-01

    The purpose is to investigate whether a change in putative mediators (negative and positive thoughts, coping strategies, and perceived control over anxious situations) precedes a change in anxiety symptoms in anxiety-disordered children and adolescents receiving cognitive behavioral therapy (CBT). Participants were 145 Dutch children (8-18 years old, M = 12.5 years, 57% girls) with a primary anxiety disorder. Assessments were completed pretreatment, in-treatment, posttreatment, and at 3-month follow-up. Sequential temporal dependencies between putative mediators and parent- and child-reported anxiety symptoms were investigated in AMOS using longitudinal Latent Difference Score Modeling. During treatment an increase of positive thoughts preceded a decrease in child-reported anxiety symptoms. An increase in three coping strategies (direct problem solving, positive cognitive restructuring, and seeking distraction) preceded a decrease in parent-reported anxiety symptoms. A reciprocal effect was found for perceived control: A decrease in parent-reported anxiety symptoms both preceded and followed an increase in perceived control. Using a longitudinal design, a temporal relationship between several putative mediators and CBT-outcome for anxious children was explored. The results suggest that a change in positive thoughts, but not negative thoughts, and several coping strategies precedes a change in symptom reduction and, therefore, at least partly support theoretical models of anxiety upon which the anxiety intervention is based.

  10. Regulation of Brown and White Adipocyte Transcriptome by the Transcriptional Coactivator NT-PGC-1α.

    Directory of Open Access Journals (Sweden)

    Jihyun Kim

    Full Text Available The β3-adrenergic receptor (AR signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β3-AR signaling highly induces the expression of transcriptional coactivator PGC-1α and its splice variant N-terminal (NT-PGC-1α, which in turn activate the transcription program of adaptive thermogenesis by co-activating a number of transcription factors. We previously reported that NT-PGC-1α is able to increase mitochondrial number and activity in cultured brown adipocytes by promoting the expression of mitochondrial and thermogenic genes. In the present study, we performed genome-wide profiling of NT-PGC-1α-responsive genes in brown adipocytes to identify genes potentially regulated by NT-PGC-1α. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, canonical pathway analysis of NT-PGC-1α-responsive genes identified several metabolic pathways including glycolysis and fatty acid synthesis. In order to validate the identified genes in vivo, we utilized the FL-PGC-1α-/- mouse that is deficient in full-length PGC-1α (FL-PGC-1α but expresses a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254. The β3-AR-induced increase of NT-PGC-1α254 in FL-PGC-1α-/- brown and white adipose tissue was closely associated with elevated expression of genes involved in thermogenesis, mitochondrial oxidative metabolism, glycolysis and fatty acid synthesis. Increased adipose tissue thermogenesis by β3-AR activation resulted in attenuation of adipose tissue expansion in FL-PGC-1α-/- adipose tissue under the high-fat diet condition. Together, the data strengthen our previous findings that NT-PGC-1

  11. Predictive Effects of Good Self-Control and Poor Regulation on Alcohol-Related Outcomes: Do Protective Behavioral Strategies Mediate?

    Science.gov (United States)

    Pearson, Matthew R.; Kite, Benjamin A.; Henson, James M.

    2016-01-01

    In the present study, we examined whether use of protective behavioral strategies mediated the relationship between self-control constructs and alcohol-related outcomes. According to the two-mode model of self-control, good self-control (planfulness; measured with Future Time Perspective, Problem Solving, and Self-Reinforcement) and poor regulation (impulsivity; measured with Present Time Perspective, Poor Delay of Gratification, Distractibility) are theorized to be relatively independent constructs rather than opposite ends of a single continuum. The analytic sample consisted of 278 college student drinkers (68% women) who responded to a battery of surveys at a single time point. Using a structural equation model based on the two-mode model of self-control, we found that good self-control predicted increased use of three types of protective behavioral strategies (Manner of Drinking, Limiting/Stopping Drinking, and Serious Harm Reduction). Poor regulation was unrelated to use of protective behavioral strategies, but had direct effects on alcohol use and alcohol problems. Further, protective behavioral strategies mediated the relationship between good self-control and alcohol use. The clinical implications of these findings are discussed. PMID:22663345

  12. Locus of control, quality of life, anxiety, and depression among Malaysian breast cancer patients: The mediating role of uncertainty.

    Science.gov (United States)

    Pahlevan Sharif, Saeed

    2017-04-01

    The main objective of this study was to investigate the mediating role of uncertainty in the relationship between locus of control with quality of life, anxiety, and depression. A descriptive and correlational survey was conducted in a private hospital in Kuala Lumpur, Malaysia. A convenience sample of 118 Malaysian breast cancer patients voluntarily participated in the study and responded to a set of questionnaires including: socio-demographic questionnaire, the short form of Locus of Control Scale, the Functional Assessment of Cancer Therapy-Breast (FACT-B), the Hospital Anxiety and Depression Scale (HADS), and the Short-Form Mishel Uncertainty in Illness Scale (SF-MUIS). The results revealed that breast cancer patients with higher internal locus of control and lower external locus of control experience a higher quality of life, lower anxiety, and lower depression. Also, uncertainty mediated the relationship between locus of control with quality of life and depression (quasi-significant). The findings indicated the need for early, targeted psychological interventions seeking to gradually shift cancer patients' locus of control from external to internal in order to improve their quality of life and reduce their depression and anxiety. Moreover, health care providers by providing relevant information to cancer patients, especially for externally oriented patients, can reduce their uncertainty which in turn would improve their quality of life. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Mediator effect of statistical process control between Total Quality Management (TQM) and business performance in Malaysian Automotive Industry

    Science.gov (United States)

    Ahmad, M. F.; Rasi, R. Z.; Zakuan, N.; Hisyamudin, M. N. N.

    2015-12-01

    In today's highly competitive market, Total Quality Management (TQM) is vital management tool in ensuring a company can success in their business. In order to survive in the global market with intense competition amongst regions and enterprises, the adoption of tools and techniques are essential in improving business performance. There are consistent results between TQM and business performance. However, only few previous studies have examined the mediator effect namely statistical process control (SPC) between TQM and business performance. A mediator is a third variable that changes the association between an independent variable and an outcome variable. This study present research proposed a TQM performance model with mediator effect of SPC with structural equation modelling, which is a more comprehensive model for developing countries, specifically for Malaysia. A questionnaire was prepared and sent to 1500 companies from automotive industry and the related vendors in Malaysia, giving a 21.8 per cent rate. Attempts were made at findings significant impact of mediator between TQM practices and business performance showed that SPC is important tools and techniques in TQM implementation. The result concludes that SPC is partial correlation between and TQM and BP with indirect effect (IE) is 0.25 which can be categorised as high moderator effect.

  14. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  15. Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial.

    Science.gov (United States)

    Green, Jonathan; Charman, Tony; McConachie, Helen; Aldred, Catherine; Slonims, Vicky; Howlin, Pat; Le Couteur, Ann; Leadbitter, Kathy; Hudry, Kristelle; Byford, Sarah; Barrett, Barbara; Temple, Kathryn; Macdonald, Wendy; Pickles, Andrew

    2010-06-19

    Results of small trials suggest that early interventions for social communication are effective for the treatment of autism in children. We therefore investigated the efficacy of such an intervention in a larger trial. Children with core autism (aged 2 years to 4 years and 11 months) were randomly assigned in a one-to-one ratio to a parent-mediated communication-focused (Preschool Autism Communication Trial [PACT]) intervention or treatment as usual at three specialist centres in the UK. Those assigned to PACT were also given treatment as usual. Randomisation was by use of minimisation of probability in the marginal distribution of treatment centre, age (42 months), and autism severity (Autism Diagnostic Observation Schedule-Generic [ADOS-G] algorithm score 12-17 or 18-24). Primary outcome was severity of autism symptoms (a total score of social communication algorithm items from ADOS-G, higher score indicating greater severity) at 13 months. Complementary secondary outcomes were measures of parent-child interaction, child language, and adaptive functioning in school. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN58133827. 152 children were recruited. 77 were assigned to PACT (London [n=26], Manchester [n=26], and Newcastle [n=25]); and 75 to treatment as usual (London [n=26], Manchester [n=26], and Newcastle [n=23]). At the 13-month endpoint, the severity of symptoms was reduced by 3.9 points (SD 4.7) on the ADOS-G algorithm in the group assigned to PACT, and 2.9 (3.9) in the group assigned to treatment as usual, representing a between-group effect size of -0.24 (95% CI -0.59 to 0.11), after adjustment for centre, sex, socioeconomic status, age, and verbal and non-verbal abilities. Treatment effect was positive for parental synchronous response to child (1.22, 0.85 to 1.59), child initiations with parent (0.41, 0.08 to 0.74), and for parent-child shared attention (0.33, -0.02 to

  16. The Effect of The Locus of Control on Organizational Citizenship Behavior The Mediating Role Perceived Organizationel Support : Case Study of A University

    OpenAIRE

    Güçel, Cem; Tokmak, İsmail; Turgut, Hakan

    2012-01-01

    The aim of this study is to examine the effects of locus of control on organizational citizenship behaviors and the mediating effect of the perceived organizational support. For this aim, firstly, the locus of control, then organizational citizenship behaviors and, finally, the mediating effect of the perceived organizational support are explained. In the application part, a questionnaire including the measures of the locus of control, organizational support and organization...

  17. THE EFFECT OF THE LOCUS OF CONTROL ON ORGANIZATIONAL CITIZENSHIP BEHAVIOR THE MEDIATING EFFECT PERCEIVED ORGANIZATIONAL SUPPORT: CASE STUDY OF A UNIVERSITY

    OpenAIRE

    GUCEL, Cem; TOKMAK, Ismail; TURGUT, Hakan

    2012-01-01

    The aim of this study is to examine the effects of locus of control on organizational citizenship behaviors and the mediating effect of the perceived organizational support. For this aim, firstly, the locus of control, then organizational citizenship behaviors and, finally, the mediating effect of the perceived organizational support are explained. In the application part, a questionnaire including the measures of the locus of control, organizational support and organizational citizenship beh...

  18. Ca2+-mediated remote control of reversible sieve tube occlusion in em>Vicia faba em>

    DEFF Research Database (Denmark)

    Furch, Alexandra C.U.; Hafke, Jens B.; Schulz, Alexander

    2007-01-01

    According to an established concept, injury of the phloem triggers local sieve plate occlusion including callose-mediated constriction and, possibly, protein plugging of the sieve pores. Sieve plate occlusion can also be achieved by distant stimuli, depends on the passage of electropotential waves...

  19. Mediation and moderation of treatment effects in randomised controlled trials of complex interventions.

    Science.gov (United States)

    Emsley, Richard; Dunn, Graham; White, Ian R

    2010-06-01

    Complex intervention trials should be able to answer both pragmatic and explanatory questions in order to test the theories motivating the intervention and help understand the underlying nature of the clinical problem being tested. Key to this is the estimation of direct effects of treatment and indirect effects acting through intermediate variables which are measured post-randomisation. Using psychological treatment trials as an example of complex interventions, we review statistical methods which crucially evaluate both direct and indirect effects in the presence of hidden confounding between mediator and outcome. We review the historical literature on mediation and moderation of treatment effects. We introduce two methods from within the existing causal inference literature, principal stratification and structural mean models, and demonstrate how these can be applied in a mediation context before discussing approaches and assumptions necessary for attaining identifiability of key parameters of the basic causal model. Assuming that there is modification by baseline covariates of the effect of treatment (i.e. randomisation) on the mediator (i.e. covariate by treatment interactions), but no direct effect on the outcome of these treatment by covariate interactions leads to the use of instrumental variable methods. We describe how moderation can occur through post-randomisation variables, and extend the principal stratification approach to multiple group methods with explanatory models nested within the principal strata. We illustrate the new methodology with motivating examples of randomised trials from the mental health literature.

  20. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    Science.gov (United States)

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8 –/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 –/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  1. Testing Mediators of Intervention Effects in Randomized Controlled Trials: An Evaluation of Three Depression Prevention Programs

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Seeley, John R.; Gau, Jeff M.

    2010-01-01

    Objective: Evaluate a new 5-step method for testing mediators hypothesized to account for the effects of depression prevention programs. Method: In this indicated prevention trial, at-risk teens with elevated depressive symptoms were randomized to a group cognitive-behavioral (CB) intervention, group supportive expressive intervention, CB…

  2. Deciphering potential mechanisms of anaerobic soil disinfestation (ASD)-mediated control of Pratylenchus penetrans

    Science.gov (United States)

    Pratylenchus penetrans is a component of the apple replant disease (ARD) causal pathogen complex. The potential role for biological mechanisms contributing to ASD-mediated suppression of P. penetrans was examined in greenhouse study using orchard soil with a history of ARD. Populations of P. penetra...

  3. The Role of Nuclear Receptor Coactivator A1B1 in Growth Factor-Mediated Mammary Tumorigenesis

    Science.gov (United States)

    2007-03-01

    chemotherapies also develop resistance to the treatment , resulting ultimately in the recurrence of breast cancer growth. Interestingly, the mechanism of...gland development, dwarfism and abnormal reproductive function [8]. I want to determine whether the loss of AIB1 in MMTV-Neu mice alters the mammary...study display dwarfism and the retardation of mammary gland growth [9]. At the 4-month time point, I similarly observed an overall decrease in mammary

  4. Systemic vascular function, measured with forearm flow mediated dilatation, in acute and stable cerebrovascular disease: a case-control study

    Directory of Open Access Journals (Sweden)

    Blacker David

    2010-10-01

    Full Text Available Abstract Background Acute ischaemic stroke is associated with alteration in systemic markers of vascular function. We measured forearm vascular function (using forearm flow mediated dilatation to clarify whether recent acute ischaemic stroke/TIA is associated with impaired systemic vascular function. Methods Prospective case control study enrolling 17 patients with recent acute ischaemic stroke/TIA and 17 sex matched controls with stroke more than two years previously. Forearm vascular function was measured using flow medicated dilatation (FMD. Results Flow mediated dilatation was 6.0 ± 1.1% in acute stroke/TIA patients and 4.7 ± 1.0% among control subjects (p = 0.18. The mean paired difference in FMD between subjects with recent acute stroke and controls was 1.25% (95% CI -0.65, 3.14; p = 0.18. Endothelium independent dilatation was measured in six pairs of participants and was similar in acute stroke/TIA patients (22.6 ± 4.3% and control subjects (19.1 ± 2.6%; p = 0.43. Conclusions Despite the small size of this study, these data indicate that recent acute stroke is not necessarily associated with a clinically important reduction in FMD.

  5. Immunohistochemical localization of steroid receptor coactivators in chondrosarcoma: an in vivo tissue microarray study.

    Science.gov (United States)

    Li, Wei; Fu, Jingshu; Bian, Chen; Zhang, Jiqiang; Xie, Zhao

    2014-12-01

    Chondrosarcoma is the second most common type of primary bone malignancy following up osteosarcoma, characterized by resistance to conventional chemotherapeutic agents and radiation regimens. The p160 family members steroid receptor coactivator-1 and -3 (SRC-1 and SRC-3) have been implied in the regulation of cancer growth, migration, invasion, metastasis and chemotherapeutic resistance; but we still lack detailed information about the levels of SRCs in chondrosarcoma. In this study, expression of SRC-1 and SRC-3 in chondrosarcoma was examined by immunohistochemistry with tissue microarrays; the four score system (0, 1, 2 and 3) was used to evaluate the staining. The results showed that there were no gender-, site- or age-differences regarding the expression of SRC-1 or SRC-3 (p>0.05); organ (bone or cartilage) -differences were only detected for SRC-1 but not SRC-3 (pchondrosarcoma, may be novel targets for the prognosis and/or treatment of chondrosarcoma, would have opened a new avenue and established foundation for studying chondrosarcoma. Copyright © 2014 Elsevier GmbH. All rights reserved.

  6. Normal postural responses preceding shoulder flexion: co-activation or asymmetric activation of transverse abdominis?

    Science.gov (United States)

    Davarian, Sanaz; Maroufi, Nader; Ebrahimi, Esmaeil; Parnianpour, Mohammad; Farahmand, Farzam

    2014-01-01

    It is suggested that activation of the transverse abdominis muscle has a stabilizing effect on the lumbar spine by raising intra-abdominal pressure without added disc compression. However, its feedforward activity has remained a controversial issue. In addition, research regarding bilateral activation of trunk muscles during a unilateral arm movement is limited. The aim of this study was to evaluate bilateral anticipatory activity of trunk muscles during unilateral arm flexion. Eighteen healthy subjects (aged 25 ± 3.96 years) participated in this study and performed 10 trials of rapid arm flexion in response to a visual stimulus. The electromyographic activity of the right anterior deltoid (AD) and bilateral trunk muscles including the transverse abdominis/internal oblique (TA/IO), superficial lumbar multifidus (SLM) and lumbar erector spine (LES) was recorded. The onset latency and anticipatory activity of the recorded trunk muscles were calculated. The first muscle activated in anticipation of the right arm flexion was the left TA/IO. The right TA/IO activated significantly later than all other trunk muscles (P 0.05). Healthy subjects showed no bilateral anticipatory co-activation of TA/IO in unilateral arm elevation. Further investigations are required to delineate normal muscle activation pattern in healthy subjects prior to prescribing bilateral activation training of transverse abdominis for subjects with chronic low back pain.

  7. [Proposal of a conceptual method of supportive care for co-active patients].

    Science.gov (United States)

    Abidli, Yamine; Piette, Danielle; Casini, Annalisa

    2015-01-01

    There is a broad consensus on the importance for health professionals to support co-active patients. However, in practice, very few "patient care partnership" approaches have been developed. We hypothesized that the lack of investment in supporting patient care partnerships is due to the lack of interest in the skills needed by caregivers to provide such support. This paper intends to address thisgap. The patient care partnership method is studied, adapted and developed from existing models. It complements, harmonizes and integrates various schools of thought arising from the need to place the patient at the center of care and life in general. The patient care partnership method includes 7 stages during which the professional accompanies the patient through the process of care. The methodological approach for training professionals is designed to ensure that professionals experience the change as well as its difficulties of the change they expect from the patient in the care relationship. This method now needs to be validated by the experience of other professionals in order define the limits of application and to allow further development.

  8. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

    DEFF Research Database (Denmark)

    Ek, J; Andersen, G; Urhammer, S A

    2001-01-01

    This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus.......This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus....

  9. CCAAT/Enhancer Binding Protein-β Is a Transcriptional Regulator of Peroxisome-Proliferator-Activated Receptor-γ Coactivator-1α in the Regenerating Liver

    OpenAIRE

    Wang, Haitao; Peiris, T. Harshani; Mowery, A.; Le Lay, John; Gao, Yan; Greenbaum, Linda E.

    2008-01-01

    The transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) is induced in the liver in response to fasting and coordinates the activation of targets necessary for increasing energy production for gluconeogenesis and ketogenesis. After partial hepatectomy, the liver must restore its mass while maintaining metabolic homeostasis to ensure survival. Here we report that PGC-1α is rapidly and dramatically induced after hepatectomy, with an amplitude of induc...

  10. Hormonal regulation of steroid receptor coactivator-1 mRNA in the male and female green anole brain.

    Science.gov (United States)

    Kerver, H N; Wade, J

    2015-03-01

    Green anole lizards are seasonal breeders, with male sexual behaviour primarily regulated by an annual increase in testosterone. Morphological, biochemical and behavioural changes associated with reproduction are activated by testosterone, generally with a greater effect in the breeding season (BS) than in the nonbreeding season (NBS). The present study investigates the possibility that differences in a steroid receptor coactivator may regulate this seasonal difference in responsiveness to testosterone. In situ hybridisation was used to examine the expression of steroid receptor coactivator-1 (SRC-1) in the brains of gonadally intact male and female green anoles across breeding states. A second experiment examined gonadectomised animals with and without testosterone treatment. Gonadally intact males had more SRC-1 expressing cells in the preoptic area and larger volumes of this region as defined by these cells than females. Main effects of both sex and season (males > females and BS > NBS) were present in cell number and volume of the ventromedial hypothalamus. An interaction between sex and season suggested that high expression in BS males was driving these effects. In hormone-manipulated animals, testosterone treatment increased both the number of SRC-1 expressing cells in and volumes of the preoptic area and amygdala. These results suggest that testosterone selectively regulates SRC-1, and that this coactivator may play a role in facilitating reproductive behaviours across both sexes. However, changes in SRC-1 expression are not likely responsible for the seasonal change in responsiveness to testosterone. © 2014 British Society for Neuroendocrinology.

  11. Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

    Science.gov (United States)

    Biron, Eric; Bédard, François

    2016-07-01

    The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Proactive and coactive interference in age-related performance in a recognition-based operation span task.

    Science.gov (United States)

    Zeintl, Melanie; Kliegel, Matthias

    2010-01-01

    Generally, older adults perform worse than younger adults in complex working memory span tasks. So far, it is unclear which processes mainly contribute to age-related differences in working memory span. The aim of the present study was to investigate age effects and the roles of proactive and coactive interference in a recognition-based version of the operation span task. Younger and older adults performed standard versions and distracter versions of the operation span task. At retrieval, participants had to recognize target words in word lists containing targets as well as proactive and/or coactive interference-related lures. Results show that, overall, younger adults outperformed older adults in the recognition of target words. Furthermore, analyses of error types indicate that, while younger adults were only affected by simultaneously presented distracter words, older adults had difficulties with both proactive and coactive interference. Results suggest that age effects in complex span tasks may not be mainly due to retrieval deficits in old age. Copyright 2009 S. Karger AG, Basel.

  13. Training through gametherapy promotes coactivation of the pelvic floor and abdominal muscles in young women, nulliparous and continents

    Directory of Open Access Journals (Sweden)

    Valeria Regina Silva

    Full Text Available ABSTRACT Introduction and objectives: Several studies have been investigated co-activation can enhance the effectveness of PFM training protocols allowing preventive and therapeutic goals in pelvic floor dysfunctions. The objective of the present study was to investigate if an abdominal-pelvic protocol of training (APT using gametherapy would allow co-activation of PFM and transversus abdominis/oblique internal (TrA/OI muscles. Patients and methods: Twenty-five nulliparous, continent, young females, with median age 24.76 (±3.76 years were evaluated using digital palpation (DP of PFM and surface electromyography of PFM and TrA/OI simultaneously, during maximal voluntary contraction (MVC, alternating PFM and TrA/OI contraction requests. All women participated on a supervised program of APT using gametherapy, that included exercises of pelvic mobilization associated to contraction of TrA/OI muscles oriented by virtual games, for 30 minutes, three times a week, in a total of 10 sessions. Electromyographic data were processed and analyzed by ANOVA - analysis of variance. Results: When MVC of TrA/OI was solicited, it was observed simultaneous increase of electromyographic activity of PFM (p=0.001 following ATP. However, EMG activity did not change significantly during MVC of PFM. Conclusion: Training using gametherapy allowed better co-activation of pelvic floor muscles in response to contraction of TrA, in young nulliparous and continent women.

  14. The Mediator subunit MED23 couples H2B mono-ubiquitination to transcriptional control and cell fate determination.

    Science.gov (United States)

    Yao, Xiao; Tang, Zhanyun; Fu, Xing; Yin, Jingwen; Liang, Yan; Li, Chonghui; Li, Huayun; Tian, Qing; Roeder, Robert G; Wang, Gang

    2015-12-02

    The Mediator complex orchestrates multiple transcription factors with the Pol II apparatus for precise transcriptional control. However, its interplay with the surrounding chromatin remains poorly understood. Here, we analyze differential histone modifications between WT and MED23(-/-) (KO) cells and identify H2B mono-ubiquitination at lysine 120 (H2Bub) as a MED23-dependent histone modification. Using tandem affinity purification and mass spectrometry, we find that MED23 associates with the RNF20/40 complex, the enzyme for H2Bub, and show that this association is critical for the recruitment of RNF20/40 to chromatin. In a cell-free system, Mediator directly and substantially increases H2Bub on recombinant chromatin through its cooperation with RNF20/40 and the PAF complex. Integrative genome-wide analyses show that MED23 depletion specifically reduces H2Bub on a subset of MED23-controlled genes. Importantly, MED23-coupled H2Bub levels are oppositely regulated during myogenesis and lung carcinogenesis. In sum, these results establish a mechanistic link between the Mediator complex and a critical chromatin modification in coordinating transcription with cell growth and differentiation. © 2015 The Authors.

  15. Fungal mediator tail subunits contain classical transcriptional activation domains.

    Science.gov (United States)

    Liu, Zhongle; Myers, Lawrence C

    2015-04-01

    Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their incorporation into Mediator but do not possess the ability to activate transcription when fused to a DNA binding domain. This suggests that Mediator fusion proteins actually are functioning in a manner similar to that of a classical DNA-bound activator rather than just recruiting Mediator. Our finding that deletion of the activation domains of S. cerevisiae Med2 and Med3, as well as C. dubliniensis Tlo1 (a Med2 ortholog), impairs the induction of certain genes shows these domains function at native promoters. Activation domains within coactivators are likely an important feature of these complexes and one that may have been uniquely leveraged by a common fungal pathogen. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  16. Improved confidence in performing nutrition and physical activity behaviours mediates behavioural change in young adults: Mediation results of a randomised controlled mHealth intervention.

    Science.gov (United States)

    Partridge, Stephanie R; McGeechan, Kevin; Bauman, Adrian; Phongsavan, Philayrath; Allman-Farinelli, Margaret

    2017-01-01

    The burden of weight gain disproportionally affects young adults. Understanding the underlying behavioural mechanisms of change in mHealth nutrition and physical activity interventions designed for young adults is important for enhancing and translating effective interventions. First, we hypothesised that knowledge, self-efficacy and stage-of-change for nutrition and physical activity behaviours would improve, and second, that self-efficacy changes in nutrition and physical activity behaviours mediate the behaviour changes observed in an mHealth RCT for prevention of weight gain. Young adults, aged 18-35 years at risk of weight gain (n = 250) were randomly assigned to an mHealth-program, TXT2BFiT, consisting of a three-month intensive phase and six-month maintenance phase or to a control group. Self-reported online surveys at baseline, three- and nine-months assessed nutrition and physical activity behaviours, knowledge, self-efficacy and stage-of-change. The mediating effect of self-efficacy was assessed in multiple PROCESS macro-models for three- and nine-month nutrition and physical activity behaviour change. Young adults randomised to the intervention increased and maintained knowledge of fruit requirements (P = 0.029) compared to controls. Intervention participants' fruit and takeaway behaviours improved to meet recommendations at nine months, with a greater proportion progressing to action or maintenance stage-of-change (P behaviours did not meet recommendations, thereby halting progress to action or maintenance stage-of-change. Indirect effects of improved nutrition and physical activity behaviours at three- and nine-months in the intervention group were explained by changes in self-efficacy, accounting for 8%-37% of the total effect. This provides insights into how the mHealth intervention achieved part of its effects and the importance of improving self-efficacy to facilitate improved eating and physical activity behaviours in young adults

  17. The effects of subjective loss of control on risk-taking behavior: the mediating role of anger

    Science.gov (United States)

    Beisswingert, Birgit M.; Zhang, Keshun; Goetz, Thomas; Fang, Ping; Fischbacher, Urs

    2015-01-01

    Based on the Appraisal Tendency Framework on the antecedents and consequences of emotions two experimental studies examined the relationship between externally caused loss of control experiences and risk-taking behavior, as well as the assumed mediation of this relationship by the emotion anger. An experimental paradigm for inducing externally caused and consequently externally attributed loss of control which should lead to experiences of anger was developed and pretested in a Pilot Study. The relationship between loss of control experiences, anger, and risk-taking behavior was investigated using two separate student samples from Germany (N = 84, 54% female) and China (N = 125; 64% female). In line with our hypotheses, results showed that anger mediated the link between subjective loss of control experiences and increasing risk-taking behavior. Multiple group comparisons revealing similar patterns in both samples affirmed the results’ cross-cultural generalizability. These results implicate that anger makes people less risk averse in the process of economic decision making. PMID:26217244

  18. The Effects of Subjective Loss of Control on Risk-taking Behavior: The Mediating Role of Anger

    Directory of Open Access Journals (Sweden)

    Birgit M. Beisswingert

    2015-06-01

    Full Text Available Based on the Appraisal Tendency Framework on the antecedents and consequences of emotions two experimental studies examined the relationship between externally caused loss of control experiences and risk-taking behavior, as well as the assumed mediation of this relationship by the emotion anger. An experimental paradigm for inducing externally caused and consequently externally attributed loss of control which should lead to experiences of anger was developed and pretested in a Pilot Study. The relationship between loss of control experiences, anger and risk-taking behavior was investigated using two separate student samples from Germany (N = 84, 54% female and China (N = 125; 64% female. In line with our hypotheses, results showed that anger mediated the link between subjective loss of control experiences and increasing risk-taking behavior. Multiple group comparisons revealing similar patterns in both samples affirmed the results’ cross-cultural generalizability. These results implicate that anger makes people less risk averse in the process of economic decision making.

  19. Gender-specific mediational links between parenting styles, parental monitoring, impulsiveness, drinking control, and alcohol-related problems.

    Science.gov (United States)

    Patock-Peckham, Julie A; King, Kevin M; Morgan-Lopez, Antonio A; Ulloa, Emilio C; Moses, Jennifer M Filson

    2011-03-01

    Recently, it has been suggested that traits may dynamically change as conditions change. One possible mechanism that may influence impulsiveness is parental monitoring. Parental monitoring reflects a knowledge regarding one's offspring's whereabouts and social connections. The aim of this investigation was to examine potential gender-specific parental influences to impulsiveness (general behavioral control), control over one's own drinking (specific behavioral control), and alcohol-related problems among individuals in a period of emerging adulthood. Direct and mediational links between parenting styles (permissive, authoritarian, and authoritative), parental monitoring, impulsiveness, drinking control, and alcohol-related problems were investigated. A multiple-group, SEM model with (316 women, 265 men) university students was examined. In general, the overall pattern among male and female respondents was distinct. For daughters, perceptions of a permissive father were indirectly linked to more alcohol-related problems through lower levels of monitoring by fathers and more impulsive symptoms. Perceptions of an authoritative father were also indirectly linked to fewer impulsive symptoms through higher levels of monitoring by fathers among daughters. For men, perceptions of a permissive mother were indirectly linked to more alcohol-related problems through lower levels of monitoring by mothers and more impulsive symptoms. For sons, perceptions of mother authoritativeness were indirectly linked to fewer alcohol-related problems through more monitoring by mothers and fewer impulsive symptoms. Monitoring by an opposite-gender parent mediated the link between parenting styles (i.e., permissive, authoritative) on impulsiveness.

  20. Convergence role of transcriptional coactivator p300 and apparent modification on HMCs metabolic memory induced by high glucose

    Directory of Open Access Journals (Sweden)

    Hong SU

    2013-03-01

    Full Text Available Objective  To investigate the protein expression of transcriptional coactivator p300, acetylated histone H3 (Ac-H3 and Ac-H4 in human renal mesangial cell (HMCs as imitative "metabolic memory" in vitro, and explore the potential role of convergence point of p300. Methods  The HMCs were divided into the following groups: ① High glucose metabolic memory model: normal glucose group (NG, 5.5mmol/L D-glucose×2d, high glucose group (HG, 25mmol/L D-glucose×2d, memory groups (M1, M2, M3, 25mmol/L D-glucose×2days + 5.5mmol/L D-glucose×3d, 6d or 9d, persisting normal glucose group (NG, 5.5mmol/L D-glucose×9d. ② Advanced glycation end products memory model: normal glucose group (NG, 5.5mmol/ L D-glucose×2d, NG+AGEs group (AGEs, 5.5mmol/L D-glucose+250µg/ml AGEs×2d; AGEs memory group (AGEs-M, 5.5mmol/L D-glucose + 250µg/ml AGEs×2d + 5.5mmol/L D-glucose×3d; BSA control group (NG+BSA, 5.5mmol/L D-glucose + 250µg/ml BSA×2d. ③ H2O2 was used to simulate oxidative stress memory model: normal glucose group (NG, 5.5mmol/L D-glucose×2d, NG+H2O2 group (H2O2, 5.5mmol/L D-glucose +100µmol/L H2O2×30min; H2O2 memory group [(5.5mmol/ L D-glucose + 100µmol/L H2O2×30min + 5.5mmol/L D-glucose×3d]; normal glucose control group (NG3, 5.5mmol/L D-glucose×3d. ④ Transfection with PKCβ2 memory model: normal glucose group (NG, 5.5mmol/L D-glucose×2d; high glucose group (HG, 25mmol/L D-glucose×2d; memory group (M, 25mmol/L D-glucose×2d + 5.5mmol/L D-glucose×3d; Ad5-null memory group (HN, 25mmol/L D-glucose + Ad5-null×2d + 5.5mmol/L D-glucose×3d; PKCβ2 memory group (PO, 25mmol/L D-glucose + Ad5-PKCβ2×2d + 5.5mmol/L D-glucose×3d; inhibitor of PKCβ2 memory group (PI, 25mmol/L D-glucose×2d + 10µmol/L CGP53353 + 5.5mmol/L D-glucose×3d. The expression of intracellular reactive oxygen species (ROS was detected by fluorescence microscope and fluorescence microplate reader. The expression levels of p300, Ac-H3, Ac-H4 and PKCβ2 proteins were

  1. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

    Science.gov (United States)

    Wang, Chuang-Wei; Yang, Lan-Yan; Chen, Chun-Bing; Ho, Hsin-Chun; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Chee-Jen; Su, Shih-Chi; Hui, Rosaline Chung-Yee; Chin, See-Wen; Huang, Li-Fang; Lin, Yang Yu-Wei; Chang, Wei-Yang; Fan, Wen-Lang; Yang, Chin-Yi; Ho, Ji-Chen; Chang, Ya-Ching; Lu, Chun-Wei; Chung, Wen-Hung

    2018-03-01

    Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. ClinicalTrials.gov NCT01276314. Ministry of Science and Technology of Taiwan.

  2. CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock.

    Directory of Open Access Journals (Sweden)

    Teruya Tamaru

    Full Text Available Intracellular circadian clocks, composed of clock genes that act in transcription-translation feedback loops, drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. Using a novel clock-perturbing peptide, we established a pivotal role for casein kinase (CK-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P in regulating central and peripheral core clocks. Subsequent analysis of the underlying mechanism showed a novel role of CRY as a repressor for protein kinase. Co-immunoprecipitation experiments and real-time monitoring of protein-protein interactions revealed that CRY-mediated periodic binding of CK2β to BMAL1 inhibits BMAL1-Ser90 phosphorylation by CK2α. The FAD binding domain of CRY1, two C-terminal BMAL1 domains, and particularly BMAL1-Lys537 acetylation/deacetylation by CLOCK/SIRT1, were shown to be critical for CRY-mediated BMAL1-CK2β binding. Reciprocally, BMAL1-Ser90 phosphorylation is prerequisite for BMAL1-Lys537 acetylation. We propose a dual negative-feedback model in which a CRY-dependent CK2-driven posttranslational BMAL1-P-BMAL1 loop is an integral part of the core clock oscillator.

  3. Phosphorylation of the Usher syndrome 1G protein SANS controls Magi2-mediated endocytosis.

    Science.gov (United States)

    Bauß, Katharina; Knapp, Barbara; Jores, Pia; Roepman, Ronald; Kremer, Hannie; Wijk, Erwin V; Märker, Tina; Wolfrum, Uwe

    2014-08-01

    The human Usher syndrome (USH) is a complex ciliopathy with at least 12 chromosomal loci assigned to three clinical subtypes, USH1-3. The heterogeneous USH proteins are organized into protein networks. Here, we identified Magi2 (membrane-associated guanylate kinase inverted-2) as a new component of the USH protein interactome, binding to the multifunctional scaffold protein SANS (USH1G). We showed that the SANS-Magi2 complex assembly is regulated by the phosphorylation of an internal PDZ-binding motif in the sterile alpha motif domain of SANS by the protein kinase CK2. We affirmed Magi2's role in receptor-mediated, clathrin-dependent endocytosis and showed that phosphorylated SANS tightly regulates Magi2-mediated endocytosis. Specific depletions by RNAi revealed that SANS and Magi2-mediated endocytosis regulates aspects of ciliogenesis. Furthermore, we demonstrated the localization of the SANS-Magi2 complex in the periciliary membrane complex facing the ciliary pocket of retinal photoreceptor cells in situ. Our data suggest that endocytotic processes may not only contribute to photoreceptor cell homeostasis but also counterbalance the periciliary membrane delivery accompanying the exocytosis processes for the cargo vesicle delivery. In USH1G patients, mutations in SANS eliminate Magi2 binding and thereby deregulate endocytosis, lead to defective ciliary transport modules and ultimately disrupt photoreceptor cell function inducing retinal degeneration. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

    International Nuclear Information System (INIS)

    Schmidt, Martina E.; Meynköhn, Anna; Habermann, Nina; Wiskemann, Joachim; Oelmann, Jan; Hof, Holger; Wessels, Sabine; Klassen, Oliver; Debus, Jürgen; Potthoff, Karin; Steindorf, Karen; Ulrich, Cornelia M.

    2016-01-01

    Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R"2 effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

  5. Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, Martina E., E-mail: m.schmidt@dkfz.de [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Meynköhn, Anna; Habermann, Nina [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Wiskemann, Joachim [Division of Medical Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Oelmann, Jan; Hof, Holger; Wessels, Sabine [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Klassen, Oliver [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany); Debus, Jürgen; Potthoff, Karin [Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg (Germany); Steindorf, Karen; Ulrich, Cornelia M. [Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg (Germany)

    2016-02-01

    Purpose: To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Methods and Materials: Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R{sup 2} effect-size measures for mediation were calculated. Results: The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. Conclusions: This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast

  6. Intervening to reduce workplace sitting: mediating role of social-cognitive constructs during a cluster randomised controlled trial.

    Science.gov (United States)

    Hadgraft, Nyssa T; Winkler, Elisabeth A H; Healy, Genevieve N; Lynch, Brigid M; Neuhaus, Maike; Eakin, Elizabeth G; Dunstan, David W; Owen, Neville; Fjeldsoe, Brianna S

    2017-03-06

    The Stand Up Victoria multi-component intervention successfully reduced workplace sitting time in both the short (three months) and long (12 months) term. To further understand how this intervention worked, we aimed to assess the impact of the intervention on four social-cognitive constructs, and examined whether these constructs mediated intervention effects on workplace sitting time at 3 and 12 months post-baseline. Two hundred and thirty one office-based workers (14 worksites, single government employer) were randomised to intervention or control conditions by worksite. The intervention comprised organisational, environmental, and individual level elements. Participant characteristics and social-cognitive constructs (perceived behavioural control, barrier self-efficacy, perceived organisational norms and knowledge) were measured through a self-administered online survey at baseline, 3 months and 12 months. Workplace sitting time (min/8 h day) was measured with the activPAL3 device. Single multi-level mediation models were performed for each construct at both time points. There were significant intervention effects at 3 months on perceived behavioural control, barrier self-efficacy and perceived organisational norms. Effects on perceived organisational norms were not significant at 12 months. Perceived behavioural control significantly mediated intervention effects at 3 months, accounting for a small portion of the total effect (indirect effect: -8.6 min/8 h day, 95% CI: -18.5, -3.6 min; 7.5% of total effect). At 12 months, barrier self-efficacy significantly mediated the intervention effects on workplace sitting time (indirect effect: -10.3 min/8 h day, 95% CI: -27.3, -2.2; 13.9% of total effect). No significant effects were observed for knowledge at either time point. Strategies that aim to increase workers' perceived control and self-efficacy over their sitting time may be helpful components of sedentary behaviour interventions in the workplace

  7. Toehold-mediated internal control to probe the near-field interaction between the metallic nanoparticle and the fluorophore

    Science.gov (United States)

    Ang, Y. S.; Yung, L. Y. L.

    2014-10-01

    Metallic nanoparticles (MNPs) are known to alter the emission of vicinal fluorophores through the near-field interaction, leading to either fluorescence quenching or enhancement. Much ambiguity remains in the experimental outcome of such a near-field interaction, particularly for bulk colloidal solution. It is hypothesized that the strong far-field interference from the inner filter effect of the MNPs could mask the true near-field MNP-fluorophore interaction significantly. Thus, in this work, a reliable internal control capable of decoupling the near-field interaction from far-field interference is established by the use of the DNA toehold concept to mediate the in situ assembly and disassembly of the MNP-fluorophore conjugate. A model gold nanoparticle (AuNP)-Cy3 system is used to investigate our proposed toehold-mediated internal control system. The maximum fluorescence enhancement is obtained for large-sized AuNP (58 nm) separated from Cy3 at an intermediate distance of 6.8 nm, while fluorescence quenching is observed for smaller-sized AuNP (11 nm and 23 nm), which is in agreement with the theoretical values reported in the literature. This work shows that the toehold-mediated internal control design can serve as a central system for evaluating the near-field interaction of other MNP-fluorophore combinations and facilitate the rational design of specific MNP-fluorophore systems for various applications.Metallic nanoparticles (MNPs) are known to alter the emission of vicinal fluorophores through the near-field interaction, leading to either fluorescence quenching or enhancement. Much ambiguity remains in the experimental outcome of such a near-field interaction, particularly for bulk colloidal solution. It is hypothesized that the strong far-field interference from the inner filter effect of the MNPs could mask the true near-field MNP-fluorophore interaction significantly. Thus, in this work, a reliable internal control capable of decoupling the near

  8. P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain.

    Science.gov (United States)

    Iioka, Takashi; Furukawa, Keizo; Yamaguchi, Akira; Shindo, Hiroyuki; Yamashita, Shunichi; Tsukazaki, Tomoo

    2003-08-01

    The paired-like homeoprotein, Cart1, is involved in skeletal development. We describe here that the general coactivator p300/CBP controls the transcription activity of Cart1 through acetylation of a lysine residue that is highly conserved in other homeoproteins. Acetylation of this residue increases the interaction between p300/CBP and Cart1 and enhances its transcriptional activation. Cart1 encodes a paired-like homeoprotein expressed selectively in chondrocyte lineage during embryonic development. Although its target gene remains unknown, gene disruption studies have revealed that Cart1 plays an important role for craniofacial bone formation as well as limb development by cooperating with another homeoprotein, Alx4. In this report, we study the functional involvement of p300/CBP, coactivators with intrinsic histone acetyltransferase (HAT) activity, in the transcriptional control of Cart1. To study the transcription activity of Cart1, a reporter construct containing a putative Cart1 binding site was transiently transfected with the expression vectors of each protein. The interaction between p300/CBP and Cart1 was investigated by glutathione S-transferase (GST) pull-down, yeast two-hybrid, and immunoprecipitation assays. In vitro acetylation assay was performed with the recombinant p300-HAT domain and Cart1 in the presence of acetyl-CoA. p300 and CBP stimulate Cart1-dependent transcription activity, and this transactivation is inhibited by E1A and Tax, oncoproteins that suppress the activity of p300/CBP. Cart1 binds to p300 in vivo and in vitro, and this requires the homeodomain of Cart 1 and N-terminal 139 amino acids of p300. Confocal microscopy analysis shows that Cart1 recruits overexpressed and endogenous p300 to a Cart1-specific subnuclear compartment. Cart1 is acetylated in vivo and sodium butyrate and trichostatin A, histone deacetylase inhibitors, markedly enhance the transcription activity of Cart1. Deletion and mutagenesis analysis identifies the 131st

  9. Delay Discounting Mediates Parent-Adolescent Relationship Quality and Risky Sexual Behavior for Low Self-Control Adolescents.

    Science.gov (United States)

    Kahn, Rachel E; Holmes, Christopher; Farley, Julee P; Kim-Spoon, Jungmeen

    2015-09-01

    Parent-adolescent relationship quality and delay discounting may play important roles in adolescents' sexual decision making processes, and levels of self-control during adolescence could act as a buffer within these factors. This longitudinal study included 219 adolescent (55 % male; mean age = 12.66 years at Wave 1; mean age = 15.10 years at Wave 2) and primary caregiver dyads. Structural equation modeling (SEM) was utilized to determine whether delay discounting mediated the association between parent-adolescent relationship quality and adolescents' risky sexual behavior and how this mediated association may differ between those with high versus low self-control. The results revealed parent-adolescent relationship quality plays a role in the development of risky sexual behavior indirectly through levels of delay discounting, but only for adolescents with low self-control. These findings could inform sex education policies and health prevention programs that address adolescent risky sexual behavior.

  10. Personal Values as a Mediator of Relations Between Perceived Parental Support and Control and Youth Substance Use.

    Science.gov (United States)

    Borca, Gabriella; Rabaglietti, Emanuela; Roggero, Antonella; Keller, Peggy; Haak, Eric; Begotti, Tatiana

    2017-10-15

    Tobacco and marijuana smoking are very popular in adolescence and there is a high rate of comorbidity between them, even in young adulthood. Parental support and control may hinder involvement in the use of these substances by promoting conventional values among adolescents. The present study investigates the relations between family functioning (parental support and control) and psychoactive substance use (tobacco and marijuana smoking) and determines whether these relationships are mediated by personal values (in terms of disapproval of deviance and beliefs about the importance of school, health and religion). 175 Italian late adolescents (17 to 20 years old) participated in this two-wave longitudinal study. Data were collected at school through an anonymous questionnaire. Greater parental control and support were directly associated with lower adolescent tobacco and marijuana use; adolescent acceptance of conventional values mediated the association between parenting and adolescent marijuana use. Findings emphasize the influence of family relationships throughout adolescence. The transmission of conventional values to adolescents may be a critical mechanism through which parenting protects adolescents from substance use, especially marijuana use.

  11. Relational aggression and psychological control in the sibling relationship: mediators of the association between maternal psychological control and adolescents' emotional adjustment.

    Science.gov (United States)

    Campione-Barr, Nicole; Lindell, Anna K; Greer, Kelly Bassett; Rose, Amanda J

    2014-08-01

    The association between mothers' psychological control and their children's emotional adjustment problems is well documented. However, processes that may explain this association are not well understood. The present study tested the idea that relational aggression and psychological control within the context of the sibling relationship may help to account for the relation between mothers' psychological control and adolescents' internalizing symptoms. Older (M = 16.46, SD = 1.35 years) and younger (M = 13.67, SD = 1.56 years) siblings from 101 dyads rated the psychological control they received from mothers and siblings, and the relational aggression they received from siblings. Despite some similarities between psychological control and relational aggression, confirmatory factor analyses provided evidence that the two sibling processes are distinct. Maternal psychological control was related to psychological control and relational aggression within the sibling relationship, which were related to adolescents' anxiety and depressed mood. In addition, sibling relational aggression was a more powerful mediator of the relationship between maternal psychological control and adolescent adjustment than sibling psychological control.

  12. Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment

    DEFF Research Database (Denmark)

    Qu, Xiaoling; Afelik, Solomon; Jensen, Jan Nygaard

    2013-01-01

    of ducts. On one hand, Ngn3 cell-intrinsically activates endocrine target genes; on the other, Ngn3 cell-extrinsically promotes lateral signaling via the Dll1>Notch>Hes1 pathway which substantially limits its ability to sustain endocrine formation. Prior to endocrine commitment, the Ngn3-mediated...... involves transcriptional repression as previously shown, but also incorporates a novel post-translational mechanism. In addition to its ability to promote endocrine fate, we provide evidence of a competing ability of Ngn3 in the patterning of multipotent progenitor cells in turn controlling the formation...

  13. Controlled Zn-mediated grafting of thin layers of bipodal diazonium salt on gold and carbon substrates.

    Science.gov (United States)

    Torréns, Mabel; Ortiz, Mayreli; Turner, Anthony P F; Beni, Valerio; O'Sullivan, Ciara K

    2015-01-07

    A controlled, rapid, and potentiostat-free method has been developed for grafting the diazonium salt (3,5-bis(4-diazophenoxy)benzoic acid tetrafluoroborate (DCOOH)) on gold and carbon substrates, based on a Zn-mediated chemical dediazonation. The highly stable thin layer organic platforms obtained were characterized by cyclic voltammetry, AFM, impedance, XP, and Raman spectroscopies. A dediazonation mechanism based on radical formation is proposed. Finally, DCOOH was proved as a linker to an aminated electroactive probe. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups.

    Science.gov (United States)

    Schinkel, Christian; Scherens, A; Köller, M; Roellecke, G; Muhr, G; Maier, C

    2009-03-17

    The Complex Regional Pain Syndrome I (CRPS I) is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet. To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP), White Blood Cell Count (WBC), Interleukins 4, 6, 8, 10, 11, 12 (p70), Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-a) and its soluble Receptors I/II, soluble Selectins (E,L,P), Substance-P (SP), and Calcitonin Gene-Related Peptide (CGRP) at different time points in venous blood from patients with acute (AC) and chronic (CC) CRPS I, patients with forearm fractures (FR), with neuralgia (NE), and from healthy volunteers (C). No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007), FR/C (CGRP p = 0.048) and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049). High interindividual variations were observed. No intra- or interindividual correlation of parameters with clinical course (e.g. chronification) or outcome was detectable. Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory

  15. Systemic inflammatory mediators in post-traumatic Complex Regional Pain Syndrome (CRPS I - longitudinal investigations and differences to control groups

    Directory of Open Access Journals (Sweden)

    Schinkel Ch

    2009-03-01

    Full Text Available Abstract Objectives The Complex Regional Pain Syndrome I (CRPS I is a disease that might affect an extremity after trauma or operation. The pathogenesis remains yet unclear. It has clinical signs of severe local inflammation as a result of an exaggerated inflammatory response but neurogenic dysregulation also contributes to it. Some studies investigated the role inflammatory mediators and cytokines; however, few longitudinal studies exist and control groups except healthy controls were not investigated yet. Methods To get further insights into the role of systemic inflammatory mediators in CRPS I, we investigated a variety of pro-, anti-, or neuro-inflammatory mediators such as C-Reactive Protein (CRP, White Blood Cell Count (WBC, Interleukins 4, 6, 8, 10, 11, 12 (p70, Interferon gamma, Tumor-Necrosis-Factor alpha (TNF-α and its soluble Receptors I/II, soluble Selectins (E, L, P, Substance-P (SP, and Calcitonin Gene-Related Peptide (CGRP at different time points in venous blood from patients with acute (AC and chronic (CC CRPS I, patients with forearm fractures (FR, with neuralgia (NE, and from healthy volunteers (C. Results No significant changes for serum parameters investigated in CRPS compared to control groups were found except for CC/C (CGRP p = 0.007, FR/C (CGRP p = 0.048 and AC/CC (IL-12 p = 0.02; TNFRI/II p = 0.01; SP p = 0.049. High interindividual variations were observed. No intra-or interindividual correlation of parameters with clinical course (e.g. chronification or outcome was detectable. Conclusion Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this

  16. Acceleration of the glycolytic flux by steroid receptor coactivator-2 is essential for endometrial decidualization.

    Directory of Open Access Journals (Sweden)

    Ramakrishna Kommagani

    2013-10-01

    Full Text Available Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of the cellular events that underpin endometrial stromal cell (ESC decidualization are well recognized, the individual gene(s and molecular pathways that drive the initiation and progression of this process remain elusive. Using a genetic mouse model and a primary human ESC culture model, we demonstrate that steroid receptor coactivator-2 (SRC-2 is indispensable for rapid steroid hormone-dependent proliferation of ESCs, a critical cell-division step which precedes ESC terminal differentiation into decidual cells. We reveal that SRC-2 is required for increasing the glycolytic flux in human ESCs, which enables rapid proliferation to occur during the early stages of the decidualization program. Specifically, SRC-2 increases the glycolytic flux through induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3, a major rate-limiting glycolytic enzyme. Similarly, acute treatment of mice with a small molecule inhibitor of PFKFB3 significantly suppressed the ability of these animals to exhibit an endometrial decidual response. Together, these data strongly support a conserved mechanism of action by which SRC-2 accelerates the glycolytic flux through PFKFB3 induction to provide the necessary bioenergy and biomass to meet the demands of a high proliferation rate observed in ESCs prior to their differentiation into decidual cells. Because deregulation of endometrial SRC-2 expression has been associated with common gynecological disorders of reproductive-age women, this signaling pathway, involving SRC-2 and PFKFB3, promises to offer new clinical approaches in the diagnosis and/or treatment of a non-receptive uterus in patients presenting idiopathic infertility, recurrent early pregnancy loss, or increased time to pregnancy.

  17. Nipbl and mediator cooperatively regulate gene expression to control limb development.

    Directory of Open Access Journals (Sweden)

    Akihiko Muto

    2014-09-01

    Full Text Available Haploinsufficiency for Nipbl, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS, the most common "cohesinopathy". It has been proposed that the effects of Nipbl-haploinsufficiency result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by Nipbl deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb, knockdown of Nipbl expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of Nipbl-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that Nipbl colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled Nipbl-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both Nipbl and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that Nipbl and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for Nipbl in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.

  18. Surface control of blastospore attachment and ligand-mediated hyphae adhesion of Candida albicans.

    Science.gov (United States)

    Varghese, Nisha; Yang, Sijie; Sejwal, Preeti; Luk, Yan-Yeung

    2013-11-14

    Adhesion on a surface via nonspecific attachment or multiple ligand-receptor interactions is a critical event for fungal infection by Candida albicans. Here, we find that the tri(ethylene glycol)- and d-mannitol-terminated monolayers do not resist the blastospore attachment, but prevent the hyphae adhesion of C. albicans. The hyphae adhesion can be facilitated by tripeptide sequences of arginine-glycine-aspartic acid (RGD) covalently decorated on a background of tri(ethylene glycol)-terminated monolayers. This adhesion mediated by selected ligands is sensitive to the scrambling of peptide sequences, and is inhibited by the presence of cyclic RGD peptides in the solution.

  19. The Mediating Role of Maladaptive Perfectionism in the Association between Psychological Control and Learned Helplessness

    Science.gov (United States)

    Filippello, Pina; Larcan, Rosalba; Sorrenti, Luana; Buzzai, Caterina; Orecchio, Susanna; Costa, Sebastiano

    2017-01-01

    Despite the extensive research on parental psychological control, no study has explored the relation between parental and teacher psychological control, maladaptive perfectionism and learned helplessness (LH). The purpose of this study was to investigate (1) whether perceived teacher psychological control predicts positively LH, (2) whether…

  20. No mediating effects of glycemic control and inflammation on the association between vitamin D and lung function in the general population.

    Science.gov (United States)

    Kaul, Anne; Gläser, Sven; Hannemann, Anke; Stubbe, Beate; Felix, Stefan B; Nauck, Matthias; Ewert, Ralf; Friedrich, Nele

    2017-04-01

    Vitamin D deficiency is discussed to be associated with lung health. While former studies focused on subjects suffering from pulmonary diseases, we aimed to investigate the association of 25-hydroxy vitamin D [25(OH)D] with lung function in the general population and examined whether mediating effects of inflammation, glycemic control or renal function exist. 1404 participants from the Study of Health in Pomerania with pulmonary function testing assessed by expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), total lung capacity and Krogh index were used. Adjusted analysis of variance, linear regression models and mediation analyses were performed. Significant positive associations between 25(OH)D levels and FEV 1 , FVC and Krogh index were found. Mediator analyses revealed no mediating effect of inflammation (fibrinogen), glycemic control (HbA1c) or renal function (eGFR) on associations with FEV 1 or FVC. With respect to Krogh-Index, the association to 25(OH)D was slightly mediated by fibrinogen with a proportion mediated of 9.7%. Significant positive associations of 25(OH)D with lung function were revealed in a general population. The proposed mediating effects of inflammation, glycemic control and renal function on these relations were not confirmed. Further studies examining the causality of the association between 25(OH)D and lung function are necessary. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Basic Psychological Needs Satisfaction Mediates the Association between Self-Control Skills and Subjective Well-Being

    Directory of Open Access Journals (Sweden)

    Hod Orkibi

    2017-06-01

    Full Text Available Although studies have shown that self-control skills (SCSs are positively linked to both personal and interpersonal outcomes in adolescent students, studies on the putative mechanisms underlying this relationship are scarce. Drawing on Self-Determination Theory and previous studies, we theorized that the association between students’ SCSs and their subjective well-being (SWB in school may be mediated by students’ perceived satisfaction of their basic psychological needs for competence, relatedness, and autonomy. The sample consisted of 1576 Israeli adolescent students (54% girls in grades 10–12 (mean age 16 enrolled in 20 schools. A mediation model was tested with structural equation modeling and a robust bootstrap method for testing indirect effects, controlling for school-level variance. The findings supported the hypothesized model and a post hoc multi-group comparison analysis yielded gender invariance in the model. The findings suggest that both girls and boys with high SCSs may perceive themselves as having greater needs satisfaction in school and consequently higher school-related SWB. Implications for policy and practice are discussed.

  2. Rif1 controls DNA replication by directing Protein Phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex.

    Science.gov (United States)

    Hiraga, Shin-Ichiro; Alvino, Gina M; Chang, Fujung; Lian, Hui-Yong; Sridhar, Akila; Kubota, Takashi; Brewer, Bonita J; Weinreich, Michael; Raghuraman, M K; Donaldson, Anne D

    2014-02-15

    Initiation of eukaryotic DNA replication requires phosphorylation of the MCM complex by Dbf4-dependent kinase (DDK), composed of Cdc7 kinase and its activator, Dbf4. We report here that budding yeast Rif1 (Rap1-interacting factor 1) controls DNA replication genome-wide and describe how Rif1 opposes DDK function by directing Protein Phosphatase 1 (PP1)-mediated dephosphorylation of the MCM complex. Deleting RIF1 partially compensates for the limited DDK activity in a cdc7-1 mutant strain by allowing increased, premature phosphorylation of Mcm4. PP1 interaction motifs within the Rif1 N-terminal domain are critical for its repressive effect on replication. We confirm that Rif1 interacts with PP1 and that PP1 prevents premature Mcm4 phosphorylation. Remarkably, our results suggest that replication repression by Rif1 is itself also DDK-regulated through phosphorylation near the PP1-interacting motifs. Based on our findings, we propose that Rif1 is a novel PP1 substrate targeting subunit that counteracts DDK-mediated phosphorylation during replication. Fission yeast and mammalian Rif1 proteins have also been implicated in regulating DNA replication. Since PP1 interaction sites are evolutionarily conserved within the Rif1 sequence, it is likely that replication control by Rif1 through PP1 is a conserved mechanism.

  3. Identification of highly effective target genes for RNAi-mediated control of emerald ash borer, Agrilus planipennis.

    Science.gov (United States)

    Rodrigues, Thais B; Duan, Jian J; Palli, Subba R; Rieske, Lynne K

    2018-03-22

    Recent study has shown that RNA interference (RNAi) is efficient in emerald ash borer (EAB), Agrilus planipennis, and that ingestion of double-stranded RNA (dsRNA) targeting specific genes causes gene silencing and mortality in neonates. Here, we report on the identification of highly effective target genes for RNAi-mediated control of EAB. We screened 13 candidate genes in neonate larvae and selected the most effective target genes for further investigation, including their effect on EAB adults and on a non-target organism, Tribolium castaneum. The two most efficient target genes selected, hsp (heat shock 70-kDa protein cognate 3) and shi (shibire), caused up to 90% mortality of larvae and adults. In EAB eggs, larvae, and adults, the hsp is expressed at higher levels when compared to that of shi. Ingestion of dsHSP and dsSHI caused mortality in both neonate larvae and adults. Administration of a mixture of both dsRNAs worked better than either dsRNA by itself. In contrast, injection of EAB.dsHSP and EAB.dsSHI did not cause mortality in T. castaneum. Thus, the two genes identified cause high mortality in the EAB with no apparent phenotype effects in a non-target organism, the red flour beetle, and could be used in RNAi-mediated control of this invasive pest.

  4. Mammalian mediator 19 mediates H1299 lung adenocarcinoma cell clone conformation, growth, and metastasis.

    Science.gov (United States)

    Xu, Lu-Lu; Guo, Shu-Liang; Ma, Su-Ren; Luo, Yong-Ai

    2012-01-01

    Mammalian mediator (MED) is a multi-protein coactivator that has been identified by several research groups. The involvement of the MED complex subunit 19 (MED 19) in the metastasis of lung adenocarcinoma cell line (H1299), which expresses the MED 19 subunit, was here investigated. When MED 19 expression was decreased by RNA interference H1299 cells demonstrated reduced clone formation, arrest in the S phase of the cell cycle, and lowered metastatic capacity. Thus, MED 19 appears to play important roles in the biological behavior of non-small cell lung carcinoma cells. These findings may be important for the development of novel lung carcinoma treatments.

  5. Antidepressant Imipramine Protects Bupivacaine-Induced Neurotoxicity in Dorsal Root Ganglion Neurons Through Coactivation of TrkA and TrkB.

    Science.gov (United States)

    Guo, Jianrong; Wang, Huan; Tao, Qiang; Sun, Shiyu; Liu, Li; Zhang, Jianping; Yang, Dawei

    2017-11-01

    In our work, we used an in vitro culture model to investigate whether antidepressant imipramine (Ip) may protect bupivacaine (Bv)-induced neurotoxicity in mouse dorsal root ganglion (DRG). Adult mouse DRG was treated with 5 mM Bv in vitro to induce neurotoxicity. DRG was then pre-treated with Ip, prior to Bv, to examine its effects on protecting Bv-induced DRG apoptosis and neurite degeneration. Ip-induced dynamic changes in Trk receptors, including TrkA/B/C and phosphor (p-)TrkA/B/C, were examined by qPCR and Western blot. TrkA and TrkB were inhibited by siRNAs to further investigate their functional role in Ip- and Bv-treated DRG. Ip protected Bv-induced apoptosis and neurite loss in DRG. Ip did not alter TrkA/B/C expressions, whereas significantly augmented protein productions of p-TrkA and p-TrkB, but not p-TrkC. SiRNA-mediated TrkA or TrkB downregulation inhibited Trk receptors, and reduced p-TrkA and p-TrkB in DRG. TrkA or TrkB downregulation alone had no effect on Ip-induced protection in Bv-injured DRG. However, co-inhibition of TrkA and TrkB significantly ameliorated the protective effect of Ip on Bv-induced apoptosis and neurite loss in DRG. Imipramine protected bupivacaine-induced neurotoxicity in DRG, likely via the co-activation of TrkA and TrkB signaling pathways. J. Cell. Biochem. 118: 3960-3967, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription.

    Science.gov (United States)

    Zangen, David; Kaufman, Yotam; Zeligson, Sharon; Perlberg, Shira; Fridman, Hila; Kanaan, Moein; Abdulhadi-Atwan, Maha; Abu Libdeh, Abdulsalam; Gussow, Ayal; Kisslov, Irit; Carmel, Liran; Renbaum, Paul; Levy-Lahad, Ephrat

    2011-10-07

    XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. Most cases are unexplained but thought to be autosomal recessive. We elucidated the genetic basis of XX-GD in a highly consanguineous Palestinian family by using homozygosity mapping and candidate-gene and whole-exome sequencing. Affected females were homozygous for a 3 bp deletion (NM_016556.2, c.600_602del) in the PSMC3IP gene, leading to deletion of a glutamic acid residue (p.Glu201del) in the highly conserved C-terminal acidic domain. Proteasome 26S subunit, ATPase, 3-Interacting Protein (PSMC3IP)/Tat Binding Protein Interacting Protein (TBPIP) is a nuclear, tissue-specific protein with multiple functions. It is critical for meiotic recombination as indicated by the known role of its yeast ortholog, Hop2. Through the C terminus (not present in yeast), PSMC3IP also coactivates ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. In cell lines, the p.Glu201del mutation abolished PSMC3IP activation of estrogen-driven transcription. Impaired estrogenic signaling can lead to ovarian dysgenesis both by affecting the size of the follicular pool created during fetal development and by failing to counteract follicular atresia during puberty. PSMC3IP joins previous genes known to be mutated in XX-GD, the FSH receptor, and BMP15, highlighting the importance of hormonal signaling in ovarian development and maintenance and suggesting a common pathway perturbed in isolated XX-GD. By analogy to other XX-GD genes, PSMC3IP is also a candidate gene for premature ovarian failure, and its role in folliculogenesis should be further investigated. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  7. Expression, purification, crystallization and preliminary crystallographic study of isolated modules of the mouse coactivator-associated arginine methyltransferase 1

    Energy Technology Data Exchange (ETDEWEB)

    Troffer-Charlier, Nathalie; Cura, Vincent; Hassenboehler, Pierre; Moras, Dino; Cavarelli, Jean, E-mail: cava@igbmc.u-strasbg.fr [IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Département de Biologie et Génomique Structurales, 1 Rue Laurent Fries, Illkirch, F-67404 (France); INSERM, U596, Illkirch, F-67400 (France); CNRS, UMR7104, Illkirch, F-67400 (France); Université Louis Pasteur, Faculté des Sciences de la Vie, Strasbourg, F-67000 (France)

    2007-04-01

    Isolated modules of mouse coactivator-associated arginine methyltransferase 1 encompassing the protein arginine N-methyltransferase catalytic domain have been overexpressed, purified and crystallized. X-ray diffraction data have been collected and have enabled determination of the structures by multiple isomorphous replacement using anomalous scattering. Coactivator-associated arginine methyltransferase 1 (CARM1) plays a crucial role in gene expression as a coactivator of several nuclear hormone receptors and also of non-nuclear receptor systems. Its recruitment by the transcriptional machinery induces protein methylation, leading to chromatin remodelling and gene activation. CARM1{sub 28–507} and two structural states of CARM1{sub 140–480} were expressed, purified and crystallized. Crystals of CARM1{sub 28–507} belong to space group P6{sub 2}22, with unit-cell parameters a = b = 136.0, c = 125.3 Å; they diffract to beyond 2.5 Å resolution using synchrotron radiation and contain one monomer in the asymmetric unit. The structure of CARM1{sub 28–507} was solved by multiple isomorphous replacement and anomalous scattering methods. Crystals of apo CARM1{sub 140–480} belong to space group I222, with unit-cell parameters a = 74.6, b = 99.0, c = 207.4 Å; they diffract to beyond 2.7 Å resolution and contain two monomers in the asymmetric unit. Crystals of CARM1{sub 140–480} in complex with S-adenosyl-l-homocysteine belong to space P2{sub 1}2{sub 1}2, with unit-cell parameters a = 74.6, b = 98.65, c = 206.08 Å; they diffract to beyond 2.6 Å resolution and contain four monomers in the asymmetric unit. The structures of apo and holo CARM1{sub 140–480} were solved by molecular-replacement techniques from the structure of CARM1{sub 28–507}.

  8. NARROW LEAF 7 controls leaf shape mediated by auxin in rice

    NARCIS (Netherlands)

    Fujino, Kenji; Matsuda, Yasuyuki; Ozawa, Kenjirou; Nishimura, Takeshi; Koshiba, Tomokazu; Fraaije, Marco W.; Sekiguchi, Hiroshi

    Elucidation of the genetic basis of the control of leaf shape could be of use in the manipulation of crop traits, leading to more stable and increased crop production. To improve our understanding of the process controlling leaf shape, we identified a mutant gene in rice that causes a significant

  9. Inhibitory Control Mediates the Association between Perceived Stress and Secure Relationship Quality

    OpenAIRE

    Toria Herd; Mengjiao Li; Dominique Maciejewski; Jacob Lee; Kirby Deater-Deckard; Brooks King-Casas; Jungmeen Kim-Spoon

    2018-01-01

    Past research has demonstrated negative associations between exposure to stressors and quality of interpersonal relationships among children and adolescents. Nevertheless, underlying mechanisms of this association remain unclear. Chronic stress has been shown to disrupt prefrontal functioning in the brain, including inhibitory control abilities, and evidence is accumulating that inhibitory control may play an important role in secure interpersonal relationship quality, including peer problems...

  10. Effortless inhibition: Habit mediates the relation between self-control and unhealthy snack consumption

    NARCIS (Netherlands)

    Adriaanse, Marieke A.|info:eu-repo/dai/nl/304823023; Kroese, Floor M.|info:eu-repo/dai/nl/313869871; Gillebaart, Marleen|info:eu-repo/dai/nl/344390365; De Ridder, Denise T D|info:eu-repo/dai/nl/070706174

    2014-01-01

    In contrast to prevailing beliefs, recent research suggests that trait self-control promotes health behavior not because those high in self-control are more successful at resisting single temptations, but rather because they develop adaptive habits. The present paper presents a first empirical test

  11. KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

    Directory of Open Access Journals (Sweden)

    Ling-Yu Wang

    2016-09-01

    Full Text Available The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. Downregulation of KDM4A leads to elevated activity of pyruvate dehydrogenase and mitochondrial oxidation, resulting in excessive accumulation of reactive oxygen species. The altered metabolic phenotypes can be partially rescued by ectopic expression of PDK1 and PDK3, indicating a KDM4A-dependent tumor metabolic regulation via PDK. Our results suggest that KDM4A is a key regulator of tumor metabolism and a potential therapeutic target for prostate cancer.

  12. Correspondent Functional Topography of the Human Left Inferior Parietal Lobule at Rest and Under Task Revealed Using Resting-State fMRI and Coactivation Based Parcellation.

    Science.gov (United States)

    Wang, Jiaojian; Xie, Sangma; Guo, Xin; Becker, Benjamin; Fox, Peter T; Eickhoff, Simon B; Jiang, Tianzi

    2017-03-01

    The human left inferior parietal lobule (LIPL) plays a pivotal role in many cognitive functions and is an important node in the default mode network (DMN). Although many previous studies have proposed different parcellation schemes for the LIPL, the detailed functional organization of the LIPL and the exact correspondence between the DMN and LIPL subregions remain unclear. Mounting evidence indicates that spontaneous fluctuations in the brain are strongly associated with cognitive performance at the behavioral level. However, whether a consistent functional topographic organization of the LIPL during rest and under task can be revealed remains unknown. Here, they used resting-state functional connectivity (RSFC) and task-related coactivation patterns separately to parcellate the LIPL and identified seven subregions. Four subregions were located in the supramarginal gyrus (SMG) and three subregions were located in the angular gyrus (AG). The subregion-specific networks and functional characterization revealed that the four anterior subregions were found to be primarily involved in sensorimotor processing, movement imagination and inhibitory control, audition perception and speech processing, and social cognition, whereas the three posterior subregions were mainly involved in episodic memory, semantic processing, and spatial cognition. The results revealed a detailed functional organization of the LIPL and suggested that the LIPL is a functionally heterogeneous area. In addition, the present study demonstrated that the functional architecture of the LIPL during rest corresponds with that found in task processing. Hum Brain Mapp 38:1659-1675, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Controlling Coaching Behaviors and Athlete Burnout: Investigating the Mediating Roles of Perfectionism and Motivation.

    Science.gov (United States)

    Barcza-Renner, Kelly; Eklund, Robert C; Morin, Alexandre J; Habeeb, Christine M

    2016-02-01

    This investigation sought to replicate and extend earlier studies of athlete burnout by examining athlete-perceived controlling coaching behaviors and athlete perfectionism variables as, respectively, environmental and dispositional antecedents of athlete motivation and burnout. Data obtained from NCAA Division I swimmers (n = 487) within 3 weeks of conference championship meets were analyzed for this report. Significant indirect effects were observed between controlling coaching behaviors and burnout through athlete perfectionism (i.e., socially prescribed, self-oriented) and motivation (i.e., autonomous, amotivation). Controlling coaching behaviors predicted athlete perfectionism. In turn, self-oriented perfectionism was positively associated with autonomous motivation and negatively associated with amotivation, while socially prescribed perfectionism was negatively associated with autonomous motivation and positively associated with controlled motivation and amotivation. Autonomous motivation and amotivation, in turn, predicted athlete burnout in expected directions. These findings implicate controlling coaching behaviors as potentially contributing to athlete perfectionism, shaping athlete motivational regulations, and possibly increasing athlete burnout.

  14. The Mediating Roles of Primary and Secondary Control in the Relationship between Body Satisfaction and Subjective Well-Being Among Middle-Aged and Older Women.

    Science.gov (United States)

    Watt, Ashli D; Konnert, Candace A; Speirs, Calandra E C

    2017-07-01

    This study examined primary and secondary control as mediators in the relationship between body satisfaction and subjective well-being (SWB) and explored age differences in the mediation model. Data from 362 women, aged 40-91 years, assessed (i) the relationships between body satisfaction, age, primary and secondary control strategies (body-specific social comparison, acceptance, and positive reappraisal), and three indices of SWB (positive affect, negative affect, and life satisfaction), (ii) the mediation effects of primary and secondary control on the relationship between body satisfaction and SWB, and (iii) whether mediational relationships were moderated by age. Body satisfaction was unrelated to age but positively related to positive affect and life satisfaction and negatively related to negative affect. Body satisfaction was also related to primary and secondary control strategies. There were significant indirect (mediated) effects of body satisfaction on all outcome variables through acceptance and positive reappraisal. These mediators were significant at all age levels, but exerted their strongest influence among younger women. This study provides new information about the mechanisms that influence the relationship between body satisfaction and SWB among a broad age range of women who are experiencing physical changes that are inconsistent with Western beauty standards. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. Effectiveness of erythrosine-mediated photodynamic antimicrobial chemotherapy on dental plaque aerobic microorganisms: A randomized controlled trial.

    Science.gov (United States)

    Bhat, Manohar; Acharya, Swathi; Prasad, Kakarla Veera Venkata; Kulkarni, Raghavendra; Bhat, Anithraj; Bhat, Devikripa

    2017-01-01

    Dental plaque is one of the predominant causes of major oral diseases. Although mechanical and chemical methods are extensively followed to control the development of plaque, plaque-related diseases still persist. Therefore, this necessitates for alternative measures of plaque control, one such alternative is photodynamic antimicrobial chemotherapy (PACT). Split mouth randomized clinical trial (CTRI/2017/03/008239) was conducted on 30 participants who reported to the hospital. Participants were asked to rinse their mouth for 1 min using 10 ml of 25 μM erythrosine solutions. Same tooth on both quadrants of the same jaw are selected as the test and control. Intervention used was halogen-based composite curing light with wavelength of 500-590 nm. Plaque sample from the control tooth and test tooth was collected before and after exposure, respectively, and sent to microbiological laboratory for colony count. Logarithmic mean and standard deviation of control group with 10 2 dilutions of aerobic microbial count were found to be 5.34 ± 0.94, and for experimental group, it was 4.47 ± 1.37. The statistical difference between mean CFU values between aerobic bacterial counts was significant ( P = 0.006). Erythrosine-mediated PACT reduces the extent of dental plaque microbial count and has a potential preventive and therapeutic use in day-to-day life and dental clinics.

  16. Synergistic co-activation increases the extent of mechanical interaction between rat ankle plantar-flexors

    Directory of Open Access Journals (Sweden)

    Chris Tijs

    2016-09-01

    Full Text Available Force transmission between rat ankle plantar-flexors has been found for physiological muscle lengths and relative positions, but only with all muscles maximally activated. The aims of this study were to assess intermuscular mechanical interactions between ankle plantar-flexors during (i fully passive conditions, (ii excitation of soleus (SO, (iii excitation of lateral gastrocnemius (LG, and (iv during co-activation of SO and LG (SO&LG. We assessed effects of proximal lengthening of LG and plantaris (PL muscles (i.e. simulating knee extension on forces exerted at the distal SO tendon (FSO and on the force difference between the proximal and distal LG+PL tendons (ΔFLG+PL of the rat. LG+PL lengthening increased FSO to a larger extent (p=0.017 during LG excitation (0.0026 N/mm than during fully passive conditions (0.0009 N/mm. Changes in FSO in response to LG+PL lengthening were lower (p=0.002 during SO only excitation (0.0056 N/mm than during SO&LG excitation (0.0101 N/mm. LG+PL lengthening changed ∆FLG+PL to a larger extent (p=0.007 during SO excitation (0.0211 N/mm than during fully passive conditions (0.0157 N/mm. In contrast, changes in ∆FLG+PL in response to LG+PL lengthening during LG excitation (0.0331 N/mm were similar (p=0.161 to that during SO&LG excitation (0.0370 N/mm. In all conditions, changes of FSO were lower than those of ∆FLG+PL. This indicates that muscle forces were transmitted not only between LG+PL and SO, but also between LG+PL and other surrounding structures. In addition, epimuscular myofascial force transmission between rat ankle plantar-flexors was enhanced by muscle activation. However, the magnitude of this interaction was limited.

  17. Mediating Mechanisms of Theory-Based Psychosocial Determinants on Behavioral Changes in a Middle School Obesity Risk Reduction Curriculum Intervention, Choice, Control, and Change.

    Science.gov (United States)

    Gray, Heewon Lee; Contento, Isobel R; Koch, Pamela A; Noia, Jennifer Di

    2016-10-01

    A limited number of school-based intervention studies have explored mediating mechanisms of theory-based psychosocial variables on obesity risk behavior changes. The current study investigated how theory-based psychosocial determinants mediated changes in energy balance-related behaviors (EBRBs) among urban youth. A secondary analysis study was conducted using data from a cluster randomized controlled trial. Data from students at 10 middle schools in New York City (n = 1136) were used. The intervention, Choice, Control, and Change curriculum, was based on social cognitive and self-determination theories. Theory-based psychosocial determinants (goal intention, cognitive outcome expectations, affective outcome expectations, self-efficacy, perceived barriers, and autonomous motivation) and EBRBs were measured with self-report questionnaires. Mediation mechanisms were examined using structural equation modeling, Results: Mediating mechanisms for daily sugar-sweetened beverage (SSB) consumption and purposeful stair climbing were identified. Models with best fit indices (root mean square error of approximation = 0.039/0.045, normed fit index = 0.916/0.882; comparative fit index = 0.945/0.932; Tucker-Lewis index = 0.896/0.882, respectively) suggested that goal intention and reduced perceived barriers were significant proximal mediators for reducing SSB consumption among both boys and girls or increasing physical activity by stair climbing among boys. Cognitive outcome expectations, affective outcome expectations, self-efficacy, and autonomous motivation indirectly mediated behavioral changes through goal intention or perceived barriers (p behavioral outcome variances. Theory-based psychosocial determinants targeted in Choice, Control, and Change in fact mediated behavior changes in middle school students. Strategies targeting these mediators might benefit future success of behavioral interventions. Further studies are needed to determine other

  18. Neurogenesis and Helplessness are Mediated by Controllability in Males but not in Females

    Science.gov (United States)

    Shors, Tracey J.; Mathew, Jason; Sisti, Helene M.; Edgecomb, Carol; Beckoff, Steven; Dalla, Christina

    2009-01-01

    Background Numerous studies have implicated neurogenesis in the hippocampus in animal models of depression, especially those related to controllability and learned helplessness. Here, we tested the hypothesis that uncontrollable, but not controllable stress would reduce cell proliferation in the hippocampus of male and female rats, and would relate to the expression of helplessness behavior. Methods To manipulate controllability, groups of male and female rats were trained in one session (acute stress) or over seven sessions (repeated stress) to escape a footshock, while yoked controls could not escape, but were exposed to the same amount of stress. Cell proliferation was assessed with immunohistochemistry of BrdU and immunofluorescence of BrdU and NeuN. Separate groups were exposed to either controllable or uncontrollable stress and their ability to learn to escape during training on a more difficult task was used as a behavioral measure of helplessness. Results Acute stress reduced cell proliferation in males, but did not affect proliferation in the female hippocampus. When animals were given the opportunity to learn to control the stress over days, males produced more cells than the yoked males without control. Repeated training with controllable stress did not influence proliferation in females. Under all conditions, males were more likely than females to express helplessness behavior, even males that were not previously stressed. Conclusions The modulation of neurogenesis by controllability was evident in males but not in females, as was the expression of helplessness behavior, despite the fact that men are less likely than women to experience depression. PMID:17306770

  19. Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial.

    Science.gov (United States)

    Tucker, Joan S; Edelen, Maria Orlando; Huang, Wenjing

    2017-03-01

    Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N = 111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention.

  20. Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial

    Science.gov (United States)

    Tucker, Joan S.; Edelen, Maria Orlando; Huang, Wenjing

    2016-01-01

    Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N=111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention. PMID:26762375

  1. Diabetes-specific emotional distress mediates the association between depressive symptoms and glycaemic control in Type 1 and Type 2 diabetes

    DEFF Research Database (Denmark)

    van Bastelaar, Kim M P; Pouwer, F; Geelhoed-Duijvestijn, P H L M

    2010-01-01

    and diabetes-specific emotional distress respectively. Linear regression was performed to examine the mediating effect of diabetes-distress. RESULTS: Complete data were available for 627 outpatients with Type 1 (n = 280) and Type 2 (n = 347) diabetes. Analyses showed that diabetes-distress mediated......OBJECTIVES: To investigate whether diabetes-specific emotional distress mediates the relationship between depression and glycaemic control in patients with Type 1 and Type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were derived from the baseline assessment of a depression in diabetes screening...... and glycaemic control, diabetes-specific emotional distress appears to be an important mediator. Addressing diabetes-specific emotional problems as part of depression treatment in diabetes patients may help improve glycaemic outcomes....

  2. Unc-51/ATG1 controls axonal and dendritic development via kinesin-mediated vesicle transport in the Drosophila brain.

    Directory of Open Access Journals (Sweden)

    Hiroaki Mochizuki

    2011-05-01

    Full Text Available Members of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.In this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II, an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM and No distributive disjunction (Nod, remains unaltered. Genetic analyses of kinesin light chain (Klc and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.Unc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of

  3. Low-noise humidity controller for imaging water mediated processes in atomic force microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Gaponenko, I., E-mail: iaroslav.gaponenko@unige.ch; Gamperle, L.; Herberg, K.; Muller, S. C.; Paruch, P. [DQMP, University of Geneva, 24 Quai E. Ansermet, 1211 Geneva 4 (Switzerland)

    2016-06-15

    We demonstrate the construction of a novel low-noise continuous flow humidity controller and its integration with a commercial variable-temperature atomic force microscope fluid cell, allowing precise control of humidity and temperature at the sample during nanoscale measurements. Based on wet and dry gas mixing, the design allows a high mechanical stability to be achieved by means of an ultrasonic atomiser for the generation of water-saturated gas, improving upon previous bubbler-based architectures. Water content in the flow is measured both at the inflow and outflow of the fluid cell, enabling the monitoring of water condensation and icing, and allowing controlled variation of the sample temperature independently of the humidity. To benchmark the performance of the controller, the results of detailed noise studies and time-based imaging of the formation of ice layers on highly oriented pyrolytic graphite are shown.

  4. Low-noise humidity controller for imaging water mediated processes in atomic force microscopy

    Science.gov (United States)

    Gaponenko, I.; Gamperle, L.; Herberg, K.; Muller, S. C.; Paruch, P.

    2016-06-01

    We demonstrate the construction of a novel low-noise continuous flow humidity controller and its integration with a commercial variable-temperature atomic force microscope fluid cell, allowing precise control of humidity and temperature at the sample during nanoscale measurements. Based on wet and dry gas mixing, the design allows a high mechanical stability to be achieved by means of an ultrasonic atomiser for the generation of water-saturated gas, improving upon previous bubbler-based architectures. Water content in the flow is measured both at the inflow and outflow of the fluid cell, enabling the monitoring of water condensation and icing, and allowing controlled variation of the sample temperature independently of the humidity. To benchmark the performance of the controller, the results of detailed noise studies and time-based imaging of the formation of ice layers on highly oriented pyrolytic graphite are shown.

  5. Low-noise humidity controller for imaging water mediated processes in atomic force microscopy

    International Nuclear Information System (INIS)

    Gaponenko, I.; Gamperle, L.; Herberg, K.; Muller, S. C.; Paruch, P.

    2016-01-01

    We demonstrate the construction of a novel low-noise continuous flow humidity controller and its integration with a commercial variable-temperature atomic force microscope fluid cell, allowing precise control of humidity and temperature at the sample during nanoscale measurements. Based on wet and dry gas mixing, the design allows a high mechanical stability to be achieved by means of an ultrasonic atomiser for the generation of water-saturated gas, improving upon previous bubbler-based architectures. Water content in the flow is measured both at the inflow and outflow of the fluid cell, enabling the monitoring of water condensation and icing, and allowing controlled variation of the sample temperature independently of the humidity. To benchmark the performance of the controller, the results of detailed noise studies and time-based imaging of the formation of ice layers on highly oriented pyrolytic graphite are shown.

  6. Month of birth, vitamin D and risk of immune-mediated disease: a case control study

    Directory of Open Access Journals (Sweden)

    Disanto Giulio

    2012-07-01

    Full Text Available Abstract Background A season of birth effect in immune-mediated diseases (ID such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB light exposure and vitamin D status during gestation. Methods The monthly distribution of births of patients with ID from the UK (n = 115,172 was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient. Results The distributions of ID births significantly differed from that of the general population (P = 5e-12 with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P P P = 0.00005 and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003. Conclusions The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.

  7. Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding.

    Science.gov (United States)

    Gourley, Shannon L; Swanson, Andrew M; Jacobs, Andrea M; Howell, Jessica L; Mo, Michelle; Dileone, Ralph J; Koleske, Anthony J; Taylor, Jane R

    2012-12-11

    Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.

  8. Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain.

    Science.gov (United States)

    Fujikake, Kazuma; Sawada, Masato; Hikita, Takao; Seto, Yayoi; Kaneko, Naoko; Herranz-Pérez, Vicente; Dohi, Natsuki; Homma, Natsumi; Osaga, Satoshi; Yanagawa, Yuchio; Akaike, Toshihiro; García-Verdugo, Jose Manuel; Hattori, Mitsuharu; Sobue, Kazuya; Sawamoto, Kazunobu

    2018-05-09

    In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB. SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts

  9. Well-being among older adults with OA: direct and mediated patterns of control beliefs, optimism and pessimism.

    Science.gov (United States)

    Sherman, Aurora M; Cotter, Kelly A

    2013-01-01

    To assess the contribution of important psychological resources (i.e. optimism, pessimism, control beliefs) to the psychological well-being of older adults with Osteoarthritis (OA); to assess the direct and mediated association of these psychosocial resources to outcomes (depressive symptoms, life satisfaction, and self-esteem). These objectives are important because OA is a significant stressor, treatments are limited, and psychological functioning is at risk for those coping with the condition, even compared to other chronic illnesses. A cross-sectional survey of 160 community-dwelling older adults with OA (81% women). Participants were not randomly selected, but nonetheless reflected the demographic makeup of the selection area. Ordinary least squares regression analyses using the PROCESS macro revealed that optimism and pessimism were associated with higher depressive symptoms and lower self-esteem indirectly through constraints beliefs. The analysis of life satisfaction showed that optimism and pessimism were each partially mediated through mastery and constraints beliefs. These results suggest that prior research, which has assessed these psychological resources as having singular relationships to outcomes, may have underestimated the importance of the relationship between these variables. We discuss possible points of intervention for older adults with OA who may experience increasing constraints beliefs over time.

  10. RISC-mediated control of selected chromatin regulators stabilizes ground state pluripotency of mouse embryonic stem cells.

    Science.gov (United States)

    Pandolfini, Luca; Luzi, Ettore; Bressan, Dario; Ucciferri, Nadia; Bertacchi, Michele; Brandi, Rossella; Rocchiccioli, Silvia; D'Onofrio, Mara; Cremisi, Federico

    2016-05-06

    Embryonic stem cells are intrinsically unstable and differentiate spontaneously if they are not shielded from external stimuli. Although the nature of such instability is still controversial, growing evidence suggests that protein translation control may play a crucial role. We performed an integrated analysis of RNA and proteins at the transition between naïve embryonic stem cells and cells primed to differentiate. During this transition, mRNAs coding for chromatin regulators are specifically released from translational inhibition mediated by RNA-induced silencing complex (RISC). This suggests that, prior to differentiation, the propensity of embryonic stem cells to change their epigenetic status is hampered by RNA interference. The expression of these chromatin regulators is reinstated following acute inactivation of RISC and it correlates with loss of stemness markers and activation of early cell differentiation markers in treated embryonic stem cells. We propose that RISC-mediated inhibition of specific sets of chromatin regulators is a primary mechanism for preserving embryonic stem cell pluripotency while inhibiting the onset of embryonic developmental programs.

  11. Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

    Science.gov (United States)

    Ramírez, Sara; Gómez-Valadés, Alicia G; Schneeberger, Marc; Varela, Luis; Haddad-Tóvolli, Roberta; Altirriba, Jordi; Noguera, Eduard; Drougard, Anne; Flores-Martínez, Álvaro; Imbernón, Mónica; Chivite, Iñigo; Pozo, Macarena; Vidal-Itriago, Andrés; Garcia, Ainhoa; Cervantes, Sara; Gasa, Rosa; Nogueiras, Ruben; Gama-Pérez, Pau; Garcia-Roves, Pablo M; Cano, David A; Knauf, Claude; Servitja, Joan-Marc; Horvath, Tamas L; Gomis, Ramon; Zorzano, Antonio; Claret, Marc

    2017-06-06

    Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage

    Directory of Open Access Journals (Sweden)

    Marie-Jo Halaby

    2015-01-01

    Full Text Available Synthesis of the p53 tumor suppressor increases following DNA damage. This increase and subsequent activation of p53 are essential for the protection of normal cells against tumorigenesis. We previously discovered an internal ribosome entry site (IRES that is located at the 5′-untranslated region (UTR of p53 mRNA and found that the IRES activity increases following DNA damage. However, the mechanism underlying IRES-mediated p53 translation in response to DNA damage is still poorly understood. In this study, we discovered that translational control protein 80 (TCP80 has increased binding to the p53 mRNA in vivo following DNA damage. Overexpression of TCP80 also leads to increased p53 IRES activity in response to DNA damage. TCP80 has increased association with RNA helicase A (RHA following DNA damage and overexpression of TCP80, along with RHA, leads to enhanced expression of p53. Moreover, we found that MCF-7 breast cancer cells with decreased expression of TCP80 and RHA exhibit defective p53 induction following DNA damage and diminished expression of its downstream target PUMA, a proapoptotic protein. Taken together, our discovery of the function of TCP80 and RHA in regulating p53 IRES and p53 induction following DNA damage provides a better understanding of the mechanisms that regulate IRES-mediated p53 translation in response to genotoxic stress.

  13. Transcriptome Analysis and Screening for Potential Target Genes for RNAi-Mediated Pest Control of the Beet Armyworm, Spodoptera exigua.

    Science.gov (United States)

    Li, Hang; Jiang, Weihua; Zhang, Zan; Xing, Yanru; Li, Fei

    2013-01-01

    The beet armyworm, Spodoptera exigua (Hübner), is a serious pest worldwide that causes significant losses in crops. Unfortunately, genetic resources for the beet armyworm is extremely scarce. To improve these resources we sequenced the transcriptome of S. exigua representing all stages including eggs, 1(st) to 5(th) instar larvae, pupae, male and female adults using the Illumina Solexa platform. We assembled the transcriptome with Trinity that yielded 31,414 contigs. Of these contigs, 18,592 were annotated as protein coding genes by Blast searches against the NCBI nr database. It has been shown that knockdown of important insect genes by dsRNAs or siRNAs is a feasible mechanism to control insect pests. The first key step towards developing an efficient RNAi-mediated pest control technique is to find suitable target genes. To screen for effective target genes in the beet armyworm, we selected nine candidate genes. The sequences of these genes were amplified using the RACE strategy. Then, siRNAs were designed and chemically synthesized. We injected 2 µl siRNA (2 µg/µl) into the 4(th) instar larvae to knock down the respective target genes. The mRNA abundance of target genes decreased to different levels (∼20-94.3%) after injection of siRNAs. Knockdown of eight genes including chitinase7, PGCP, chitinase1, ATPase, tubulin1, arf2, tubulin2 and arf1 caused a significantly high level of mortality compared to the negative control (Ppest control.

  14. Surface-Chemistry-Mediated Control of Individual Magnetic Helical Microswimmers in a Swarm.

    Science.gov (United States)

    Wang, Xiaopu; Hu, Chengzhi; Schurz, Lukas; De Marco, Carmela; Chen, Xiangzhong; Pané, Salvador; Nelson, Bradley J

    2018-05-31

    Magnetic helical microswimmers, also known as artificial bacterial flagella (ABFs), perform 3D navigation in various liquids under low-strength rotating magnetic fields by converting rotational motion to translational motion. ABFs have been widely studied as carriers for targeted delivery and release of drugs and cells. For in vivo/ in vitro therapeutic applications, control over individual groups of swimmers within a swarm is necessary for several biomedical applications such as drug delivery or small-scale surgery. In this work, we present the selective control of individual swimmers in a swarm of geometrically and magnetically identical ABFs by modifying their surface chemistry. We confirm experimentally and analytically that the forward/rotational velocity ratio of ABFs is independent of their surface coatings when the swimmers are operated below their step-out frequency (the frequency requiring the entire available magnetic torque to maintain synchronous rotation). We also show that ABFs with hydrophobic surfaces exhibit larger step-out frequencies and higher maximum forward velocities compared to their hydrophilic counterparts. Thus, selective control of a group of swimmers within a swarm of ABFs can be achieved by operating the selected ABFs at a frequency that is below their step-out frequencies but higher than the step-out frequencies of unselected ABFs. The feasibility of this method is investigated in water and in biologically relevant solutions. Selective control is also demonstrated inside a Y-shaped microfluidic channel. Our results present a systematic approach for realizing selective control within a swarm of magnetic helical microswimmers.

  15. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation

    Science.gov (United States)

    Huebsch, Nathaniel; Lippens, Evi; Lee, Kangwon; Mehta, Manav; Koshy, Sandeep T.; Darnell, Max C.; Desai, Rajiv M.; Madl, Christopher M.; Xu, Maria; Zhao, Xuanhe; Chaudhuri, Ovijit; Verbeke, Catia; Kim, Woo Seob; Alim, Karen; Mammoto, Akiko; Ingber, Donald E.; Duda, Georg N.; Mooney, David J.

    2015-12-01

    The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel’s elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel’s elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direct therapeutic stem cell behaviours in situ.

  16. Controllable synthesis of metal selenide heterostructures mediated by Ag2Se nanocrystals acting as catalysts

    Science.gov (United States)

    Zhou, Jiangcong; Huang, Feng; Xu, Ju; Wang, Yuansheng

    2013-09-01

    Ag2Se nanocrystals were demonstrated to be novel semiconductor mediators, or in other word catalysts, for the growth of semiconductor heterostructures in solution. This is a result of the unique feature of Ag2Se as a fast ion conductor, allowing foreign cations to dissolve and then to heterogrow the second phase. Using Ag2Se nanocrystals as catalysts, dimeric metal selenide heterostructures such as Ag2Se-CdSe and Ag2Se-ZnSe, and even multi-segment heterostructures such as Ag2Se-CdSe-ZnSe and Ag2Se-ZnSe-CdSe, were successfully synthesized. Several interesting features were found in the Ag2Se based heterogrowth. At the initial stage of heterogrowth, a layer of the second phase forms on the surface of an Ag2Se nanosphere, with a curved junction interface between the two phases. With further growth of the second phase, the Ag2Se nanosphere tends to flatten the junction surface by modifying its shape from sphere to hemisphere in order to minimize the conjunct area and thus the interfacial energy. Notably, the crystallographic relationship of the two phases in the heterostructure varies with the lattice parameters of the second phase, in order to reduce the lattice mismatch at the interface. Furthermore, a small lattice mismatch at the interface results in a straight rod-like second phase, while a large lattice mismatch would induce a tortuous product. The reported results may provide a new route for developing novel selenide semiconductor heterostructures which are potentially applicable in optoelectronic, biomedical, photovoltaic and catalytic fields.Ag2Se nanocrystals were demonstrated to be novel semiconductor mediators, or in other word catalysts, for the growth of semiconductor heterostructures in solution. This is a result of the unique feature of Ag2Se as a fast ion conductor, allowing foreign cations to dissolve and then to heterogrow the second phase. Using Ag2Se nanocrystals as catalysts, dimeric metal selenide heterostructures such as Ag2Se-CdSe and Ag2Se

  17. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

    Science.gov (United States)

    Sakata, Ichiro; Park, Won-Mee; Walker, Angela K.; Piper, Paul K.; Chuang, Jen-Chieh; Osborne-Lawrence, Sherri

    2012-01-01

    The peptide hormone ghrelin is released from a distinct group of gastrointestinal cells in response to caloric restriction, whereas its levels fall after eating. The mechanisms by which ghrelin secretion is regulated remain largely unknown. Here, we have used primary cultures of mouse gastric mucosal cells to investigate ghrelin secretion, with an emphasis on the role of glucose. Ghrelin secretion from these cells upon exposure to different d-glucose concentrations, the glucose antimetabolite 2-deoxy-d-glucose, and other potential secretagogues was assessed. The expression profile of proteins involved in glucose transport, metabolism, and utilization within highly enriched pools of mouse ghrelin cells and within cultured ghrelinoma cells was also determined. Ghrelin release negatively correlated with d-glucose concentration. Insulin blocked ghrelin release, but only in a low d-glucose environment. 2-Deoxy-d-glucose prevented the inhibitory effect of high d-glucose exposure on ghrelin release. mRNAs encoding several facilitative glucose transporters, hexokinases, the ATP-sensitive potassium channel subunit Kir6.2, and sulfonylurea type 1 receptor were expressed highly within ghrelin cells, although neither tolbutamide nor diazoxide exerted direct effects on ghrelin secretion. These findings suggest that direct exposure of ghrelin cells to low ambient d-glucose stimulates ghrelin release, whereas high d-glucose and glucose metabolism within ghrelin cells block ghrelin release. Also, low d-glucose sensitizes ghrelin cells to insulin. Various glucose transporters, channels, and enzymes that mediate glucose responsiveness in other cell types may contribute to the ghrelin cell machinery involved in regulating ghrelin secretion under these different glucose environments, although their exact roles in ghrelin release remain uncertain. PMID:22414807

  18. Environmental and cortisol-mediated control of Ca(2+) uptake in tilapia (Oreochromis mossambicus).

    Science.gov (United States)

    Lin, Chia-Hao; Kuan, Wei-Chun; Liao, Bo-Kai; Deng, Ang-Ni; Tseng, Deng-Yu; Hwang, Pung-Pung

    2016-04-01

    Ca(2+) is a vital element for many physiological processes in vertebrates, including teleosts, which live in aquatic environments and acquire Ca(2+) from their surroundings. Ionocytes within the adult gills or larval skin are critical sites for transcellular Ca(2+) uptake in teleosts. The ionocytes of zebrafish were found to contain transcellular Ca(2+) transporters, epithelial Ca(2+) channel (ECaC), plasma membrane Ca(2+)-ATPase 2 (PMCA2), and Na(+)/Ca(2+) exchanger 1b (NCX1b), providing information about the molecular mechanism of transcellular Ca(2+) transports mediated by ionocytes in fish. However, more evidence is required to establish whether or not a similar mechanism of transcellular Ca(2+) transport also exists in others teleosts. In the present study, ecac, pmca2, and ncx1 were found to be expressed in the branchial ionocytes of tilapia, thereby providing further support for the mechanism of transcellular Ca(2+) transport through ionocytes previously proposed for zebrafish. In addition, we also reveal that low Ca(2+) water treatment of tilapia stimulates Ca(2+) uptake and expression of ecac and cyp11b (the latter encodes a cortisol-synthesis enzyme). Treatment of tilapia with exogenous cortisol (20 mg/l) enhanced both Ca(2+) influx and ecac expression. Therefore, increased cyp11b expression is suggested to enhance Ca(2+) uptake capacity in tilapia exposed to low Ca(2+) water. Furthermore, the application of cortisol receptor antagonists revealed that cortisol may regulate Ca(2+) uptake through glucocorticoid and/or mineralocorticoid receptor (GR and/or MR) in tilapia. Taken together, the data suggest that cortisol may activate GR and/or MR to execute its hypercalcemic action by stimulating ecac expression in tilapia.

  19. Analysis of PGC-1α variants Gly482Ser and Thr612Met concerning their PPARγ2-coactivation function

    International Nuclear Information System (INIS)

    Nitz, Inke; Ewert, Agnes; Klapper, Maja; Doering, Frank

    2007-01-01

    Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1α gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-γ 2 (PPARγ2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1α and PPARγ2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1α and Pro12Ala polymorphism in PPARγ2 do not affect the functional integrity of these proteins

  20. Nontranscriptional regulation of SYK by the coactivator OCA-B is required at multiple stages of B cell development.

    Science.gov (United States)

    Siegel, Rachael; Kim, Unkyu; Patke, Alina; Yu, Xin; Ren, Xiaodi; Tarakhovsky, Alexander; Roeder, Robert G

    2006-05-19

    OCA-B was originally identified as a nuclear transcriptional coactivator that is essential for antigen-driven immune responses. The later identification of a membrane bound, myristoylated form of OCA-B suggested additional, unique functions in B cell signaling pathways. This study has shown that OCA-B also functions in the pre-B1-to-pre-B2 cell transition and, most surprisingly, that it directly interacts with SYK, a tyrosine kinase critical for pre-BCR and BCR signaling. This unprecedented type of interaction-a transcriptional coactivator with a signaling kinase-occurs in the cytoplasm and directly regulates SYK stability. This study indicates that OCA-B is required for pre-BCR and BCR signaling at multiple stages of B cell development through its nontranscriptional regulation of SYK. Combined with the deregulation of OCA-B target genes, this may help explain the multitude of defects observed in B cell development and immune responses of Oca-b-/- mice.

  1. Computational stability of human knee joint at early stance in Gait: Effects of muscle coactivity and anterior cruciate ligament deficiency.

    Science.gov (United States)

    Sharifi, M; Shirazi-Adl, A; Marouane, H

    2017-10-03

    As one of the most complex and vulnerable structures of body, the human knee joint should maintain dynamic equilibrium and stability in occupational and recreational activities. The evaluation of its stability and factors affecting it is vital in performance evaluation/enhancement, injury prevention and treatment managements. Knee stability often manifests itself by pain, hypermobility and giving-way sensations and is usually assessed by the passive joint laxity tests. Mechanical stability of both the human knee joint and the lower extremity at early stance periods of gait (0% and 5%) were quantified here for the first time using a hybrid musculoskeletal model of the lower extremity. The roles of muscle coactivity, simulated by setting minimum muscle activation at 0-10% levels and ACL deficiency, simulated by reducing ACL resistance by up to 85%, on the stability margin as well as joint biomechanics (contact/muscle/ligament forces) were investigated. Dynamic stability was analyzed using both linear buckling and perturbation approaches at the final deformed configurations in gait. The knee joint was much more stable at 0% stance than at 5% due to smaller ground reaction and contact forces. Muscle coactivity, when at lower intensities (knee joint at the heel strike. It also markedly diminishes forces in lateral hamstrings (by up to 39%) and contact forces on the lateral plateau (by up to 17%). Current work emphasizes the need for quantification of the lower extremity stability margin in gait. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Controllable synthesis and characterization of CdS quantum dots by a microemulsion-mediated hydrothermal method

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Rongrong; Han, Boning; Yang, Lin, E-mail: yanglin@hbu.edu.cn; Yang, Yanmin; Xu, Ying; Mai, Yaohua, E-mail: yaohuamai@hbu.edu.cn

    2016-04-15

    CdS QDs were successfully synthesized through a chemical reaction between cadmium acetate dehydrate and thioacetamide by using a microemulsion-mediated hydrothermal method. The properties of as-prepared CdS QDs can be controlled by using Emulsifier OP and CTAB surfactant, which produce a universal cubic phase and an unusual hexagonal phase, respectively. As a comparison, CdS QDs prepared by CTAB exhibit a better crystallinity and dispersibility. A possible mechanism involving the critical role of surfactant in the formation of crystal structure has also been explored in this paper. It is also found that the crystal size gradually increase with the increase of temperature, and the observation of red-shift in the absorption and emission peaks gives a clear evidence of the quantum confinement effect. All the desired properties of CdS QDs synthesized in this study imply the possibility of the preparation of high quality QDs under the appropriate reaction conditions.

  3. Pulse-bandwidth dependence of coherent phase control of resonance-mediated (2+1) three-photon absorption

    International Nuclear Information System (INIS)

    Gandman, Andrey; Chuntonov, Lev; Rybak, Leonid; Amitay, Zohar

    2007-01-01

    We study in detail coherent phase control of femtosecond resonance-mediated (2+1) three-photon absorption and its dependence on the spectral bandwidth of the excitation pulse. The regime is the weak-field regime of third perturbative order. The corresponding interference mechanism involves a group of three-photon excitation pathways that are on resonance with the intermediate state and a group of three-photon excitation pathways that are near resonant with it. The model system of the study is atomic sodium (Na), for which experimental and numerical-theoretical results are obtained. Prominent among the results is our finding that with simple proper pulse shaping an increase in the excitation bandwidth leads to a corresponding increase in the enhancement of the three-photon absorption over the absorption induced by the (unshaped) transform-limited pulse. For example, here, a 40 nm bandwidth leads to an order-of-magnitude enhancement over the transform-limited absorption

  4. Incorporation of hyaluronic acid into collagen scaffolds for the control of chondrocyte-mediated contraction and chondrogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tang Shunqing [Department of Biomedical Engineering, Jinan University, Guangzhou 510632 (China); Spector, Myron [Tissue Engineering, VA Boston Healthcare System, Boston, MA 02130 (United States)

    2007-09-15

    Hyaluronic acid (HA), a principal matrix molecule in many tissues, is present in high amounts in articular cartilage. HA contributes in unique ways to the physical behavior of the tissue, and has been shown to have beneficial effects on chondrocyte activity. The goal of this study was to incorporate graduated amounts of HA into type I collagen scaffolds for the control of chondrocyte-mediated contraction and chondrogenesis in vitro. The results demonstrated that the amount of contraction of HA/collagen scaffolds by adult canine articular chondrocytes increased with the HA content of the scaffolds. The greatest amount of chondrogenesis after two weeks was found in the scaffolds which had undergone the most contraction. HA can play a useful role in adjusting the mechanical behavior of tissue engineering scaffolds and chondrogenesis in chondrocyte-seeded scaffolds.

  5. Global efficiency of structural networks mediates cognitive control in mild cognitive impairment

    NARCIS (Netherlands)

    Berlot, R. (Rok); Metzler-Baddeley, C. (Claudia); M.A. Ikram (Arfan); Jones, D.K. (Derek K.); O'Sullivan, M.J. (Michael J.)

    2016-01-01

    markdownabstract__Background:__ Cognitive control has been linked to both the microstructure of individual tracts and the structure of whole-brain networks, but their relative contributions in health and disease remain unclear. __Objective:__ To determine the contribution of both localized white

  6. Agrobacterium-mediated transformation of black cherry for flowering control and insect resistance

    Science.gov (United States)

    Ying Wang; Paula M. Pijut

    2014-01-01

    Black cherry is one of the most valuable hardwood species for cabinetry, furniture, and veneer. The goal of this study was to develop transgenic black cherry plants with reproductive sterility and enhanced insect resistance. Black cherry TERMINAL FLOWER 1 (PsTFL1) was overexpressed under the control of the CaMV 35S promoter in black cherry via

  7. Spinal sensory projection neuron responses to spinal cord stimulation are mediated by circuits beyond gate control.

    Science.gov (United States)

    Zhang, Tianhe C; Janik, John J; Peters, Ryan V; Chen, Gang; Ji, Ru-Rong; Grill, Warren M

    2015-07-01

    Spinal cord stimulation (SCS) is a therapy used to treat intractable pain with a putative mechanism of action based on the Gate Control Theory. We hypothesized that sensory projection neuron responses to SCS would follow a single stereotyped response curve as a function of SCS frequency, as predicted by the Gate Control circuit. We recorded the responses of antidromically identified sensory projection neurons in the lumbar spinal cord during 1- to 150-Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). The relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit accounted for a subset of neuronal responses to SCS but could not account for the full range of observed responses. Heterogeneous responses were classifiable into three additional groups and were reproduced using computational models of spinal microcircuits representing other interactions between nociceptive and nonnociceptive sensory inputs. Intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, suggesting that GABAA neurotransmission plays a broad role in regulating projection neuron activity. These in vivo and computational results challenge the Gate Control Theory as the only mechanism underlying SCS and refine our understanding of the effects of SCS on spinal sensory neurons within the framework of contemporary understanding of dorsal horn circuitry. Copyright © 2015 the American Physiological Society.

  8. Young-Age Gender Differences in Mathematics Mediated by Independent Control or Uncontrollability

    Science.gov (United States)

    Zirk-Sadowski, Jan; Lamptey, Charlotte; Devine, Amy; Haggard, Mark; Szucs, Dénes

    2014-01-01

    We studied whether the origins of math anxiety can be related to a biologically supported framework of stress induction: (un)controllability perception, here indicated by self-reported independent efforts in mathematics. Math anxiety was tested in 182 children (8- to 11-year-olds). "Latent factor modeling" was used to test hypotheses on…

  9. Microbial- and isothiocyanate-mediated control of Phytophthora and Pythium species

    Science.gov (United States)

    M.F. Cohen; E. Yamamoto; E. Condeso; B.L. Anacker; N. Rank; M. Mazzola

    2008-01-01

    Plant pathogens of the oomycete lineage share common susceptibilities to many biotic and abiotic stresses. We are investigating the potential of antagonistic bacteria, isothiocyanates, and mycophagous amoebae to control diseases caused by Phytophthora spp., including the etiologic agent of sudden oak death, Phytophthora ramorum (...

  10. Development of suicidality within socioeconomic context: mediation effect of parental control and anomie.

    Science.gov (United States)

    Heydari, Arash; Teymoori, Ali; Nasiri, Hedayat

    Despite some scientific research on suicide as one of the most serious social and mental health problems in Iran, there is still lack of research on the effective structural and socio-familial factors contributing to the issue in Iran. The purpose of this study is to investigate some of the effective variables conditioning suicidality while also establishing a synthetic model. Three hundred-fifty university students (165 males, 185 females) were randomly chosen from Shahid Chamran University, Ahvaz, Iran. The participants were asked to complete a package of self-report questionnaires including subjective socioeconomic status (SES), feeling of anomie, perceived parental control, and suicidality. The results show that all correlations among variables are significant. For testing the theoretical model, results of standardized regression coefficients suggest that SES has direct effect on suicidality and indirect effect via anomie and parental control. In addition, parental control has direct effects on suicidality and indirect effect via anomie as well. The findings confirm the expected paths hypothesized among variables which are consistent with the theories of Durkheim, Merton, Kohn, and Agnew. It implies that the development of suicidality takes place within socioeconomic context through the influence of parental control and feeling of anomie.

  11. Mediator binding to UASs is broadly uncoupled from transcription and cooperative with TFIID recruitment to promoters.

    Science.gov (United States)

    Grünberg, Sebastian; Henikoff, Steven; Hahn, Steven; Zentner, Gabriel E

    2016-11-15

    Mediator is a conserved, essential transcriptional coactivator complex, but its in vivo functions have remained unclear due to conflicting data regarding its genome-wide binding pattern obtained by genome-wide ChIP Here, we used ChEC-seq, a method orthogonal to ChIP, to generate a high-resolution map of Mediator binding to the yeast genome. We find that Mediator associates with upstream activating sequences (UASs) rather than the core promoter or gene body under all conditions tested. Mediator occupancy is surprisingly correlated with transcription levels at only a small fraction of genes. Using the same approach to map TFIID, we find that TFIID is associated with both TFIID- and SAGA-dependent genes and that TFIID and Mediator occupancy is cooperative. Our results clarify Mediator recruitment and binding to the genome, showing that Mediator binding to UASs is widespread, partially uncoupled from transcription, and mediated in part by TFIID. © 2016 The Authors.

  12. Nuclear Receptor Cofactors in PPARγ-Mediated Adipogenesis and Adipocyte Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Emily Powell

    2007-01-01

    Full Text Available Transcriptional cofactors are integral to the proper function and regulation of nuclear receptors. Members of the peroxisome proliferator-activated receptor (PPAR family of nuclear receptors are involved in the regulation of lipid and carbohydrate metabolism. They modulate gene transcription in response to a wide variety of ligands, a process that is mediated by transcriptional coactivators and corepressors. The mechanisms by which these cofactors mediate transcriptional regulation of nuclear receptor function are still being elucidated. The rapidly increasing array of cofactors has brought into focus the need for a clear understanding of how these cofactors interact in ligand- and cell-specific manners. This review highlights the differential effects of the assorted cofactors regulating the transcriptional action of PPARγ and summarizes the recent advances in understanding the physiological functions of corepressors and coactivators.

  13. Home blood pressure monitoring, secure electronic messaging and medication intensification for improving hypertension control: a mediation analysis.

    Science.gov (United States)

    Ralston, J D; Cook, A J; Anderson, M L; Catz, S L; Fishman, P A; Carlson, J; Johnson, R; Green, B B

    2014-01-01

    We evaluated the role of home monitoring, communication with pharmacists, medication intensification, medication adherence and lifestyle factors in contributing to the effectiveness of an intervention to improve blood pressure control in patients with uncontrolled essential hypertension. We performed a mediation analysis of a published randomized trial based on the Chronic Care Model delivered over a secure patient website from June 2005 to December 2007. Study arms analyzed included usual care with a home blood pressure monitor and usual care with home blood pressure monitor and web-based pharmacist care. Mediator measures included secure messaging and telephone encounters; home blood pressure monitoring; medications intensification and adherence and lifestyle factors. Overall fidelity to the Chronic Care Model was assessed with the Patient Assessment of Chronic Care (PACIC) instrument. The primary outcome was percent of participants with blood pressure (BP) <140/90 mm Hg. At 12 months follow-up, patients in the web-based pharmacist care group were more likely to have BP <140/90 mm Hg (55%) compared to patients in the group with home blood pressure monitors only (37%) (p = 0.001). Home blood pressure monitoring accounted for 30.3% of the intervention effect, secure electronic messaging accounted for 96%, and medication intensification for 29.3%. Medication adherence and self-report of fruit and vegetable intake and weight change were not different between the two study groups. The PACIC score accounted for 22.0 % of the main intervention effect. The effect of web-based pharmacist care on improved blood pressure control was explained in part through a combination of home blood pressure monitoring, secure messaging, and antihypertensive medication intensification.

  14. Determination of inmune response and inflammation mediators in tears: Changes in dry eye and glaucoma as compared to healthy controls.

    Science.gov (United States)

    Benitez-Del-Castillo Sánchez, J; Morillo-Rojas, M D; Galbis-Estrada, C; Pinazo-Duran, M D

    2017-05-01

    To determine the expression profile of immune response and inflammation (IRI) mediator molecules in tears from patients with dry eye (DE), and those suspected of having or have primary open-angle glaucoma (POAG) under treatment and compare them with healthy controls. A prospective observational cohort study including 107 participants sub-divided into: healthy controls (CG; n=30), patients with DE (DEG; n=41) and patients suspected of having or have POAG and on hypotensive treatment (POAG-G; n=36). Tear samples were collected by capillary to be processed using a multi-immunoassay system based on flow cytometry (Luminex R-200 ®), in order to determine the interleukins (IL): 1β, 2, 4, 5, 6, and 10, and the growth factors: Tumour necrosis alpha (TNF-α), vascular endothelial (VEGF), and granulocyte-macrophage colony stimulating- (GM-CSF). Data were processed using the SPSS 20.0 program. Molecules that significantly increased in tears from DEG vs. POAG-G patients were: IL-1 (P=.01), IL-6 (P=.004), IL-10 (P=.04), whereas VEGF significantly decreased in the DEG. The POAG-G showed significantly higher IL-6 values (P<.0001) as compared to the CG. When comparing both the DEG and POAG-G, significant differences were observed in tear expression of IL-4 (P=.004), IL-6 (P=.002), TNF-α (P=.03), GM-CSF (P=.03), and VEGF (P=.002). The increased expression of IRI mediators in tears from patients with DE or POAG strongly demonstrated the importance of immune response in both pathologies. However, the different molecules involved also suggest distinct signalling pathways for these processes that still require further research. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  15. Cross-site randomized control trial of the Social ABCs caregiver-mediated intervention for toddlers with autism spectrum disorder.

    Science.gov (United States)

    Brian, Jessica A; Smith, Isabel M; Zwaigenbaum, Lonnie; Bryson, Susan E

    2017-10-01

    To evaluate the efficacy of the Social ABCs parent-mediated intervention for toddlers with suspected or confirmed autism spectrum disorder (ASD), through a cross-site randomized control trial, sixty-three parent-toddler dyads (toddler age: 16-30 months) were randomized into treatment (Social ABCs) or control (service-as-usual) conditions. Video data were obtained at three key time-points: Baseline; Post-training (PT; week 12); and Follow-Up (week 24). Analyses included 62 dyads. Treatment allocation significantly accounted for PT gains, all favouring the Treatment group, in (1) child functional vocal responsiveness to parent prompts (R 2  = 0.43, P social orienting (R 2  = 0.06, P = 0.054); gains in parent smiling significantly predicted increases in child smiling and social orienting. Parents in the treatment condition reported significant gains in self-efficacy following the intervention (P = 0.009). No differential effects emerged for performance on standardized measures. The Social ABCs is a relatively low-resource, efficacious intervention, with potential to be a cost-effective means of intervening at the first signs of possible ASD. Autism Res 2017, 10: 1700-1711. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Clinical Trial Title: Social ABCs for Toddlers with Signs of Autism Spectrum Disorder: RCT of a Parent-Mediated Intervention http//ClinicalTrials.gov identifier: NCT02428452. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  16. Fluid-Mediated Stochastic Self-Assembly at Centimetric and Sub-Millimetric Scales: Design, Modeling, and Control

    Directory of Open Access Journals (Sweden)

    Bahar Haghighat

    2016-08-01

    Full Text Available Stochastic self-assembly provides promising means for building micro-/nano-structures with a variety of properties and functionalities. Numerous studies have been conducted on the control and modeling of the process in engineered self-assembling systems constituted of modules with varied capabilities ranging from completely reactive nano-/micro-particles to intelligent miniaturized robots. Depending on the capabilities of the constituting modules, different approaches have been utilized for controlling and modeling these systems. In the quest of a unifying control and modeling framework and within the broader perspective of investigating how stochastic control strategies can be adapted from the centimeter-scale down to the (sub-millimeter-scale, as well as from mechatronic to MEMS-based technology, this work presents the outcomes of our research on self-assembly during the past few years. As the first step, we leverage an experimental platform to study self-assembly of water-floating passive modules at the centimeter scale. A dedicated computational framework is developed for real-time tracking, modeling and control of the formation of specific structures. Using a similar approach, we then demonstrate controlled self-assembly of microparticles into clusters of a preset dimension in a microfluidic chamber, where the control loop is closed again through real-time tracking customized for a much faster system dynamics. Finally, with the aim of distributing the intelligence and realizing programmable self-assembly, we present a novel experimental system for fluid-mediated programmable stochastic self-assembly of active modules at the centimeter scale. The system is built around the water-floating 3-cm-sized Lily robots specifically designed to be operative in large swarms and allows for exploring the whole range of fully-centralized to fully-distributed control strategies. The outcomes of our research efforts extend the state-of-the-art methodologies

  17. Seed-mediated growth and manipulation of Au nanorods via size-controlled synthesis of Au seeds

    International Nuclear Information System (INIS)

    Liu Juncheng; Duggan, Jennifer N.; Morgan, Joshua; Roberts, Christopher B.

    2012-01-01

    Seed-mediated growth of gold (Au) nanorods with highly controllable length, width, and aspect ratio was accomplished via carefully size-controlled synthesis of the original Au seeds. A slow dynamic growth of Au nanoparticle seeds was observed after reduction of the Au salt (i.e., hydrogen tetrachloroaurate (III) hydrate) by sodium borohydride (NaBH 4 ) in the presence of cetyltrimethyl ammonium bromide (CTAB). As such, the size of the Au nanoparticle seeds can therefore be manipulated through control over the duration of the reaction period (i.e., aging times of 2, 8, 48, 72, and 144 h were used in this study). These differently sized Au nanoparticles were subsequently used as seeds for the growth of Au nanorods, where the additions of Au salt, CTAB, AgNO 3 , and ascorbic acid were employed. Smaller Au nanoparticle seeds obtained via short growth/aging time resulted in Au nanorods with higher aspect ratio and thus longer longitudinal surface plasmon wavelength (LSPW). The larger Au nanoparticle seeds obtained via longer growth/aging time resulted in Au nanorods with lower aspect ratio and shorter LSPW.

  18. cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses.

    Science.gov (United States)

    Hahn, William O; Butler, Noah S; Lindner, Scott E; Akilesh, Holly M; Sather, D Noah; Kappe, Stefan Hi; Hamerman, Jessica A; Gale, Michael; Liles, W Conrad; Pepper, Marion

    2018-01-25

    Sensing of pathogens by host pattern recognition receptors is essential for activating the immune response during infection. We used a nonlethal murine model of malaria (Plasmodium yoelii 17XNL) to assess the contribution of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) to the development of humoral immunity. Despite previous reports suggesting a critical, intrinsic role for cGAS in early B cell responses, cGAS-deficient (cGAS-/-) mice had no defect in the early expansion or differentiation of Plasmodium-specific B cells. As the infection proceeded, however, cGAS-/- mice exhibited higher parasite burdens and aberrant germinal center and memory B cell formation when compared with littermate controls. Antimalarial drugs were used to further demonstrate that the disrupted humoral response was not B cell intrinsic but instead was a secondary effect of a loss of parasite control. These findings therefore demonstrate that cGAS-mediated innate-sensing contributes to parasite control but is not intrinsically required for the development of humoral immunity. Our findings highlight the need to consider the indirect effects of pathogen burden in investigations examining how the innate immune system affects the adaptive immune response.

  19. Seed-mediated synthesis of silver nanocrystals with controlled sizes and shapes in droplet microreactors separated by air.

    Science.gov (United States)

    Zhang, Lei; Wang, Yi; Tong, Limin; Xia, Younan

    2013-12-17

    Silver nanocrystals with uniform sizes were synthesized in droplet microreactors through seed-mediated growth. The key to the success of this synthesis is the use of air as a carrier phase to generate the droplets. The air not only separates the reaction solution into droplets but also provides O2 for the generation of reducing agent (glycolaldehyde). It also serves as a buffer space for the diffusion of NO, which is formed in situ due to the oxidative etching of Ag nanocrystals with twin defects. For the first time, we were able to generate Ag nanocrystals with controlled sizes and shapes in continuous production by using droplet microreactors. For Ag nanocubes, their edge lengths could be readily controlled in the range of 30-100 nm by varying the reaction time, the amount of seeds, and the concentration of AgNO3 in the droplets. Furthermore, we demonstrated the synthesis of Ag octahedra in the droplet microreactors. We believe that the air-driven droplet generation device can be extended to other noble metals for the production of nanocrystals with controlled sizes and shapes.

  20. Neutrophil and Alveolar Macrophage-Mediated Innate Immune Control of Legionella pneumophila Lung Infection via TNF and ROS.

    Directory of Open Access Journals (Sweden)

    Pascal Ziltener

    2016-04-01

    Full Text Available Legionella pneumophila is a facultative intracellular bacterium that lives in aquatic environments where it parasitizes amoeba. However, upon inhalation of contaminated aerosols it can infect and replicate in human alveolar macrophages, which can result in Legionnaires' disease, a severe form of pneumonia. Upon experimental airway infection of mice, L. pneumophila is rapidly controlled by innate immune mechanisms. Here we identified, on a cell-type specific level, the key innate effector functions responsible for rapid control of infection. In addition to the well-characterized NLRC4-NAIP5 flagellin recognition pathway, tumor necrosis factor (TNF and reactive oxygen species (ROS are also essential for effective innate immune control of L. pneumophila. While ROS are essential for the bactericidal activity of neutrophils, alveolar macrophages (AM rely on neutrophil and monocyte-derived TNF signaling via TNFR1 to restrict bacterial replication. This TNF-mediated antibacterial mechanism depends on the acidification of lysosomes and their fusion with L. pneumophila containing vacuoles (LCVs, as well as caspases with a minor contribution from cysteine-type cathepsins or calpains, and is independent of NLRC4, caspase-1, caspase-11 and NOX2. This study highlights the differential utilization of innate effector pathways to curtail intracellular bacterial replication in specific host cells upon L. pneumophila airway infection.

  1. Deterministic creation and stabilization of entanglement in circuit QED by homodyne-mediated feedback control

    International Nuclear Information System (INIS)

    Liu Zhuo; Kuang Luelin; Hu Kai; Xu Luting; Wei Suhua; Guo Lingzhen; Li Xinqi

    2010-01-01

    In a solid-state circuit QED system, we demonstrate that a homodyne-current-based feedback can create and stabilize highly entangled two-qubit states in the presence of a moderate noisy environment. Particularly, we present an extended analysis for the current-based Markovian feedback, which leads to an improved feedback scheme. We show that this is essential to achieve a desirable control effect by the use of dispersive measurement.

  2. Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence.

    Science.gov (United States)

    Lamas, Bruno; Michel, Marie-Laure; Waldschmitt, Nadine; Pham, Hang-Phuong; Zacharioudaki, Vassiliki; Dupraz, Louise; Delacre, Myriam; Natividad, Jane M; Costa, Gregory Da; Planchais, Julien; Sovran, Bruno; Bridonneau, Chantal; Six, Adrien; Langella, Philippe; Richard, Mathias L; Chamaillard, Mathias; Sokol, Harry

    2017-08-08

    In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 ( CARD9 ), a key innate immunity gene, is required to shape a normal gut microbiota. Card9 -/- mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli . Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms. C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 -/- mice. To explore the impact of Card9 -/- microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9 -/- ( Card9 -/- →GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota-host immune system interactions were assessed by quantitative PCR analysis. CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium -induced colitis was observed in Card9 -/- →GF mice. The microbiota of Card9 -/- mice failed to outcompete the monosaccharide-consuming C. rodentium , worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 -/- mice. CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017

  3. CRISPR-Cas9-Mediated Genome Editing and Transcriptional Control in Yarrowia lipolytica.

    Science.gov (United States)

    Schwartz, Cory; Wheeldon, Ian

    2018-01-01

    The discovery and adaptation of RNA-guided nucleases has resulted in the rapid development of efficient, scalable, and easily accessible synthetic biology tools for targeted genome editing and transcriptional control. In these systems, for example CRISPR-Cas9 from Streptococcus pyogenes, a protein with nuclease activity is targeted to a specific nucleotide sequence by a short RNA molecule, whereupon binding it cleaves the targeted nucleotide strand. To extend this genome-editing ability to the industrially important oleaginous yeast Yarrowia lipolytica, we developed a set of easily usable and effective CRISPR-Cas9 episomal vectors. In this protocols chapter, we first present a method by which arbitrary protein-coding genes can be disrupted via indel formation after CRISPR-Cas9 targeting. A second method demonstrates how the same CRISPR-Cas9 system can be used to induce markerless gene cassette integration into the genome by inducing homologous recombination after DNA cleavage by Cas9. Finally, we describe how a catalytically inactive form of Cas9 fused to a transcriptional repressor can be used to control transcription of native genes in Y. lipolytica. The CRISPR-Cas9 tools and strategies described here greatly increase the types of genome editing and transcriptional control that can be achieved in Y. lipolytica, and promise to facilitate more advanced engineering of this important oleaginous host.

  4. Neo-Geometric Copper Nanocrystals by Competitive, Dual Surfactant-Mediated Facet Adsorption Controlling Skin Permeation

    Directory of Open Access Journals (Sweden)

    Karmani Murugan

    2016-11-01

    Full Text Available Neogeometric copper nanoparticles (CuNPs have various applications yet its synthesis still proves to be challenging with regards to self-assembly and uniformity control. This study aimed to synthesize shape-specific CuNPs in the biomedical application of ascertaining skin permeation and retention of the CuNPs as a drug delivery system. The approach to the shape design involved the dual control of two surfactants to direct the shape organisation of the nanoparticles (NPs while an interesting aspect of the study showed the competitive adsorption of the surfactants onto the nanocrystal facets to direct facet growth. The resulting copper nanoparticles were characterised using X-ray diffraction (XRD and electron diffraction spectra analysis (EDS for elemental and crystalline analysis. Thermogravimetric Analysis (TGA identified the degradation of the surfactant coat and the synthesis of a novel copper-polymer complex and extensive transmission electron microscopy (TEM was conducted to determine the nanoparticle morphology. Epidermal skin tissue served as the model for permeation studies of five idealistic nano-geometries and investigated its application in drug delivery with regards to cellular internalisation and transbarrier transport of the geometric CuNPs. A mechanistic consideration for shape control is discussed.

  5. Biodiversity mediates top-down control in eelgrass ecosystems: a global comparative-experimental approach.

    Science.gov (United States)

    Duffy, J Emmett; Reynolds, Pamela L; Boström, Christoffer; Coyer, James A; Cusson, Mathieu; Donadi, Serena; Douglass, James G; Eklöf, Johan S; Engelen, Aschwin H; Eriksson, Britas Klemens; Fredriksen, Stein; Gamfeldt, Lars; Gustafsson, Camilla; Hoarau, Galice; Hori, Masakazu; Hovel, Kevin; Iken, Katrin; Lefcheck, Jonathan S; Moksnes, Per-Olav; Nakaoka, Masahiro; O'Connor, Mary I; Olsen, Jeanine L; Richardson, J Paul; Ruesink, Jennifer L; Sotka, Erik E; Thormar, Jonas; Whalen, Matthew A; Stachowicz, John J

    2015-07-01

    Nutrient pollution and reduced grazing each can stimulate algal blooms as shown by numerous experiments. But because experiments rarely incorporate natural variation in environmental factors and biodiversity, conditions determining the relative strength of bottom-up and top-down forcing remain unresolved. We factorially added nutrients and reduced grazing at 15 sites across the range of the marine foundation species eelgrass (Zostera marina) to quantify how top-down and bottom-up control interact with natural gradients in biodiversity and environmental forcing. Experiments confirmed modest top-down control of algae, whereas fertilisation had no general effect. Unexpectedly, grazer and algal biomass were better predicted by cross-site variation in grazer and eelgrass diversity than by global environmental gradients. Moreover, these large-scale patterns corresponded strikingly with prior small-scale experiments. Our results link global and local evidence that biodiversity and top-down control strongly influence functioning of threatened seagrass ecosystems, and suggest that biodiversity is comparably important to global change stressors. © 2015 John Wiley & Sons Ltd/CNRS.

  6. Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo.

    Science.gov (United States)

    Douam, Florian; Soto Albrecht, Yentli E; Hrebikova, Gabriela; Sadimin, Evita; Davidson, Christian; Kotenko, Sergei V; Ploss, Alexander

    2017-08-15

    role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies. Copyright © 2017 Douam et al.

  7. Light-activated control of protein channel assembly mediated by membrane mechanics

    Science.gov (United States)

    Miller, David M.; Findlay, Heather E.; Ces, Oscar; Templer, Richard H.; Booth, Paula J.

    2016-12-01

    Photochemical processes provide versatile triggers of chemical reactions. Here, we use a photoactivated lipid switch to modulate the folding and assembly of a protein channel within a model biological membrane. In contrast to the information rich field of water-soluble protein folding, there is only a limited understanding of the assembly of proteins that are integral to biological membranes. It is however possible to exploit the foreboding hydrophobic lipid environment and control membrane protein folding via lipid bilayer mechanics. Mechanical properties such as lipid chain lateral pressure influence the insertion and folding of proteins in membranes, with different stages of folding having contrasting sensitivities to the bilayer properties. Studies to date have relied on altering bilayer properties through lipid compositional changes made at equilibrium, and thus can only be made before or after folding. We show that light-activation of photoisomerisable di-(5-[[4-(4-butylphenyl)azo]phenoxy]pentyl)phosphate (4-Azo-5P) lipids influences the folding and assembly of the pentameric bacterial mechanosensitive channel MscL. The use of a photochemical reaction enables the bilayer properties to be altered during folding, which is unprecedented. This mechanical manipulation during folding, allows for optimisation of different stages of the component insertion, folding and assembly steps within the same lipid system. The photochemical approach offers the potential to control channel assembly when generating synthetic devices that exploit the mechanosensitive protein as a nanovalve.

  8. ATM Mediates pRB Function To Control DNMT1 Protein Stability and DNA Methylation

    Science.gov (United States)

    Suzuki, Misa; Hayashi, Naoyuki; Kobayashi, Masahiko; Sasaki, Nobunari; Nishiuchi, Takumi; Doki, Yuichiro; Okamoto, Takahiro; Kohno, Susumu; Muranaka, Hayato; Kitajima, Shunsuke; Yamamoto, Ken-ichi

    2013-01-01

    The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression. PMID:23754744

  9. Basomedial amygdala mediates top–down control of anxiety and fear

    Science.gov (United States)

    Adhikari, Avishek; Lerner, Talia N.; Finkelstein, Joel; Pak, Sally; Jennings, Joshua H.; Davidson, Thomas J.; Ferenczi, Emily; Gunaydin, Lisa A.; Mirzabekov, Julie J.; Ye, Li; Kim, Sung-Yon; Lei, Anna; Deisseroth, Karl

    2016-01-01

    Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway. PMID:26536109

  10. Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Bassam R Ali

    Full Text Available Hereditary haemorrhagic telangiectasia (HHT is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W out of thirteen mutants in the Zona Pellucida (ZP domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional

  11. Control of room-temperature defect-mediated ferromagnetism in VO{sub 2} films

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Tsung-Han, E-mail: tyang3@ncsu.edu [NSF Center for Advanced Materials and Smart Structures, Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695-7907 (United States); Nori, Sudhakar; Mal, Siddhartha; Narayan, Jagdish [NSF Center for Advanced Materials and Smart Structures, Department of Materials Science and Engineering, North Carolina State University, Raleigh, NC 27695-7907 (United States)

    2011-09-15

    We report interesting ferromagnetic properties and their control in a vanadium-based oxide system driven by stoichiometric defects. Vanadium oxide (VO{sub 2}) thin films were grown on c-plane sapphire substrates by a pulsed laser deposition technique under different ambient conditions. The ferromagnetism of the epitaxial VO{sub 2} films can be switched on and off by altering the cooling ambient parameters. In addition, the saturated magnetic moments and coercivity of the VO{sub 2} films were found to be a function of the oxygen partial pressure during the growth process. The room-temperature ferromagnetic properties of VO{sub 2} films were correlated with the nature of the microstructure and the growth parameters. The origin of the induced magnetic properties are qualitatively understood to stem from intrinsic structural and stoichiometric defects.

  12. Cell Density Control of Staphylococcal Virulence Mediated by an Octapeptide Pheromone

    Science.gov (United States)

    Ji, Guangyong; Beavis, Ronald C.; Novick, Richard P.

    1995-12-01

    Some bacterial pathogens elaborate and secrete virulence factors in response to environmental signals, others in response to a specific host product, and still others in response to no discernible cue. In this study, we have demonstrated that the synthesis of Staphylococcus aureus virulence factors is controlled by a density-sensing system that utilizes an octapeptide produced by the organism itself. The octapeptide activates expression of the agr locus, a global regulator of the virulence response. This response involves the reciprocal regulation of genes encoding surface proteins and those encoding secreted virulence factors. As cells enter the postexponential phase, surface protein genes are repressed by agr and secretory protein genes are subsequently activated. The intracellular agr effector is a regulatory RNA, RNAIII, whose transcription is activated by an agr-encoded signal transduction system for which the octapeptide is the ligand.

  13. Competitive excitation and osmotic-pressure-mediated control of lasing modes in cholesteric liquid crystal microshells

    Science.gov (United States)

    Lin, Ya-Li; Gong, Ling-Li; Che, Kai-Jun; Li, Sen-Sen; Chu, Cheng-Xu; Cai, Zhi-Ping; Yang, Chaoyong James; Chen, Lu-Jian

    2017-05-01

    We examined the end-pumped lasing behaviors of dye doped cholesteric liquid crystal (DDCLC) microshells which were fabricated by glass capillary microfluidics. Several kinds of mode resonances, including distributed feedback, Fabry-Pérot (FP), and whispering gallery (WG) modes, can be robustly constructed in each individual DDCLC microshell by varying the beam diameter, namely, tuning the DDCLC gain area. The FP and WG modes were further confirmed experimentally, and the corresponding lasing mechanisms are clearly revealed from the unique material characteristics of DDCLC and the geometrical structure of the microshell. Additionally, we demonstrated that the osmotic pressure can be used to shrink/expand the microshell, productively tuning the excitation of lasing modes in a controlled manner. We wish our findings can provide a new insight into the design of DDCLC microlasers with tunable optical properties.

  14. Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2

    DEFF Research Database (Denmark)

    de Boer, Michiel P; Meijer, Rick I; Richter, Erik

    2016-01-01

    Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulin's vasoactive effects through AMP......-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular...... endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin...

  15. Assertive Anger Mediates Effects of Dialectical Behaviour-informed Skills Training for Borderline Personality Disorder: A Randomized Controlled Trial.

    Science.gov (United States)

    Kramer, Ueli; Pascual-Leone, Antonio; Berthoud, Laurent; de Roten, Yves; Marquet, Pierre; Kolly, Stéphane; Despland, Jean-Nicolas; Page, Dominique

    2016-05-01

    Dialectical behaviour therapy (DBT)-informed skills training for borderline personality disorder (BPD) aims at the development of specific emotion regulation skills in patients, particularly with regard to the regulation of problematic anger. While the effects of dialectical behaviour skills training have been shown, their processes of change are rarely examined. Neacsiu, Rizvi and Linehan (2010) found that patient's self-reported use of emotion regulation skills was a mediator of therapeutic change in these treatments; however, they found no effect for problematic anger. From an integrative perspective on anger (Pascual-Leone & Greenberg, 2007; Pascual-Leone & Paivio, 2013), there are several forms of anger, varying in their degree of therapeutic productivity. The present add-on randomized controlled trial included n = 41 patients with BPD (n = 21 DBT-informed skills training versus n = 20 treatment as usual). The first study examined the outcome of the DBT-informed skills training encompassing basic components of training in mindfulness, distress tolerance, interpersonal effectiveness and emotion regulation. Results showed that symptom reduction was significantly greater in the DBT-informed skills training, compared with the treatment as usual. The second study used process assessment, for which all patient completers underwent a 50-min-long psychological interview both early and late in treatment, which was rated using the Classification of Affective Meaning States. DBT-informed skills training produced increased levels of primary 'assertive' anger, as compared with the treatment as usual, whereas no effect was found for 'rejecting' secondary anger. Most importantly, we showed that changes in assertive anger mediated the reported symptom reduction, in particular in patient's social roles. We discuss these results in the context of underlying mechanisms of change in DBT skills group treatments, in particular towards developing more productive forms of

  16. Gibberellin mediates daylength-controlled differentiation of vegetative meristems in strawberry (Fragaria × ananassa Duch

    Directory of Open Access Journals (Sweden)

    Moritz Thomas

    2009-02-01

    Full Text Available Abstract Background Differentiation of long and short shoots is an important developmental trait in several species of the Rosaceae family. However, the physiological mechanisms controlling this differentiation are largely unknown. We have studied the role of gibberellin (GA in regulation of shoot differentiation in strawberry (Fragaria × ananassa Duch. cv. Korona. In strawberry, differentiation of axillary buds to runners (long shoot or to crown branches (short shoot is promoted by long-day and short-day conditions, respectively. Formation of crown branches is a prerequisite for satisfactory flowering because inflorescences are formed from the apical meristems of the crown. Results We found that both prohexadione-calcium and short photoperiod inhibited runner initiation and consequently led to induction of crown branching. In both cases, this correlated with a similar decline in GA1 level. Exogenous GA3 completely reversed the effect of prohexadione-calcium in a long photoperiod, but was only marginally effective in short-day grown plants. However, transfer of GA3-treated plants from short days to long days restored the normal runner formation. This did not occur in plants that were not treated with GA3. We also studied GA signalling homeostasis and found that the expression levels of several GA biosynthetic, signalling and target genes were similarly affected by prohexadione-calcium and short photoperiod in runner tips and axillary buds, respectively. Conclusion GA is needed for runner initiation in strawberry, and the inhibition of GA biosynthesis leads to the formation of crown branches. Our findings of similar changes in GA levels and in GA signalling homeostasis after prohexadione-calcium and short-day treatments, and photoperiod-dependent responsiveness of the axillary buds to GA indicate that GA plays a role also in the photoperiod-regulated differentiation of axillary buds. We propose that tightly regulated GA activity may control

  17. A Coincidence Detection Mechanism Controls PX-BAR Domain-Mediated Endocytic Membrane Remodeling via an Allosteric Structural Switch.

    Science.gov (United States)

    Lo, Wen-Ting; Vujičić Žagar, Andreja; Gerth, Fabian; Lehmann, Martin; Puchkov, Dymtro; Krylova, Oxana; Freund, Christian; Scapozza, Leonardo; Vadas, Oscar; Haucke, Volker

    2017-11-20

    Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P 2 ) at endocytic sites. Structural, biochemical, and cell biological data show that SNX9 is autoinhibited in solution. Binding to PI(3,4)P 2 via its PX-BAR domain, and concomitant association with AP2 via sequences in the linker region, releases SNX9 autoinhibitory contacts to enable membrane constriction. Our results reveal a mechanism for restricting the latent membrane remodeling activity of BAR domain proteins to allow spatiotemporal coupling of membrane constriction to the progression of the endocytic pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Disintegration mediated controlled release supersaturating solid dispersion formulation of an insoluble drug: design, development, optimization, and in vitro evaluation.

    Science.gov (United States)

    Verma, Sanjay; Rudraraju, Varma S

    2015-02-01

    The objective of this study was to develop a solid dispersion based controlled release system for drug substances that are poorly soluble in water. A wax-based disintegration mediated controlled release system was designed based on the fact that an amorphous drug can crystallize out from hydrophilic matrices. For this study, cilostazol (CIL) was selected as the model drug, as it exhibits poor aqueous solubility. An amorphous solid dispersion was prepared to assist the drug to attain a supersaturated state. Povidone was used as carrier for solid dispersion (spray drying technique), hydrogenated vegetable oil (HVO) as wax matrix former, and sodium carboxymethyl cellulose (NaCMC) as a disintegrant. The extreme vertices mixture design (EVMD) was applied to optimize the designed and developed composition. The optimized formulation provided a dissolution pattern which was equivalent to the predicted curve, ascertaining that the optimal formulation could be accomplished with EVMD. The release profile of CIL was described by the Higuchi's model better than zero-order, first-order, and Hixson-Crowell's model, which indicated that the supersaturation state of CIL dominated to allow drug release by diffusion rather than disintegration regulated release as is generally observed by Hixson-Crowell's model. The optimized composition was evaluated for disintegration, dissolution, XRD, and stability studies. It was found that the amorphous state as well as the dissolution profile of CIL was maintained under the accelerated conditions of 40°C/75% RH for 6 months.

  19. Foodborne Infectious Diseases Mediated by Inappropriate Infection Control in Food Service Businesses and Relevant Countermeasures in Korea.

    Science.gov (United States)

    Park, Jong Myong; You, Young-Hyun; Cho, Hyun-Min; Hong, Ji Won; Ghim, Sa-Youl

    2017-06-01

    The objective of this review is to propose an appropriate course of action for improving the guidelines followed by food handlers for control of infection. For this purpose, previous epidemiological reports related to acute gastroenteritis in food service businesses mediated by food handlers were intensively analyzed. Relevant studies were identified in international databases. We selected eligible papers reporting foodborne infectious disease outbreaks. Among primary literature collection, the abstract of each article was investigated to find cases that absolutely identified a causative factor to be food handlers' inappropriate infection control and the taxon of causative microbial agents by epidemiological methodologies. Information about the sites (type of food business) where the outbreaks occurred was investigated. A wide variety of causative microbial agents has been investigated, using several epidemiological methods. These agents have shown diverse propagation pathways based on their own molecular pathogenesis, physiology, taxonomy, and etiology. Depending on etiology, transmission, propagation, and microbiological traits, we can predict the transmission characteristics of pathogens in food preparation areas. The infected food workers have a somewhat different ecological place in infection epidemiology as compared to the general population. However, the current Korean Food Safety Act cannot propose detailed guidelines. Therefore, different methodologies have to be made available to prevent further infections.

  20. Sutureless liver repair and hemorrhage control using laser-mediated fusion of human albumin as a solder.

    Science.gov (United States)

    Wadia, Y; Xie, H; Kajitani, M

    2001-07-01

    Major liver trauma has a high mortality because of immediate exsanguination and a delayed morbidity from septicemia, peritonitis, biliary fistulae, and delayed secondary hemorrhage. We evaluated laser soldering using liquid albumin for welding liver injuries. Fourteen lacerations (6 x 2 cm) and 13 nonanatomic resection injuries (raw surface, 8 x 2 cm) were repaired. An 805-nm laser was used to weld 53% liquid albumin-indocyanine green solder to the liver surface, reinforcing it by welding a free autologous omental scaffold. The animals were heparinized and hepatic inflow occlusion was used for vascular control. For both laceration and resection injuries, 16 soldering repairs were evaluated acutely at 3 hours. Eleven animals were evaluated chronically, two at 2 weeks and nine at 4 weeks. All 27 laser mediated-liver repairs had minimal blood loss compared with the suture controls. No dehiscence, hemorrhage, or bile leakage was seen in any of the laser repairs after 3 hours. All 11 chronic repairs healed without complication. This modality effectively seals the liver surface, joins lacerations with minimal thermal injury, and works independently of the patient's coagulation status.

  1. The mediating effect of Mediterranean diet on the relation between smoking and colorectal cancer: a case-control study.

    Science.gov (United States)

    Kontou, Niki; Psaltopoulou, Theodora; Soupos, Nick; Polychronopoulos, Evangelos; Xinopoulos, Dimitrios; Linos, Athena; Panagiotakos, Demosthenes B

    2013-10-01

    The protective role of Mediterranean diet (MD) and the detrimental effect of smoking on colorectal cancer (CRC) have already been shown. The aim of this work was to evaluate the potential mediating effect of MD on the association between the aforementioned factor (smoking) and CRC. It is a case-control study. Two hundred fifty consecutive patients with CRC (63 ± 12 years, 59% males) and 250 age-sex group-matched controls, both from the area of Attica, were studied. Various socio-demographic, clinical, lifestyle (including detailed smoking habits) and dietary characteristics were measured. Adherence to the MD was evaluated using the MedDietScore (theoretical range 0-55). Each unit increase in the MedDietScore was associated with 13% lower likelihood of CRC (P Smoking habits were associated with 2.9-fold the likelihood of CRC among participants who were away from the MD (i.e. MedDietScore smoking habits with CRC, suggesting indirect benefits of adherence to this dietary pattern with regards to CRC morbidity and mortality.

  2. Diffusion-controlled oxygen reduction on multi-copper oxidase-adsorbed carbon aerogel electrodes without mediator

    Energy Technology Data Exchange (ETDEWEB)

    Tsujimura, S.; Kamitaka, Y.; Kano, K. [Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto (Japan)

    2007-12-15

    Bioelectrocatalytic reduction of O{sub 2} into water was archived at diffusion-controlled rate by using enzymes (laccase from Trametes sp. and bilirubin oxidase from Myrothecium verrucaria, which belong to the family of multi-copper oxidase) adsorbed on mesoporous carbon aerogel particle without a mediator. The current density was predominantly controlled by the diffusion of dissolved O{sub 2} in rotating-disk electrode experiments, and reached a value as large as 10 mA cm{sup -2} at 1 atm O{sub 2}, 25 C, and 8,000 rpm on the laccase-adsorbed electrode. The overpotential of the bioelectrocatalytic reduction of O{sub 2} was 0.4-0.55 V smaller than that observed on a Pt disk electrode. Without any optimization, the laccase-adsorbed biocathode showed stable current intensity of the O{sub 2} reduction in an air-saturated buffer at least for 10 days under continuous flow system. (Abstract Copyright [2007], Wiley Periodicals, Inc.)

  3. Sleep-Related Safety Behaviors and Dysfunctional Beliefs Mediate the Efficacy of Online CBT for Insomnia: A Randomized Controlled Trial.

    Science.gov (United States)

    Lancee, Jaap; Eisma, Maarten C; van Straten, Annemieke; Kamphuis, Jan H

    2015-01-01

    Several trials have demonstrated the efficacy of online cognitive behavioral therapy (CBT) for insomnia. However, few studies have examined putative mechanisms of change based on the cognitive model of insomnia. Identification of modifiable mechanisms by which the treatment works may guide efforts to further improve the efficacy of insomnia treatment. The current study therefore has two aims: (1) to replicate the finding that online CBT is effective for insomnia and (2) to test putative mechanism of change (i.e., safety behaviors and dysfunctional beliefs). Accordingly, we conducted a randomized controlled trial in which individuals with insomnia were randomized to either online CBT for insomnia (n = 36) or a waiting-list control group (n = 27). Baseline and posttest assessments included questionnaires assessing insomnia severity, safety behaviors, dysfunctional beliefs, anxiety and depression, and a sleep diary. Three- and six-month assessments were administered to the CBT group only. Results show moderate to large statistically significant effects of the online treatment compared to the waiting list on insomnia severity, sleep measures, sleep safety behaviors, and dysfunctional beliefs. Furthermore, dysfunctional beliefs and safety behaviors mediated the effects of treatment on insomnia severity and sleep efficiency. Together, these findings corroborate the efficacy of online CBT for insomnia, and suggest that these effects were produced by changing maladaptive beliefs, as well as safety behaviors. Treatment protocols for insomnia may specifically be enhanced by more focused attention on the comprehensive fading of sleep safety behaviors, for instance through behavioral experiments.

  4. Activator Gcn4 Employs Multiple Segments of Med15/Gal11, Including the KIX Domain, to Recruit Mediator to Target Genes in Vivo*♦

    OpenAIRE

    Jedidi, Iness; Zhang, Fan; Qiu, Hongfang; Stahl, Stephen J.; Palmer, Ira; Kaufman, Joshua D.; Nadaud, Philippe S.; Mukherjee, Sujoy; Wingfield, Paul T.; Jaroniec, Christopher P.; Hinnebusch, Alan G.

    2009-01-01

    Mediator is a multisubunit coactivator required for initiation by RNA polymerase II. The Mediator tail subdomain, containing Med15/Gal11, is a target of the activator Gcn4 in vivo, critical for recruitment of native Mediator or the Mediator tail subdomain present in sin4Δ cells. Although several Gal11 segments were previously shown to bind Gcn4 in vitro, the importance of these interactions for recruitment of Mediator and transcriptional activation by Gcn4 in cells was unknown. We show that i...

  5. Coping Styles Mediate the Relationship Between Self-esteem, Health Locus of Control, and Health-Promoting Behavior in Chinese Patients With Coronary Heart Disease.

    Science.gov (United States)

    Zou, Huijing; Tian, Qian; Chen, Yuxia; Cheng, Cheng; Fan, Xiuzhen

    Health-promoting behavior plays an important role in reducing the burden of coronary heart disease. Self-esteem and health locus of control may contribute to health-promoting behavior, and coping styles may mediate these associations. The aims of our study were to examine whether self-esteem and health locus of control are associated with health-promoting behavior and examine the possible mediating effect of coping styles in patients with coronary heart disease. Health-promoting behavior, self-esteem, health locus of control, and coping styles were assessed in 272 hospitalized patients (60 ± 12 years, 61% male) with coronary heart disease. Hierarchical regression analysis was conducted to analyze the relationships between health-promoting behavior and other variables. Mediation effect was examined according to the methods of Baron and Kenny. The mean score for health-promoting behavior was 2.57 ± 0.51; 38.2% of patients (n = 104) scored lower than 2.5. Self-esteem (β = .139, P locus of control and health-promoting behavior. Confrontation plays a mediating role in the association among self-esteem, internal health locus of control, and health-promoting behavior. Strategies should be undertaken to encourage the use of confrontation coping style, which will facilitate health-promoting behavior.

  6. Compartmentalized Regulation of Parkin-Mediated Mitochondrial Quality Control in the Drosophila Nervous System In Vivo

    Science.gov (United States)

    Sung, Hyun; Tandarich, Lauren C.; Nguyen, Kenny

    2016-01-01

    In neurons, the normal distribution and selective removal of mitochondria are considered essential for maintaining the functions of the large asymmetric cell and its diverse compartments. Parkin, a E3 ubiquitin ligase associated with familial Parkinson's disease, has been implicated in mitochondrial dynamics and removal in cells including neurons. However, it is not clear how Parkin functions in mitochondrial turnover in vivo, or whether Parkin-dependent events of the mitochondrial life cycle occur in all neuronal compartments. Here, using the live Drosophila nervous system, we investigated the involvement of Parkin in mitochondrial dynamics, distribution, morphology, and removal. Contrary to our expectations, we found that Parkin-deficient animals do not accumulate senescent mitochondria in their motor axons or neuromuscular junctions; instead, they contain far fewer axonal mitochondria, and these displayed normal motility behavior, morphology, and metabolic state. However, the loss of Parkin did produce abnormal tubular and reticular mitochondria restricted to the motor cell bodies. In addition, in contrast to drug-treated, immortalized cells in vitro, mature motor neurons rarely displayed Parkin-dependent mitophagy. These data indicate that the cell body is the focus of Parkin-dependent mitochondrial quality control in neurons, and argue that a selection process allows only healthy mitochondria to pass from cell bodies to axons, perhaps to limit the impact of mitochondrial dysfunction. SIGNIFICANCE STATEMENT Parkin has been proposed to police mitochondrial fidelity by binding to dysfunctional mitochondria via PTEN (phosphatase and tensin homolog)-induced putative kinase 1 (PINK1) and targeting them for autophagic degradation. However, it is unknown whether and how the PINK1/Parkin pathway regulates the mitochondrial life cycle in neurons in vivo. Using Drosophila motor neurons, we show that parkin disruption generates an abnormal mitochondrial network in cell

  7. A Technology-Mediated Behavioral Weight Gain Prevention Intervention for College Students: Controlled, Quasi-Experimental Study.

    Science.gov (United States)

    West, Delia Smith; Monroe, Courtney M; Turner-McGrievy, Gabrielle; Sundstrom, Beth; Larsen, Chelsea; Magradey, Karen; Wilcox, Sara; Brandt, Heather M

    2016-06-13

    Both men and women are vulnerable to weight gain during the college years, and this phenomenon is linked to an increased risk of several chronic diseases and mortality. Technology represents an attractive medium for the delivery of weight control interventions focused on college students, given its reach and appeal among this population. However, few technology-mediated weight gain prevention interventions have been evaluated for college students. This study examined a new technology-based, social media-facilitated weight gain prevention intervention for college students. Undergraduates (n =58) in two sections of a public university course were allocated to either a behavioral weight gain prevention intervention (Healthy Weight, HW; N=29) or a human papillomavirus (HPV) vaccination awareness intervention (control; N=29). All students were enrolled, regardless of initial body weight or expressed interest in weight management. The interventions delivered 8 lessons via electronic newsletters and Facebook postings over 9 weeks, which were designed to foster social support and introduce relevant educational content. The HW intervention targeted behavioral strategies to prevent weight gain and provided participants with a Wi-Fi-enabled scale and an electronic physical activity tracker to facilitate weight regulation. A repeated-measures analysis of variance was conducted to examine within- and between-group differences in measures of self-reported weight control practices and objectively measured weight. Use of each intervention medium and device was objectively tracked, and intervention satisfaction measures were obtained. Students remained weight stable (HW: -0.48+1.9 kg; control: -0.45+1.4 kg), with no significant difference between groups over 9 weeks (P =.94). However, HW students reported a significantly greater increase in the number of appropriate weight control strategies than did controls (2.1+4.5 vs -1.1+3.4, respectively; P =.003) and there was no increase in

  8. Morphological control of strontium oxalate particles by PSMA-mediated precipitation reaction

    Energy Technology Data Exchange (ETDEWEB)

    Yu Jiaguo [State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070 (China)]. E-mail: jiaguoyu@yahoo.com; Tang Hua [State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070 (China); Cheng Bei [State Key Laboratory of Advanced Technology for Material Synthesis and Processing, Wuhan University of Technology, Wuhan 430070 (China)

    2005-05-15

    In this paper, strontium oxalate particles with different morphologies could be easily obtained by a precipitation reaction of sodium oxalate with strontium chloride in the absence and presence of poly-(styrene-alt-maleic acid) (PSMA). The as-prepared products were characterized with scanning electron microscopy and X-ray diffraction. The effects of pH, aging time and concentration of PSMA on the phase structures and morphologies of the as-prepared strontium oxalate particles were investigated and discussed. The results showed that strontium oxalate particles with various morphologies, such as, bi-pyramids, rods, peanuts, and spherical particles, etc., could be obtained by varying the experimental conditions. PSMA promoted the formation of strontium oxalate dihydrate (SOD) phase. Suitable pH values (pH 7 and 8) favor the formation of the peanut-shaped SrC{sub 2}O{sub 4} particles. This research may provide new insight into the control of morphologies and phase structures of strontium oxalate particles and the biomimetic synthesis of novel inorganic materials.

  9. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma.

    Science.gov (United States)

    Baranski, Zuzanna; Booij, Tijmen H; Cleton-Jansen, Anne-Marie; Price, Leo S; van de Water, Bob; Bovée, Judith V M G; Hogendoorn, Pancras C W; Danen, Erik H J

    2015-07-01

    Conventional high-grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti-apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G2 cell-cycle arrest; Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  10. A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism.

    Science.gov (United States)

    Shah, Meera; Su, Dan; Scheliga, Judith S; Pluskal, Tomáš; Boronat, Susanna; Motamedchaboki, Khatereh; Campos, Alexandre Rosa; Qi, Feng; Hidalgo, Elena; Yanagida, Mitsuhiro; Wolf, Dieter A

    2016-08-16

    The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  11. Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement

    Science.gov (United States)

    Louie, Gordon; Noel, Joseph P.; Baran, Phil S.; Palfey, Bruce; Moore, Bradley S.

    2013-01-01

    Flavoproteins catalyze a diversity of fundamental redox reactions and are one of the most studied enzyme families1,2. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate1,3,4. Here we report that the bacterial flavoenzyme EncM5,6 catalyzes the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(β-carbonyl). The crystal structure of EncM with bound substrate mimics coupled with isotope labeling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unanticipated stable flavin oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization. PMID:24162851

  12. Topographically mediated controls on aboveground biomass across a mediterranean-type landscape

    Science.gov (United States)

    Dahlin, K.; Asner, G. P.; Field, C. B.

    2009-12-01

    Aboveground biomass accumulation is a useful metric for evaluating habitat restoration and ecosystem services projects, in addition to being a robust measure of carbon sequestration. However, at the landscape scale non-anthropogenic controls on biomass accumulation are poorly understood. In this study we combined field measurements, high resolution data from the NASA JPL Airborne Visible/Infrared Imaging Spectrometer (AVIRIS), and the Carnegie Airborne Observatory (CAO) airborne light detection and ranging (lidar) system to create a comprehensive map of aboveground biomass across a patchy mediterranean-type landscape (Jasper Ridge Biological Preserve, Stanford, CA). Candidate explanatory variables (e.g. slope, elevation, incident solar radiation) were developed using a geologic map and a digital elevation model derived from the lidar data. Finally, candidate variables were tested, and a model was produced to predict aboveground biomass from environmental data. Though many of the explanatory variables have only indirect effects on plant growth, the model permits inferences to be made about the relative importance of light, water, temperature, and edaphic characteristics on carbon accumulation in mediterranean-type systems.

  13. A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Meera Shah

    2016-08-01

    Full Text Available The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer.

  14. Control of GABARAP-mediated autophagy by the Golgi complex, centrosome and centriolar satellites.

    Science.gov (United States)

    Joachim, Justin; Tooze, Sharon A

    2018-01-01

    Within minutes of induction of autophagy by amino-acid starvation in mammalian cells, multiple autophagosomes form throughout the cell cytoplasm. During their formation, the autophagosomes sequester cytoplasmic material and deliver it to lysosomes for degradation. How these organelles can be so rapidly formed and how their formation is acutely regulated are major questions in the autophagy field. Protein and lipid trafficking from diverse cell compartments contribute membrane to, or regulate the formation of the autophagosome. In addition, recruitment of Atg8 (in yeast), and the ATG8-family members (in mammalian cells) to autophagosomes is required for efficient autophagy. Recently, it was discovered that the centrosome and centriolar satellites regulate autophagosome formation by delivery of an ATG8-family member, GABARAP, to the forming autophagosome membrane, the phagophore. We propose that GABARAP regulates phagophore expansion by activating the ULK complex, the amino-acid controlled initiator complex. This finding reveals a previously unknown link between the centrosome, centriolar satellites and autophagy. © 2017 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.

  15. NAMPT-mediated salvage synthesis of NAD+ controls morphofunctional changes of macrophages.

    Directory of Open Access Journals (Sweden)

    Gerda Venter

    Full Text Available Functional morphodynamic behavior of differentiated macrophages is strongly controlled by actin cytoskeleton rearrangements, a process in which also metabolic cofactors ATP and NAD(H (i.e. NAD+ and NADH and NADP(H (i.e. NADP+ and NADPH play an essential role. Whereas the link to intracellular ATP availability has been studied extensively, much less is known about the relationship between actin cytoskeleton dynamics and intracellular redox state and NAD+-supply. Here, we focus on the role of nicotinamide phosphoribosyltransferase (NAMPT, found in extracellular form as a cytokine and growth factor, and in intracellular form as one of the key enzymes for the production of NAD+ in macrophages. Inhibition of NAD+ salvage synthesis by the NAMPT-specific drug FK866 caused a decrease in cytosolic NAD+ levels in RAW 264.7 and Maf-DKO macrophages and led to significant downregulation of the glycolytic flux without directly affecting cell viability, proliferation, ATP production capacity or mitochondrial respiratory activity. Concomitant with these differential metabolic changes, the capacity for phagocytic ingestion of particles and also substrate adhesion of macrophages were altered. Depletion of cytoplasmic NAD+ induced cell-morphological changes and impaired early adhesion in phagocytosis of zymosan particles as well as spreading performance. Restoration of NAD+ levels by NAD+, NMN, or NADP+ supplementation reversed the inhibitory effects of FK866. We conclude that direct coupling to local, actin-based, cytoskeletal dynamics is an important aspect of NAD+'s cytosolic role in the regulation of morphofunctional characteristics of macrophages.

  16. NAMPT-Mediated Salvage Synthesis of NAD+ Controls Morphofunctional Changes of Macrophages

    Science.gov (United States)

    Venter, Gerda; Oerlemans, Frank T. J. J.; Willemse, Marieke; Wijers, Mietske; Fransen, Jack A. M.; Wieringa, Bé

    2014-01-01

    Functional morphodynamic behavior of differentiated macrophages is strongly controlled by actin cytoskeleton rearrangements, a process in which also metabolic cofactors ATP and NAD(H) (i.e. NAD+ and NADH) and NADP(H) (i.e. NADP+ and NADPH) play an essential role. Whereas the link to intracellular ATP availability has been studied extensively, much less is known about the relationship between actin cytoskeleton dynamics and intracellular redox state and NAD+-supply. Here, we focus on the role of nicotinamide phosphoribosyltransferase (NAMPT), found in extracellular form as a cytokine and growth factor, and in intracellular form as one of the key enzymes for the production of NAD+ in macrophages. Inhibition of NAD+ salvage synthesis by the NAMPT-specific drug FK866 caused a decrease in cytosolic NAD+ levels in RAW 264.7 and Maf-DKO macrophages and led to significant downregulation of the glycolytic flux without directly affecting cell viability, proliferation, ATP production capacity or mitochondrial respiratory activity. Concomitant with these differential metabolic changes, the capacity for phagocytic ingestion of particles and also substrate adhesion of macrophages were altered. Depletion of cytoplasmic NAD+ induced cell-morphological changes and impaired early adhesion in phagocytosis of zymosan particles as well as spreading performance. Restoration of NAD+ levels by NAD+, NMN, or NADP+ supplementation reversed the inhibitory effects of FK866. We conclude that direct coupling to local, actin-based, cytoskeletal dynamics is an important aspect of NAD+’s cytosolic role in the regulation of morphofunctional characteristics of macrophages. PMID:24824795

  17. Mediator phosphorylation prevents stress response transcription during non-stress conditions.

    Science.gov (United States)

    Miller, Christian; Matic, Ivan; Maier, Kerstin C; Schwalb, Björn; Roether, Susanne; Strässer, Katja; Tresch, Achim; Mann, Matthias; Cramer, Patrick

    2012-12-28

    The multiprotein complex Mediator is a coactivator of RNA polymerase (Pol) II transcription that is required for the regulated expression of protein-coding genes. Mediator serves as an end point of signaling pathways and regulates Pol II transcription, but the mechanisms it uses are not well understood. Here, we used mass spectrometry and dynamic transcriptome analysis to investigate a functional role of Mediator phosphorylation in gene expression. Affinity purification and mass spectrometry revealed that Mediator from the yeast Saccharomyces cerevisiae is phosphorylated at multiple sites of 17 of its 25 subunits. Mediator phosphorylation levels change upon an external stimulus set by exposure of cells to high salt concentrations. Phosphorylated sites in the Mediator tail subunit Med15 are required for suppression of stress-induced changes in gene expression under non-stress conditions. Thus dynamic and differential Mediator phosphorylation contributes to gene regulation in eukaryotic cells.

  18. Drosophila MBF1 is a co-activator for Tracheae Defective and contributes to the formation of tracheal and nervous systems

    Czech Academy of Sciences Publication Activity Database

    Liu, Q. X.; Jindra, Marek; Ueda, H.; Hiromi, Y.; Hirose, S.

    2003-01-01

    Roč. 130, - (2003), s. 719-728 ISSN 0950-1991 R&D Projects: GA ČR GA204/00/0811 Institutional research plan: CEZ:AV0Z5007907 Keywords : TDF * MBF1 * co-activator Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.663, year: 2003

  19. Activation of a PGC-1-related Coactivator (PRC)-dependent Inflammatory Stress Program Linked to Apoptosis and Premature Senescence*

    Science.gov (United States)

    Gleyzer, Natalie; Scarpulla, Richard C.

    2013-01-01

    PGC-1-related coactivator (PRC), a growth-regulated member of the PGC-1 coactivator family, contributes to the expression of the mitochondrial respiratory apparatus. PRC also orchestrates a robust response to metabolic stress by promoting the expression of multiple genes specifying inflammation, proliferation, and metabolic reprogramming. Here, we demonstrate that this PRC-dependent stress program is activated during apoptosis and senescence, two major protective mechanisms against cellular dysfunction. Both PRC and its targets (IL1α, SPRR2D, and SPRR2F) were rapidly induced by menadione, an agent that promotes apoptosis through the generation of intracellular oxidants. Menadione-induced apoptosis and the PRC stress program were blocked by the antioxidant N-acetylcysteine. The PRC stress response was also activated by the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38), an inducer of premature senescence in tumor cells. Cells treated with SN-38 displayed morphological characteristics of senescence and express senescence-associated β-galactosidase activity. In contrast to menadione, the SN-38 induction of the PRC program occurred over an extended time course and was antioxidant-insensitive. The potential adaptive function of the PRC stress response was investigated by treating cells with meclizine, a drug that promotes glycolytic energy metabolism and has been linked to cardio- and neuroprotection against ischemia-reperfusion injury. Meclizine increased lactate production and was a potent inducer of the PRC stress program, suggesting that PRC may contribute to the protective effects of meclizine. Finally, c-MYC and PRC were coordinately induced under all conditions tested, implicating c-MYC in the biological response to metabolic stress. The results suggest a general role for PRC in the adaptive response to cellular dysfunction. PMID:23364789

  20. Diabetes-specific emotional distress mediates the association between depressive symptoms and glycaemic control in Type 1 and Type 2 diabetes.

    NARCIS (Netherlands)

    Bastelaar, K.M. van; Pouwer, F.; Geelhoed-Duijvestijn, P.H.; Tack, C.J.J.; Bazelmans, E.; Beekman, A.T.; Heine, R.J.; Snoek, F.J.

    2010-01-01

    OBJECTIVES: To investigate whether diabetes-specific emotional distress mediates the relationship between depression and glycaemic control in patients with Type 1 and Type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were derived from the baseline assessment of a depression in diabetes screening

  1. Do Different ADHD-Related Etiological Risks Involve Specific Neuropsychological Pathways? An Analysis of Mediation Processes by Inhibitory Control and Delay Aversion

    Science.gov (United States)

    Pauli-Pott, Ursula; Dalir, Silke; Mingebach, Tanja; Roller, Alisa; Becker, Katja

    2013-01-01

    Background: Inhibitory control (IC) has been regarded as a neuropsychological basic deficit and as an endophenotype of attention deficit/hyperactivity disorder (ADHD). Implicated here are mediation processes between etiological factors and ADHD symptoms. We thus analyze whether and to what extent executive IC and delay aversion (DA; i.e.,…

  2. Self-Efficacy and Social Support Mediate the Relationship between Internal Health Locus of Control and Health Behaviors in College Students

    Science.gov (United States)

    Marr, Joni; Wilcox, Sara

    2015-01-01

    Background: Internal health locus of control has been associated with positive health outcomes and behaviors. Understanding the mechanisms of this relationship are key to designing and implementing effective health behavior intervention programs. Purpose: The purpose was to examine whether self-efficacy and social support mediate the relationship…

  3. The coping with depression course: Short term outcomes and mediating effects of a randomized controlled trial in the treatment of subclinical depression

    NARCIS (Netherlands)

    Allart-van Dam, E.; Hosman, C.M.H.; Hoogduin, C.A.L.; Schaap, C.P.D.R.

    2003-01-01

    This article reports on a randomized controlled trial investigating the short-term effectiveness of the Coping With Depression course in a sample of adults seriously at risk of developing major depression. In addition, possible mediating properties of several proximal outcome variables were

  4. The Coping with Depression course : Short-term outcomes and mediating effects of a randomized controlled trial in the treatment of subclinical depression

    NARCIS (Netherlands)

    Allart-van Dam, E; Hosman, CMH; Hoogduin, CAL; Schaap, CPDR

    2003-01-01

    This article reports on a randomized controlled trial investigating the short-term effectiveness of the Coping With Depression course in a sample of adults seriously at risk of developing major depression. In addition, possible mediating properties of several proximal outcome variables were

  5. Child Effortful Control as a Mediator of Parenting Practices on Externalizing Behavior: Evidence for a Sex-Differentiated Pathway across the Transition from Preschool to School

    Science.gov (United States)

    Chang, Hyein; Olson, Sheryl L.; Sameroff, Arnold J.; Sexton, Holly R.

    2011-01-01

    An explanatory model for children's development of disruptive behavior across the transition from preschool to school was tested. It was hypothesized that child effortful control would mediate the effects of parenting on children's externalizing behavior and that child sex would moderate these relations. Participants were 241 children (123 boys)…

  6. Parent-Mediated Intervention for One-Year-Olds Screened as At-Risk for Autism Spectrum Disorder: A Randomized Controlled Trial

    Science.gov (United States)

    Watson, Linda R.; Crais, Elizabeth R.; Baranek, Grace T.; Turner-Brown, Lauren; Sideris, John; Wakeford, Linn; Kinard, Jessica; Reznick, J. Steven; Martin, Katrina L.; Nowell, Sallie W.

    2017-01-01

    Theoretically, interventions initiated with at-risk infants prior to the point in time a definitive autism spectrum disorder (ASD) diagnosis can be made will improve outcomes. Pursuing this idea, we tested the efficacy of a parent-mediated early intervention called Adapted Responsive Teaching (ART) via a randomized controlled trial with 87…

  7. Deletion of the transcriptional coactivator PGC1α in skeletal muscles is associated with reduced expression of genes related to oxidative muscle function

    International Nuclear Information System (INIS)

    Hatazawa, Yukino; Minami, Kimiko; Yoshimura, Ryoji; Onishi, Takumi; Manio, Mark Christian; Inoue, Kazuo; Sawada, Naoki; Suzuki, Osamu; Miura, Shinji; Kamei, Yasutomi

    2016-01-01

    The expression of the transcriptional coactivator PGC1α is increased in skeletal muscles during exercise. Previously, we showed that increased PGC1α leads to prolonged exercise performance (the duration for which running can be continued) and, at the same time, increases the expression of branched-chain amino acid (BCAA) metabolism-related enzymes and genes that are involved in supplying substrates for the TCA cycle. We recently created mice with PGC1α knockout specifically in the skeletal muscles (PGC1α KO mice), which show decreased mitochondrial content. In this study, global gene expression (microarray) analysis was performed in the skeletal muscles of PGC1α KO mice compared with that of wild-type control mice. As a result, decreased expression of genes involved in the TCA cycle, oxidative phosphorylation, and BCAA metabolism were observed. Compared with previously obtained microarray data on PGC1α-overexpressing transgenic mice, each gene showed the completely opposite direction of expression change. Bioinformatic analysis of the promoter region of genes with decreased expression in PGC1α KO mice predicted the involvement of several transcription factors, including a nuclear receptor, ERR, in their regulation. As PGC1α KO microarray data in this study show opposing findings to the PGC1α transgenic data, a loss-of-function experiment, as well as a gain-of-function experiment, revealed PGC1α’s function in the oxidative energy metabolism of skeletal muscles. - Highlights: • Microarray analysis was performed in the skeletal muscle of PGC1α KO mice. • Expression of genes in the oxidative energy metabolism was decreased. • Bioinformatic analysis of promoter region of the genes predicted involvement of ERR. • PGC1α KO microarray data in this study show the mirror image of transgenic data.

  8. An online community improves adherence in an internet-mediated walking program. Part 1: results of a randomized controlled trial.

    Science.gov (United States)

    Richardson, Caroline R; Buis, Lorraine R; Janney, Adrienne W; Goodrich, David E; Sen, Ananda; Hess, Michael L; Mehari, Kathleen S; Fortlage, Laurie A; Resnick, Paul J; Zikmund-Fisher, Brian J; Strecher, Victor J; Piette, John D

    2010-12-17

    Approximately half of American adults do not meet recommended physical activity guidelines. Face-to-face lifestyle interventions improve health outcomes but are unlikely to yield population-level improvements because they can be difficult to disseminate, expensive to maintain, and inconvenient for the recipient. In contrast, Internet-based behavior change interventions can be disseminated widely at a lower cost. However, the impact of some Internet-mediated programs is limited by high attrition rates. Online communities that allow participants to communicate with each other by posting and reading messages may decrease participant attrition. Our objective was to measure the impact of adding online community features to an Internet-mediated walking program on participant attrition and average daily step counts. This randomized controlled trial included sedentary, ambulatory adults who used email regularly and had at least 1 of the following: overweight (body mass index [BMI] ≥ 25), type 2 diabetes, or coronary artery disease. All participants (n = 324) wore enhanced pedometers throughout the 16-week intervention and uploaded step-count data to the study server. Participants could log in to the study website to view graphs of their walking progress, individually-tailored motivational messages, and weekly calculated goals. Participants were randomized to 1 of 2 versions of a Web-based walking program. Those randomized to the "online community" arm could post and read messages with other participants while those randomized to the "no online community" arm could not read or post messages. The main outcome measures were participant attrition and average daily step counts over 16 weeks. Multiple regression analyses assessed the effect of the online community access controlling for age, sex, disease status, BMI, and baseline step counts. Both arms significantly increased their average daily steps between baseline and the end of the intervention period, but there were no

  9. Examination of mid-intervention mediating effects on objectively assessed sedentary time among children in the Transform-Us! cluster-randomized controlled trial.

    Science.gov (United States)

    Carson, Valerie; Salmon, Jo; Arundell, Lauren; Ridgers, Nicola D; Cerin, Ester; Brown, Helen; Hesketh, Kylie D; Ball, Kylie; Chinapaw, Mai; Yildirim, Mine; Daly, Robin M; Dunstan, David W; Crawford, David

    2013-05-20

    The optimal targets and strategies for effectively reducing sedentary behavior among young people are unknown. Intervention research that explores changes in mediated effects as well as in outcome behaviors is needed to help inform more effective interventions. Therefore, the purpose of this study was to examine the mid-intervention mediating effects on children's objectively assessed classroom and total weekday sedentary time in the Transform-Us! intervention. The results are based on 293 children, aged 7- to 9-years-old at baseline, from 20 schools in Melbourne, Australia. Each school was randomly allocated to one of four groups, which targeted reducing sedentary time in the school and family settings (SB; n = 74), increasing or maintaining moderate- to vigorous-intensity physical activity in the school and family settings (PA; n = 75), combined SB and PA (SB + PA; n = 80), or the current practice control (C; n = 64). Baseline and mid-intervention data (5-9 months) were collected in 2010 and analyzed in 2012. Classroom and total weekday sedentary time was objectively assessed using ActiGraph accelerometers. The hypothesized mediators including, child enjoyment, parent and teacher outcome expectancies, and child perceived access to standing opportunities in the classroom environment, were assessed by questionnaire. The SB + PA group spent 13.3 min/day less in weekday sedentary time at mid-intervention compared to the control group. At mid-intervention, children in the SB group had higher enjoyment of standing in class (0.9 units; 5-unit scale) and all intervention groups had more positive perceptions of access to standing opportunities in the classroom environment (0.3-0.4 units; 3-unit scale), compared to the control group. However, none of the hypothesized mediator variables had an effect on sedentary time; thus, no mediating effects were observed. While beneficial intervention effects were observed on some hypothesized mediating

  10. Opening the Gender Diversity Black Box: Causality of Perceived Gender Equity & Locus of Control and Mediation of Work Engagement in Employee Well-being

    OpenAIRE

    Radha R. Sharma

    2015-01-01

    The study is aimed at assessing the role of perceived gender equity and locus of control in employee well-being at the workplace and ascertaining if work engagement mediates between perceived gender equity, locus of control, and employee well-being (measured through optimism, general satisfaction with life and work, and executive burnout). Adopting a personal survey method data was collected from 373 managers (both males and females) from the public and private sectors representing manufactur...

  11. Opening the gender diversity black box: causality of perceived gender equity and locus of control and mediation of work engagement in employee well-being

    OpenAIRE

    Sharma, Radha R.; Sharma, Neha P.

    2015-01-01

    The study is aimed at assessing the role of perceived gender equity and locus of control in employee well-being at the workplace and ascertaining if work engagement mediates between perceived gender equity, locus of control, and employee well-being (measured through optimism, general satisfaction with life and work, and executive burnout). Adopting a personal survey method data was collected from 373 managers (both males and females) from the public and private sectors representing manufactur...

  12. WD40 domain of Apc1 is critical for the coactivator-induced allosteric transition that stimulates APC/C catalytic activity.

    Science.gov (United States)

    Li, Qiuhong; Chang, Leifu; Aibara, Shintaro; Yang, Jing; Zhang, Ziguo; Barford, David

    2016-09-20

    The anaphase-promoting complex/cyclosome (APC/C) is a large multimeric cullin-RING E3 ubiquitin ligase that orchestrates cell-cycle progression by targeting cell-cycle regulatory proteins for destruction via the ubiquitin proteasome system. The APC/C assembly comprises two scaffolding subcomplexes: the platform and the TPR lobe that together coordinate the juxtaposition of the catalytic and substrate-recognition modules. The platform comprises APC/C subunits Apc1, Apc4, Apc5, and Apc15. Although the role of Apc1 as an APC/C scaffolding subunit has been characterized, its specific functions in contributing toward APC/C catalytic activity are not fully understood. Here, we report the crystal structure of the N-terminal domain of human Apc1 (Apc1N) determined at 2.2-Å resolution and provide an atomic-resolution description of the architecture of its WD40 (WD40 repeat) domain (Apc1(WD40)). To understand how Apc1(WD40) contributes to APC/C activity, a mutant form of the APC/C with Apc1(WD40) deleted was generated and evaluated biochemically and structurally. We found that the deletion of Apc1(WD40) abolished the UbcH10-dependent ubiquitination of APC/C substrates without impairing the Ube2S-dependent ubiquitin chain elongation activity. A cryo-EM structure of an APC/C-Cdh1 complex with Apc1(WD40) deleted showed that the mutant APC/C is locked into an inactive conformation in which the UbcH10-binding site of the catalytic module is inaccessible. Additionally, an EM density for Apc15 is not visible. Our data show that Apc1(WD40) is required to mediate the coactivator-induced conformational change of the APC/C that is responsible for stimulating APC/C catalytic activity by promoting UbcH10 binding. In contrast, Ube2S activity toward APC/C substrates is not dependent on the initiation-competent conformation of the APC/C.

  13. Controlled and selective placement of boron subphthalocyanines on either chain end of polymers synthesized by nitroxide mediated polymerization

    Directory of Open Access Journals (Sweden)

    Benoît H. Lessard

    2015-10-01

    Full Text Available In previous studies, we synthesized the first organic light emitting diode (OLED using boron subphthalocyanines (BsubPcs based polymers. When designing new polymer materials for organic electronic applications such as OLEDs or organic photovoltaic (OPV devices it is important to consider not only the contribution of each monomer but also the polymer chain ends. In this paper we establish a post-polymerization strategy to couple BsubPcs onto either the α- or the ω-chain end using chemically selective BsubPc derivatives. We outline how the chain ends of two representative polymers, poly(styrene (PS and poly(n-butylacrylate (BA, synthesized by nitroxide mediated polymerization (NMP, using BlocBuilder-MA as the initiating species, can be chemically modified by the incorporation of BsubPc chromophores. The addition of the BsubPc chromophore was confirmed through the use of a photodiode array detector (PDA connected in-line with a gel permeation chromatography (GPC setup. These findings represent the first reported method for the controlled and selective placement of a BsubPc chromophores on either end of a polymer produced by NMP. This strategy will therefore be utilized to make next generation BsubPc polymers for OLEDs and OPV devices. The extremely high molar extinction coefficient of BsubPc also make these polymers ideally suited for dye-labelling of polymers.

  14. Functional electrical stimulation mediated by iterative learning control and 3D robotics reduces motor impairment in chronic stroke

    Directory of Open Access Journals (Sweden)

    Meadmore Katie L

    2012-06-01

    Full Text Available Abstract Background Novel stroke rehabilitation techniques that employ electrical stimulation (ES and robotic technologies are effective in reducing upper limb impairments. ES is most effective when it is applied to support the patients’ voluntary effort; however, current systems fail to fully exploit this connection. This study builds on previous work using advanced ES controllers, and aims to investigate the feasibility of Stimulation Assistance through Iterative Learning (SAIL, a novel upper limb stroke rehabilitation system which utilises robotic support, ES, and voluntary effort. Methods Five hemiparetic, chronic stroke participants with impaired upper limb function attended 18, 1 hour intervention sessions. Participants completed virtual reality tracking tasks whereby they moved their impaired arm to follow a slowly moving sphere along a specified trajectory. To do this, the participants’ arm was supported by a robot. ES, mediated by advanced iterative learning control (ILC algorithms, was applied to the triceps and anterior deltoid muscles. Each movement was repeated 6 times and ILC adjusted the amount of stimulation applied on each trial to improve accuracy and maximise voluntary effort. Participants completed clinical assessments (Fugl-Meyer, Action Research Arm Test at baseline and post-intervention, as well as unassisted tracking tasks at the beginning and end of each intervention session. Data were analysed using t-tests and linear regression. Results From baseline to post-intervention, Fugl-Meyer scores improved, assisted and unassisted tracking performance improved, and the amount of ES required to assist tracking reduced. Conclusions The concept of minimising support from ES using ILC algorithms was demonstrated. The positive results are promising with respect to reducing upper limb impairments following stroke, however, a larger study is required to confirm this.

  15. Does self-efficacy mediate functional change in older adults participating in an exercise program after hip fracture? A randomized control trial

    Science.gov (United States)

    Latham, Nancy K.; Ni, Pengsheng; Jette, Alan M.

    2015-01-01

    Objectives This study examined whether self-efficacy mediated the effect of the HIP Rehab exercise program on activity limitations in older adults after hip fracture, and whether the mediation effect was different between different gender and age groups. Design Randomized controlled trial (RCT) Setting Community Participants Two hundred and thirty two participants aged 79±9.4 years with hip fracture were randomly assigned to intervention (n=120) or attention control (n=112) groups. Interventions The 6-month intervention, the HIP Rehab, is a functionally-oriented, home-based exercise program. Data was collected at baseline, post-intervention (6 months), and follow-up (9 months). Main outcome measure Activity Measure for Post-Acute Care (AM-PAC) Results The mediation effect of the HIP Rehab exercise program on Basic Mobility function through self-efficacy for exercise was significant at 9 months (βindirect=0.21). Similarly, the mediation effect of the intervention on Daily Activity function through self-efficacy for exercise was significant at 9 months (βindirect=0.49). In subgroup analyses, the mediation effect was significant at 9 months in the younger group (≤79 years old) in comparison to the older group, and was significant in females in comparison to males. Conclusion Self-efficacy may play a partial mediating role for the effect on some longer-term functional outcomes in the HIP Rehab intervention. The results suggest that program components that target self-efficacy should be incorporated in the future hip fracture rehabilitation interventions. Age and gender of the targeted participants may also need to be considered when developing interventions. PMID:25701101

  16. Does self-efficacy mediate functional change in older adults participating in an exercise program after hip fracture? A randomized controlled trial.

    Science.gov (United States)

    Chang, Feng-Hang; Latham, Nancy K; Ni, Pengsheng; Jette, Alan M

    2015-06-01

    To examine whether self-efficacy mediated the effect of the Home-based Post-Hip Fracture Rehabilitation program on activity limitations in older adults after hip fracture and whether the mediating effect was different between sex and age groups. Randomized controlled trial. Community. Participants with hip fracture (N=232; mean age ± SD, 79±9.4y) were randomly assigned to intervention (n=120, 51.7%) and attention control (n=112, 48.3%) groups. The 6-month intervention, the Home-based Post-Hip Fracture Rehabilitation, is a functionally oriented, home-based exercise program. Data were collected at baseline, postintervention (6mo), and follow-up (9mo). Activity Measure for Post-Acute Care. The mediating effect of the Home-based Post-Hip Fracture Rehabilitation program on Basic Mobility function through self-efficacy for exercise was significant at 9 months (βindirect=.21). Similarly, the mediating effect of the intervention on Daily Activity function through self-efficacy for exercise was significant at 9 months (βindirect=.49). In subgroup analyses, the mediating effect was significant at 9 months in the younger group (age, ≤79y) in comparison to the older group and was significant in women in comparison to men. Self-efficacy may play a partial mediating role in the effect on some longer-term functional outcomes in the Home-based Post-Hip Fracture Rehabilitation intervention. The results suggest that program components that target self-efficacy should be incorporated in future hip fracture rehabilitation interventions. Age and sex of the targeted participants may also need to be considered when developing interventions. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  17. Mediating effects of resistance training skill competency on health-related fitness and physical activity: the ATLAS cluster randomised controlled trial.

    Science.gov (United States)

    Smith, Jordan J; Morgan, Philip J; Plotnikoff, Ronald C; Stodden, David F; Lubans, David R

    2016-01-01

    The purpose of this study was to examine the mediating effect of resistance training skill competency on percentage of body fat, muscular fitness and physical activity among a sample of adolescent boys participating in a school-based obesity prevention intervention. Participants were 361 adolescent boys taking part in the Active Teen Leaders Avoiding Screen-time (ATLAS) cluster randomised controlled trial: a school-based program targeting the health behaviours of economically disadvantaged adolescent males considered "at-risk" of obesity. Body fat percentage (bioelectrical impedance), muscular fitness (hand grip dynamometry and push-ups), physical activity (accelerometry) and resistance training skill competency were assessed at baseline and post-intervention (i.e., 8 months). Three separate multi-level mediation models were analysed to investigate the potential mediating effects of resistance training skill competency on each of the study outcomes using a product-of-coefficients test. Analyses followed the intention-to-treat principle. The intervention had a significant impact on the resistance training skill competency of the boys, and improvements in skill competency significantly mediated the effect of the intervention on percentage of body fat and the combined muscular fitness score. No significant mediated effects were found for physical activity. Improving resistance training skill competency may be an effective strategy for achieving improvements in body composition and muscular fitness in adolescent boys.

  18. HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E.

    Science.gov (United States)

    Chikata, Takayuki; Tran, Giang Van; Murakoshi, Hayato; Akahoshi, Tomohiro; Qi, Ying; Naranbhai, Vivek; Kuse, Nozomi; Tamura, Yoshiko; Koyanagi, Madoka; Sakai, Sachiko; Nguyen, Dung Hoai; Nguyen, Dung Thi; Nguyen, Ha Thu; Nguyen, Trung Vu; Oka, Shinichi; Martin, Maureen P; Carrington, Mary; Sakai, Keiko; Nguyen, Kinh Van; Takiguchi, Masafumi

    2018-03-01

    HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control. IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1

  19. Mediating effect of perceived overweight on the association between actual obesity and intention for weight control; role of race, ethnicity, and gender

    Directory of Open Access Journals (Sweden)

    Shervin Assari

    2015-01-01

    Full Text Available Background: Although obesity is expected to be associated with intention to reduce weight, this effect may be through perceived overweight. This study tested if perceived overweight mediates the association between actual obesity and intention to control weight in groups based on the intersection of race and gender. For this purpose, we compared Non-Hispanic White men, Non-Hispanic White women, African American men, African American women, Caribbean Black men, and Caribbean Black women. Methods: National Survey of American Life, 2001-2003 included 5,810 American adults (3516 African Americans, 1415 Caribbean Blacks, and 879 Non-Hispanic Whites. Weight control intention was entered as the main outcome. In the first step, we fitted race/gender specific logistic regression models with the intention for weight control as outcome, body mass index as predictor and sociodemographics as covariates. In the next step, to test mediation, we added perceived weight to the model. Results: Obesity was positively associated with intention for weight control among all race × gender groups. Perceived overweight fully mediated the association between actual obesity and intention for weight control among Non-Hispanic White women, African American men, and Caribbean Black men. The mediation was only partial for Non-Hispanic White men, African American women, and Caribbean Black women. Conclusions: The complex relation between actual weight, perceived weight, and weight control intentions depends on the intersection of race and gender. Perceived overweight plays a more salient role for Non-Hispanic White women and Black men than White men and Black women. Weight loss programs may benefit from being tailored based on race and gender. This finding also sheds more light to the disproportionately high rate of obesity among Black women in US.

  20. Kin28 regulates the transient association of Mediator with core promoters.

    Science.gov (United States)

    Jeronimo, Célia; Robert, François

    2014-05-01

    Mediator is an essential, broadly used eukaryotic transcriptional coactivator. How and what Mediator communicates from activators to RNA polymerase II (RNAPII) remains an open question. Here we performed genome-wide location profiling of Saccharomyces cerevisiae Mediator subunits. Mediator is not found at core promoters but rather occupies the upstream activating sequence, upstream of the pre-initiation complex. In the absence of Kin28 (CDK7) kinase activity or in cells in which the RNAPII C-terminal domain is mutated to replace Ser5 with alanine, however, Mediator accumulates at core promoters together with RNAPII. We propose that Mediator is released quickly from promoters after phosphorylation of Ser5 by Kin28 (CDK7), which also allows for RNAPII to escape from the promoter.

  1. Emerging functions of multi-protein complex Mediator with special emphasis on plants.

    Science.gov (United States)

    Malik, Naveen; Agarwal, Pinky; Tyagi, Akhilesh

    2017-10-01

    Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.

  2. Beyond total treatment effects in randomised controlled trials: Baseline measurement of intermediate outcomes needed to reduce confounding in mediation investigations.

    Science.gov (United States)

    Landau, Sabine; Emsley, Richard; Dunn, Graham

    2018-06-01

    Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise. Investigators increasingly carry out explanatory analyses to decompose total treatment effects into components that are mediated by an intermediate continuous outcome and a non-mediated part. Traditional mediation analysis might be performed based on (A) post-treatment values of the intermediate and clinical outcomes alone, (B) respective change scores or (C) conditioning on baseline measures of both intermediate and clinical outcomes. Using causal diagrams and Monte Carlo simulation, we investigated the performance of the three competing mediation approaches. We considered a data generating model that included three possible confounding processes involving baseline variables: The first two processes modelled baseline measures of the clinical variable or the intermediate variable as common causes of post-treatment measures of these two variables. The third process allowed the two baseline variables themselves to be correlated due to past common causes. We compared the analysis models implied by the competing mediation approaches with this data generating model to hypothesise likely biases in estimators, and tested these in a simulation study. We applied the methods to a randomised trial of pragmatic rehabilitation in patients with chronic fatigue syndrome, which examined the role of limiting activities as a mediator. Estimates of causal mediation effects derived by approach (A) will be biased if one of

  3. Singlet oxygen explicit dosimetry to predict long-term local tumor control for BPD-mediated photodynamic therapy

    Science.gov (United States)

    Kim, Michele M.; Penjweini, Rozhin; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, photosensitizer photobleaching rate, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (Φ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted singlet oxygen [1O2]rx was investigated as a dosimetric quantity for PDT outcome. The ability of [1O2]rx to predict the long-term local tumor control rate (LCR) for BPD-mediated PDT was examined. Mice bearing radioactivelyinduced fibrosarcoma (RIF) tumors were treated with different in-air fluences (250, 300, and 350 J/cm2) and in-air ϕ (75, 100, and150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 3 hours. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [1O2]rx. Φ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Kaplan-Meier analyses for LCR were done for an endpoint of tumor volume defined as the product of the timeintegral of photosensitizer concentration and Φ at a 3 mm tumor depth. Preliminary studies show that [1O2]rx better correlates with LCR and is an effective dosimetric quantity that can predict treatment outcome.

  4. Singlet oxygen explicit dosimetry to predict long-term local tumor control for Photofrin-mediated photodynamic therapy

    Science.gov (United States)

    Penjweini, Rozhin; Kim, Michele M.; Ong, Yi Hong; Zhu, Timothy C.

    2017-02-01

    Although photodynamic therapy (PDT) is an established modality for the treatment of cancer, current dosimetric quantities do not account for the variations in PDT oxygen consumption for different fluence rates (φ). In this study we examine the efficacy of reacted singlet oxygen concentration ([1O2]rx) to predict long-term local control rate (LCR) for Photofrin-mediated PDT. Radiation-induced fibrosarcoma (RIF) tumors in the right shoulders of female C3H mice are treated with different in-air fluences of 225-540 J/cm2 and in-air fluence rate (φair) of 50 and 75 mW/cm2 at 5 mg/kg Photofrin and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 630 nm wavelength. [1O2]rx is calculated by using a macroscopic model based on explicit dosimetry of Photofrin concentration, tissue optical properties, tissue oxygenation and blood flow changes during PDT. The tumor volume of each mouse is tracked for 90 days after PDT and Kaplan-Meier analyses for LCR are performed based on a tumor volume defined as a temporal integral of photosensitizer concentration and Φ at a 3 mm tumor depth. φ is calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. Our preliminary studies show that [1O2]rx is the best dosimetric quantity that can predict tumor response and correlate with LCR. Moreover, [1O2]rx calculated using the blood flow changes was in agreement with [1O2]rx calculated based on the actual tissue oxygenation.

  5. Mediator Undergoes a Compositional Change during Transcriptional Activation.

    Science.gov (United States)

    Petrenko, Natalia; Jin, Yi; Wong, Koon Ho; Struhl, Kevin

    2016-11-03

    Mediator is a transcriptional co-activator recruited to enhancers by DNA-binding activators, and it also interacts with RNA polymerase (Pol) II as part of the preinitiation complex (PIC). We demonstrate that a single Mediator complex associates with the enhancer and core promoter in vivo, indicating that it can physically bridge these transcriptional elements. However, the Mediator kinase module associates strongly with the enhancer, but not with the core promoter, and it dissociates from the enhancer upon depletion of the TFIIH kinase. Severing the kinase module from Mediator by removing the connecting subunit Med13 does not affect Mediator association at the core promoter but increases occupancy at enhancers. Thus, Mediator undergoes a compositional change in which the kinase module, recruited via Mediator to the enhancer, dissociates from Mediator to permit association with Pol II and the PIC. As such, Mediator acts as a dynamic bridge between the enhancer and core promoter. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Intercultural Mediation

    OpenAIRE

    Dragos Marian Radulescu; Denisa Mitrut

    2012-01-01

    The Intercultural Mediator facilitates exchanges between people of different socio-cultural backgrounds and acts as a bridge between immigrants and national and local associations, health organizations, services and offices in order to foster integration of every single individual. As the use mediation increases, mediators are more likely to be involved in cross-cultural mediation, but only the best mediators have the opportunity to mediate cross border business disputes or international poli...

  7. Functional disability in patients with low back pain: the mediator role of suffering and beliefs about pain control in patients receiving physical and chiropractic treatment.

    Science.gov (United States)

    Pereira, M Graça; Roios, Edite; Pereira, Marta

    Low back pain is the leading cause of disability worldwide. There is evidence that depression, anxiety, and external locus of control are negative predictors of functional disability in low back patients. This study focused on the mediator role of suffering and beliefs about pain control in the relationship between psychological morbidity and functional disability in patients receiving physical therapy and chiropractic treatment for chronic low back pain. The sample included 213 patients receiving chiropractic treatment and 125 receiving physical therapy, who answered the following instruments: Beliefs about Pain Control Questionnaire; Inventory of Subjective Experiences of Suffering in Illness; Oswestry Low Back Pain Disability Questionnaire; and the Hospital Anxiety and Depression Scales. Suffering was a mediator in the relationship between depression and functional disability in both treatment groups. Only beliefs related to external chance events mediated the relationship between depression and functional disability in the physical therapy group, but not in the chiropratic teratment group. Intervention should focus on suffering regardless of the type of treatment and target beliefs about pain control, in patients receiving physical therapy treatment since they seem to play a key role in functional disability in patients with low back pain. Copyright © 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

  8. Carob pod insoluble fiber exerts anti-atherosclerotic effects in rabbits through sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α.

    Science.gov (United States)

    Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Lahera, Vicente; de las Heras, Natalia

    2014-09-01

    The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ⋅ kg(-1) ⋅ d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ⋅ kg(-1) ⋅ d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-α (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-β (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of

  9. MECHANISM AND REGULATION OF NONSENSE-MEDIATED MRNA DECAY (NMD, AN ESSENTIAL QUALITY CONTROL SYSTEM OF PLANTS

    Directory of Open Access Journals (Sweden)

    D. Silhavy

    2008-09-01

    Full Text Available In eukaryotic cell, various quality control mechanisms have evolved to ensure that only perfect mRNAs could be translated. Nonsense-mediated mRNA decay (NMD is a quality control system that identifies and eliminates mRNAs containing premature termination codons, thereby preventing the accumulation of potentially harmful truncated proteins. While NMD is well-characterized in yeast, in invertebrates and in mammals, plant NMD is poorly understood. In yeast and in invertebrates unusually long 3'untranslated regions (3'UTRs render an mRNA subject to NMD, while in mammals' 3'UTR located introns trigger NMD. UPF1, 2 and 3 are the key trans-acting NMD factors in yeast as well as in animals. However, in mammals, the core components of the Exon Junction Complex (Mago, Y14, eIF4A3 and MLN51 are also required for NMD. It was proposed that long 3’UTR-induced NMD is the ancient type and that it was changed to a more complex intron-based NMD in mammals. To better understand the evolution of eukaryotic NMD systems, we have studied the NMD machinery of plants, as plants are outgroup relative to fungi and animals. We have elaborated various transient assays to analyze plant NMD. Using these assays we defined the cis elements of plant NMD and characterized several trans-acting plant NMD factors. We demonstrated that two plant NMD pathways co-exist, one pathway, as yeast or invertebrate NMD systems, eliminates mRNAs with long 3'UTRs, while a distinct pathway, like mammalian NMD, degrades mRNAs harbouring 3'UTR-located introns. We showed that UPF1, UPF2, and SMG-7 are involved in both plant NMD pathways, whereas Mago and Y14 are required only for intron-based NMD. We also provide evidence that the molecular mechanism of long 3'UTR-based plant NMD resembles yeast NMD, while the intron-based NMD is similar to mammalian NMD. Moreover we have found that the SMG-7 component of plant NMD is targeted by NMD suggesting that plant NMD is autoregulated. We propose that in

  10. TORCing up metabolic control in the brain.

    Science.gov (United States)

    Hietakangas, Ville; Cohen, Stephen M

    2008-05-01

    Transducer of regulated CREB activity 2 (TORC2) is a coactivator of CREB and an important regulator of energy balance in mammals through control of gluconeogenesis in the liver. In this issue of Cell Metabolism, Wang and coworkers (2008) report an intriguing role for Drosophila TORC in the neuronal regulation of metabolism.

  11. SAD1, an RNA polymerase I subunit A34.5 of rice, interacts with Mediator and controls various aspects of plant development.

    Science.gov (United States)

    Li, Weiqiang; Yoshida, Akiko; Takahashi, Megumu; Maekawa, Masahiko; Kojima, Mikiko; Sakakibara, Hitoshi; Kyozuka, Junko

    2015-01-01

    The DWARF14 (D14) gene of rice functions within the signaling pathway of strigolactones, a group of plant hormones that inhibits shoot branching. We isolated a recessive mutant named super apical dormant (sad1-1) from a suppressor screen of d14-1. The growth of tillers (vegetative shoot branches) is suppressed in both the d14-1 sad1-1 double mutant and the sad1-1 single mutant. In addition, the sad1-1 mutant shows pleiotropic defects throughout development. SAD1 encodes an ortholog of RPA34.5, a subunit of RNA polymerase I (Pol I). Consequently, the level of ribosomal RNA (rRNA) is severely reduced in the sad1-1 mutant. These results indicate that proper ribosome function is a prerequisite for normal development in plants. The Arabidopsis ortholog of SAD1 was previously isolated as a Mediator-interacting protein. Here we show that SAD1 interacts physically with the Mediator complex through direct binding with OsMED4, a component of the middle module of the Mediator complex in rice. It is known that Mediator interacts with Pol II, which transcribes mRNAs and functions as a central regulator of transcription. This study indicates a novel aspect of Mediator function in Pol I-controlled rRNA transcription. TFIIF2 and RPC53 are the counterparts of RPA34.5 in Pol II and Pol III, respectively. We demonstrate that the rice orthologs of these proteins also interact with OsMED4. Our results suggest that interaction with MED4 in the Mediator complex is a common feature of the three types of RNA polymerases. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

  12. The Effect of Social Support on Glycemic Control in Patients with Type 2 Diabetes Mellitus: The Mediating Roles of Self-Efficacy and Adherence

    Directory of Open Access Journals (Sweden)

    Yechang Shao

    2017-01-01

    Full Text Available Ample evidence suggests that social support, self-efficacy, and adherence significantly, independently, and together affect glycemic control in patients with type 2 diabetes mellitus (T2DM, but the pathway from social support to glycemic control remains unclear. This study hypothesized that the effect of social support on glycemic control was mediated sequentially by self-efficacy and adherence. Patients with T2DM were recruited from two hospitals in Guangzhou, China, from January 1 to July 31, 2014, and their sociodemographic clinical data and their assessments on social support, self-efficacy, and adherence were obtained from medical records and self-completed questionnaires. Of the 532 patients who participated, 35% achieved glycemic control (i.e., HbA1c < 7%. Social support, self-efficacy, and adherence had significant correlations with each other and with glycemic control (P<0.05. Regression analyses and structural equation modeling showed that better social support was associated to better patient self-efficacy, which, in turn, was associated with better medical adherence, which was associated with improved glycemic control, and the relationship between social support and glycemic