WorldWideScience

Sample records for cooperative signaling roles

  1. Cooperative ethylene receptor signaling

    OpenAIRE

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

  2. Cooperation of endothelin-1 signaling with melanosomes plays a role in developing and/or maintaining human skin hyperpigmentation

    Directory of Open Access Journals (Sweden)

    Daiki Murase

    2015-10-01

    Full Text Available Skin hyperpigmentation is characterized by increased melanin synthesis and deposition that can cause significant psychosocial and psychological distress. Although several cytokine-receptor signaling cascades contribute to the formation of ultraviolet B-induced cutaneous hyperpigmentation, their possible involvement in other types of skin hyperpigmentation has never been clearly addressed. Since our continuous studies using skin specimens from more than 30 subjects with ethnic skin diversity emphasized a consistent augmentation in the expression of endothelin-1 (ET-1 and its receptor (Endothelin B receptor, ET-B in hyperpigmented lesions, including senile lentigos (SLs, the precise function of ET-1 signaling was investigated in the present study. In line with previous studies, ET-1 significantly induced melanogenesis followed by increases in melanosome transport in melanocytes and in its transfer to keratinocytes while inhibition of ET-B function substantially depressed melanogenic ability in tissue-cultured SLs. Additionally, in agreement with a previous report that the formation of autophagosomes rather than melanosomes is stimulated according to starvation or defective melanosome production, ET-1 was found to remarkably augment the expression of components necessary for early melanosome formation, indicating its counteraction against autophagy-targeting melanosome degradation in melanocytes. Despite the lack of substantial impact of ET-1 on keratinocyte melanogenic functions, the expression of ET-1 was enhanced following melanosome uptake by keratinocytes. Taken together, our data suggest that ET-1 plays a substantial role in the development and/or maintenance of skin hyperpigmentation in reciprocal cooperation with increased melanosome incorporation.

  3. Signaling emotion and reason in cooperation.

    Science.gov (United States)

    Levine, Emma E; Barasch, Alixandra; Rand, David; Berman, Jonathan Z; Small, Deborah A

    2018-05-01

    We explore the signal value of emotion and reason in human cooperation. Across four experiments utilizing dyadic prisoner dilemma games, we establish three central results. First, individuals infer prosocial feelings and motivations from signals of emotion. As a result, individuals believe that a reliance on emotion signals that one will cooperate more so than a reliance on reason. Second, these beliefs are generally accurate-those who act based on emotion are more likely to cooperate than those who act based on reason. Third, individuals' behavioral responses towards signals of emotion and reason depend on their own decision mode: those who rely on emotion tend to conditionally cooperate (that is, cooperate only when they believe that their partner has cooperated), whereas those who rely on reason tend to defect regardless of their partner's signal. These findings shed light on how different decision processes, and lay theories about decision processes, facilitate and impede cooperation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  4. Extracellular Electrophysiological Measurements of Cooperative Signals in Astrocytes Populations

    Science.gov (United States)

    Mestre, Ana L. G.; Inácio, Pedro M. C.; Elamine, Youssef; Asgarifar, Sanaz; Lourenço, Ana S.; Cristiano, Maria L. S.; Aguiar, Paulo; Medeiros, Maria C. R.; Araújo, Inês M.; Ventura, João; Gomes, Henrique L.

    2017-01-01

    Astrocytes are neuroglial cells that exhibit functional electrical properties sensitive to neuronal activity and capable of modulating neurotransmission. Thus, electrophysiological recordings of astroglial activity are very attractive to study the dynamics of glial signaling. This contribution reports on the use of ultra-sensitive planar electrodes combined with low noise and low frequency amplifiers that enable the detection of extracellular signals produced by primary cultures of astrocytes isolated from mouse cerebral cortex. Recorded activity is characterized by spontaneous bursts comprised of discrete signals with pronounced changes on the signal rate and amplitude. Weak and sporadic signals become synchronized and evolve with time to higher amplitude signals with a quasi-periodic behavior, revealing a cooperative signaling process. The methodology presented herewith enables the study of ionic fluctuations of population of cells, complementing the single cells observation by calcium imaging as well as by patch-clamp techniques. PMID:29109679

  5. Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms

    OpenAIRE

    Yu, Chunjie; Yang, Qiong; Chen, Yuhong; Wang, Demin; Levine, Ross; Crispino, John; Wen, Qiang; Huang, Zan

    2016-01-01

    Background Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown. Results In this study, we f...

  6. Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms.

    Science.gov (United States)

    Yu, Chunjie; Yang, Qiong; Chen, Yuhong; Wang, Demin; Levine, Ross; Crispino, John; Wen, Qiang; Huang, Zan

    2016-01-01

    Myeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown. In this study, we further tested their functions in MPL W515L-induced myeloproliferative neoplasms (MPNs) by substituting either or both of them with phenylalanine in MPL W515L (termed as MPL515/625, MPL515/630 and MPL515/625/630, respectively). In vitro, MPL515/630 but not MPL515/625 or MPL515/625/630 retained the ability to induce TPO-independent proliferation and increase colony-forming unit megakaryocytes (CFU-Mk). Accordingly, differential activation of the downstream signaling by four mutants was observed and constitutively active STAT5 or AKT instead of STAT3 partially compensated MPL515/625/630 function. Further support this, STAT5-deficiency impaired MPL W515L-induced CFU-Mk expansion. In vivo, MPL515/630 but not MPL515/625 or MPL515/625/630 induced typical features of MPNs with high WBC and platelet counts, splenomegaly, hepatomegaly and hypercellularity in the bone marrow. Surprisingly, MPL515/625 also caused hypercellularity of bone marrow and splenomegaly without any other significant features. We also observed differential effects of the four mutants on progenitors, myeloid cells and megakaryocytes. Our studies have revealed distinct features of tyrosine sites 625 and 630 in mediating MPL W515L-induced megakaryocyte hyperproliferation and MPNs. Our study also suggests that MPL cytosolic phosphorylated Y625 and flanking amino acids could become targets for pharmacologic inhibition in MPNs.

  7. The Inner Eye Theory of Laughter: Mindreader Signals Cooperator Value

    Directory of Open Access Journals (Sweden)

    Wonil Edward Jung

    2003-01-01

    Full Text Available In this hypothesis paper, I propose a three-component set of jointly necessary and sufficient trigger criteria for all cases of involuntary laughter. The theory incorporates concepts from the theory of mind in cognitive science. I then examine the information content of the laughter signal from a game theoretic perspective. I conclude that laughter is a signal of cooperator value as it provides information on the laugher's empathy with the attributed mental states and her sympathy levels for all affected by the laugh-inducing situation. Laughter also indicates what types of mental representations children, autistic people, nonhuman primates and adults possess and can falsify.

  8. The Teacher's Role in Implementing Cooperative Learning in the Classroom.

    NARCIS (Netherlands)

    Gillies, R.; Ashman, A.; Terwel, J.

    2008-01-01

    The teacher’s role in implementing cooperative learning in the classroom provides a comprehensive overview of the theories, research outcomes, challenges and issues in guided cooperative learning. In many chapters there are clear guidelines and discussion about how cooperative learning practices can

  9. Second-chance signal transduction explains cooperative flagellar switching.

    Science.gov (United States)

    Zot, Henry G; Hasbun, Javier E; Minh, Nguyen Van

    2012-01-01

    The reversal of flagellar motion (switching) results from the interaction between a switch complex of the flagellar rotor and a torque-generating stationary unit, or stator (motor unit). To explain the steeply cooperative ligand-induced switching, present models propose allosteric interactions between subunits of the rotor, but do not address the possibility of a reaction that stimulates a bidirectional motor unit to reverse direction of torque. During flagellar motion, the binding of a ligand-bound switch complex at the dwell site could excite a motor unit. The probability that another switch complex of the rotor, moving according to steady-state rotation, will reach the same dwell site before that motor unit returns to ground state will be determined by the independent decay rate of the excited-state motor unit. Here, we derive an analytical expression for the energy coupling between a switch complex and a motor unit of the stator complex of a flagellum, and demonstrate that this model accounts for the cooperative switching response without the need for allosteric interactions. The analytical result can be reproduced by simulation when (1) the motion of the rotor delivers a subsequent ligand-bound switch to the excited motor unit, thereby providing the excited motor unit with a second chance to remain excited, and (2) the outputs from multiple independent motor units are constrained to a single all-or-none event. In this proposed model, a motor unit and switch complex represent the components of a mathematically defined signal transduction mechanism in which energy coupling is driven by steady-state and is regulated by stochastic ligand binding. Mathematical derivation of the model shows the analytical function to be a general form of the Hill equation (Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40: iv-vii).

  10. HPV16 E6 and E6AP differentially cooperate to stimulate or augment Wnt signaling

    International Nuclear Information System (INIS)

    Sominsky, Sophia; Kuslansky, Yael; Shapiro, Beny; Jackman, Anna; Haupt, Ygal; Rosin-Arbesfeld, Rina; Sherman, Levana

    2014-01-01

    The present study investigated the roles of E6 and E6AP in the Wnt pathway. We showed that E6 levels are markedly reduced in cells in which Wnt signaling is activated. Coexpression of wild-type or mutant E6AP (C820A) in Wnt-activated cells stabilized E6 and enhanced Wnt/β-catenin/TCF transcription. Expression of E6AP alone in nonstimulated cells elevated β-catenin level, promoted its nuclear accumulation, and activated β-catenin/TCF transcription. A knockdown of E6AP lowered β-catenin levels. Coexpression with E6 intensified the activities of E6AP. Further experiments proved that E6AP/E6 stabilize β-catenin by protecting it from proteasomal degradation. This function was dependent on the catalytic activity of E6AP, the kinase activity of GSK3β and the susceptibility of β-catenin to GSK3β phosphorylation. Thus, this study identified E6AP as a novel regulator of the Wnt signaling pathway, capable of cooperating with E6 in stimulating or augmenting Wnt/β-catenin signaling, thereby possibly contributing to HPV carcinogenesis. - Highlights: • The roles of E6 and E6AP in the Wnt pathway were investigated. • E6AP stabilizes E6 and enhances E6 activity in augmentation of Wnt signaling. • E6AP cooperates with E6 to stabilize β-catenin and stimulate Wnt/β-catenin signaling. • E6AP and E6 act through different mechanisms to augment or stimulate Wnt signaling

  11. HPV16 E6 and E6AP differentially cooperate to stimulate or augment Wnt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Sominsky, Sophia, E-mail: sophia.tab@gmail.com [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Kuslansky, Yael, E-mail: ykuslansky@gmail.com [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Shapiro, Beny, E-mail: benyshap@gmail.com [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Jackman, Anna, E-mail: jackman@post.tau.ac.il [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Haupt, Ygal, E-mail: ygal.haupt@petermac.org [Research Division, The Peter MacCallum Cancer Centre, East Melbourne (Australia); Rosin-Arbesfeld, Rina, E-mail: arina@post.tau.ac.il [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel); Sherman, Levana, E-mail: lsherman@post.tau.ac.il [Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2014-11-15

    The present study investigated the roles of E6 and E6AP in the Wnt pathway. We showed that E6 levels are markedly reduced in cells in which Wnt signaling is activated. Coexpression of wild-type or mutant E6AP (C820A) in Wnt-activated cells stabilized E6 and enhanced Wnt/β-catenin/TCF transcription. Expression of E6AP alone in nonstimulated cells elevated β-catenin level, promoted its nuclear accumulation, and activated β-catenin/TCF transcription. A knockdown of E6AP lowered β-catenin levels. Coexpression with E6 intensified the activities of E6AP. Further experiments proved that E6AP/E6 stabilize β-catenin by protecting it from proteasomal degradation. This function was dependent on the catalytic activity of E6AP, the kinase activity of GSK3β and the susceptibility of β-catenin to GSK3β phosphorylation. Thus, this study identified E6AP as a novel regulator of the Wnt signaling pathway, capable of cooperating with E6 in stimulating or augmenting Wnt/β-catenin signaling, thereby possibly contributing to HPV carcinogenesis. - Highlights: • The roles of E6 and E6AP in the Wnt pathway were investigated. • E6AP stabilizes E6 and enhances E6 activity in augmentation of Wnt signaling. • E6AP cooperates with E6 to stabilize β-catenin and stimulate Wnt/β-catenin signaling. • E6AP and E6 act through different mechanisms to augment or stimulate Wnt signaling.

  12. Using reservoir-engineering to convert a coherent signal in optomechanics with small optomechanical cooperativity

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Tao, E-mail: suiyueqiaoqiao@163.com [Key Lab of Coherent Light, Atomic and Molecular Spectroscopy, Ministry of Education, and College of Physics, Jilin University, Changchun 130012 (China); College of Physics, Tonghua Normal University, Tonghua 134000 (China); Wang, Tie [Department of Physics, College of Science, Yanbian University, Yanji, Jilin 133002 (China); Fu, Changbao [College of Physics, Tonghua Normal University, Tonghua 134000 (China); Su, Xuemei, E-mail: suxm@jlu.edu.cn [Key Lab of Coherent Light, Atomic and Molecular Spectroscopy, Ministry of Education, and College of Physics, Jilin University, Changchun 130012 (China)

    2017-05-10

    Optomechanical dark mode plays a central role in effective mechanically-mediated conversion of two different cavity fields. In this paper, we present a more efficient method to utilize the dark mode to transfer a coherent signal. When an auxiliary cavity mode is exploited, two approaches are proposed to effectively eliminate the optomechanical bright mode, and only the optomechanical dark mode is left to facilitate state transfer. Even with small cooperativity and different losses for the two target modes, the internal cavity mode-conversion efficiency can also reach unity. - Highlights: • Reservoir-engineering is used for state conversion. • The optomechanical bright mode can be absolutely eliminated. • Small cooperativity and different losses are feasible for ideal conversion efficiency.

  13. The Role of Ontogeny in the Evolution of Human Cooperation.

    Science.gov (United States)

    Tomasello, Michael; Gonzalez-Cabrera, Ivan

    2017-09-01

    To explain the evolutionary emergence of uniquely human skills and motivations for cooperation, Tomasello et al. (2012, in Current Anthropology 53(6):673-92) proposed the interdependence hypothesis. The key adaptive context in this account was the obligate collaborative foraging of early human adults. Hawkes (2014, in Human Nature 25(1):28-48), following Hrdy (Mothers and Others, Harvard University Press, 2009), provided an alternative account for the emergence of uniquely human cooperative skills in which the key was early human infants' attempts to solicit care and attention from adults in a cooperative breeding context. Here we attempt to reconcile these two accounts. Our composite account accepts Hrdy's and Hawkes's contention that the extremely early emergence of human infants' cooperative skills suggests an important role for cooperative breeding as adaptive context, perhaps in early Homo. But our account also insists that human cooperation goes well beyond these nascent skills to include such things as the communicative and cultural conventions, norms, and institutions created by later Homo and early modern humans to deal with adult problems of social coordination. As part of this account we hypothesize how each of the main stages of human ontogeny (infancy, childhood, adolescence) was transformed during evolution both by infants' cooperative skills "migrating up" in age and by adults' cooperative skills "migrating down" in age.

  14. Experiential Role of Artefacts in Cooperative Design

    OpenAIRE

    Vyas, Dhaval; Heylen, Dirk K.J.; Nijholt, Antinus; van der Veer, Gerrit C.; Caroll, J.M.

    2009-01-01

    The role of material artefacts in supporting distributed and co-located work practices has been well acknowledged within the HCI and CSCW research. In this paper, we show that in addition to their ecological, coordinative and organizational support, artefacts also play an ‘experiential’ role. In this case, artefacts not only improve efficiency or have a purely functional role (e.g. allowing people to complete tasks quickly), but the presence and manifestations of these artefacts bring quality...

  15. Experiential Role of Artefacts in Cooperative Design

    NARCIS (Netherlands)

    Vyas, Dhaval; Heylen, Dirk K.J.; Nijholt, Antinus; van der Veer, Gerrit C.; Caroll, J.M.

    2009-01-01

    The role of material artefacts in supporting distributed and co-located work practices has been well acknowledged within the HCI and CSCW research. In this paper, we show that in addition to their ecological, coordinative and organizational support, artefacts also play an ‘experiential’ role. In

  16. Role of Cooperatives in Small and Medium Scale Enterprises (SMEs ...

    African Journals Online (AJOL)

    The paper examined the contributions of cooperatives to small and medium scale enterprises (SME) development, identified the challenges and to suggested ways of strengthening this role. The paper argued that SMEs are the key to Nigeria‟s prosperity, but that past efforts by the government to promote SMEs has not ...

  17. Wnt ligands signal in a cooperative manner to promote foregut organogenesis

    OpenAIRE

    Miller, Mayumi F.; Cohen, Ethan David; Baggs, Julie E.; Lu, Min Min; Hogenesch, John B.; Morrisey, Edward E.

    2012-01-01

    Endoderm-mesenchyme cross-talk is a central process in the development of foregut-derived organs. How signaling pathways integrate the activity of multiple ligands to guide organ development is poorly understood. We show that two Wnt ligands, Wnt2 and Wnt7b, cooperatively induce Wnt signaling without affecting the stabilization of the Wnt canonical effector β-catenin despite it being necessary for Wnt2–Wnt7b cooperativity. Wnt2–Wnt7b cooperation is specific for mesenchymal cell lineages and t...

  18. Cooperative learning with role play in Chinese pharmacology education.

    Science.gov (United States)

    Wang, Jun; Hu, Xiamin; Xi, Jinglei

    2012-03-01

    Cooperative learning (CL) and role play are both efficient educational tools for enhancing Chinese student active learning and communication skills. This study was designed to obtain student feedback on the format of CL together with role play in the study of pharmacology in Chinese pharmaceutical undergraduates. CL was used in the self-study of new drugs used clinically but neglected in textbook and class teaching, so that groups of students were assigned to become "specialists" in one area of new drugs. Then, these "specialists" taught their new-found knowledge to other groups in role play approach involving an interaction between the pharmacist and a patient. Student perceptions of CL together with role play were examined using an eight-item survey instrument. Students were satisfied with CL together with role play. Majority of the students believed this teaching method enhanced their learning experience, made them gain more pharmacological expertise, increased the awareness of their career in future and self-educational abilities, and fostered their cooperation spirit and confidence. The materials on CL and role play were also believed pertinent. Only 63.4-76.5% and 63.1-37.3% of the students thought "CL and role-play were very funny" and "I felt very relaxed during CL together with role-play", respectively. CL together with role play is an efficient educational tool for enhancing student active-learning and communication skills. But Chinese students will take some time to adapt to this new teaching method.

  19. The Signalling Role of Promotion in Japan

    OpenAIRE

    Okamura, Kazuaki

    2011-01-01

    Under asymmetric information conditions regarding worker productivity between current and prospective employers, a worker's promotion signals his/her productivity. In this Paper, we tested the signalling role of promotion, using Japanese micro-level data. We found that among lower-level positions, promotion seems to signal a worker's ability, and both the business cycle and foreign-capital ratio of his/her company significantly strengthen this effects. These results suggest that external labo...

  20. The role of cooperatives in food safety management of fresh produce chains: Case studies in four strawberry cooperatives

    NARCIS (Netherlands)

    Kirezieva, K.K.; Bijman, J.; Jacxsens, L.; Luning, P.A.

    2016-01-01

    Recent outbreaks with fresh produce have raised questions regarding management of quality and safety in the complex supply chains, where cooperatives play a central role. The overall objective of this article was to investigate the role of cooperatives in food quality and safety management in the

  1. Roles of STATs signaling in cardiovascular diseases.

    Science.gov (United States)

    Kishore, Raj; Verma, Suresh K

    2012-04-01

    In cardiac and many other systems, chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine, serine or threonine phosphorylation to transfer the messages to the genetic machinery. However, the activation of the Janus kinases (JAKs) and their downstream signal transducer and activator of transcription (STATs) proteins is both characteristic of and unique to cytokine and growth factor signaling which plays a central role in heart physiology. Dysregulation of JAK-STAT signaling is associated with various cardiovascular diseases. The molecular signaling and specificity of the JAK-STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the STAT signaling pathway that will enhance our ability to design rational therapeutic strategies for stress-induced heart failure.

  2. Role of Smad signaling in kidney disease.

    Science.gov (United States)

    Zhang, Yanhua; Wang, Songyan; Liu, Shengmao; Li, Chunguang; Wang, Ji

    2015-12-01

    Smads are the key intermediates of canonical transforming growth factor-beta (TGF-β) signaling. These intermediates are divided into three distinct subgroups based on their role in TGF-β family signal transduction: Receptor-regulated Smads (R-Smads) 1, 2, 3, 5 and 8, common Smad4, and inhibitory Smads6 and 7. TGF-β signaling through Smad pathway involves phosphorylation, ubiquitination, sumoylation, acetylation, and protein-protein interactions with mitogen-activated protein kinases, PI3K-Akt/PKB, and Wnt/GSK-3. Several studies have suggested that upregulation or downregulation of TGF-β/Smad signaling pathways may be a pathogenic mechanism in the progression of chronic kidney disease. Smad2 and 3 are the two major downstream R-Smads in TGF-β-mediated renal fibrosis, while Smad7 also controls renal inflammation. In this review, we characterize the role of Smads in kidney disease, describe the molecular mechanisms, and discuss the potential of Smads as a therapeutic target in chronic kidney disease.

  3. Blind Compressed Sensing Parameter Estimation of Non-cooperative Frequency Hopping Signal

    Directory of Open Access Journals (Sweden)

    Chen Ying

    2016-10-01

    Full Text Available To overcome the disadvantages of a non-cooperative frequency hopping communication system, such as a high sampling rate and inadequate prior information, parameter estimation based on Blind Compressed Sensing (BCS is proposed. The signal is precisely reconstructed by the alternating iteration of sparse coding and basis updating, and the hopping frequencies are directly estimated based on the results. Compared with conventional compressive sensing, blind compressed sensing does not require prior information of the frequency hopping signals; hence, it offers an effective solution to the inadequate prior information problem. In the proposed method, the signal is first modeled and then reconstructed by Orthonormal Block Diagonal Blind Compressed Sensing (OBD-BCS, and the hopping frequencies and hop period are finally estimated. The simulation results suggest that the proposed method can reconstruct and estimate the parameters of noncooperative frequency hopping signals with a low signal-to-noise ratio.

  4. Smart Training, Smart Learning: The Role of Cooperative Learning in Training for Youth Services.

    Science.gov (United States)

    Doll, Carol A.

    1997-01-01

    Examines cooperative learning in youth services and adult education. Discusses characteristics of cooperative learning techniques; specific cooperative learning techniques (brainstorming, mini-lecture, roundtable technique, send-a-problem problem solving, talking chips technique, and three-step interview); and the role of the trainer. (AEF)

  5. When cooperation begets cooperation: the role of key individuals in galvanizing support.

    Science.gov (United States)

    McAuliffe, Katherine; Wrangham, Richard; Glowacki, Luke; Russell, Andrew F

    2015-12-05

    Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in--and provide testable hypotheses of--two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? © 2015 The Author(s).

  6. A signal combining technique based on channel shortening for cooperative sensor networks

    KAUST Repository

    Hussain, Syed Imtiaz; Alouini, Mohamed-Slim; Hasna, Mazen Omar

    2010-01-01

    The cooperative relaying process needs proper coordination among the communicating and the relaying nodes. This coordination and the required capabilities may not be available in some wireless systems, e.g. wireless sensor networks where the nodes are equipped with very basic communication hardware. In this paper, we consider a scenario where the source node transmits its signal to the destination through multiple relays in an uncoordinated fashion. The destination can capture the multiple copies of the transmitted signal through a Rake receiver. We analyze a situation where the number of Rake fingers N is less than that of the relaying nodes L. In this case, the receiver can combine N strongest signals out of L. The remaining signals will be lost and act as interference to the desired signal components. To tackle this problem, we develop a novel signal combining technique based on channel shortening. This technique proposes a processing block before the Rake reception which compresses the energy of L signal components over N branches while keeping the noise level at its minimum. The proposed scheme saves the system resources and makes the received signal compatible to the available hardware. Simulation results show that it outperforms the selection combining scheme. ©2010 IEEE.

  7. A signal combining technique based on channel shortening for cooperative sensor networks

    KAUST Repository

    Hussain, Syed Imtiaz

    2010-06-01

    The cooperative relaying process needs proper coordination among the communicating and the relaying nodes. This coordination and the required capabilities may not be available in some wireless systems, e.g. wireless sensor networks where the nodes are equipped with very basic communication hardware. In this paper, we consider a scenario where the source node transmits its signal to the destination through multiple relays in an uncoordinated fashion. The destination can capture the multiple copies of the transmitted signal through a Rake receiver. We analyze a situation where the number of Rake fingers N is less than that of the relaying nodes L. In this case, the receiver can combine N strongest signals out of L. The remaining signals will be lost and act as interference to the desired signal components. To tackle this problem, we develop a novel signal combining technique based on channel shortening. This technique proposes a processing block before the Rake reception which compresses the energy of L signal components over N branches while keeping the noise level at its minimum. The proposed scheme saves the system resources and makes the received signal compatible to the available hardware. Simulation results show that it outperforms the selection combining scheme. ©2010 IEEE.

  8. The roles of incentives and voluntary cooperation for contractual compliance

    OpenAIRE

    Gächter, Simon; Kessler, Esther; Königstein, Manfred

    2011-01-01

    Efficiency under contractual incompleteness often requires voluntary cooperation in situations where self-regarding incentives for contractual compliance are present as well. Here we provide a comprehensive experimental analysis based on the gift-exchange game of how explicit and implicit incentives affect cooperation. We first show that there is substantial cooperation under non-incentive compatible contracts. Incentive-compatible contracts induce best-reply effort and crowd out any voluntar...

  9. The role of physical space in labour–management cooperation

    DEFF Research Database (Denmark)

    Ilsøe, Anna; Felbo-Kolding, Jonas

    2018-01-01

    Many studies on labour–management relations have focused on formal cooperation in manufacturing. This calls for further research and theory development on labour–management interactions in private service companies, where cooperation practices appear to be less formal. In this article, a typology...... of cooperation between managers and employees is developed, based on a microsociological study conducted in the Danish retail trade in 2013. Drawing on six indepth case studies, the article identifies four different physical spaces of labour–management cooperation: open collective, closed collective, open...

  10. Vehicle speed guidance strategy at signalized intersection based on cooperative vehicle infrastructure system

    Directory of Open Access Journals (Sweden)

    Fengyuan JIA

    2017-10-01

    Full Text Available In order to reduce stopping time of vehicle at a signalized intersection, aiming at the difficulty, even the impossibility to obtain real-time queue length of intersection in third and fourth-tier cities in China sometimes, a speed guidance strategy based on cooperative vehicle infrastructure system is put forward and studied. For validating the strategy, the traffic signal timing data of the intersection at Hengshan Road and North Fengming Lake Road in Wuhu is collected by a vehicular traffic signal reminder system which is designed. The simulation experiments using the acquired data are done by software VISSIM. The simulation results demonstrate that the strategy under high and low traffic flow can effectively decrease the link travel-time, reducing average ratio is 9.2 % and 13.0 %, respectively, and the effect under low traffic flow is better than that under high traffic flow. The strategy improves efficiency of traffic at a signalized intersection and provides an idea for the application of vehicle speed guidance based on cooperative vehicle infrastructure system.

  11. The Role of Notch Signaling Pathway in Breast Cancer Pathogenesis

    Science.gov (United States)

    2005-07-01

    breast cancer cells, I tested whether ErbB2 overexpression will cooperate with Notch in HMLE cells. While overexpression of activated Notch1 failed to...tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers , also failed to transform HMLE cells. These observations suggested...cooperation between Notch1IC and ErbB2 signaling in transforming HMLE cells. Breast cancers typically do not harbor oncogenic Ras mutations; nevertheless

  12. Role of cooperative companies in sustainable rice production and ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-03-15

    Mar 15, 2010 ... poverty in Guilan state of Iran, thus cooperative companies should be organized and supported by government. Key words: Cooperative companies, rural households, rice, income, employment. INTRODUCTION. Almost half ... education and trainnig, neglect of agriculture and low investment are major ...

  13. Role of Cooperatives in Small and Medium Scale Enterprises (SMEs ...

    African Journals Online (AJOL)

    First Lady

    2012-10-27

    Oct 27, 2012 ... Enterprises (SMEs) Development in Nigeria: Challenges and the Way ... Nigerian governments have been spending an immense amount of money obtained from ... (SMEDAN) to facilitating access to credit, technology and market for the .... Information; Cooperation among Cooperatives and Concern for the.

  14. Role of delay-based reward in the spatial cooperation

    Science.gov (United States)

    Wang, Xu-Wen; Nie, Sen; Jiang, Luo-Luo; Wang, Bing-Hong; Chen, Shi-Ming

    2017-01-01

    Strategy selection in games, a typical decision making, usually brings noticeable reward for players which have discounted value if the delay appears. The discounted value is measure: earning sooner with a small reward or later with a delayed larger reward. Here, we investigate effects of delayed rewards on the cooperation in structured population. It is found that delayed reward supports the spreading of cooperation in square lattice, small-world and random networks. In particular, intermediate reward differences between delays impel the highest cooperation level. Interestingly, cooperative individuals with the same delay time steps form clusters to resist the invasion of defects, and cooperative individuals with lowest delay reward survive because they form the largest clusters in the lattice.

  15. The role of cooperatives in sustaining the livelihoods of rural communities: The case of rural cooperatives in Shurugwi District, Zimbabwe

    Directory of Open Access Journals (Sweden)

    Smart Mhembwe

    2017-04-01

    Full Text Available The main focus of the research was to analyse the role of cooperatives in sustaining the livelihoods of local rural communities in Shurugwi District in Zimbabwe. Descriptive survey design was used in this mixed method approach to the study. A questionnaire, interviews and observation methods were employed as the main research instruments. Purposive sampling technique was adopted and data were collected from government officials and from members of the six cooperatives in Shurugwi District. A total of 50 research participants were involved in the study. It was found that cooperatives were established as a strategy to sustain livelihoods of rural communities. With the adoption of cooperatives, people in the rural communities managed to generate employment, boost food production, empower the marginalised, especially women, and promote social cohesion and integration, thereby improving their livelihoods and reducing poverty. Most cooperatives face a number of challenges that include lack of financial support, poor management and lack of management skills, and lack of competitive markets to sell their produce. The study recommends that the government and the banking sector render financial support to cooperatives in rural communities to allow them to expand and diversify their business operations; constant training on leadership and management skills is provided to cooperatives’ members. There is also a need for cooperatives, especially those in the agricultural sector, to form some producer associations so as to easily market their produce. Lastly, the study recommends that future research should focus on investigating issues that hinder the growth of the cooperative movement in rural communities of Zimbabwe. It is hoped that policy-makers, the academia and communities would benefit from the study.

  16. Trastuzumab Resistance: Role for Notch Signaling

    Directory of Open Access Journals (Sweden)

    Kinnari Mehta

    2009-01-01

    Full Text Available Epidermal growth factor receptor-2 (ErbB-2/HER2 is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy. However, resistance to trastuzumab remains a major concern, most notably in women with metastatic breast cancer. Numerous mechanisms that include overexpression of alternate receptor tyrosine kinases and/or loss of critical tumor suppressors have been proposed in the last several years to elucidate trastuzumab resistance. Here we review the many possible mechanisms of action that could contribute to resistance, and novel therapies to prevent or reverse the resistant phenotype. Moreover, we provide a critical role for Notch signaling cross-talk with overlapping or new signaling networks in trastuzumab-resistant breast.

  17. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway.

    Science.gov (United States)

    Larrivée, Bruno; Prahst, Claudia; Gordon, Emma; del Toro, Raquel; Mathivet, Thomas; Duarte, Antonio; Simons, Michael; Eichmann, Anne

    2012-03-13

    Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Evidence for cooperative signal triggering at the extracellular loops of the TSH receptor.

    Science.gov (United States)

    Kleinau, Gunnar; Jaeschke, Holger; Mueller, Sandra; Raaka, Bruce M; Neumann, Susanne; Paschke, Ralf; Krause, Gerd

    2008-08-01

    The mechanisms governing transition of the thyroid stimulating hormone (TSH) receptor (TSHR) from basal to active conformations are poorly understood. Considering that constitutively activating mutations (CAMs) and inactivating mutations in each of the extracellular loops (ECLs) trigger only partial TSHR activation or inactivation, respectively, we hypothesized that full signaling occurs via multiple extracellular signal propagation events. Therefore, individual CAMs in the extracellular region were combined to create double and triple mutants. In support of our hypothesis, combinations of mutants in the ECLs are in some cases additive, while in others they are even synergistic, with triple mutant I486A/I568V/V656F exhibiting a 70-fold increase in TSH-independent signaling. The proximity but likely different spatial orientation of the residues of activating and inactivating mutations in each ECL supports a dual functionality to facilitate signal induction and conduction, respectively. This is the first report for G-protein coupled receptors, suggesting that multiple and cooperative signal propagating events at all three ECLs are required for full receptor activation. Our findings provide new insights concerning molecular signal transmission from extracellular domains toward the transmembrane helix bundle of the glycoprotein hormone receptors.

  19. The role of emotions in the maintenance of cooperative behaviors

    Science.gov (United States)

    Zhang, Chunyan; Zhang, Jianlei; Weissing, Franz J.

    2014-04-01

    Our attention is focused on how individual emotions influence collective behaviors, which captures an aspect of reality missing from past studies: free riders may suffer some stress, which could adapt jointly with the individual stress intensity and size of the gaming group. With an evolutionary game theoretical approach, we gain the fixation probability for one mutant cooperator to invade and dominate the whole defecting population. When the stress intensity exceeds a threshold, natural selection favors cooperators replacing defectors in a finite population. We further infer that lower stress intensity is sufficient for one mutant cooperator to become fixed with an advantageous probability in a larger population. Moreover, when the gaming group is smaller than the population size, the more the return from the public goods, the lower the threshold of stress intensity required to facilitate the full dominance of cooperators. We hope our studies may show that individual sentiments or psychological activities will open up novel explanations for the puzzle of collective actions.

  20. Cooperative monitoring and its role in regional security

    Energy Technology Data Exchange (ETDEWEB)

    Biringer, K.; Olsen, J.; Lincoln, R.; Wehling, F. [and others

    1997-03-01

    Cooperative monitoring systems can play an important part in promoting the implementation of regional cooperative security agreements. These agreements advance the national security interests of the United States in a post Cold War environment. Regional issues as widely varying as nuclear nonproliferation, trade and environmental pollution can be the source of tensions which may escalate to armed conflict which could have global implications. The Office of National Security Policy Analysis at the US Department of Energy (DOE) has an interest in seeking ways to promote regional cooperation that can reduce the threats posed by regional conflict. DOE technologies and technical expertise can contribute to developing solutions to a wide variety of these international problems. Much of this DOE expertise has been developed in support of the US nuclear weapons and arms control missions. It is now being made available to other agencies and foreign governments in their search for regional security and cooperation. This report presents two examples of interest to DOE in which monitoring technologies could be employed to promote cooperation through experimentation. The two scenarios include nuclear transparency in Northeast Asia and environmental restoration in the Black Sea. Both offer the potential for the use of technology to promote regional cooperation. The issues associated with both of these monitoring applications are presented along with examples of appropriate monitoring technologies, potential experiments and potential DOE contributions to the scenarios.

  1. The Economic Role and Limitations of Cooperatives: An Investment Cash Flow Derivation

    OpenAIRE

    Peterson, H. Christopher

    1992-01-01

    The economic role and limitations of cooperatives are derived using an approach based on investment cash flows and net present value. Cooperatives are viewed as an option for member investment as well as an option for member patronage. The investment approach yields results similar to the traditional paradigms that focus on patronage. In addition, the approach makes more explicit the impact of member investment on cooperative existence, valuation, performance measurement, and strategy options.

  2. The role of cooperatives in the Georgian wine industry

    Directory of Open Access Journals (Sweden)

    Kvariani Levani

    2015-01-01

    Full Text Available The potential of the Georgian wine industry is not fully utilized. High fragmentation of agricultural land leads to limited production that restricts farmers' access to capital resources, finances, and markets, and prevents further development of the Georgian wine industry. Grape collectors and wine makers need help to join their capital and efforts, to gain economies of scale in production and marketing by jointly accessing agricultural inputs. This study aims to identify the importance of farmer cooperatives for grape producers in the Georgian wine industry in order to overcome inefficiency in the sector. Furthermore, this research project investigates the barriers and driving forces of smallholder grape farmers or wine makers to join cooperatives. Semi-structured interviews were conducted with stakeholders of the Georgian wine industry in order to assess different perspectives on the importance and benefits of farmer cooperatives in the local context. The interview results permit economic analysis of transaction costs, agency theory and property rights in the context of the nascent cooperative movement in the Georgian wine industry. The interviews revealed that development of agriculture cooperatives in the Georgian wine industry is strongly dependent on both farmer enthusiasm and governmental support.1

  3. Role of nuclear bodies in apoptosis signalling.

    Science.gov (United States)

    Krieghoff-Henning, Eva; Hofmann, Thomas G

    2008-11-01

    Promyelocytic leukemia nuclear bodies (PML NBs) are dynamic macromolecular multiprotein complexes that recruit and release a plethora of proteins. A considerable number of PML NB components play vital roles in apoptosis, senescence regulation and tumour suppression. The molecular basis by which PML NBs control these cellular responses is still just beginning to be understood. In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity. Moreover, in response to death-receptor activation, PML NBs may act as nuclear depots that release apoptotic factors, such as the FLASH (FLICE-associated huge) protein, to amplify the death signal. PML NBs are also associated with other nuclear domains including Cajal bodies and nucleoli and share apoptotic regulators with these domains, implying crosstalk between NBs in apoptosis regulation. In conclusion, PML NBs appear to regulate cell death decisions through different, pathway-specific molecular mechanisms.

  4. An Analysis of the North Carolina Cooperative Extension Service's Role in Bridging the Digital Divide

    Science.gov (United States)

    Alston, Antoine J.; Hilton, Lashawn; English, Chastity Warren; Elbert, Chanda; Wakefield, Dexter

    2011-01-01

    The study reported here sought to determine the perception of North Carolina County Cooperative Extension directors in regard to the North Carolina Cooperative Extension Service's role in bridging the digital divide. It was perceived by respondents that variables such as income, education, gender, disability status, race/ethnicity, age, and…

  5. The Role of Child Characteristics and Peer Experiences in the Development of Peer Cooperation

    NARCIS (Netherlands)

    Endedijk, Hinke M.; Cillessen, Antonius H. N.; Bekkering, Harold; Cox, R.F.A; Hunnius, Sabine

    Cooperation with peers is challenging for young children, and there are large individual differences in the development of cooperation. The roles of child characteristics and peer experiences for peer interaction during free play have been studied extensively, but it is unclear which factors predict

  6. Role of cooperative companies in sustainable rice production and ...

    African Journals Online (AJOL)

    This study was conducted in the districts of Guilan state of Iran to assess the impact of cooperative companies on the economic condition of rice farmers in the Guilan state. The research was conducted in the 2005 to 2007 periods. Three hundred respondents were selected for the study comprising equal number of ...

  7. Promoting cooperation by preventing exploitation: The role of network structure

    Science.gov (United States)

    Utkovski, Zoran; Stojkoski, Viktor; Basnarkov, Lasko; Kocarev, Ljupco

    2017-08-01

    A growing body of empirical evidence indicates that social and cooperative behavior can be affected by cognitive and neurological factors, suggesting the existence of state-based decision-making mechanisms that may have emerged by evolution. Motivated by these observations, we propose a simple mechanism of anonymous network interactions identified as a form of generalized reciprocity—a concept organized around the premise "help anyone if helped by someone'—and study its dynamics on random graphs. In the presence of such a mechanism, the evolution of cooperation is related to the dynamics of the levels of investments (i.e., probabilities of cooperation) of the individual nodes engaging in interactions. We demonstrate that the propensity for cooperation is determined by a network centrality measure here referred to as neighborhood importance index and discuss relevant implications to natural and artificial systems. To address the robustness of the state-based strategies to an invasion of defectors, we additionally provide an analysis which redefines the results for the case when a fraction of the nodes behave as unconditional defectors.

  8. The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways.

    Science.gov (United States)

    Vajjhala, Parimala R; Ve, Thomas; Bentham, Adam; Stacey, Katryn J; Kobe, Bostjan

    2017-06-01

    The innate immune system is the first line of defense against infection and responses are initiated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). PRRs also detect endogenous danger-associated molecular patterns (DAMPs) that are released by damaged or dying cells. The major PRRs include the Toll-like receptor (TLR) family members, the nucleotide binding and oligomerization domain, leucine-rich repeat containing (NLR) family, the PYHIN (ALR) family, the RIG-1-like receptors (RLRs), C-type lectin receptors (CLRs) and the oligoadenylate synthase (OAS)-like receptors and the related protein cyclic GMP-AMP synthase (cGAS). The different PRRs activate specific signaling pathways to collectively elicit responses including the induction of cytokine expression, processing of pro-inflammatory cytokines and cell-death responses. These responses control a pathogenic infection, initiate tissue repair and stimulate the adaptive immune system. A central theme of many innate immune signaling pathways is the clustering of activated PRRs followed by sequential recruitment and oligomerization of adaptors and downstream effector enzymes, to form higher-order arrangements that amplify the response and provide a scaffold for proximity-induced activation of the effector enzymes. Underlying the formation of these complexes are co-operative assembly mechanisms, whereby association of preceding components increases the affinity for downstream components. This ensures a rapid immune response to a low-level stimulus. Structural and biochemical studies have given key insights into the assembly of these complexes. Here we review the current understanding of assembly of immune signaling complexes, including inflammasomes initiated by NLR and PYHIN receptors, the myddosomes initiated by TLRs, and the MAVS CARD filament initiated by RIG-1. We highlight the co-operative assembly mechanisms during assembly of each of these complexes. Copyright

  9. Making good cider out of bad apples – Signaling expectations boosts cooperation among would-be free riders

    DEFF Research Database (Denmark)

    Nagatsu, Michiru; Larsen, Karen; Karabegovic, Mia

    2018-01-01

    The present study investigates how group-cooperation heuristics boost voluntary contributions in a repeated public goods game. We manipulate two separate factors in a two-person public goods game: i) group composition (Selfish Subjects vs. Conditional Cooperators) and ii) common knowledge about...... group composition (Information vs. No Information). In addition, we let the subjects signal expectations of the other’s contributions in the experiment’s second phase. Common knowledge of Selfish type alone slightly dampens contributions but dramatically increases contributions when signaling...

  10. Role of Notch signaling in the mammalian heart

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, X.L.; Liu, J.C. [Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Donghu District, Nanchang, Jiangxi (China)

    2013-12-12

    Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.

  11. The functional role of Notch signaling in human gliomas

    DEFF Research Database (Denmark)

    Stockhausen, Marie-Thérése; Kristoffersen, Karina; Poulsen, Hans Skovgaard

    2010-01-01

    have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now...... firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic...

  12. Role of investment heterogeneity in the cooperation on spatial public goods game.

    Science.gov (United States)

    Yuan, Wu-Jie; Xia, Cheng-Yi

    2014-01-01

    Public cooperation plays a significant role in the survival and maintenance of biological species, to elucidate its origin thus becomes an interesting question from various disciplines. Through long-term development, the public goods game has proven to be a useful tool, where cooperator making contribution can beat again the free-rides. Differentiating from the traditional homogeneous investment, individual trend of making contribution is more likely affected by the investment level of his neighborhood. Based on this fact, we here investigate the impact of heterogeneous investment on public cooperation, where the investment sum is mapped to the proportion of cooperators determined by parameter α. Interestingly, we find, irrespective of interaction networks, that the increment of α (increment of heterogeneous investment) is beneficial for promoting cooperation and even guarantees the complete cooperation dominance under weak replication factor. While this promotion effect can be attributed to the formation of more robust cooperator clusters and shortening END period. Moreover, we find that this simple mechanism can change the potential interaction network, which results in the change of phase diagrams. We hope that our work may shed light on the understanding of the cooperative behavior in other social dilemmas.

  13. How Public High School Students Assume Cooperative Roles to Develop Their EFL Speaking Skills

    Directory of Open Access Journals (Sweden)

    Julie Natalie Parra Espinel

    2010-12-01

    Full Text Available This study describes an investigation we carried out in order to identify how the specific roles that 7th grade public school students assumed when they worked cooperatively were related to their development of speaking skills in English. Data were gathered through interviews, field notes, students’ reflections and audio recordings. The findings revealed that students who were involved in cooperative activities chose and assumed roles taking into account preferences, skills and personality traits. In the same manner, when learners worked together, their roles were affected by each other and they put into practice some social strategies with the purpose of supporting their embryonic speaking development.

  14. The role of external partners in regional cooperation projects in the Middle East

    OpenAIRE

    Raphael Bar-El; Miki Malul

    2008-01-01

    This article analyzes the extent to which external partners contribute to the internalization of externalities arising from regional cooperation in the Middle East, that is, the degree to which they help increase welfare gains generated by the projects. This is classified by extent, intensity, and sectors of cooperation. Externalities are defined macroeconomically and sociopolitically. The results show that the international community does play a role in the internalization of externalities. ...

  15. The role of neuroimmune signaling in alcoholism.

    Science.gov (United States)

    Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan; Coleman, Leon G

    2017-08-01

    Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies. This article is part of the Special Issue entitled "Alcoholism". Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Helping as a signal and the effect of a potential audience during provisioning visits in a cooperative bird

    NARCIS (Netherlands)

    McDonald, Paul G.; Te Marvelde, Luc; Kazem, Anahita J. N.; Wright, Jonathan

    Research on cooperative breeding has begun to focus on direct fitness benefits gained by helpers, particularly when individuals are unrelated to those they assist. There has been considerable interest in helping possibly operating as a signal, either to show off individual quality to potential mates

  17. Signalling role of skeletal muscle during exercise

    NARCIS (Netherlands)

    Catoire, M.

    2014-01-01

    Abstract

    Upon acute exercise skeletal muscle is immediately and heavily recruited, while other organs appear to play only a minor role during exercise. These other organs show significant changes and improvements in function, although they are not directly targeted by

  18. Promote or hinder? The role of punishment in the emergence of cooperation.

    Science.gov (United States)

    Gao, Shiping; Wu, Te; Nie, Suli; Wang, Long

    2015-12-07

    Investigation of anti-social punishment has shaken the positive role of punishment in the evolution of cooperation. However, punishment is ubiquitous in nature, and the centralized, apposed to decentralized, punishment is more favored by certain modern societies in particular. To explore the underlying principle of such phenomenon, we study the evolution of cooperation in the context of pro- and anti-social punishments subject to two distinct patterns: costly centralized and decentralized punishments. The results suggest that the pattern of punishment has a great effect on the role of punishment in the evolution of cooperation. In the absence of anti-social punishment, the costly centralized punishment is more effective in promoting the emergence of cooperation. Anti-social punishment can subvert the positive role of punishment when anti- and pro-social punishments are in the same pattern. However, driven by centralized pro-social punishment, cooperation can be more advantageous than defection even in the presence of decentralized anti-social punishment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Effects of gender and role selection in cooperative learning groups on science inquiry achievement

    Science.gov (United States)

    Affhalter, Maria Geralyn

    An action research project using science inquiry labs and cooperative learning groups examined the effects of same-gender and co-educational classrooms on science achievement and teacher-assigned or self-selected group roles on students' role preferences. Fifty-nine seventh grade students from a small rural school district participated in two inquiry labs in co-educational classrooms or in an all-female classroom, as determined by parents at the beginning of the academic year. Students were assigned to the same cooperative groups for the duration of the study. Pretests and posttests were administered for each inquiry-based science lab. Posttest assessments included questions for student reflection on role assignment and role preference. Instruction did not vary and a female science teacher taught all class sections. The same-gender classroom and co-ed classrooms produced similar science achievement scores on posttests. Students' cooperative group roles, whether teacher-assigned or self-selected, produced similar science achievement scores on posttests. Male and female students shared equally in favorable and unfavorable reactions to their group roles during the science inquiry labs. Reflections on the selection of the leader role revealed a need for females in co-ed groups to be "in charge". When reflecting on her favorite role of leader, one female student in a co-ed group stated, "I like to have people actually listen to me".

  20. Role of Dopamine Signaling in Drug Addiction.

    Science.gov (United States)

    Chen, Wan; Nong, Zhihuan; Li, Yaoxuan; Huang, Jianping; Chen, Chunxia; Huang, Luying

    2017-01-01

    Addiction is a chronic, relapsing disease of the brain that includes drug-induced compulsive seeking behavior and consumption of drugs. Dopamine (DA) is considered to be critical in drug addiction due to reward mechanisms in the midbrain. In this article, we review the major animal models in addictive drug experiments in vivo and in vitro. We discuss the relevance of the structure and pharmacological function of DA receptors. To improve the understanding of the role of DA receptors in reward pathways, specific brain regions, including the Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, and Habenula, are highlighted. These factors contribute to the development of novel therapeutic targets that act at DA receptors. In addiction, the development of neuroimaging method will increase our understanding of the mechanisms underlying drug addiction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Analysis of Emission Effects Related to Drivers’ Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections

    Directory of Open Access Journals (Sweden)

    Ruohua Liao

    2018-01-01

    Full Text Available Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers’ compliance behaviors. To quantify the effects of drivers’ compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO2, NOx, HC, and CO emissions. CO2 was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively.

  2. Analysis of Emission Effects Related to Drivers' Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections.

    Science.gov (United States)

    Liao, Ruohua; Chen, Xumei; Yu, Lei; Sun, Xiaofei

    2018-01-12

    Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers' compliance behaviors. To quantify the effects of drivers' compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany) to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP)-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO₂, NO x , HC, and CO emissions. CO₂ was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively.

  3. Analysis of Emission Effects Related to Drivers’ Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections

    Science.gov (United States)

    Liao, Ruohua; Yu, Lei; Sun, Xiaofei

    2018-01-01

    Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers’ compliance behaviors. To quantify the effects of drivers’ compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany) to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP)-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO2, NOx, HC, and CO emissions. CO2 was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively. PMID:29329214

  4. The Role of Multi Purpose Cooperative in Developing Economic Independence or SME’s

    Directory of Open Access Journals (Sweden)

    Partono Thomas

    2017-03-01

    Full Text Available Cooperatives are seen as one of the important instrument to improve economic and social conditions of societies, to arouse the spirit of initiative and improving the general knowledge and technical skills of the society. On the present cooperatives members are business people of small medium scale enterprises (SMEs which need a guidance or development. The purpose of this study is to describe the role of cooperatives in small medium scale enterprises (SMEs development. The method used is descriptive qualitative. Data collection techniques used are observation, documentation and interview.The results of research showed that KSU Padurenan Jaya is a multi-purpose cooperatives that has five business units i.e. save loan, store, embroidery service, marketing, research and development. KSU Padurenan Jaya was instrumental in developing the small medium scale enterprises (SMEs embroidery and convection consists of (1 aspects of the market, by following the events of the exhibition or expo, online marketing, providing material needs in the cooperative store, and create innovative products according to consumer taste. (2 the aspect of technology, by socialization and demonstration of the use technology of embroidery machines, embroidery design with computer programs, internet information technology for promoting and marketing product, And to optimize the use of the machine by provide services embroidery using advanced machine in cooperation so that can improve the productivity and efficiency of the business. (3 the aspect of the capital, by providing save loan service with simple procedures, mentoring to access other sources of financing.

  5. Local and Sustainable Food Supply: The Role of European Retail Consumer Co-operatives

    Directory of Open Access Journals (Sweden)

    Martin Hingley

    2012-03-01

    Full Text Available  This paper investigates the rationale for local and sustainable food systems and retailer co-operatives as their entry points within local conditions. Emphasis is on localised food networks and connection between socially as well as environmentally sustainable production, distribution and consumption. Investigated is the premise that co-operative organisational structures, for reasons of their long-term socially responsible origins are at the forefront of development of local and sustainable food systems and are thereby in a position to offer a specific contribution to market development. Two key research questions are proposed: Firstly, is there a pre-determination of co-operatives to issues of sustainable and local food sourcing given the historical and practical context of their ethical/socially responsible and stakeholder-based business model? Secondly, do co-ops express support for re-localising food systems and what contribution do they make concerning sustainable food and their relationships with local food suppliers? The method of investigation is through a two country retailer co-operative sector analysis and comparison (Finland and Italy. The enquiry is qualitative and exploratory in nature in the form of an embedded, multiple case design. The paper makes practical and theoretical contribution to knowledge concerning interpretation of ‘localness’ in food, the role of co-operatives and the co-operative ethos in sustainable food systems and the development of the local food economy. Results of the study show a positive relationship between co-operative ethos and (social sustainability in local food, but the de-centralised nature of retailer co-operation also provides a barrier to replication of good practice.

  6. The cluster panacea?: Questioning the role of cooperative shrimp aquaculture in Vietnam

    NARCIS (Netherlands)

    Tran Thi Thu Ha, Ha; Bush, S.R.; Dijk, van H.

    2013-01-01

    This paper analyses the role of ‘clustering’ as a form of cooperative production to improve the environmental performance of shrimp farmers and facilitating them to upgrade their position in the global value chain. Comparing intensive and extensive shrimp farmer clusters in Ca Mau province, Vietnam,

  7. The Role of Inhibitory Control in Children's Cooperative Behaviors during a Structured Puzzle Task

    Science.gov (United States)

    Giannotta, Fabrizia; Burk, William J.; Ciairano, Silvia

    2011-01-01

    This study examined the role of inhibitory control (measured by Stroop interference) in children's cooperative behaviors during a structured puzzle task. The sample consisted of 250 8-, 10-, and 12-year-olds (117 girls and 133 boys) attending classrooms in three primary schools in Northern Italy. Children individually completed an elaborated…

  8. Design and Implementation of an Emergency Vehicle Signal Preemption System Based on Cooperative Vehicle-Infrastructure Technology

    OpenAIRE

    Yinsong Wang; Zhizhou Wu; Xiaoguang Yang; Luoyi Huang

    2013-01-01

    Emergency vehicle is an important part of traffic flow. The efficiency, reliability, and safety of emergency vehicle operations dropped due to increasing traffic congestion. With the advancement of the wireless communication technologies and the development of the vehicle-to-vehicle (v2v) and vehicle-to-infrastructure (v2i) systems, called Cooperative Vehicle-Infrastructure System (CVIS), there is an opportunity to provide appropriate traffic signal preemption for emergency vehicle based on r...

  9. Is Cooperative Memory Special? The Role of Costly Errors, Context, and Social Network Size When Remembering Cooperative Actions

    Directory of Open Access Journals (Sweden)

    Tim Winke

    2017-10-01

    Full Text Available Theoretical studies of cooperative behavior have focused on decision strategies, such as tit-for-tat, that depend on remembering a partner’s last choices. Yet, an empirical study by Stevens et al. (2011 demonstrated that human memory may not meet the requirements that needed to use these strategies. When asked to recall the previous behavior of simulated partners in a cooperative memory task, participants performed poorly, making errors in 10–24% of the trials. However, we do not know the extent to which this task taps specialized cognition for cooperation. It may be possible to engage participants in more cooperative, strategic thinking, which may improve memory. On the other hand, compared with other situations, a cooperative context may already engage improved memory via cheater detection mechanisms. This study investigated the specificity of memory in cooperative contexts by varying (1 the costs of errors in memory by making forgetting defection more costly and (2 whether the recall situation is framed as a cooperative or neutral context. Also, we investigated whether variation in participants’ social network size could account for individual differences observed in memory accuracy. We found that neither including differential costs for misremembering defection nor removing the cooperative context influenced memory accuracy for cooperation. Combined, these results suggest that memory accuracy is robust to differences in the cooperative context: Adding more strategic components does not help accuracy, and removing cooperative components does not hurt accuracy. Social network size, however, did correlate with memory accuracy: People with larger networks remembered the events better. These findings suggest that cooperative memory does not seem to be special compared with other forms of memory, which aligns with previous work demonstrating the domain generality of memory. However, the demands of interacting in a large social network may

  10. Role of Estrogen Receptor Signaling in Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    Roy, S.S.; Vadlamudi, R.K.

    2012-01-01

    Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis

  11. The Role of Vietnam in The ASEAN Regional Security Cooperation: From Mechanism Construction to Dispute Settlement

    Directory of Open Access Journals (Sweden)

    Li Chunxia

    2016-12-01

    Full Text Available In the context of the integration of ASEAN, Vietnam recognized that the strategic role of ASEAN is in its diplomacy. At the same time, to further improve the status in the region and in the international community, Vietnam has actively been participating in ASEAN affairs. Vietnam not only promoted the integration process of ASEAN, but also promoted the political security cooperation of ASEAN, in which Vietnam has advantages and wants to play a leading role. On the one hand, Vietnam promotes the construction of political security cooperation mechanisms, such as ARF, ADMM+, and so on; on the other hand, Vietnam took the South China Sea as a common concern, actively appeals for a common ASEAN position, to maximize its own benefit. Vietnam will further enhance and consolidate its status and role in ASEAN in the future.

  12. Role of Interdisciplinary Cooperation in Process of Documentation of Cultural Heritage

    Directory of Open Access Journals (Sweden)

    Jindřich Hodač

    2011-12-01

    Full Text Available This paper is focused on presentation of results of long-term interdisciplinary cooperation in a process of documentation of Cultural Heritage. There are two sides joined in this cooperation. The first side is a ,,submitter” - in our case it means architect-historian (Mr. Rykl. The second side is a ,,contractor” - in our case it means surveyorphotogrammetrist (Mr. Hodač and his students. We are cooperating mostly on projects of metrical documentation of Culture Heritage buildings and sites. Our cooperation is realizing mainly in bachelor„s/master’s projects. Other opportunity for our collaboration is our course [1]. We are offering this course to students of two faculties/specializations (surveyors + architects. Beside the wide range of real results (2D drawings, 3D models, photomaps etc. we also collected quite a lot of experience with process of collaboration itself. Cooperation and communication of submitter and contactor are playing key roles for successful project. It is possible to generally expect that submitter will give the ,,task” and contractor will try to find proper technology to solve it. The process of communication should be permanent because new circumstances and findings are arising all the time. It is very important for all together to find common language across specializations to understand each other. Surveyors are ,,slightly pressed” to get more knowledge about historical building constructions. Architects-historians should get basic awareness about various recent technologies for metrical documentation and its ,,pros and cons”.

  13. Quantifying the Role of Homophily in Human Cooperation Using Multiplex Evolutionary Game Theory.

    Directory of Open Access Journals (Sweden)

    Alessandro Di Stefano

    Full Text Available Nature shows as human beings live and grow inside social structures. This assumption allows us to explain and explore how it may shape most of our behaviours and choices, and why we are not just blindly driven by instincts: our decisions are based on more complex cognitive reasons, based on our connectedness on different spaces. Thus, human cooperation emerges from this complex nature of social network. Our paper, focusing on the evolutionary dynamics, is intended to explore how and why it happens, and what kind of impact is caused by homophily among people. We investigate the evolution of human cooperation using evolutionary game theory on multiplex. Multiplexity, as an extra dimension of analysis, allows us to unveil the hidden dynamics and observe non-trivial patterns within a population across network layers. More importantly, we find a striking role of homophily, as the higher the homophily between individuals, the quicker is the convergence towards cooperation in the social dilemma. The simulation results, conducted both macroscopically and microscopically across the network layers in the multiplex, show quantitatively the role of homophily in human cooperation.

  14. The Gulf Cooperation Council countries – economic structures, recent developments and role in the global economy

    OpenAIRE

    Michael Sturm; Jan Strasky; Petra Adolf; Dominik Peschel

    2008-01-01

    In the wake of high and rising oil prices since 2003, the member states of the Gulf Cooperation Council (GCC) have seen dynamic economic development, enhancing their role in the global economy as investors and trade partners. Real GDP growth has been buoyant, with non-oil activity expanding faster than oil GDP. Macroeconomic developments have also been characterised by large fiscal and current account surpluses as a result of rising oil revenues, notwithstanding fiscal expansion and rapid imp...

  15. ANALYSIS OF THE ROLE OF AGRICULTURAL COOPERATIVES' IN FUNDING PROCESSING MILLS IN CROSS RIVER STATE, NIGERIA

    OpenAIRE

    Adinya, I.B; Odey S.O.; Oniah M.O; Umeh G.N; Agiopu, B.F; Ogbonna ,K.I.

    2008-01-01

    A study was undertaken to determine the role of agricultural co-operative societies as institutional source of finance to processing mills in Cross River State, Nigeria. Data were obtained from a random sample of 150 respondents in the study area by means of structured questionnaire. The first stage involved random selection of fifteen local government areas from eighteen local government areas in Cross River State. This was followed by random selection of one village in each of the fifteen l...

  16. The Role of Ghrelin and Ghrelin Signaling in Aging.

    Science.gov (United States)

    Amitani, Marie; Amitani, Haruka; Cheng, Kai-Chun; Kairupan, Timothy Sean; Sameshima, Nanami; Shimoshikiryo, Ippei; Mizuma, Kimiko; Rokot, Natasya Trivena; Nerome, Yasuhito; Owaki, Tetsuhiro; Asakawa, Akihiro; Inui, Akio

    2017-07-12

    With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism.

  17. Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation

    OpenAIRE

    Sehat, Bita; Andersson, Sandra; Vasilcanu, Radu; Girnita, Leonard; Larsson, Olle

    2007-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF-1R) plays numerous crucial roles in cancer biology. The majority of knowledge on IGF-1R signaling is concerned with its role in the activation of the canonical phosphatidyl inositol-3 kinase (PI3K)/Akt and MAPK/ERK pathways. However, the role of IGF-1R ubiquitination in modulating IGF-1R function is an area of current research. In light of this we sought to determine the relationship between IGF-1R phosphorylation, ubiquitination, and...

  18. Coevolution of honest signaling and cooperative norms by cultural group selection.

    Science.gov (United States)

    Scheuring, István

    2010-08-01

    Evolution of cooperative norms is studied in a population where individual and group level selection are both in operation. Individuals play indirect reciprocity game within their group and follow second order norms. Individuals are norm-followers, and imitate their successful group mates. Aside from direct observation individuals can be informed about the previous actions and reputations by information transferred by others. A potential donor estimates the reputation of a potential receiver either by her own observation or by the opinion of the majority of others (indirect observation). Following a previous study (Scheuring, 2009) we assume that norms determine only the probabilities of actions, and mutants can differ in these probabilities. Similarly, we assume that individuals follow a stochastic information transfer strategy. The central question is whether cooperative norm and honest social information transfer can emerge in a population where initially only non-cooperative norms were present, and the transferred information was not sufficiently honest. It is shown that evolution can lead to a cooperative state where information transferred in a reliable manner, where generous cooperative strategies are dominant. This cooperative state emerges along a sharp transition of norms. We studied the characteristics of actions and strategies in this transition by classifying the stochastic norms, and found that a series of more and more judging strategies invade each other before the stabilization of the so-called generous judging strategy. Numerical experiments on the coevolution of social parameters (e.g. probability of direct observation and the number of indirect observers) reveal that it is advantageous to lean on indirect observation even if information transfer is much noisier than for direct observation, which is because to follow the majorities' opinion suppresses information noise meaningfully.

  19. Wnt Signaling Cascades and the Roles of Syndecan Proteoglycans

    DEFF Research Database (Denmark)

    Pataki, Csilla A; Couchman, John R; Brábek, Jan

    2015-01-01

    /planar cell polarity and Wnt/calcium signaling. Syndecans are type I transmembrane proteoglycans with a long evolutionary history, being expressed in all Bilateria and in almost all cell types. Both Wnt pathways have been extensively studied over the past 30 years and shown to have roles during development...... and in a multitude of diseases. Although the first evidence for interactions between syndecans and Wnts dates back to 1997, the number of studies connecting these pathways is low, and many open questions remained unanswered. In this review, syndecan's involvement in Wnt signaling pathways as well as some...

  20. The role of leadership in bridging the cultural divide within university-industry cooperative research centres

    DEFF Research Database (Denmark)

    Mahdad, Maral; Bogers, Marcel; Piccaluga, Andrea

    The purpose of this study is to understand the role of leadership in bridging the cultural gap within university-industry cooperative research centres. Many different aspects of university-industry collaborations have been researched, but the role of leadership in such organizations has not been...... and employees representatives from both the company and the university within eight joint laboratories of Telecom Italia. We find that leadership theories help to shed light on the performance of university-industry collaboration. We specifically identify charismatic leadership at the individual level followed...... provide specific insights that advance the literature in management of university-industry collaborations as well as leadership theories....

  1. Role of TRIM33 in Wnt signaling during mesendoderm differentiation.

    Science.gov (United States)

    Xia, Xiaojie; Zuo, Feifei; Luo, Maoguo; Sun, Ye; Bai, Jianbo; Xi, Qiaoran

    2017-10-01

    Tripartite motif 33 (TRIM33), a member of the transcription intermediate factor 1 (TIF1) family of transcription cofactors, mediates transforming growth factor-beta (TGF-β) signaling through its PHD-Bromo cassette in mesendoderm differentiation during early mouse embryonic development. However, the role of the TRIM33 RING domain in embryonic differentiation is less clear. Here, we report that TRIM33 mediates Wnt signaling by directly regulating the expression of a specific subset of Wnt target genes, and this action is independent of its RING domain. We show that TRIM33 interacts with β-catenin, a central player in Wnt signaling in mouse embryonic stem cells (mESCs). In contrast to previous reports in cancer cell lines, the RING domain does not appear to function as the E3 ligase for β-catenin, since neither knockout nor overexpression of TRIM33 had an effect on β-catenin protein levels in mESCs. Furthermore, we show that although TRIM33 seems to be dispensable for Wnt signaling through a reporter assay, loss of TRIM33 significantly impairs the expression of a subset of Wnt target genes, including Mixl1, in a Wnt signaling-dependent manner. Together, our results indicate that TRIM33 regulates Wnt signaling independent of the E3 ligase activity of its RING domain for β-catenin in mESCs.

  2. Diversity and Cooperation

    OpenAIRE

    Bruner, Justin Pearce

    2014-01-01

    The present dissertation is an exploration of the effect of diversity on social contract formation and the evolution of cooperation. This work stems from the pioneering efforts of economist Arthur Robson, who first explored the role of costless pre-game communication in strategic interactions. When communication is permitted, individuals playing a game can condition their behavior on the signal received from their counterpart. For my purposes, I interpret these signals as racial markers or cu...

  3. Roles of Zinc Signaling in the Immune System.

    Science.gov (United States)

    Hojyo, Shintaro; Fukada, Toshiyuki

    2016-01-01

    Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival. Zn deficiency depresses both innate and adaptive immune responses. However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn. There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli. In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk between Zn and immune-related signaling guides the normal development and function of immune cells.

  4. Intraflagellar Transport (IFT) Role in Ciliary Assembly, Resorption and Signalling

    DEFF Research Database (Denmark)

    Pedersen, Lotte B; Rosenbaum, Joel L

    2008-01-01

    Cilia and flagella have attracted tremendous attention in recent years as research demonstrated crucial roles for these organelles in coordinating a number of physiologically and developmentally important signaling pathways, including the platelet-derived growth factor receptor (PDGFR) alpha, Sonic...... hedgehog, polycystin, and Wnt pathways. In addition, the realization that defective assembly or function of cilia can cause a plethora of diseases and developmental defects ("ciliopathies") has increased focus on the mechanisms by which these antenna-like, microtubular structures assemble. Ciliogenesis...... mechanisms and functions of IFT. In addition to a general, up-to-date description of IFT, we discuss mechanisms by which proteins are selectively targeted to the ciliary compartment, with special focus on the ciliary transition zone. Finally, we briefly review the role of IFT in cilia-mediated signaling...

  5. The Role of Cooperation and Information Exchange in Transnational River Basins: the Zambezi River case

    Science.gov (United States)

    Castelletti, A.; Giuliani, M.; Soncini-Sessa, R.

    2012-12-01

    The presence of multiple, institutionally independent but physically interconnected decision-makers is a distinctive features of many water resources systems, especially of transnational river basins. The adoption of a centralized approach to study the optimal operation of these systems, as mostly done in the water resources literature, is conceptually interesting to quantify the best achievable performance, but of little practical impact given the real political and institutional setting. Centralized management indeed assumes a cooperative attitude and full information exchange by the involved parties. However, when decision-makers belong to different countries or institutions, it is very likely that they act considering only their local objectives, producing global externalities that negatively impact on other objectives. In this work we adopt a Multi-Agent Systems framework, which naturally allows to represent a set of self-interested agents (decision-makers and/or stakeholders) acting in a distributed decision-making process. According to this agent-based approach, each agent represents a decision-maker, whose decisions are defined by an explicit optimization problem considering only the agent's local interests. In particular, this work assesses the role of information exchange and increasing level of cooperation among originally non-cooperative agents. The Zambezi River basin is used to illustrate the methodology: the four largest reservoirs in the basin (Ithezhithezhi, Kafue-Gorge, Kariba and Cahora Bassa) are mainly operated for maximizing the economic revenue from hydropower energy production with considerably negative effects on the aquatic ecosystem in the Zambezi delta due to the alteration of the natural flow regime. We comparatively analyse the ideal centralized solution and the current situation where all the decision-makers act independently and non-cooperatively. Indeed, although a new basin-level institution called Zambezi Watercourse Commission

  6. Role of protein dynamics in transmembrane receptor signalling

    DEFF Research Database (Denmark)

    Wang, Yong; Bugge, Katrine Østergaard; Kragelund, Birthe Brandt

    2018-01-01

    Cells are dependent on transmembrane receptors to communicate and transform chemical and physical signals into intracellular responses. Because receptors transport 'information', conformational changes and protein dynamics play a key mechanistic role. We here review examples where experiment...... to function. Because the receptors function in a heterogeneous environment and need to be able to switch between distinct functional states, they may be particularly sensitive to small perturbations that complicate studies linking dynamics to function....

  7. The role of cooperation and parasites in non-linear replicator delayed extinctions

    International Nuclear Information System (INIS)

    Sardanyes, Josep; Sole, Ricard V.

    2007-01-01

    In the present work we study the role of cooperation and parasites on extinction delayed transitions for self-replicating species with catalytic activity. We first use a one-dimensional continuous equation to study the dynamics of both single autocatalytic replicator and symmetric two-member hypercycles, where two well-defined phases involving survival and extinction of replicators are shown to exist. Extinction dynamics is analyzed numerically and analytically and under both deterministic and stochastic scenarios. A ghost is also found for the single autocatalytic replicator and for the asymmetric hypercycle, with an extinction time delay following the square-root scaling law near bifurcation threshold. We find that the extinction delay is longer for the two-member hypercycle than for the single autocatalytic species, indicating that cooperation among replicators might involve to spend a longer time in the bottle-neck region of the ghost. The asymmetry of the network is shown to prolong the extinction time. We also show that an attached parasite decreases the time spent in the bottle-neck region of the ghost, thus accelerating extinction in these systems of replicators. Nevertheless the effect of the parasite is not so important when replicators catalytically cooperate, being the two-member hypercycle less sensitive to the parasite than the autocatalytic species. Here the hypercycle asymmetry can also significantly increase the delaying capacity. These features make the hypercycle to undergo a longer extinction delay, thus increasing the memory effect of the ghost. We finally explore the role of the ghost in fluctuating media, where the extinction delayed transition is shown to increase the survival probability of cooperating catalytic species

  8. Essential role of Stat6 in IL-4 signalling.

    Science.gov (United States)

    Takeda, K; Tanaka, T; Shi, W; Matsumoto, M; Minami, M; Kashiwamura, S; Nakanishi, K; Yoshida, N; Kishimoto, T; Akira, S

    1996-04-18

    Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system. IL-4 activates two distinct signalling pathways through tyrosine phosphorylation of Stat6, a signal transducer and activator of transcription, and of a 170K protein called 4PS. To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting. We report here that in the mutant mice, expression of CD23 and major histocompatibility complex (MHC) class II in resting B cells was not enhanced in response to IL-4. IL-4 induced B-cell proliferation costimulated by anti-IgM antibody was abolished. The T-cell proliferative response was also notably reduced. Furthermore, production of Th2 cytokines from T cells as well as IgE and IgG1 responses after nematode infection were profoundly reduced. These findings agreed with those obtained in IL-4 deficient mice or using antibodies to IL-4 and the IL-4 receptor. We conclude that Stat6 plays a central role in exerting IL-4 mediated biological responses.

  9. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Directory of Open Access Journals (Sweden)

    Shellese A. Cannonier

    2015-08-01

    Full Text Available Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung, directly invade into bone (head and neck or originate from the bone (melanoma, chondrosarcoma where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  10. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    Energy Technology Data Exchange (ETDEWEB)

    Cannonier, Shellese A.; Sterling, Julie A., E-mail: Julie.sterling@vanderbilt.edu [Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235 (United States); Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335 (United States); Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235 (United States)

    2015-08-26

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.

  11. The Role of Hedgehog Signaling in Tumor Induced Bone Disease

    International Nuclear Information System (INIS)

    Cannonier, Shellese A.; Sterling, Julie A.

    2015-01-01

    Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors

  12. The duality of gaze: Eyes extract and signal social information during sustained cooperative and competitive dyadic gaze

    Directory of Open Access Journals (Sweden)

    Michelle eJarick

    2015-09-01

    Full Text Available In contrast to nonhuman primate eyes, which have a dark sclera surrounding a dark iris, human eyes have a white sclera that surrounds a dark iris. This high contrast morphology allows humans to determine quickly and easily where others are looking and infer what they are attending to. In recent years an enormous body of work has used photos and schematic images of faces to study these aspects of social attention, e.g., the selection of the eyes of others and the shift of attention to where those eyes are directed. However, evolutionary theory holds that humans did not develop a high contrast morphology simply to use the eyes of others as attentional cues; rather they sacrificed camouflage for communication, that is, to signal their thoughts and intentions to others. In the present study we demonstrate the importance of this by taking as our starting point the hypothesis that a cornerstone of nonverbal communication is the eye contact between individuals and the time that it is held. In a single simple study we show experimentally that the effect of eye contact can be quickly and profoundly altered merely by having participants, who had never met before, play a game in a cooperative or competitive manner. After the game participants were asked to make eye contact for a prolonged period of time (10 minutes. Those who had played the game cooperatively found this terribly difficult to do, repeatedly talking and breaking gaze. In contrast, those who had played the game competitively were able to stare quietly at each other for a sustained period. Collectively these data demonstrate that when looking at the eyes of a real person one both acquires and signals information to the other person. This duality of gaze is critical to nonverbal communication, with the nature of that communication shaped by the relationship between individuals, e.g., cooperative or competitive.

  13. dsRNA-Dependent Protein Kinase PKR and its Role in Stress, Signaling and HCV Infection

    Directory of Open Access Journals (Sweden)

    Eliane F. Meurs

    2012-10-01

    Full Text Available The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eIF2a. As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most viral infections, indicating that PKR may play other roles in the cell other than just acting as an antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter protein and/or using its kinase activity. Here we review the role of PKR as an eIF2a kinase, its participation in the regulation of the NF-kB, p38MAPK and insulin pathways, and we focus on its role during infection with the hepatitis C virus (HCV. PKR binds the HCV IRES RNA, cooperates with some functions of the HCV core protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter protein and as an eIF2a-kinase, and in cooperation with the di-ubiquitin-like protein ISG15. Developing pharmaceutical inhibitors of PKR may help in resolving some viral infections as well as stress-related damages.

  14. What Role for Emotions in Cooperating Robots? - The Case of RH3-Y

    Science.gov (United States)

    Dessimoz, Jean-Daniel; Gauthey, Pierre-François

    The paper reviews key aspects of emotions in the context of cooperating robots (mostly, robots cooperating with humans), and gives numerous concrete examples from RH-Y robots. Emotions have been first systematically studied in relation to human expressions, and then the shift has come towards a machine-based replication. Emotions appear to result from changes, from convergence or deviation between status and goals; they trigger appropriate activities, are commonly represented in 2D or 3D affect space, and can be made visible by facial expressions. While specific devices are sometimes created, emotive expressions seem to be conveniently rendered by a set of facial images or more simply by some icons; they can also possibly be parameterized in a few dimensions for continuous modulation. In fact however, internal forces for activities and changes may be expressed in many ways other than faces: screens, panels, and operational behaviors. Relying on emotions ensures useful aspects, such as experience reuse, legibility or communication. But it also includes limits such as due to the nature of robots, of interactive media, and even of the very domain of emotions. For our goal, the design of effective and efficient, cooperating robots, in domestic applications, communication and interaction play key roles; best practices become evident after experimental verification; and our experience gained so far, over 10 years and more, points at a variety of successful strategic attitudes and expression modes, much beyond classic human emotions and facial or iconic images.

  15. Role of cooperation activities for capacity building of Romanian Regulatory Authority (CNCAN)

    International Nuclear Information System (INIS)

    Biro, L.; Ciurea-Ercau, C.

    2010-01-01

    With a slow but active nuclear development program of sector since 1980, Romanian regulatory authority had to permanently adapt to the changes in national and international environment in order ensure continuously increase of capacity building and effectiveness, commensurate with the growing nuclear sector. Limited human resources available at the national level put the Romanian Regulatory Authority in the position of building the Technical Support Organization as part of its on organization. International cooperation played an important role in capacity building of Romanian regulatory body and providing necessary assistance in performing regulatory activities or support in development of regulatory framework. Fellowships and technical visits, workshops and training courses provided through IAEA TC at national or regional level, technical assistance provided by European Commission (EC) through PHARE Projects, all provided valuable contribution in assuring training of regulatory staff and development of proper regulatory framework in Romania. Therefore, Romanian Regulatory Authority is putting a strong accent on strengthening and promoting international cooperation through IAEA Technical Cooperation Programme, Molls between regulatory bodies, as one of the key elements in supporting capacity building of regulatory authorities in countries having small or embarking on nuclear power program. Building networks between training centers and research facilities and establishments of regional training centers represent one of the future viable options in preserving knowledge in nuclear field. (author)

  16. Tie2 signaling cooperates with TNF to promote the pro-inflammatory activation of human macrophages independently of macrophage functional phenotype.

    Science.gov (United States)

    García, Samuel; Krausz, Sarah; Ambarus, Carmen A; Fernández, Beatriz Malvar; Hartkamp, Linda M; van Es, Inge E; Hamann, Jörg; Baeten, Dominique L; Tak, Paul P; Reedquist, Kris A

    2014-01-01

    Angiopoietin (Ang) -1 and -2 and their receptor Tie2 play critical roles in regulating angiogenic processes during development, homeostasis, tumorigenesis, inflammation and tissue repair. Tie2 signaling is best characterized in endothelial cells, but a subset of human and murine circulating monocytes/macrophages essential to solid tumor formation express Tie2 and display immunosuppressive properties consistent with M2 macrophage polarization. However, we have recently shown that Tie2 is strongly activated in pro-inflammatory macrophages present in rheumatoid arthritis patient synovial tissue. Here we examined the relationship between Tie2 expression and function during human macrophage polarization. Tie2 expression was observed under all polarization conditions, but was highest in IFN-γ and IL-10 -differentiated macrophages. While TNF enhanced expression of a common restricted set of genes involved in angiogenesis and inflammation in GM-CSF, IFN-γ and IL-10 -differentiated macrophages, expression of multiple chemokines and cytokines, including CXCL3, CXCL5, CXCL8, IL6, and IL12B was further augmented in the presence of Ang-1 and Ang-2, via Tie2 activation of JAK/STAT signaling. Conditioned medium from macrophages stimulated with Ang-1 or Ang-2 in combination with TNF, sustained monocyte recruitment. Our findings suggest a general role for Tie2 in cooperatively promoting the inflammatory activation of macrophages, independently of polarization conditions.

  17. Vasoprotection by Dietary Supplements and Exercise: Role of TNFα Signaling

    Directory of Open Access Journals (Sweden)

    Hanrui Zhang

    2012-01-01

    Full Text Available Vascular dysfunction contributes to the pathogenesis of various cardiovascular diseases. Dietary supplements, including fish oil, dietary fibers, and various natural products, and exercise training exert vasoprotective effects. However, the mechanisms underlying the vasoprotective benefits of dietary supplements and physical activity demand extensive investigation. Accumulating evidence suggests that inflammatory cytokine tumor necrosis factor-alpha (TNFα plays a pivotal role in the dysregulation of macrovascular and microvascular function. TNFα induces vascular inflammation, monocyte adhesion to endothelial cells, vascular oxidative stress, apoptosis, and atherogenic response and participates in the regulation of thrombosis and coagulation through multiple signaling pathways involving NFκB, Sp1, activator protein 1, JNK, p38, STAT3, and so forth. Dietary supplements and exercise training decrease TNFα production and ameliorate TNFα-mediated pathological changes in vasculature. Thus, the inhibitory effects of dietary supplements and physical exercise on TNFα production and TNFα signaling may contribute to their vasoprotective properties.

  18. The role of insulin receptor signaling in the brain.

    Science.gov (United States)

    Plum, Leona; Schubert, Markus; Brüning, Jens C

    2005-03-01

    The insulin receptor (IR) is expressed in various regions of the developing and adult brain, and its functions have become the focus of recent research. Insulin enters the central nervous system (CNS) through the blood-brain barrier by receptor-mediated transport to regulate food intake, sympathetic activity and peripheral insulin action through the inhibition of hepatic gluconeogenesis and reproductive endocrinology. On a molecular level, some of the effects of insulin converge with those of the leptin signaling machinery at the point of activation of phosphatidylinositol 3-kinase (PI3K), resulting in the regulation of ATP-dependent potassium channels. Furthermore, insulin inhibits neuronal apoptosis via activation of protein kinase B in vitro, and it regulates phosphorylation of tau, metabolism of the amyloid precursor protein and clearance of beta-amyloid from the brain in vivo. These findings indicate that neuronal IR signaling has a direct role in the link between energy homeostasis, reproduction and the development of neurodegenerative diseases.

  19. Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes.

    Science.gov (United States)

    Rajasekhar, Pradeep; Poole, Daniel P; Veldhuis, Nicholas A

    2017-01-01

    Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein. © 2017 Elsevier Inc. All rights reserved.

  20. Role of chrysin on expression of insulin signaling molecules

    Directory of Open Access Journals (Sweden)

    Kottireddy Satyanarayana

    2015-01-01

    Full Text Available Background: Currently available drugs are unsuccessful for the treatment of tye-2 diabetes due to their adverseside-effects. Hence, a search for novel drugs, especially ofplant origin, continues. Chrysin (5,7-dihydroxyflavone is a flavonoid, natural component of traditional medicinal herbs, present in honey, propolis and many plant extracts that hasbeen used in traditional medicine around the world to treat numerous ailments. Objective: The present study was aimed to identify the protective role of chrysin on the expression of insulin-signaling molecules in the skeletal muscle of high fat and sucrose-induced type-2 diabetic adult male rats. Materials and Methods: The oral effective dose of chrysin (100 mg/kg body weight was given once a day until the end of the study (30 days post-induction of diabetes to high fat diet-induced diabetic rats.At the end of the experimental period, fasting blood glucose, oral glucose tolerance, serum lipid profile, lipid peroxidation (LPO and free radical generation, as well as the levels of insulin signaling molecules and tissue glycogen in the gastrocnemius muscle were assessed. Results: Diabetic rats showed impaired glucose tolerance and impairment in insulin signaling molecules (IR, IRS-1, p-IRS-1Tyr 632 , p- Akt Thr308 , glucose transporter subtype 4 [GLUT4] proteins and glycogen concentration. Serum insulin, lipid profile, LPO and free radical generation were found to be increased in diabetic control rats.The treatment with chrysin normalized the altered levels of blood glucose, serum insulin, lipid profile, LPO and insulin signaling molecules as well as GLUT4 proteins. Conclusion: Our present findings indicate that chrysin improves glycemic control through activation of insulin signal transduction in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic male rats.

  1. Dual roles for spike signaling in cortical neural populations

    Directory of Open Access Journals (Sweden)

    Dana eBallard

    2011-06-01

    Full Text Available A prominent feature of signaling in cortical neurons is that of randomness in the action potential. The output of a typical pyramidal cell can be well fit with a Poisson model, and variations in the Poisson rate repeatedly have been shown to be correlated with stimuli. However while the rate provides a very useful characterization of neural spike data, it may not be the most fundamental description of the signaling code. Recent data showing γ frequency range multi-cell action potential correlations, together with spike timing dependent plasticity, are spurring a re-examination of the classical model, since precise timing codes imply that the generation of spikes is essentially deterministic. Could the observed Poisson randomness and timing determinism reflect two separate modes of communication, or do they somehow derive from a single process? We investigate in a timing-based model whether the apparent incompatibility between these probabilistic and deterministic observations may be resolved by examining how spikes could be used in the underlying neural circuits. The crucial component of this model draws on dual roles for spike signaling. In learning receptive fields from ensembles of inputs, spikes need to behave probabilistically, whereas for fast signaling of individual stimuli, the spikes need to behave deterministically. Our simulations show that this combination is possible if deterministic signals using γ latency coding are probabilistically routed through different members of a cortical cell population at different times. This model exhibits standard features characteristic of Poisson models such as orientation tuning post-stimulus histograms and exponential interval histograms. In addition it makes testable predictions that follow from the γ latency coding.

  2. An obligatory role of mind bomb-1 in notch signaling of mammalian development.

    Directory of Open Access Journals (Sweden)

    Bon-Kyoung Koo

    2007-11-01

    Full Text Available The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur and Mind bomb (Mib, cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood.Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2(-/- mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants.Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.

  3. The emerging roles of agricultural insurance and farmers cooperatives on sustainable rice productions in Indonesia

    Science.gov (United States)

    Lopulisa, C.; Rismaneswati; Ramlan, A.; Suryani, I.

    2018-05-01

    Rice is the main staple food of most Asian countries including Indonesia. Most of the rice producers are constituted by small individual farmers characterized with mostly landless, have a less farming capitals and less access to pool resources and of course are confronted with various risk. Agriculture is faced with a lot of uncertainly most of which are not within the control of farmers. Global climatic change, climatic disasters, fluctuation of global economic and competitiveness of multinational company make difficulties of farmers to pursue his sustainable farming activity. The challenge and the role of government is to reduce uncertainly and to improve resiliency of the small farmer. Agriculture insurance shall focus on risk factors that are difficult to manage or cannot be managed by small farmers and it is should be viewed as just one aspect of the “holistic” risk management strategy. Technology, market, consumer, behaviour, development will always move forward, and no individual farmers can adapt this change alone, so small farmers need to corporate with each other that can optimized the resources they have. Cooperative could create possibilities, value added, shortening the supplied chain, made a product more effective and efficient, and finally can complete in domestic and global markets. Therefore, agriculture insurance as well a farmer cooperative may play an important role on sustainability of rice production in Indonesia. Nowadays and in the future agriculture sustainability is a not merely of technology problems but also a matter of economic-social-culture and politic issues within local, national, and international context.

  4. Role of Notch Signaling in Human Breast Cancer Pathogenesis

    Science.gov (United States)

    2006-11-01

    transform HMLE cells. Similarly, overexpression of ErbB2, a receptor tyrosine kinase upstream of Ras normally found overexpressed in many breast cancers ...Assess Notch-Ras cooperation in breast cancers in vivo: Since the major observation in this project has been the cooperation of Notch and Ras in HMLE ...metastasis. The in vitro cooperation between Notch and Ras in HMLE cells is mimicked in naturally arising breast cancers in vivo. Further dissection of the

  5. Role of update dynamics in the collective cooperation on the spatial snowdrift games: Beyond unconditional imitation and replicator dynamics

    International Nuclear Information System (INIS)

    Xia Chengyi; Wang Juan; Wang Li; Sun Shiwen; Sun Junqing; Wang Jinsong

    2012-01-01

    Highlights: ► We investigate the role of update rules in the spatial snowdrift game on regular lattices. ► Compared with UI and replicator rules, the cooperation can be further promoted by the Moran rule. ► f c and the cluster formation pattern for these three update rules are carefully explored. ► The frequency of cooperators is insensitive to the random initial set of players. - Abstract: In this paper, we investigate the role of update or imitation rules in the spatial snowdrift game on regular lattices. Three different update rules, including unconditional imitation (UI), replicator dynamics (RD) and the Moran process, are utilized to update the strategies of focal players during the game process in the spatial snowdrift on the lattice. We observe that the aggregate cooperation level between players is largely elevated by using the Moran process in the spatial snowdrift game, when compared to the UI or replicator dynamics. Meanwhile, we carefully explore the dynamical evolution of frequency of cooperators and the cluster formation pattern for these three update rules. Moreover, it is also shown that the evolutionary behavior under the Moran update is independent of and insensitive to the randomly initial configurations of cooperators and defectors. The current results clearly indicate that the introduction of moderate randomness in the strategy update will highly promote the maintenance and persistence of cooperation among selfish individuals, which will be greatly instrumental to deeply understand the evolution of cooperation within many natural, biological and social systems.

  6. Classical and alternative NF-κB signaling cooperate in regulating adipocyte differentiation and function

    DEFF Research Database (Denmark)

    Weidemann, A.; Lovas, A.; Rauch, A.

    2016-01-01

    Background and objective:Inflammation of adipose tissue (AT) is a central mediator of insulin resistance. However, the molecular mechanisms triggered by inflammatory cells are not fully understood. The aim of this study was to analyze the metabolic functions of lymphotoxin-β-receptor (LTβ...... to adipocytes. The molecular mechanism was elucidated by chromatin immunoprecipitation and combinatorial treatment with α-LTβR and tumor necrosis factor (TNF).Results:RelB FatKO mice showed improved insulin sensitivity despite increased adiposity and adipocyte hypertrophy. LTβR-induced activation of p52-Rel.......Conclusions:Our data describe an anti-adipogenic action of LTβR signaling and a novel synergism of alternative and classical NF-κB signaling in the regulation of adipocytes. In conclusion, this strong synergism between the two NF-κB pathways shows a method to inhibit adipocyte differentiation and to improve insulin...

  7. Cooperation of an RNA Packaging Signal and a Viral Envelope Protein in Coronavirus RNA Packaging

    OpenAIRE

    Narayanan, Krishna; Makino, Shinji

    2001-01-01

    Murine coronavirus mouse hepatitis virus (MHV) produces a genome-length mRNA, mRNA 1, and six or seven species of subgenomic mRNAs in infected cells. Among these mRNAs, only mRNA 1 is efficiently packaged into MHV particles. MHV N protein binds to all MHV mRNAs, whereas envelope M protein interacts only with mRNA 1. This M protein-mRNA 1 interaction most probably determines the selective packaging of mRNA 1 into MHV particles. A short cis-acting MHV RNA packaging signal is necessary and suffi...

  8. Rethinking the Role of Pedagogical Assistants: Establishing Cooperation between Roma Families and Schools in Serbia

    Directory of Open Access Journals (Sweden)

    Jelena Starčević

    2016-12-01

    Full Text Available The aim of the present paper is to examine the risks and challenges related to the cooperation of pedagogical assistants (PAs with Roma parents/ families and their work with Roma pupils, as well as to offer further insight into ways to overcome these risks and challenges. Roma pupils and parents/ families face numerous difficulties in education, which are reflected in prejudice, stereotypes and discrimination. The education policy measure of introducing PAs, formerly known as Roma teaching assistants, to the Serbian education system aimed to contribute to the learning and social participation of Roma pupils and to establish cooperation between school staff and Roma parents. The further segregation of Roma pupils and the reduced engagement of teachers in supporting Roma pupils and fostering communication with Roma parents are seen as possible risks related to the engagement of PAs. In order to minimise the risks, we propose a framework for defining and understanding the roles of teachers and PAs from an intercultural perspective. Relying on two concepts – intercultural sensitivity (IS and intercultural competence (IC – we elaborate the necessity of perceiving cultural differences in accordance with an ethnorelative world view, on the part of both teachers and PAs. In addition, we outline the cognitive, affective and behavioural aspects of IC that we believe teachers and PAs should possess. Further recommendations regarding the engagement of PAs and the minimisation of risks and challenges are proposed.

  9. The Role of Russia in the International Anti-terrorism Cooperation

    Directory of Open Access Journals (Sweden)

    Айказ Акопович Уранян

    2016-12-01

    Full Text Available This article examines the role of Russia in the international anti-terrorism cooperation. The author analyzes Russian anti-terrorist activities since the war in Chechnya in 1990s till nowadays. The article notes that the state performs regularly with useful profile initiatives on the world arena and operates within the framework of the international law in the decision making process and during the operations. Particular attention is paid to the events that occurred in 2015, when Russia began a struggle against terrorism in Syria, becoming the only state that carries out anti-terrorist actions according to the official handling of the legitimate president of Syria: the author evaluates the data of events and makes forecast on the development of the situation in the foreseeable future.

  10. The role of nuclear societies in the promotion of international cooperation

    International Nuclear Information System (INIS)

    Velez, C.

    1992-01-01

    International cooperation in the peaceful uses of atomic energy started with the Atoms for Peace initiative in 1955. The satisfaction of the foreseeable world demand for electricity requires a large increase in nuclear power. Such an increase will not be realized unless a number of current nuclear issues, both real and perceived, are resolved first. Most of the problems have acquired an international character and many of them are amenable only to international treatments. The nuclear societies can have an important role in this development. The last years of the present century will be decisive for the immediate future of nuclear power. The nuclear societies should coordinate efforts, join forces and speak out with one clear and distinct voice in all important issues

  11. Cooperative Monitoring Center Occasional Paper/4: Missile Control in South Asia and the Role of Cooperative Monitoring Technology

    Energy Technology Data Exchange (ETDEWEB)

    Kamal, N.; Sawhney, P.

    1998-10-01

    The succession of nuclear tests by India and Pakistan in May 1998 has changed the nature of their missile rivalry, which is only one of numerous manifestations of their relationship as hardened adversaries, deeply sensitive to each other's existing and evolving defense capabilities. The political context surrounding this costly rivalry remains unmediated by arms control measures or by any nascent prospect of detente. As a parallel development, sensible voices in both countries will continue to talk of building mutual confidence through openness to avert accidents, misjudgments, and misinterpretations. To facilitate a future peace process, this paper offers possible suggestions for stabilization that could be applied to India's and Pakistan's missile situation. Appendices include descriptions of existing missile agreements that have contributed to better relations for other countries as well as a list of the cooperative monitoring technologies available to provide information useful in implementing subcontinent missile regimes.

  12. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

    International Nuclear Information System (INIS)

    Ichihara, Sahoko; Yamada, Yoshiji; Kawai, Yoshichika; Osawa, Toshihiko; Furuhashi, Koichi; Duan Zhiwen; Ichihara, Gaku

    2007-01-01

    Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-α, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-κB and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-κB signaling

  13. Autophagic dedifferentiation induced by cooperation between TOR inhibitor and retinoic acid signals in budding tunicates.

    Science.gov (United States)

    Kawamura, Kaz; Yoshida, Takuto; Sekida, Satoko

    2018-01-15

    Asexual bud development in the budding tunicate Polyandrocarpa misakiensis involves transdifferentiation of multipotent epithelial cells, which is triggered by retinoic acid (RA), and thrives under starvation after bud isolation from the parent. This study aimed to determine cell and molecular mechanisms of dedifferentiation that occur during the early stage of transdifferentiation. During dedifferentiation, the numbers of autophagosomes, lysosomes, and secondary lysosomes increased remarkably. Mitochondrial degradation and exosome discharge also occurred in the atrial epithelium. Autophagy-related gene 7 (Atg7) and lysosomal proton pump A gene (PumpA) were activated during the dedifferentiation stage. When target of rapamycin (TOR) inhibitor was administered to growing buds without isolating them from the parent, phagosomes and secondary lysosomes became prominent. TOR inhibitor induced Atg7 only in the presence of RA. In contrast, when growing buds were treated with RA, lysosomes, secondary lysosomes, and mitochondrial degradation were prematurely induced. RA significantly activated PumpA in a retinoid X receptor-dependent manner. Our results indicate that in P. misakiensis, TOR inhibition and RA signals act in synergy to accomplish cytoplasmic clearance for dedifferentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Kinematics fingerprints of leader and follower role-taking during cooperative joint actions.

    Science.gov (United States)

    Sacheli, Lucia Maria; Tidoni, Emmanuele; Pavone, Enea Francesco; Aglioti, Salvatore Maria; Candidi, Matteo

    2013-05-01

    Performing online complementary motor adjustments is quintessential to joint actions since it allows interacting people to coordinate efficiently and achieve a common goal. We sought to determine whether, during dyadic interactions, signaling strategies and simulative processes are differentially implemented on the basis of the interactional role played by each partner. To this aim, we recorded the kinematics of the right hand of pairs of individuals who were asked to grasp as synchronously as possible a bottle-shaped object according to an imitative or complementary action schedule. Task requirements implied an asymmetric role assignment so that participants performed the task acting either as (1) Leader (i.e., receiving auditory information regarding the goal of the task with indications about where to grasp the object) or (2) Follower (i.e., receiving instructions to coordinate their movements with their partner's by performing imitative or complementary actions). Results showed that, when acting as Leader, participants used signaling strategies to enhance the predictability of their movements. In particular, they selectively emphasized kinematic parameters and reduced movement variability to provide the partner with implicit cues regarding the action to be jointly performed. Thus, Leaders make their movements more "communicative" even when not explicitly instructed to do so. Moreover, only when acting in the role of Follower did participants tend to imitate the Leader, even in complementary actions where imitation is detrimental to joint performance. Our results show that mimicking and signaling are implemented in joint actions according to the interactional role of the agent, which in turn is reflected in the kinematics of each partner.

  15. The present status of International Nuclear Cooperation of Korea and the expectations from PNC's role

    International Nuclear Information System (INIS)

    Kim, S.C.

    1992-01-01

    The international cooperation activities for peaceful uses of nuclear energy in Korea started with the cooperation and assistance provided by advanced countries in the early 1960s when a feasibility study for a nuclear power reactor was carried out for its introduction into the Korean power system. Currently, we have 9 nuclear energy cooperation agreements concluded with foreign governments and also maintain cooperation relations with power companies, research institutes, A/E companies, manufacturers, etc. in 15 countries. The international cooperation activities cover a wide range of nuclear industries from design of nuclear power plant to nuclear fuel cycle, but need to expand into exchange of co-operation for noncommercial nuclear safety and cultural aspects. It is relatively simple and easy to realize international nuclear cooperation on commercial base such as nuclear reactor procurement contract, but unfavorable result can be expected from noncommercial transactions

  16. Electric energy cooperation in the Baltic Sea region and the role of Russia in it

    Directory of Open Access Journals (Sweden)

    Zverev Yuri

    2013-06-01

    Full Text Available This article examines cooperation in the electric energy sector in the Baltic region. The author explores the existing undersea HVDC power exchange projects. It is emphasised that cooperation in the electric energy sector is concentrated largely in the EU member states despite earlier plans to establish the Baltic energy ring, which would also include Russia and Belarus. The author stresses that one of the most acute problems for the EU today is overcoming isolation of the energy systems of the Baltic States (Lithuania, Latvia, and Estonia from that of the major part of the EU. This task has become especially relevant after the closing of the Ignalina NPP (Lithuania, which used to be the primary energy source for the three Baltic States. The article examines key projects of the construction of new international power transmission lines in the framework of the Baltic Energy Market Interconnection Plan (BEMIP and the prospects of the Visaginas NPP (Lithuania in solving energy problems of the Baltic States. The author analyses Russia’s role in the electric energy market and focuses on a possible increase of the country’s energy market share following the construction of the Baltic NPP and the export of generated electric energy to Poland, Lithuania, Germany, and Sweden. The author concludes that the prospects of Russia’s energy export to the Baltic Sea region will be determined not only by technological, economic and market factors, but rather by the general state of relations between Russia and the EU. Moreover, a lot depends on Lithuania’s decision on the construction of the Visaginas NPP, as well as the way the EU and the Baltic States solve the problem of energy supply in case the NPP project is terminated.

  17. Seed producer cooperatives in the Ethiopian seed sector and their role in seed supply improvement: A review

    NARCIS (Netherlands)

    Sisay, D.T.; Verhees, F.J.H.M.; Trijp, van J.C.M.

    2017-01-01

    The role of seed producer cooperatives (SPCs) in the Ethiopian seed sector and their contribution to seed supply improvement have received attention from researchers, policymakers, and development partners. However, limited work has been done in reviewing and documenting their involvement in the

  18. The role of purinergic signalling in exocrine pancreas

    DEFF Research Database (Denmark)

    Haanes, Kristian Agmund

    ATP is a fundamentally important molecule in intracellular processes, especially recognised as the molecular source of energy. ATP is however also released as a signal from most cell types, and extracellular signalling by ATP goes under the common name purinergic signalling and it includes releas...

  19. Role of Netrin-1 Signaling in Nerve Regeneration

    Directory of Open Access Journals (Sweden)

    Xin-Peng Dun

    2017-02-01

    Full Text Available Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5 A–D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality. Netrin-1 and its receptor are continuously expressed in the adult nervous system and are differentially regulated after nerve injury. In the adult spinal cord and optic nerve, Netrin-1 has been considered as an inhibitor that contributes to axon regeneration failure after injury. In the peripheral nervous system, Netrin-1 receptors are expressed in Schwann cells, the cell bodies of sensory neurons and the axons of both motor and sensory neurons. Netrin-1 is expressed in Schwann cells and its expression is up-regulated after peripheral nerve transection injury. Recent studies indicated that Netrin-1 plays a positive role in promoting peripheral nerve regeneration, Schwann cell proliferation and migration. Targeting of the Netrin-1 signaling pathway could develop novel therapeutic strategies to promote peripheral nerve regeneration and functional recovery.

  20. Central Role of ULK1 in Type I Interferon Signaling

    Directory of Open Access Journals (Sweden)

    Diana Saleiro

    2015-04-01

    Full Text Available We provide evidence that the Unc-51-like kinase 1 (ULK1 is activated during engagement of the type I interferon (IFN receptor (IFNR. Our studies demonstrate that the function of ULK1 is required for gene transcription mediated via IFN-stimulated response elements (ISRE and IFNγ activation site (GAS elements and controls expression of key IFN-stimulated genes (ISGs. We identify ULK1 as an upstream regulator of p38α mitogen-activated protein kinase (MAPK and establish that the regulatory effects of ULK1 on ISG expression are mediated possibly by engagement of the p38 MAPK pathway. Importantly, we demonstrate that ULK1 is essential for antiproliferative responses and type I IFN-induced antineoplastic effects against malignant erythroid precursors from patients with myeloproliferative neoplasms. Together, these data reveal a role for ULK1 as a key mediator of type I IFNR-generated signals that control gene transcription and induction of antineoplastic responses.

  1. Brazils Role in environmental governance: Analysis of possibilities for increased Brazil-Norway cooperation

    Energy Technology Data Exchange (ETDEWEB)

    Valberg, Anna Helene

    2011-07-01

    This report examines the role played by Brazil in connection with certain international negotiations, such as the climate negotiations and the CBD. It identifies the driving factors that have influenced environmental politics and standards in Brazil, and take note of conflicts that must be discussed when Norway is seeking expanded cooperation with Brazil. In line with the mandate, FNI identifies areas of particular interest for further collaboration between the two countries, and recommend directions for supplementary Norwegian policy-making in light of a broadened scope for Norway-Brazil interaction. In recent years, the Norwegian government has initiated an extensive process aimed at reducing emissions from deforestation and forest degradation (REDD). This is the most obvious shared environmental scope between Norway and Brazil. However, given the large body of literature that already exists on this field, this report will concentrate instead on issues more on the outskirts of the REDD discourse, such as biodiversity conservation, biofuel efficiency and challenges concerning hydropower, all of which threaten to impact negatively on the Amazonian areas. In our recommendations, we cite tangible examples to illustrate issues where we believe lessons learnt in Norway may have applicability to Brazil.(auth)

  2. The role of oligomerization and cooperative regulation in protein function: the case of tryptophan synthase.

    Directory of Open Access Journals (Sweden)

    M Qaiser Fatmi

    Full Text Available The oligomerization/co-localization of protein complexes and their cooperative regulation in protein function is a key feature in many biological systems. The synergistic regulation in different subunits often enhances the functional properties of the multi-enzyme complex. The present study used molecular dynamics and Brownian dynamics simulations to study the effects of allostery, oligomerization and intermediate channeling on enhancing the protein function of tryptophan synthase (TRPS. TRPS uses a set of α/β-dimeric units to catalyze the last two steps of L-tryptophan biosynthesis, and the rate is remarkably slower in the isolated monomers. Our work shows that without their binding partner, the isolated monomers are stable and more rigid. The substrates can form fairly stable interactions with the protein in both forms when the protein reaches the final ligand-bound conformations. Our simulations also revealed that the α/β-dimeric unit stabilizes the substrate-protein conformation in the ligand binding process, which lowers the conformation transition barrier and helps the protein conformations shift from an open/inactive form to a closed/active form. Brownian dynamics simulations with a coarse-grained model illustrate how protein conformations affect substrate channeling. The results highlight the complex roles of protein oligomerization and the fine balance between rigidity and dynamics in protein function.

  3. The role of cooperatives in overcoming the barriers to adoption of renewable energy

    International Nuclear Information System (INIS)

    Viardot, Eric

    2013-01-01

    Recently, cooperatives have been created to promote the use of renewable energy (RE) most notably in Canada, the US, UK, Denmark or Germany. In order to develop the adoption of RE, the cooperatives have to seek to influence the behaviour of their members so that they switch from the use of traditional fossil energy to RE. This paper examines the various barriers to adoption of RE and the way cooperatives are circumventing those obstacles in order to develop the use of RE. This study surveyed a sample of 9 cooperatives from countries where governments are subsidizing the use of RE. The paper identifies a set of specific barriers to the adoption of RE by consumers. It also reveals that cooperatives effectively contribute to the uptake of RE with community-based social marketing initiatives that are lowering those barriers successfully. Those initiatives are related to educational communication, low prices, local offers with complementary services, and cooperative distribution. The paper put forwards a framework for the assessment of how each of those initiatives contributes to the diminishing of each of the barriers to adoption of RE. - Highlights: • We examine the barriers to adoption of renewable energy by RE cooperatives. • We have identified the main significant barriers to adoption of RE by consumers. • Cooperatives apply community-based marketing initiatives to ease the uptake of RE. • We evaluate how each marketing initiatives diminish the barriers to adoption of RE

  4. Cutthroat cooperation : The effects of team role decisions on adaptation to alternative reward structures

    NARCIS (Netherlands)

    Beersma, Bianca; Hollenbeck, John R.; Conlon, Donald E.; Humphrey, Stephen E.; Moon, Henry; Ilgen, Daniel R.

    Structural Adaptation Theory proposes that it is more difficult for teams to change from competitive to cooperative reward conditions than it is for them to change in the opposite direction, and this has been labeled the cutthroat cooperation effect [Johnson, M. D., Hollenbeck, J. R., Ilgen, D. R.,

  5. Cutthroat cooperation: the effects of team role decisions on adaptation to alternative reward structures

    NARCIS (Netherlands)

    Beersma, B.; Hollenbeck, J.R.; Conlon, D.E.; Humphrey, S.E.; Moon, H.; Ilgen, D.R.

    2009-01-01

    Structural Adaptation Theory proposes that it is more difficult for teams to change from competitive to cooperative reward conditions than it is for them to change in the opposite direction, and this has been labeled the cutthroat cooperation effect [Johnson, M. D., Hollenbeck, J. R., Ilgen, D. R.,

  6. Modeling the role of negative cooperativity in metabolic regulation and homeostasis.

    Directory of Open Access Journals (Sweden)

    Eliot C Bush

    Full Text Available A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.

  7. Social capital: its role in cooperation dilemmas and the coordination of actions

    Directory of Open Access Journals (Sweden)

    René Millán

    2015-05-01

    Full Text Available This work sustains the thesis that the concept of social capital must be understood as an element that helps to solve dilemmas of collective action. The concept is theoretically and in practice useful as it can be related to social cooperation problems. To sustain that statement, I present first the problem of cooperation as a dilemma between individual interest —or maximization strategies— and collective action. It is sustained that social capital confirms that, contrary to game theory, cooperate is rational and convenient. Then, it is established how it is conceived the relationship between social capital and cooperation in Coleman, Putnam and Ostrom. It is stressed the formation of incentives to overcome dilemmas of collective action. Finally, I develop a criticism to the critics made to social capital in order to establish its possibilities in generalizing social cooperation.

  8. Investigating the role of conflict management strategy on development of cooperative management

    Directory of Open Access Journals (Sweden)

    Hosseinali Aziziha

    2014-03-01

    Full Text Available This paper presents an empirical study to investigate the effect of conflict management strategies on development of cooperative culture in one of Iranian auto industries. The proposed study adopts a Putnam and Wilson’s questionnaire (1982 [Putnam, L. L., & Wilson, C. E. (1982. Communication strategies in organizational conflicts: Reliability and validity of a measurement scale. Communication Yearbook, 6, 629-652.] for measuring different components of conflict management. In addition, the study also designs a questionnaire for measuring cooperative culture. Cronbach alphas are calculated for conflict management and cooperative cultures as 0.76 and 0.79, respectively. Using Spearman correlation ratio as well as regression technique, the study has determined that three components of conflict management strategies including cooperation, competition and compromise could significantly contribute of development of cooperative culture.

  9. The role of the agricultural credit cooperatives in the fertilizer market in Turkey

    International Nuclear Information System (INIS)

    Akcay, Y.; Cicek, A.; Akay, M.; Sayili, M.; Uzunoez, M.

    1999-01-01

    Agriculture has a certain degree of importance in the development and developing countries in the world. It is necessary to increase agricultural production and productivity to counter balance increasing food demand. To be able to reach to the goal, inputs one of which is fertilizer used in the agricultural production should be used in the optimum amount in the modern agriculture. Increasing the productivity in the agricultural production depends on the transformation of economic unity of the farms (Karacan, 1991). However, approximately 85 percentage of the farmers in Turkey has made agricultural activity on the farm land which is smaller than that of 100 decar (1 decar = 1000 m 2 ). This case has shown that there is a domination of the type of small family farms in Turkish agriculture. These farms generally have insufficient capital, saving, modern equipment, input usage and credit. This farm structure has increased the importance of the agricultural credit cooperatives (ACC) providing credit either inputs or cash. And also ACC have played an important role to transfer finance from government to farmers (Muelayim, 1995). The first main goal of the study is to determine the role of the ACC having a great importance in the fertilizer market in Turkey. The second goal is to evaluate the relationship between farmers-ACC and farmers-private fertilizer agent in the selected region, central district of Tokat province. Also the problems that the farmers faced and the preference of buying fertilizer from either ACC or private fertilizer agent of the farmers and some suggestions related to the subjects were investigated. Refs. 12 (author)

  10. The role of nuclear localization signal in parvovirus life cycle.

    Science.gov (United States)

    Liu, Peng; Chen, Shun; Wang, Mingshu; Cheng, Anchun

    2017-04-14

    Parvoviruses are small, non-enveloped viruses with an approximately 5.0 kb, single-stranded DNA genome. Usually, the parvovirus capsid gene contains one or more nuclear localization signals (NLSs), which are required for guiding the virus particle into the nucleus through the nuclear pore. However, several classical NLSs (cNLSs) and non-classical NLSs (ncNLSs) have been identified in non-structural genes, and the ncNLSs can also target non-structural proteins into the nucleus. In this review, we have summarized recent research findings on parvovirus NLSs. The capsid protein of the adeno-associated virus has four potential nuclear localization sequences, named basic region 1 (BR), BR2, BR3 and BR4. BR3 was identified as an NLS by fusing it with green fluorescent protein. Moreover, BR3 and BR4 are required for infectivity and virion assembly. In Protoparvovirus, the canine parvovirus has a common cNLS located in the VP1 unique region, similar to parvovirus minute virus of mice (MVM) and porcine parvovirus. Moreover, an ncNLS is found in the C-terminal region of MVM VP1/2. Parvovirus B19 also contains an ncNLS in the C-terminal region of VP1/2, which is essential for the nuclear transport of VP1/VP2. Approximately 1 or 2 cNLSs and 1 ncNLS have been reported in the non-structural protein of bocaviruses. Understanding the role of the NLS in the process of parvovirus infection and its mechanism of nuclear transport will contribute to the development of therapeutic vaccines and novel antiviral medicines.

  11. The Role of Cholecystokinin in Peripheral Taste Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Ryusuke Yoshida

    2017-10-01

    Full Text Available Cholecystokinin (CCK is a gut hormone released from enteroendocrine cells. CCK functions as an anorexigenic factor by acting on CCK receptors expressed on the vagal afferent nerve and hypothalamus with a synergistic interaction between leptin. In the gut, tastants such as amino acids and bitter compounds stimulate CCK release from enteroendocrine cells via activation of taste transduction pathways. CCK is also expressed in taste buds, suggesting potential roles of CCK in taste signaling in the peripheral taste organ. In the present study, we focused on the function of CCK in the initial responses to taste stimulation. CCK was coexpressed with type II taste cell markers such as Gα-gustducin, phospholipase Cβ2, and transient receptor potential channel M5. Furthermore, a small subset (~30% of CCK-expressing taste cells expressed a sweet/umami taste receptor component, taste receptor type 1 member 3, in taste buds. Because type II taste cells are sweet, umami or bitter taste cells, the majority of CCK-expressing taste cells may be bitter taste cells. CCK-A and -B receptors were expressed in both taste cells and gustatory neurons. CCK receptor knockout mice showed reduced neural responses to bitter compounds compared with wild-type mice. Consistently, intravenous injection of CCK-Ar antagonist lorglumide selectively suppressed gustatory nerve responses to bitter compounds. Intravenous injection of CCK-8 transiently increased gustatory nerve activities in a dose-dependent manner whereas administration of CCK-8 did not affect activities of bitter-sensitive taste cells. Collectively, CCK may be a functionally important neurotransmitter or neuromodulator to activate bitter nerve fibers in peripheral taste tissues.

  12. The Role of Interpretation and Diagnosis in Signal Processing

    Science.gov (United States)

    1988-01-01

    122b. TELEPHONE (Incude Area Code) 2cOFIESYMBOL Elisabeth Colford - RLE Contract Reports I(617)258-5871I DO Form 1473, JUN 84 Previous editions ame...6] S. Lee, E. Milios, R. Greiner , and J. Rossiter. Signal ab- stractions in the machine analysis of radar signals for ice profiling. In International

  13. REVIEW ARTICLE: Bioluminescent signals and the role of reflectors

    Science.gov (United States)

    Herring, Peter J.

    2000-11-01

    Organisms in a well lit environment use optical signals derived from the selective reflection of ambient light. In a dim or dark environment it is very difficult (because of low photon numbers) to detect the contrast between light reflected from the organism and that from the background, and many organisms use bioluminescent signals instead. The use of such signals on land is largely restricted to sexual signalling by the luminous beetles, but in the deep ocean their use is widespread, involving both many different organisms and a range of uses which parallel those of reflective signals on land. Some bioluminescent signals rely almost entirely on an optically unmodified light source (e.g. a secretion) but others depend upon complex optical structures, particularly reflectors, in the light-emitting organs. Reflectors in the light organs of many shrimp, squid and fish are based on constructive interference systems but employ different biological materials. They and other structures modify the angular, spectral and intensity distributions of bioluminescent signals. The ready availability of highly efficient biological reflectors has been a formative influence in the evolution of bioluminescent signalling in the sea.

  14. Success and failure of firms' innovation co-operations: The role of intermediaries and reciprocity

    DEFF Research Database (Denmark)

    Cantner, U.; Meder, A.; Wolf, T.

    2011-01-01

    attempts to fill this gap by investigating the possible presence of two problems in co-operation: the lack of intermediation and of reciprocity. Based on data gathered for firms in two German regions and one French region, we find that the success of co-operation projects depends on the perceived...... importance, rather than on the perceived quality, of intermediate actors. Hence, the major problem for intermediating suitable partners is more related to communication than it is a programmatic issue. Trust and reciprocity in co-operation between firms is found to be relevant ex-post in the sense of being...

  15. The role of Drosophila mushroom body signaling in olfactory memory.

    Science.gov (United States)

    McGuire, S E; Le, P T; Davis, R L

    2001-08-17

    The mushroom bodies of the Drosophila brain are important for olfactory learning and memory. To investigate the requirement for mushroom body signaling during the different phases of memory processing, we transiently inactivated neurotransmission through this region of the brain by expressing a temperature-sensitive allele of the shibire dynamin guanosine triphosphatase, which is required for synaptic transmission. Inactivation of mushroom body signaling through alpha/beta neurons during different phases of memory processing revealed a requirement for mushroom body signaling during memory retrieval, but not during acquisition or consolidation.

  16. EPA's Role with the Organization for Economic Cooperation and Development (OECD)

    Science.gov (United States)

    The Organization for Economic Cooperation and Development (OECD) brings together the governments of countries committed to democracy and the market economy from around the world to support sustainable economic growth.

  17. Current and future role of agreements for cooperation as the framework for international nuclear commerce

    International Nuclear Information System (INIS)

    Brush, P.N.

    1976-01-01

    An agreement for cooperation in the civil use of atomic energy was established by Congress as the primary vehicle for ensuring that the benefits of cooperation outweigh the risks. The elements and nature of the agreement for cooperation are reviewed in this article. The evolution of some of the more significant provisions of the agreements and the type of activities conducted under them are discussed. The question is raised as to whether or not these agreements for cooperation are strong enough in the light of nations of the world becoming more concerned with the implications of burgeoning nuclear power activities. The question, ''Should these agreements be elevated to the status of treaties.'' is asked also

  18. Aging in Caenorhabditis elegans; the role of Wnt signalling

    NARCIS (Netherlands)

    Lezzerini, M.

    2015-01-01

    Aging is a universal biological process, broadly characterized by the gradual decline of a multitude of physiological functions, ultimately resulting in organismal death. Wnt signaling is a major and highly conserved developmental pathway that guides many important events during organismal

  19. The role of international cooperation regarding safety assessment development in the SKB research program

    International Nuclear Information System (INIS)

    Eng, T.; Ahlstrom, P.

    1989-01-01

    Cooperation and exchange of information with organizations in foreign countries regarding nuclear waste management constitutes an important part of the overall research and development activities of SKB. In the safety assessment of a repository for spent nuclear fuel natural phenomena have to be described with different kinds of models based on both general and site specific data. The international cooperation efforts to achieve models and methods for this type of descriptions, and where SKB are largely part, is summarized in this paper

  20. Adolescents' responses to marital conflict: The role of cooperative marital conflict.

    Science.gov (United States)

    Zhou, Nan; Buehler, Cheryl

    2017-10-01

    Not all youth exposed to hostile marital interactions develop negative responses to marital conflict. Cooperative marital conflict has long been considered as an important way of managing conflict and may serve as an important context in which hostility might convey during marital interactions. In light of little prior attention placed on the positive side of conflict processes, the main and moderating effects of cooperative marital conflict on youth responses to marital conflict were examined in a sample of 416 2-parent families using a multimethod, 2-year prospective design. Cooperative marital conflict was associated with decreases in youth emotional dysregulation, perceived threat, and behavioral dysregulation, and increases in constructive family representations and coping efficacy. As a specific dimension of cooperation, effective conflict resolution was associated uniquely with elevated youth coping efficacy, and decreased emotional and behavioral dysregulation; marital warmth was associated uniquely with increased constructive family representations. Significant interactions between marital hostility and marital cooperation also were found. These findings highlight the importance of examining cooperation above and beyond hostility in studies of marital conflict in order to better understand youth development during early adolescence. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. The potential role of oral pH in the persistence of Trichomonas gallinae in Cooper's Hawks (Accipiter cooperii).

    Science.gov (United States)

    Urban, Elizabeth H; Mannan, R William

    2014-01-01

    Trichomoniasis, caused by the protozoan Trichomonas gallinae, affects a variety of species worldwide including avivorious raptors. Existing information suggests that the disease is most prevalent in young birds, and differential susceptibility to trichomoniasis among individuals in different age groups was documented in Cooper's Hawks (Accipiter cooperii) nesting in Tucson, Arizona. In that population, 85% of nestling Cooper's Hawks had T. gallinae in their oral cavity, compared to only 1% of breeding-age hawks. Trichomonads generally are sensitive to environmental pH and we explored the possibility that differences in oral pH may contribute to the differential prevalence of infection between age groups. We measured the pH of the fluid in the oral cavity in 375 Cooper's Hawks from three age groups (nestlings, fledglings, and breeding age) in Tucson, Arizona, in 2010 and 2011 and clinically tested for T. gallinae in a subsample of hawks. Oral pH of nestlings (∼ 6.8) was 7.3 times less acidic than in fledgling or breeding Cooper's Hawks (∼ 6.1). The incidence of T. gallinae was higher in nestlings (16%) than in either fledglings or breeding hawks (0%). Our findings indicate that oral pH becomes more acidic in Cooper's Hawks soon after they leave the nest. Trichomonas gallinae thrives when pH is between 6.5 and 7.5 (optimum 7.2), but is less viable in more acidic conditions. Higher levels of acidity in the oral cavity of fledglings and breeding Cooper's Hawks may reduce their susceptibility to trichomoniasis, and play a role in the differential prevalence of infection among age groups.

  2. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

    Science.gov (United States)

    Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

    2016-01-01

    Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

  3. Role of international cooperation in treatment and disposal of radioactive wastes

    International Nuclear Information System (INIS)

    Ikeda, Kaname

    1984-01-01

    The necessity of international cooperation in the treatment and disposal or management of radioactive wastes has been recognized more strongly recently, and the IAEA held the international congress in May, 1983. The safety techniques for this problem are likely to be resolved, but the public acceptance has become the factor hindering the development of nuclear power. It is important to advance international cooperation, aiming at the early establishment of the internationally common guide line to obtain the international consensus. In Japan, effort has been exerted to device to limit the quantity of waste formation, and the treatment of volume reduction and solidifying stabilization has been applied to the wastes formed. Thus, 490,000 drums of 200 l were stored in respective nuclear facilities as of September, 1983. The high level radioactive wastes from the reprocessing of spent fuel reached only 154 m 3 and is stored in the reprocessing plant. The bilateral cooperation of Japan with USA, FRG, Australia and the People's Republic of China, and the multinaional cooperation in the NEA of OECD and IAEA regarding this problem are reported. Japan must exert efforts to obtain the understanding and cooperation of local society and international consensus to resolve the problem. (Kako, I.)

  4. Investigating the role of Clinical Nurse Consultants in one health district from multiple stakeholder perspectives: a cooperative inquiry.

    Science.gov (United States)

    Walsh, Kenneth; Bothe, Janine; Edgar, Denise; Beaven, Geraldine; Burgess, Bernadette; Dickson, Vhari; Dunn, Stephen; Horning, Lynda; Jensen, Janice; Kandl, Bronia; Nonu, Miriam; Owen, Fran; Moss, Cheryle

    2015-01-01

    The impetus for this research came from a group of 11 Clinical Nurse Consultants (CNCs) within a health service in NSW, Australia, who wanted to investigate the CNC role from multiple stakeholder perspectives. With support from academic researchers, the CNCs designed and implemented the study. The aim of this research project was to investigate the role of the CNC from the multiple perspectives of CNCs and other stakeholders who work with CNCs in the Health District. This was a co-operative inquiry that utilised qualitative descriptive research approach. Co-operative inquiry methods enabled 11 CNCs to work as co-researchers and to conduct the investigation. The co-researchers implemented a qualitative descriptive design for the research and used interviews (7) and focus groups (16) with CNC stakeholders (n = 103) to gather sufficient data to investigate the role of the CNC in the organisation. Thematic analysis was undertaken to obtain the results. The CNC role is invaluable to all stakeholders and it was seen as the "glue" which holds teams together. Stakeholder expectations of the CNC role were multiple and generally agreed. Five themes derived from the data are reported as "clinical leadership as core", "making a direct difference to patient care", "service development as an outcome", "role breadth or narrowness and boundaries", and "career development". There was clear appreciation of the work that CNCs do in their roles, and the part that the CNC role plays in achieving quality health outcomes. The role of the CNC is complex and the CNCs themselves often negotiate these complexities to ensure beneficial outcomes for the patient and organisation. For the wider audience this study has given further insights into the role of these nurses and the perspectives of those with whom they work.

  5. The Role of Signals in Online Auction Purchase Decisions

    Directory of Open Access Journals (Sweden)

    Cypryjański Jacek

    2015-06-01

    Full Text Available There is a growing interest in behavioural economics contradicting the empirical prediction of rational choice theory once applied to online auctions. The issue is of particular relevance due to the large use of online auctions and the anticipated growth in the future. Online auctions combine the conventional auction model with information technology. However, information asymmetry within such auctions causes risks and uncertainties that influence consumer purchase intentions. The research investigates online consumers’ behaviour. The Authors suggest that due to the high perceived risk of the online buying process consumers are prompted to use cues of seller’ reputation. In a series of six experiments conducted via the auction site Allegro.pl in Poland a number of signals from auction web pages has been manipulated to influence purchase intention. The results suggest that several signals can be used to stimulate online customers’ behaviour. The results of these experiments indicate that buyers are more susceptible to the influence of “visual” signals than signals that require greater involvement of the buyer (to read information. The conducted experiments contribute to a more comprehensive understanding of online auction users’ behaviour. And finally it provides some managerial implications to increase online auction effectiveness from the seller’s perspective.

  6. Protein phosphorylation and its role in archaeal signal transduction

    Science.gov (United States)

    Esser, Dominik; Hoffmann, Lena; Pham, Trong Khoa; Bräsen, Christopher; Qiu, Wen; Wright, Phillip C.; Albers, Sonja-Verena; Siebers, Bettina

    2016-01-01

    Reversible protein phosphorylation is the main mechanism of signal transduction that enables cells to rapidly respond to environmental changes by controlling the functional properties of proteins in response to external stimuli. However, whereas signal transduction is well studied in Eukaryotes and Bacteria, the knowledge in Archaea is still rather scarce. Archaea are special with regard to protein phosphorylation, due to the fact that the two best studied phyla, the Euryarchaeota and Crenarchaeaota, seem to exhibit fundamental differences in regulatory systems. Euryarchaeota (e.g. halophiles, methanogens, thermophiles), like Bacteria and Eukaryotes, rely on bacterial-type two-component signal transduction systems (phosphorylation on His and Asp), as well as on the protein phosphorylation on Ser, Thr and Tyr by Hanks-type protein kinases. Instead, Crenarchaeota (e.g. acidophiles and (hyper)thermophiles) only depend on Hanks-type protein phosphorylation. In this review, the current knowledge of reversible protein phosphorylation in Archaea is presented. It combines results from identified phosphoproteins, biochemical characterization of protein kinases and protein phosphatases as well as target enzymes and first insights into archaeal signal transduction by biochemical, genetic and polyomic studies. PMID:27476079

  7. Redox Signaling in Skeletal Muscle: Role of Aging and Exercise

    Science.gov (United States)

    Ji, Li Li

    2015-01-01

    Skeletal muscle contraction is associated with the production of ROS due to altered O[subscript 2] distribution and flux in the cell. Despite a highly efficient antioxidant defense, a small surplus of ROS, such as hydrogen peroxide and nitric oxide, may serve as signaling molecules to stimulate cellular adaptation to reach new homeostasis largely…

  8. Role of IRS-2 in insulin and cytokine signalling.

    Science.gov (United States)

    Sun, X J; Wang, L M; Zhang, Y; Yenush, L; Myers, M G; Glasheen, E; Lane, W S; Pierce, J H; White, M F

    1995-09-14

    The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. It regulates gene expression and stimulates mitogenesis, and appears to mediate insulin/IGF-1-stimulated glucose transport. Thus, survival of the IRS-1-/- mouse with only mild resistance to insulin was surprising. This dilemma is provisionally resolved with our discovery of a second IRS-signalling protein. We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. IRS-2 is expressed in many cells, including tissues from IRS-1-/- mice, and may be essential for signalling by several receptor systems.

  9. Role of WNT signaling in epididymal sperm maturation.

    Science.gov (United States)

    Cheng, Jin-Mei; Tang, Ji-Xin; Li, Jian; Wang, Yu-Qian; Wang, Xiu-Xia; Zhang, Yan; Chen, Su-Ren; Liu, Yi-Xun

    2018-02-01

    Spermatozoa maturation, a process required for spermatozoa to acquire progressive motility and the ability to fertilize ova, primarily occurs in the caput and corpus of the epididymis. Despite considerable efforts, the factor(s) promoting epididymal sperm maturation remains unclear. Recently, WNT signaling has been implicated in epididymal sperm maturation. To further investigate WNT signaling function in epididymal sperm maturation, we generated Wntless conditional knockout mice (Wls cKO), Wls flox/flox ; Lcn5-Cre. In these mice, WNTLESS (WLS), a conserved membrane protein required for all WNT protein secretion, was specifically disrupted in the principal cells of the caput epididymidis. Immunoblot analysis showed that WLS was significantly reduced in the caput epididymidis of Wls cKO mice. In the caput epididymidis of Wls cKO mice, WNT 10A and WNT 2b, which are typically secreted by the principal cells of the caput epididymis, were not secreted. Interestingly, sperm motility analysis showed that the WLS deficiency in the caput epididymidis had no effect on sperm motility. Moreover, fertility tests showed that Wls cKO male mice had normal fertility. These results indicate that the disruption of WLS in principal cells of the caput epididymidis inhibits WNT protein secretion but has no effect on sperm motility and male fertility, suggesting that WNT signaling in the caput epididymidis may be dispensable for epididymal sperm maturation in mice.

  10. Comparison and evaluation of the roles of tomato farmer cooperatives in Taiwan and The Netherlands

    NARCIS (Netherlands)

    Lin, B.-S.

    2012-01-01

    Tomato is one of the most popular vegetables all over the world and the production was 145 million tonnes in 2011. In Taiwan and The Netherlands, tomato also became an important vegetable nowadays. In both countries, the farmer cooperatives are the way to help farmers accessing markets. However,

  11. THE ROLE OF COOPERATION AND TEAMWORK BETWEEN PEOPLE WITH DIFFERENT NATIONALITIES IN TRANSITION COUNTRIES

    Directory of Open Access Journals (Sweden)

    Suada Ajdarpašić

    2016-04-01

    Full Text Available A topic that tells a lot about us as human beings, about our abilities and virtues is the fact that shows and explains how much we are able to work together and make collective decisions in the operating process. How much people are willing to cooperate, plan, organize, coordinate, manage and control the situation, depends on many factors. In continuation of my work, I will explain how much people are willing to provide the support to their colleagues, friends and random people in teamwork when making decisions on a specific field, and also the cooperation process between the people on many stages in transition countries. This work comes down to personal study, where, I have based on the questionnaire dedicated to the students, academic and administrative staff at the different Universities and Secondary schools of Kosovo. What is their general perception about cooperation and teamwork, its quality, advantages and disadvantages, its reflection on success or failure, the significance of individual and collective decisions, current and future application of, friendships with other ethnicity, and many other issues, it is stated in the further work. According to the data collected it can be said that the interviewed people are familiar in a large % with the process of cooperation, whether in a small group but also in a large group. However, why is it applied or not you will read throughout this paper.

  12. Changing Roles of a University Cooperative Extension Service in Response to Social Change

    Science.gov (United States)

    Barnes, Thelma C.

    2013-01-01

    Researchers have acknowledged that cooperative extension organizations should rethink dominant agricultural foci and be more inclusive of nontraditional audiences. An extension organization in the southeastern United States has experienced declining workshop participation, requests for technical assistance, and local office visits. These declines…

  13. Preschoolers' Understanding of the Role of Communication and Cooperation in Establishing Property Rights

    Science.gov (United States)

    Rossano, Federico; Fiedler, Lydia; Tomasello, Michael

    2015-01-01

    Property as a social "agreement" comprises both a communicative component, in which someone makes a claim that she is entitled to some piece of property, and a cooperative component, in which others in the community respect that claim as legitimate. In the current study, preschool children were (a) given the opportunity to mark some…

  14. Intention recognition, commitment and their roles in the evolution of cooperation from artificial intelligence techniques to evolutionary game theory models

    CERN Document Server

    Han, The Anh

    2013-01-01

    This original and timely monograph describes a unique self-contained excursion that reveals to the readers the roles of two basic cognitive abilities, i.e. intention recognition and arranging commitments, in the evolution of cooperative behavior. This book analyses intention recognition, an important ability that helps agents predict others’ behavior, in its artificial intelligence and evolutionary computational modeling aspects, and proposes a novel intention recognition method. Furthermore, the book presents a new framework for intention-based decision making and illustrates several ways in which an ability to recognize intentions of others can enhance a decision making process. By employing the new intention recognition method and the tools of evolutionary game theory, this book introduces computational models demonstrating that intention recognition promotes the emergence of cooperation within populations of self-regarding agents. Finally, the book describes how commitment provides a pathway to the evol...

  15. Multiple roles and therapeutic implications of Akt signaling in cancer

    Directory of Open Access Journals (Sweden)

    Emiliano Calvo

    2009-06-01

    Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors

  16. Determine the Role of Canonical Wnt Signaling in Ovarian Tumorigenesis

    Science.gov (United States)

    2015-12-01

    Cancer Res, 2007. 13(14): p. 4042-5. 10. Mann, B., et al., Target genes of beta-catenin-T cell -factor/ lymphoid -enhancer- factor signaling in human...triggers innate immunity. Cell Host Microbe 12(4): 558–570. 34. Lundholm M, et al. (2014) Prostate tumor-derived exosomes down-regulate NKG2D... cell -extrinsic pathway through which natural killer cells eliminate cancer cells . Nat Cell Biol 15(7):818–828. 57. Ishii KJ, Akira S (2006) Innate

  17. The role of retinoic acid signaling in thymic function

    DEFF Research Database (Denmark)

    Wendland, Kerstin; Sitnik, Katarzyna; Kotarsky, Knut

    maturation and homeostasis is required for the generation of a functional T cell pool. TEC development and differenti-ation is dependent on crosstalk with immune and stromal cells in the thymus and previous work of our group has suggested RA as a potential key player in this process. To study the role of RA...

  18. Interorganizational Cooperation

    Science.gov (United States)

    2016-10-12

    Administrative Services Officer , Office of Congressional and Intergovernmental Affairs, Office of the Chief Financial Officer , Office of the Chief ...Nations. • Clarifies the role of the United States Agency for International Development (USAID) Office of Transition Initiatives and its relationship...Centralize interorganizational cooperation within the command group. Under this model, the chief of staff or a special staff officer within the command

  19. The Role of Delay and Connectivity in Throughput Reduction of Cooperative Decentralized Wireless Networks

    Directory of Open Access Journals (Sweden)

    Ahmed Alkhayyat

    2015-01-01

    Full Text Available We proposed a multiple relay selection protocol for decentralized wireless networks. The proposed relays selection protocol aims to address three issues: (1 selecting relays within the coverage area of the source and destination to ensure that the relays are positioned one hop away from the destination, (2 ensuring that the best node (best relays with less distance and attenuation from the destination access the channel first, and (3 ensuring that the proposed relays selection is collision-free. Our analysis also considers three important characteristics of decentralized wireless networks that are directly affected by cooperation: delay, connectivity, and throughput. The main goal of this paper is to demonstrate that improving connectivity and increasing number of relays reduce the throughput of cooperative decentralized wireless networks; consequently, a trade-off equation has been derived.

  20. The protective role of vitamin d signaling in non-melanoma skin cancer.

    OpenAIRE

    Bikle, Daniel; Bikle, DD; Jiang, Y

    2013-01-01

    Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting th

  1. THE ROLE OF FINANCIAL INSTRUMENTS ON THE GROWTH OF ITALIAN SOCIAL COOPERATIVES

    OpenAIRE

    Francesco Agliata; Caterina Ferrone; Danilo Tuccillo

    2014-01-01

    The Third Sector in Italy records a slow but constant growth due to the increase of the number of entities but not of their dimension. The difficulties in financial management, generated by a low attraction of debt and equity financial resources and a low level of managerial skills characterized the non profit organizations. Focused on the social cooperatives, the article describe the effects on the financial structure of innovative financial instruments as the participative loan. In the last...

  2. The role of bilateral agreements for cooperation in establishing international norms for nuclear exportation

    International Nuclear Information System (INIS)

    Rowden, M.A.; Kraemer, J.R.

    1986-01-01

    It seems unlikely that a broad multilateral political consensus on the appropriate nuclear control norms will soon be achieved. Bilateral nuclear cooperation agreements will continue to be the dominant political instruments governing international nuclear commerce. Recent developments make the authors optimistic that flexible implementation of the Nuclear Non-Proliferation Act of 1978 will permit a more effective U.S. policy in the field of nuclear commerce. (CW) [de

  3. The role of informing society and international cooperation in improving the nuclear 'image'

    International Nuclear Information System (INIS)

    Kazakevich, Yu.; Biryukova, P.

    2001-01-01

    The goal of this report is an endeavor to estimate the meaning of international contacts and cooperation for the public acknowledgement of the atomic energy and technologies. In this report the potential ways of working with the public in Chelyabinsk region taking into account its specific features have been suggested. The conclusion contains practical recommendations about the organization of working with the public and directions of activity. (authors)

  4. Role of notch signaling in osteoimmunology-from the standpoint of osteoclast differentiation

    NARCIS (Netherlands)

    Duan, Li; Ren, Yijin

    The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Osteoimmunology comprises the interplay between the immune system and bone metabolism. Osteoclasts, cells that resorb bone, play a crucial role in bone metabolism. In this review, we

  5. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Science.gov (United States)

    Shi, Juan; Chi, Shuhong; Xue, Jing; Yang, Jiali; Li, Feng; Liu, Xiaoming

    2016-01-01

    The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases. PMID:27110577

  6. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Juan Shi

    2016-01-01

    Full Text Available The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs, a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

  7. Novel roles for phospholipase C in plant stress signalling and development

    NARCIS (Netherlands)

    Zhang, Q.

    2017-01-01

    For many years, efforts have been made to explore PLC signaling in plants. Compared to the classical PLC signaling pathway, a different picture is emerging for plants. Several roles for PLC in plant development and stress responses have been claimed but genetic evidence for this is mostly missing.

  8. Technological Cooperation Networks at Bio-Manguinhos: the Role of Information and Communication Technologies

    Directory of Open Access Journals (Sweden)

    Lázaro Pereira de Oliveira

    2015-01-01

    Full Text Available This article identifies and discusses the contribution of information and communication technologies (ICTs to the technological cooperation projects of Bio-Manguinhos, a pharmaceutical manufacturer that belongs to Osvaldo Cruz Foundation (FIOCRUZ, responsible for producing vaccines, reagents and biopharmaceuticals, with priority on meeting the needs of the Brazilian public health system. It is a case study with a qualitative approach for descriptive and explanatory purposes. The data were collected from 14 interviews conducted with managers of research and development (R&D projects with high relevance to the organization. The results allow concluding that the ICTs requiring greater interdependence between partners and two-way knowledge flows have not yet been used. They also show the importance of closer cooperation between the information technology (IT and R&D areas. A future positioning of Bio-Manguinhos as a technological center focused on discovery and sale of new active ingredients can favor the use of tools that promote greater integration between the partners of technology cooperation networks.

  9. Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

    Directory of Open Access Journals (Sweden)

    Silvia Mazzotta

    2016-10-01

    Full Text Available Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

  10. Role of IGF-I Signaling in Muscle Bone Interactions

    Science.gov (United States)

    Bikle, Daniel D; Tahimic, Candice; Chang, Wenhan; Wang, Yongmei; Philippou, Anastassios; Barton, Elisabeth R.

    2015-01-01

    Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. PMID:26453498

  11. Androgenic signaling systems and their role in behavioral evolution.

    Science.gov (United States)

    Fuxjager, Matthew J; Schuppe, Eric R

    2018-06-05

    Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd

  12. The role of autoshaping in cooperative two-player games between starlings.

    Science.gov (United States)

    Reboreda, J C; Kacelnik, A

    1993-07-01

    We report a study of the behavior of starlings in laboratory situations inspired by the "prisoner's dilemma." Our purpose is to investigate some possible mechanisms for the maintenance of cooperation by reciprocity and to investigate the process of autoshaping at a trial-by-trial level. In Experiment 1, pairs of starlings housed in adjacent cages played a discrete-trial "game" in which food could be obtained only by "cooperation." In this game, pecking at a response key eliminated the opportunity to obtain food but produced food for the partner. If neither bird pecked, neither had the opportunity to obtain food in that trial. Some level of cooperation persisted for several sessions whether the birds had been pretrained for a high or low probability of pecking at the key. The probability of a cooperative response was higher after trials in which the partner responded (and a reward was obtained) than after trials in which neither bird responded (and no reward was obtained), but the probability of a response was even higher after trials in which the same bird had responded, even though no reward was obtained by the actor in these trials. This behavior did not require visual presence of another player, because similar results were obtained in Experiment 2 (a replicate of Experiment 1 in which the members of the pair could not see each other) and in Experiment 3, a game in which each starling played with a computer responding with "tit for tat." Using an omission schedule, in which food was given in all trials in which the bird did not peck, Experiment 4 showed that pecking could be maintained by autoshaping. In this experiment, overall probability of pecking decreased with experience, due to a drop in the tendency to peck in consecutive trials. The probability of pecking in trials following a reinforced trial did not decrease with experience. An implementation of the Rescorla-Wagner model for this situation was capable of reproducing molar, but not molecular, aspects

  13. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    Directory of Open Access Journals (Sweden)

    Balapal S. Basavarajappa

    2015-10-01

    Full Text Available One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS, which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD. Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.

  14. Role of Polyphenols and Other Phytochemicals on Molecular Signaling

    Directory of Open Access Journals (Sweden)

    Swapna Upadhyay

    2015-01-01

    Full Text Available Optimized nutrition through supplementation of diet with plant derived phytochemicals has attracted significant attention to prevent the onset of many chronic diseases including cardiovascular impairments, cancer, and metabolic disorder. These phytonutrients alone or in combination with others are believed to impart beneficial effects and play pivotal role in metabolic abnormalities such as dyslipidemia, insulin resistance, hypertension, glucose intolerance, systemic inflammation, and oxidative stress. Epidemiological and preclinical studies demonstrated that fruits, vegetables, and beverages rich in carotenoids, isoflavones, phytoestrogens, and phytosterols delay the onset of atherosclerosis or act as a chemoprotective agent by interacting with the underlying pathomechanisms. Phytochemicals exert their beneficial effects either by reducing the circulating levels of cholesterol or by inhibiting lipid oxidation, while others exhibit anti-inflammatory and antiplatelet activities. Additionally, they reduce neointimal thickening by inhibiting proliferation of smooth muscle cells and also improve endothelium dependent vasorelaxation by modulating bioavailability of nitric-oxide and voltage-gated ion channels. However, detailed and profound knowledge on specific molecular targets of each phytochemical is very important to ensure safe use of these active compounds as a therapeutic agent. Thus, this paper reviews the active antioxidative, antiproliferative, anti-inflammatory, or antiangiogenesis role of various phytochemicals for prevention of chronic diseases.

  15. Post-conflict reconciliation and development in Nicaragua: The role of cooperatives and collective action

    OpenAIRE

    Utting, Peter; Chamorro, Amalia; Bacon, Christopher

    2014-01-01

    This paper examines how cooperatives affected and were affected by the profound political, economic and social transitions that have occurred in Nicaragua in recent decades. It pays particular attention to the shift from the post-revolutionary Sandinista regime of the 1980s to the "neoliberal" regime of the 1990s and early 2000s. In the early 1990s, a peace accord ended years of civil war and the Sandinista government was voted out of office by a coalition of Centrist and Right-wing parties. ...

  16. Functional adaptation in female rats: the role of estrogen signaling.

    Directory of Open Access Journals (Sweden)

    Susannah J Sample

    Full Text Available Sex steroids have direct effects on the skeleton. Estrogen acts on the skeleton via the classical genomic estrogen receptors alpha and beta (ERα and ERβ, a membrane ER, and the non-genomic G-protein coupled estrogen receptor (GPER. GPER is distributed throughout the nervous system, but little is known about its effects on bone. In male rats, adaptation to loading is neuronally regulated, but this has not been studied in females.We used the rat ulna end-loading model to induce an adaptive modeling response in ovariectomized (OVX female Sprague-Dawley rats. Rats were treated with a placebo, estrogen (17β-estradiol, or G-1, a GPER-specific agonist. Fourteen days after OVX, rats underwent unilateral cyclic loading of the right ulna; half of the rats in each group had brachial plexus anesthesia (BPA of the loaded limb before loading. Ten days after loading, serum estrogen concentrations, dorsal root ganglion (DRG gene expression of ERα, ERβ, GPER, CGRPα, TRPV1, TRPV4 and TRPA1, and load-induced skeletal responses were quantified. We hypothesized that estrogen and G-1 treatment would influence skeletal responses to cyclic loading through a neuronal mechanism. We found that estrogen suppresses periosteal bone formation in female rats. This physiological effect is not GPER-mediated. We also found that absolute mechanosensitivity in female rats was decreased, when compared with male rats. Blocking of adaptive bone formation by BPA in Placebo OVX females was reduced.Estrogen acts to decrease periosteal bone formation in female rats in vivo. This effect is not GPER-mediated. Gender differences in absolute bone mechanosensitivity exist in young Sprague-Dawley rats with reduced mechanosensitivity in females, although underlying bone formation rate associated with growth likely influences this observation. In contrast to female and male rats, central neuronal signals had a diminished effect on adaptive bone formation in estrogen-deficient female rats.

  17. Social acceptance of renewable energy innovations: The role of technology cooperation in urban Mexico

    International Nuclear Information System (INIS)

    Mallett, Alexandra

    2007-01-01

    Much discussion of technology transfer and the adoption of renewable energy innovations overlooks the importance of social acceptance. Using mainly qualitative analytical techniques, empirical evidence was obtained from the experiences of those involved in solar water heaters in Mexico City (e.g. technicians, industry representatives, local government officials, community representatives/end users) in order to explain social acceptance of these renewable energy innovations. In particular, this paper evaluates Rogers' [2005. Diffusion of Innovations. Free Press, New York.] technology adoption model (using an 'active' definition of social acceptance), which claims that adoption comes about through a decision-making process occurring in stages-knowledge, persuasion, implementation and confirmation and can be traced to a number of factors such as relative advantage, complexity, and triability. This paper argues that while Rogers' technology adoption model is a useful tool to explain social acceptance, this approach needs to be revised to adequately reflect the effects of technology cooperation, an integral part of technology adoption. Furthermore, this paper asserts that those forms of technology cooperation in which active participants are from various sectors and interact continuously throughout the process is most effective in eliciting social acceptance of renewable energy innovations

  18. The role of radiation therapy in pediatric oncology as assessed by cooperative clinical trials

    International Nuclear Information System (INIS)

    D'Angio, G.J.

    1985-01-01

    Major advances have been made in pediatric oncology, and many are due to the advent of the cooperative clinical trial. This important research tool was originally developed for the testing of various therapeutic strategies for the management of children with acute leukemia. Such trials were eminently successful, as the consistently better long-term survival rates for children with this hitherto uniformly lethal disease can attest. The method soon found favor for the investigation of patients with so-called solid tumors. These trails were originally concerned with the elucidation of the value of various chemotherapeutic agents. Radiation therapists soon became involved, however, and this discipline became more heavily represented in study design and data analyses. Much radiation therapy information has been gained, some through prospective, randomized clinical investigations and some through retrospective reviews of roentgen therapy as it was employed in protocols accenting other aspects of care. Voluminous, important radiation therapy data have been deduced through the latter retrospective kinds of analyses, but this review will be confined largely to the published results of prospective, randomized cooperative clinical trials where radiation therapy was a governing variable. Certain investigations of historical interest will also be cited together with other results that established important principles even though not so rigorous in design

  19. The autoimmunity risk variant LYP-W620 cooperates with CSK in the regulation of TCR signaling.

    Directory of Open Access Journals (Sweden)

    María Luisa de la Puerta

    Full Text Available The protein tyrosine phosphatase LYP, a key regulator of TCR signaling, presents a single nucleotide polymorphism, C1858T, associated with several autoimmune diseases such as type I diabetes, rheumatoid arthritis, and lupus. This polymorphism changes an R by a W in the P1 Pro rich motif of LYP, which binds to CSK SH3 domain, another negative regulator of TCR signaling. Based on the analysis of the mouse homologue, Pep, it was proposed that LYP and CSK bind constitutively to inhibit LCK and subsequently TCR signaling. The detailed study of LYP/CSK interaction, here presented, showed that LYP/CSK interaction was inducible upon TCR stimulation, and involved LYP P1 and P2 motifs, and CSK SH3 and SH2 domains. Abrogating LYP/CSK interaction did not preclude the regulation of TCR signaling by these proteins.

  20. Role of Receptor Tyrosine Kinase Signaling in Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Feng Liu

    2016-06-01

    Full Text Available Renal fibrosis can be induced in different renal diseases, but ultimately progresses to end stage renal disease. Although the pathophysiologic process of renal fibrosis have not been fully elucidated, it is characterized by glomerulosclerosis and/or tubular interstitial fibrosis, and is believed to be caused by the proliferation of renal inherent cells, including glomerular epithelial cells, mesangial cells, and endothelial cells, along with defective kidney repair, renal interstitial fibroblasts activation, and extracellular matrix deposition. Receptor tyrosine kinases (RTKs regulate a variety of cell physiological processes, including metabolism, growth, differentiation, and survival. Many studies from in vitro and animal models have provided evidence that RTKs play important roles in the pathogenic process of renal fibrosis. It is also showed that tyrosine kinases inhibitors (TKIs have anti-fibrotic effects in basic research and clinical trials. In this review, we summarize the evidence for involvement of specific RTKs in renal fibrosis process and the employment of TKIs as a therapeutic approach for renal fibrosis.

  1. Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling.

    Directory of Open Access Journals (Sweden)

    Suresh Marada

    2015-08-01

    Full Text Available The G protein-coupled receptor (GPCR Smoothened (Smo is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice.

  2. Signaling Role of Fructose Mediated by FINS1/FBP in Arabidopsis thaliana

    Science.gov (United States)

    Cho, Young-Hee; Yoo, Sang-Dong

    2011-01-01

    Sugars are evolutionarily conserved signaling molecules that regulate the growth and development of both unicellular and multicellular organisms. As sugar-producing photosynthetic organisms, plants utilize glucose as one of their major signaling molecules. However, the details of other sugar signaling molecules and their regulatory factors have remained elusive, due to the complexity of the metabolite and hormone interactions that control physiological and developmental programs in plants. We combined information from a gain-of-function cell-based screen and a loss-of-function reverse-genetic analysis to demonstrate that fructose acts as a signaling molecule in Arabidopsis thaliana. Fructose signaling induced seedling developmental arrest and interacted with plant stress hormone signaling in a manner similar to that of glucose. For fructose signaling responses, the plant glucose sensor HEXOKINASE1 (HXK1) was dispensable, while FRUCTOSE INSENSITIVE1 (FINS1), a putative FRUCTOSE-1,6-BISPHOSPHATASE, played a crucial role. Interestingly, FINS1 function in fructose signaling appeared to be independent of its catalytic activity in sugar metabolism. Genetic analysis further indicated that FINS1–dependent fructose signaling may act downstream of the abscisic acid pathway, in spite of the fact that HXK1–dependent glucose signaling works upstream of hormone synthesis. Our findings revealed that multiple layers of controls by fructose, glucose, and abscisic acid finely tune the plant autotrophic transition and modulate early seedling establishment after seed germination. PMID:21253566

  3. Role of Glycolytic Intermediates in Global Regulation and Signal Transduction. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Liao, J.C.

    2000-05-08

    The goal of this project is to determine the role of glycolytic intermediates in regulation of cell physiology. It is known that many glycolytic intermediates are involved in regulation of enzyme activities at the kinetic level. However, little is known regarding the role of these metabolites in global regulation and signal transduction. This project aims to investigate the role of glycolytic intermediates in the regulation of gene expression.

  4. Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation.

    Science.gov (United States)

    Franco, Heather L; Yao, Humphrey H-C

    2012-01-01

    The chromosome status of the mammalian embryo initiates a multistage process of sexual development in which the bipotential reproductive system establishes itself as either male or female. These events are governed by intricate cell-cell and interorgan communication that is regulated by multiple signaling pathways. The hedgehog signaling pathway was originally identified for its key role in the development of Drosophila, but is now recognized as a critical developmental regulator in many species, including humans. In addition to its developmental roles, the hedgehog signaling pathway also modulates adult organ function, and misregulation of this pathway often leads to diseases, such as cancer. The hedgehog signaling pathway acts through its morphogenetic ligands that signal from ligand-producing cells to target cells over a specified distance. The target cells then respond in a graded manner based on the concentration of the ligands that they are exposed to. Through this unique mechanism of action, the hedgehog signaling pathway elicits cell fate determination, epithelial-mesenchymal interactions, and cellular homeostasis. Here, we review current findings on the roles of hedgehog signaling in the sexually dimorphic development of the reproductive organs with an emphasis on mammals and comparative evidence in other species.

  5. IL-12-mediated STAT4 signaling and TCR signal strength cooperate in the induction of CD40L in human and mouse CD8+ T cells.

    Science.gov (United States)

    Stark, Regina; Hartung, Anett; Zehn, Dietmar; Frentsch, Marco; Thiel, Andreas

    2013-06-01

    CD40L is one of the key molecules bridging the activation of specific T cells and the maturation of professional and nonprofessional antigen-presenting cells including B cells. CD4(+) T cells have been regarded as the major T-cell subset that expresses CD40L upon cognate activation; however, we demonstrate here that a putative CD8(+) helper T-cell subset expressing CD40L is induced in human and murine CD8(+) T cells in vitro and in mice immunized with antigen-pulsed dendritic cells. IL-12 and STAT4-mediated signaling was the major instructive cytokine signal boosting the ability of CD8(+) T cells to express CD40L both in vitro and in vivo. Additionally, TCR signaling strength modulated CD40L expression in CD8(+) T cells after primary differentiation in vitro as well as in vivo. The induction of CD40L in CD8(+) T cells regulated by IL-12 and TCR signaling may enable CD8(+) T cells to respond autonomously of CD4(+) T cells. Thus, we propose that under proinflammatory conditions, a self-sustaining positive feedback loop could facilitate the efficient priming of T cells stimulated by high affinity peptide displaying APCs. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity.

    Science.gov (United States)

    Wang, Dashan

    2018-06-01

    The aim of this paper is to clarify the critical role of GPCR signaling in T cell immunity. The G protein-coupled receptors (GPCRs) are the most common targets in current pharmaceutical industry, and represent the largest and most versatile family of cell surface communicating molecules. GPCRs can be activated by a diverse array of ligands including neurotransmitters, chemokines as well as sensory stimuli. Therefore, GPCRs are involved in many key cellular and physiological processes, such as sense of light, taste and smell, neurotransmission, metabolism, endocrine and exocrine secretion. In recent years, GPCRs have been found to play an important role in immune system. T cell is an important type of immune cell, which plays a central role in cell-mediated immunity. A variety of GPCRs and their signaling mediators (RGS proteins, GRKs and β-arrestin) have been found to express in T cells and involved T cell-mediated immunity. We will summarize the role of GPCR signaling and their regulatory molecules in T cell activation, homeostasis and function in this article. GPCR signaling plays an important role in T cell activation, homeostasis and function. GPCR signaling is critical in regulating T cell immunity.

  7. The role of the Hedgehog signaling pathway in cancer: A comprehensive review

    Directory of Open Access Journals (Sweden)

    Ana Marija Skoda

    2018-02-01

    Full Text Available The Hedgehog (Hh signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh], Patched receptor (Ptch1, Ptch2, Smoothened receptor (Smo, Suppressor of fused homolog (Sufu, kinesin protein Kif7, protein kinase A (PKA, and cyclic adenosine monophosphate (cAMP. The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

  8. Nonlinear signaling on biological networks: The role of stochasticity and spectral clustering

    Science.gov (United States)

    Hernandez-Hernandez, Gonzalo; Myers, Jesse; Alvarez-Lacalle, Enrique; Shiferaw, Yohannes

    2017-03-01

    Signal transduction within biological cells is governed by networks of interacting proteins. Communication between these proteins is mediated by signaling molecules which bind to receptors and induce stochastic transitions between different conformational states. Signaling is typically a cooperative process which requires the occurrence of multiple binding events so that reaction rates have a nonlinear dependence on the amount of signaling molecule. It is this nonlinearity that endows biological signaling networks with robust switchlike properties which are critical to their biological function. In this study we investigate how the properties of these signaling systems depend on the network architecture. Our main result is that these nonlinear networks exhibit bistability where the network activity can switch between states that correspond to a low and high activity level. We show that this bistable regime emerges at a critical coupling strength that is determined by the spectral structure of the network. In particular, the set of nodes that correspond to large components of the leading eigenvector of the adjacency matrix determines the onset of bistability. Above this transition the eigenvectors of the adjacency matrix determine a hierarchy of clusters, defined by its spectral properties, which are activated sequentially with increasing network activity. We argue further that the onset of bistability occurs either continuously or discontinuously depending upon whether the leading eigenvector is localized or delocalized. Finally, we show that at low network coupling stochastic transitions to the active branch are also driven by the set of nodes that contribute more strongly to the leading eigenvector. However, at high coupling, transitions are insensitive to network structure since the network can be activated by stochastic transitions of a few nodes. Thus this work identifies important features of biological signaling networks that may underlie their biological

  9. The role of learning-related dopamine signals in addiction vulnerability.

    Science.gov (United States)

    Huys, Quentin J M; Tobler, Philippe N; Hasler, Gregor; Flagel, Shelly B

    2014-01-01

    Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signaling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical, and experimental accounts of phasic dopamine signaling, with implications for the role of learning-related dopamine signaling in addiction and related disorders. We describe the theoretical and behavioral characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations. We then use recent insights from an animal model that highlights individual variation in learning during a Pavlovian conditioning paradigm to describe overlapping aspects of incentive salience attribution and model-free learning. We argue that this provides a computationally coherent account of some features of addiction. © 2014 Elsevier B.V. All rights reserved.

  10. The role of the Public Private Partnership (PPP) in Cross Border Cooperation (CBC) as strategic practice in the EU Policies and cooperation tools for 2014-2020

    OpenAIRE

    Lussi, Manoela

    2014-01-01

    2012/2013 There is an increasingly widespread acknowledgement among all active actors in the development co-operation sector that the Public Private Partnership (PPP) can be a new important tool, not only to build important infrastructure (public works) but also to provide services to the citizens at central and local level as well as to have a strategic value in the Cross-Border Co-operation (CBC) in the next future. The European Commission defines PPPs in a rather broad and general wa...

  11. Aluminum stress and its role in the phospholipid signaling pathway in plants and possible biotechnological applications.

    Science.gov (United States)

    Poot-Poot, Wilberth; Hernandez-Sotomayor, Soledad M Teresa

    2011-10-01

    An early response of plants to environmental signals or abiotic stress suggests that the phospholipid signaling pathway plays a pivotal role in these mechanisms. The phospholipid signaling cascade is one of the main systems of cellular transduction and is related to other signal transduction mechanisms. These other mechanisms include the generation of second messengers and their interactions with various proteins, such as ion channels. This phospholipid signaling cascade is activated by changes in the environment, such as phosphate starvation, water, metals, saline stres, and plant-pathogen interactions. One important factor that impacts agricultural crops is metal-induced stress. Because aluminum has been considered to be a major toxic factor for agriculture conducted in acidic soils, many researchers have focused on understanding the mechanisms of aluminum toxicity in plants. We have contributed the last fifteen years in this field by studying the effects of aluminum on phospholipid signaling in coffee, one of the Mexico's primary crops. We have focused our research on aluminum toxicity mechanisms in Coffea arabica suspension cells as a model for developing future contributions to the biotechnological transformation of coffee crops such that they can be made resistant to aluminum toxicity. We conclude that aluminum is able to not only generate a signal cascade in plants but also modulate other signal cascades generated by other types of stress in plants. The aim of this review is to discuss possible involvement of the phospholipid signaling pathway in the aluminum toxicity response of plant cells. Copyright © 2011 Wiley Periodicals, Inc.

  12. The role of International Atomic Energy Agency (IAEA) Technical Cooperation (TC) programs in enhancing socioeconomic development in Sudan

    Energy Technology Data Exchange (ETDEWEB)

    Salih, A Y.S. [Development Studies and Research Institute, University of Khartoum, Khartoum (Sudan)

    2006-04-15

    The main objective of this study is to reflect the role of nuclear Techniques in development through the IAEA provision of the technical cooperation (TC) projects in Sudan, and to show their impact on socio-economic activities, improvement of infrastructures, technology transfer, and whether the targeted institutes become economically self-reliant. This study as an analytical study uses secondary sources, namely reports from IAEA and coordinators of the projects. The study also uses primary data received mainly through conducting interviews with stake holders. The study has come out with some main findings: that the IAEA technical assistances played a major role in addressing pressing issues such as socio-economic development, sustainable development and management of different fields related to application of nuclear technology. The TC assistance depends on the local component of the country, also it depends on Sudan payments of it is annual share to the IAEA technical cooperation. The important role played by Sudan Atomic Energy Commission (SAEC) in its capacity as the national coordinating body with respect to Technical Cooperation (TC) is highly appreciated. The total number of projects increased rapidly from 16 projects in 1959 to 55 projects in 2005 in different fields includes human health, agriculture, animal production, waste management, water resources, ... etc. The TC projects are associated with the country's development programmes framework (CPF) and support socio-economic activities. The management of TC projects activated at the national level were successful and have significant impact, particularly in human heath, agriculture, instrumentation and Non Destructive Testing. All the TC projects provided their funds mainly from IAEA, and assistance received from IAEA is highly effective. Sudan TC Programme had achieved a high implementation rate, where most of the projects attained their objectives, showing good results in socio-economic and infra

  13. The role of International Atomic Energy Agency (IAEA) Technical Cooperation (TC) programs in enhancing socioeconomic development in Sudan

    International Nuclear Information System (INIS)

    Salih, A.Y.S.

    2006-04-01

    The main objective of this study is to reflect the role of nuclear Techniques in development through the IAEA provision of the technical cooperation (TC) projects in Sudan, and to show their impact on socio-economic activities, improvement of infrastructures, technology transfer, and whether the targeted institutes become economically self-reliant. This study as an analytical study uses secondary sources, namely reports from IAEA and coordinators of the projects. The study also uses primary data received mainly through conducting interviews with stake holders. The study has come out with some main findings: that the IAEA technical assistances played a major role in addressing pressing issues such as socio-economic development, sustainable development and management of different fields related to application of nuclear technology. The TC assistance depends on the local component of the country, also it depends on Sudan payments of it is annual share to the IAEA technical cooperation. The important role played by Sudan Atomic Energy Commission (SAEC) in its capacity as the national coordinating body with respect to Technical Cooperation (TC) is highly appreciated. The total number of projects increased rapidly from 16 projects in 1959 to 55 projects in 2005 in different fields includes human health, agriculture, animal production, waste management, water resources, ... etc. The TC projects are associated with the country's development programmes framework (CPF) and support socio-economic activities. The management of TC projects activated at the national level were successful and have significant impact, particularly in human heath, agriculture, instrumentation and Non Destructive Testing. All the TC projects provided their funds mainly from IAEA, and assistance received from IAEA is highly effective. Sudan TC Programme had achieved a high implementation rate, where most of the projects attained their objectives, showing good results in socio-economic and infra

  14. Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish.

    Science.gov (United States)

    Nakahara, Yoshinari; Muto, Akihiko; Hirabayashi, Ryo; Sakuma, Tetsushi; Yamamoto, Takashi; Kume, Shoen; Kikuchi, Yutaka

    2016-05-01

    The adenohypophysis (AH) consists of six distinct types of hormone-secreting cells. In zebrafish, although proper differentiation of all AH cell types has been shown to require Notch signaling within a period of 14-16 h postfertilization (hpf), the mechanisms underlying this process remain to be elucidated. Herein, we observed using the Notch inhibitor dibenzazepine (DBZ) that Notch signaling also contributed to AH cell specification beyond 16 hpf. Specification of distinct cell types was perturbed by DBZ treatment for different time frames, suggesting that AH cells are specified by Notch-dependent and cell-type-specific mechanisms. We also found that two hes-family genes, her4.1 and hey1, were expressed in the developing AH under the influence of Notch signaling. her4.1 knockdown reduced expression of proopiomelanocortin a (pomca), growth hormone (gh), and prolactin, whereas hey1 was responsible only for gh expression. Simultaneous loss of both Her4.1 and Hey1 produced milder phenotypes than that of DBZ-treated embryos. Moreover, DBZ treatment from 18 hpf led to a significant down-regulation of both gh and pomca genes only when combined with injection of a subthreshold level of her4.1-morpholino. These observations suggest that multiple downstream effectors, including Her4.1 and Hey1, mediate Notch signaling during AH cell specification. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  15. Roles of Notch1 Signaling in Regulating Satellite Cell Fates Choices and Postnatal Skeletal Myogenesis.

    Science.gov (United States)

    Shan, Tizhong; Xu, Ziye; Wu, Weiche; Liu, Jiaqi; Wang, Yizhen

    2017-11-01

    Adult skeletal muscle stem cells, also called satellite cells, are indispensable for the growth, maintenance, and regeneration of the postnatal skeletal muscle. Satellite cells, predominantly quiescent in mature resting muscles, are activated after skeletal muscle injury or degeneration. Notch1 signaling is an evolutionarily conserved pathway that plays crucial roles in satellite cells homeostasis and postnatal skeletal myogenesis and regeneration. Activation of Notch1 signaling promotes the muscle satellite cells quiescence and proliferation, but inhibits differentiation of muscle satellite cells. Notably, the new roles of Notch1 signaling during late-stage of skeletal myogenesis including in post-differentiation myocytes and post-fusion myotubes have been recently reported. Here, we mainly review and discuss the regulatory roles of Notch1 in regulating satellite cell fates choices and skeletal myogenesis. J. Cell. Physiol. 232: 2964-2967, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. The Role of Cgrp-Receptor Component Protein (Rcp in Cgrp-Mediated Signal Transduction

    Directory of Open Access Journals (Sweden)

    M. A. Prado

    2001-01-01

    Full Text Available The calcitonin gene-related peptide (CGRP-receptor component protein (RCP is a 17-kDa intracellular peripheral membrane protein required for signal transduction at CGRP receptors. To determine the role of RCP in CGRP-mediated signal transduction, RCP was depleted from NIH3T3 cells using antisense strategy. Loss of RCP protein correlated with loss of cAMP production by CGRP in the antisense cells. In contrast, loss of RCP had no effect on CGRP-mediated binding; therefore RCP is not acting as a chaperone for the CGRP receptor. Instead, RCP is a novel signal transduction molecule that couples the CGRP receptor to the cellular signal transduction machinery. RCP thus represents a prototype for a new class of signal transduction proteins that are required for regulation of G protein-coupled receptors.

  17. The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer

    Science.gov (United States)

    Li, Yiwei; Wang, Zhiwei; Kong, Dejuan

    2010-01-01

    Multiple cellular signaling pathways have been involved in the processes of cancer cell invasion and metastasis. Among many signaling pathways, Wnt and Hedgehog (Hh) signaling pathways are critically involved in embryonic development, in the biology of cancer stem cells (CSCs) and in the acquisition of epithelial to mesenchymal transition (EMT), and thus this article will remain focused on Wnt and Hh signaling. Since CSCs and EMT are also known to be responsible for cancer cell invasion and metastasis, the Wnt and Hedgehog signaling pathways are also intimately associated with cancer invasion and metastasis. Emerging evidence suggests the beneficial role of chemopreventive agents commonly known as nutraceutical in cancer. Among many such agents, soy isoflavones, curcumin, green tea polyphenols, 3,3′-diindolylmethane, resveratrol, lycopene, vitamin D, etc. have been found to prevent, reverse, or delay the carcinogenic process. Interestingly, these agents have also shown to prevent or delay the progression of cancer, which could in part be due to their ability to attack CSCs or EMT-type cells by attenuating the Wnt and Hedgehog signaling pathways. In this review, we summarize the current state of our knowledge on the role of Wnt and Hedgehog signaling pathways, and their targeted inactivation by chemopreventive agents (nutraceuticals) for the prevention of tumor progression and/or treatment of human malignancies. PMID:20711635

  18. AKT-independent PI3-K signaling in cancer – emerging role for SGK3

    International Nuclear Information System (INIS)

    Bruhn, Maressa A; Pearson, Richard B; Hannan, Ross D; Sheppard, Karen E

    2013-01-01

    The phosphoinositide 3-kinase (PI3-K) signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT) signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK) family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling

  19. The role of cooperative iceberg capsize during ice-shelf disintegration

    Science.gov (United States)

    Wilder, W. G.; Burton, J. C.; Amundson, J. M.; Cathles, L. M.; Zhang, W. W.

    2011-12-01

    The physical processes responsible for the sudden, rapid collapse of Antarctic ice-shelves (Larsen B, in 2002; Wilkins, in 2008) are poorly understood. Observations are limited to a handful of satellite images. Thus we have undertaken a series of laboratory-scale experiments using a water-filled tank and "ice" made from buoyant plastic blocks to investigate these processes. Previous experiments have quantified how gravitational potential energy of single-iceberg capsize is converted to other forms of energy [described in Burton et al., submitted], including hydrodynamic forms that may feed back on the ice shelf to cause additional calving. The new experiments reported here examine the energetics of hydrodynamically coupled icebergs that exhibit collective behaviors qualitatively similar to features observed in satellite imagery. Our results suggest that there is a critical proximity at which icebergs will capsize in the same direction an overwhelming majority of the time (cooperative capsize), and a significant part of the gravitational potential energy is converted into translational kinetic energy. We speculate that the residual translational energy observed in our experiments may explain the significant expansion rate (~1 meter/second) of collapsing Antarctic ice-shelves. Burton, J. C., J. M. Amundson, D. S. Abbot, A. Boghosian, L. M. Cathles, S. Correa-Legisos, K. N. Darnell, N. Guttenberg, D. M. Holland, and D. R. MacAyeal. submitted. Laboratory investigations of iceberg-capsize dynamics, energy dissipation and tsunamigenesis. J. Geophys. Res.

  20. Sustainable Relations in International Development Cooperation Projects: The Role of Organizational Climate

    Directory of Open Access Journals (Sweden)

    Cosimo Rota

    2011-10-01

    Full Text Available  The importance of the human side of project management to assess the success of international development project has not been fully considered yet. An analysis of the literature on the project success definition, focused on the success criteria and success factors, was carried out. The organization’s effectiveness, in terms of Relations Sustainability, emerged as a criteria integrating the "time, cost, performance" approach to define a project success. Based on previous research contributions on the factors influencing the organization’s effectiveness, the paper expands the analysis of the influence of Organizational Climate on the Relation Sustainability between project manager and project team involved in international cooperation for development. The statistical methods used include confirmatory factors analysis and structural equation modeling. The results carry implications for project management identifying five dimensions of Organizational Climate (trust, innovation, social cohesion, communication and job challenge influencing Relations Sustainability. This finding suggests that Organizational Climate contributes to project success by creating trust, stimulating commitment and generating satisfaction to overcome conflicts between project manager and project team.

  1. The role of host traits, season and group size on parasite burdens in a cooperative mammal.

    Directory of Open Access Journals (Sweden)

    Hermien Viljoen

    Full Text Available The distribution of parasites among hosts is often characterised by a high degree of heterogeneity with a small number of hosts harbouring the majority of parasites. Such patterns of aggregation have been linked to variation in host exposure and susceptibility as well as parasite traits and environmental factors. Host exposure and susceptibility may differ with sexes, reproductive effort and group size. Furthermore, environmental factors may affect both the host and parasite directly and contribute to temporal heterogeneities in parasite loads. We investigated the contributions of host and parasite traits as well as season on parasite loads in highveld mole-rats (Cryptomys hottentotus pretoriae. This cooperative breeder exhibits a reproductive division of labour and animals live in colonies of varying sizes that procreate seasonally. Mole-rats were parasitised by lice, mites, cestodes and nematodes with mites (Androlaelaps sp. and cestodes (Mathevotaenia sp. being the dominant ecto- and endoparasites, respectively. Sex and reproductive status contributed little to the observed parasite prevalence and abundances possibly as a result of the shared burrow system. Clear seasonal patterns of parasite prevalence and abundance emerged with peaks in summer for mites and in winter for cestodes. Group size correlated negatively with mite abundance while it had no effect on cestode burdens and group membership affected infestation with both parasites. We propose that the mode of transmission as well as social factors constrain parasite propagation generating parasite patterns deviating from those commonly predicted.

  2. Altruistic Behavior and Cooperation: The Role of Intrinsic Expectation When Reputational Information is Incomplete

    Directory of Open Access Journals (Sweden)

    Jacintha Ellers

    2010-01-01

    Full Text Available Altruistic behavior is known to be conditional on the level of altruism of others. However, people often have no information, or incomplete information, about the altruistic reputation of others, for example when the reputation was obtained in a different social or economic context. As a consequence, they have to estimate the other's altruistic intentions. Using an economic game, we showed that without reputational information people have intrinsic expectations about the altruistic behavior of others, which largely explained their own altruistic behavior. This implies that when no information is available, intrinsic expectations can be as powerful a driver of altruistic behavior as actual knowledge about other people's reputation. Two strategies appeared to co-exist in our study population: participants who expected others to be altruistic and acted even more altruistically themselves, while other participants had low expected altruism scores and acted even less altruistically than they expected others to do. We also found evidence that generosity in economic games translates into benefits for other social contexts: a reputation of financial generosity increased the attractiveness of partners in a social cooperative game. This result implies that in situations with incomplete information, the fitness effects of indirect reciprocity are cumulative across different social contexts.

  3. The health migration crisis: the role of four Organisation for Economic Cooperation and Development countries.

    Science.gov (United States)

    Pond, Bob; McPake, Barbara

    2006-04-29

    The crisis of human resources for health that is affecting low-income countries and especially sub-Saharan Africa has been attributed, at least in part, to increasing rates of migration of qualified health staff to high-income countries. We describe the conditions in four Organisation for Economic Cooperation and Development (OECD) health labour markets that have led to increasing rates of immigration. Popular explanations of these trends include ageing populations, growing incomes, and feminisation of the health workforce. Although these explanations form part of the larger picture, analysis of the forces operating in the four countries suggests that specific policy measures largely unrelated to these factors have driven growing demand for health staff. On this basis we argue that specific policy measures are equally capable of reversing these trends and avoiding the exploitation of low-income countries' scarce resources. These policies should seek to ensure local stability in health labour markets so that shortages of staff are not solved via the international brain drain.

  4. Establishing cooperation in a mixed-motive social dilemma. An fMRI study investigating the role of social value orientation and dispositional trust.

    Science.gov (United States)

    Emonds, Griet; Declerck, Carolyn H; Boone, Christophe; Seurinck, Ruth; Achten, Rik

    2014-02-01

    When people are confronted with social dilemmas, their decision-making strategies tend to be associated with individual social preferences; prosocials have an intrinsic willingness to cooperate, while proselfs need extrinsic motivators signaling personal gain. In this study, the biological roots for the proselfs/prosocials concept are explored by investigating the neural correlates of cooperative versus defect decisions when participants engage in a series of one-shot, anonymous prisoner's dilemma situations. Our data are in line with previous studies showing that prosocials activate several social cognition regions of the brain more than proselfs (here: medial prefrontal cortex, temporo-parietal junction, and precuneus BA 7 (Brodmann area 7), and that dispositional trust positively affects prosocials' decisions to cooperate. At the neural level, however, dispositional trust appears to exert a greater marginal effect on brain activity of proselfs in three social cognition regions, which does not translate into an increase in cooperation. An event-related analysis shows that cooperating prosocials show significantly more activation in the precuneus (BA 7) than proselfs. Based on previous research, we interpret this result to be consistent with prosocials' enhanced tendency to infer the intentions of others in social dilemma games, and the importance of establishing norm congruence when they decide to cooperate.

  5. Theoretical component of national financial, economic and cooperative education in Western Ukraine (second half of XIX-XX centuries and its role in economic management of the region

    Directory of Open Access Journals (Sweden)

    Holubka M. M.

    2016-06-01

    Full Text Available In the article, the theoretical components of the development of national financial and economic as well as cooperative education in the Western territories of Ukraine in the second half of the XIX-the beginning of the XX century and its role in economic management in the region were covered. The methodology and the general essence of the financial and economic as well as cooperative education, and its significant influence on the community were analyzed. Importance and significance of financial and economic as well as cooperative education for realizing the opportunities for the self-understanding of a human as an economically active member of the nation was identified. The development of the financial and economic as well as cooperative education of the population that has proved a key role in these processes and various institutions of self-education partnerships was analyzed. The broad functionality of such associations and the transformation of the main goal of its activities from educational proper to educational, financial and economic was revealed. The basic achievements of associations and associates in terms of the support for the establishment of various organizations for the business purposes, cooperatives, educational institutions, professional courses, publishing, organization of specialized events, financial institutions and their importance to financial, economic and cooperative education were described.

  6. Gratefully received, gratefully repaid: the role of perceived fairness in cooperative interactions.

    Directory of Open Access Journals (Sweden)

    Lawrence K Ma

    Full Text Available It is well documented that people would remunerate fair behaviours and penalize unfair behaviours. It is argued that individuals' reactions following the receipt of a gift depend on the perceived intentions of the donors. Fair intentions should prompt positive affect, like gratitude, triggering cooperative behaviours; while intended unfairness should trigger negative affect, like anger, fostering anti-social actions. It is, however, contended that when people lack information to infer others' intention they may use 'normative' beliefs about fairness - what a typical fair individual 'should' do in these circumstances - to guide their behaviour. In this experiment we examined this assertion. We had 122 participants play a one-shot, double-anonymous game with half playing as potential helpers (P1s and half as recipients (P2s. Whether a participant was a P1 or P2 was chance-determined and all participants knew this. P1s decided whether to help P2s and whether to make their help unconditional (no repayment needed or conditional (full or 'taxed' repayment. P2s decided whether to accept the offer and whatever conditions attached but were blind to the list of helping options available to P1s. We anticipated that recipients would refer to the 'injunctive norm' that 'fair people should help "for free" when it is only by chance that they are in a position to help'. Therefore, without knowing P1s' different helping options, unconditional offers should be rated by recipients as fairer than conditional offers, and this should be linked to greater gratitude with greater gratitude linked to greater reciprocation. Path analyses confirmed this serial mediation. The results showed that recipients of unconditional offers, compared to conditional ones, interpreted the helpers' motives as more helpful, experienced greater gratitude and were more eager to reciprocate. The behavioural data further revealed that, when given a latter option to default, 38% of recipients

  7. Role of Mitochondrial Reverse Electron Transport in ROS Signaling: Potential Roles in Health and Disease

    Directory of Open Access Journals (Sweden)

    Filippo Scialò

    2017-06-01

    Full Text Available Reactive Oxygen Species (ROS can cause oxidative damage and have been proposed to be the main cause of aging and age-related diseases including cancer, diabetes and Parkinson's disease. Accordingly, mitochondria from old individuals have higher levels of ROS. However, ROS also participate in cellular signaling, are instrumental for several physiological processes and boosting ROS levels in model organisms extends lifespan. The current consensus is that low levels of ROS are beneficial, facilitating adaptation to stress via signaling, whereas high levels of ROS are deleterious because they trigger oxidative stress. Based on this model the amount of ROS should determine the physiological effect. However, recent data suggests that the site at which ROS are generated is also instrumental in determining effects on cellular homeostasis. The best example of site-specific ROS signaling is reverse electron transport (RET. RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. RET has been shown to be instrumental for the activation of macrophages in response to bacterial infection, re-organization of the electron transport chain in response to changes in energy supply and adaptation of the carotid body to changes in oxygen levels. In Drosophila melanogaster, stimulating RET extends lifespan. Here, we review what is known about RET, as an example of site-specific ROS signaling, and its implications for the field of redox biology.

  8. Traumatic Brain Injury: Exploring the Role of Cooperative Extension in Kansas Communities

    Science.gov (United States)

    Sellers, Debra M.; Garcia, Jane Mertz

    2012-01-01

    TBI"options" helps survivors of traumatic brain injury and their families identify, locate, and contact helpful organizations in their local communities to promote successful living. This article discusses the role of county agents in the program and the support offered by community partners. Results of pre- and post-surveys for both…

  9. The role of cGMP signalling in regulating life cycle progression of Plasmodium.

    OpenAIRE

    Hopp, CS; Bowyer, PW; Baker, DA

    2012-01-01

    The 3′-5′-cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) is the main mediator of cGMP signalling in the malaria parasite. This article reviews the role of PKG in Plasmodium falciparum during gametogenesis and blood stage schizont rupture, as well as the role of the Plasmodium berghei orthologue in ookinete differentiation and motility, and liver stage schizont development. The current views on potential effector proteins downstream of PKG and the mechanisms that may regu...

  10. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    International Nuclear Information System (INIS)

    Mann, Monica; Cortez, Valerie; Vadlamudi, Ratna K.

    2011-01-01

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications

  11. Epigenetics of Estrogen Receptor Signaling: Role in Hormonal Cancer Progression and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mann, Monica; Cortez, Valerie [Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States); Vadlamudi, Ratna K., E-mail: vadlamudi@uthscsa.edu [Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX 78229 (United States)

    2011-03-29

    Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

  12. Elsevier Trophoblast Research Award lecture: The multifaceted role of Nodal signaling during mammalian reproduction.

    Science.gov (United States)

    Park, C B; Dufort, D

    2011-03-01

    Nodal, a secreted signaling protein in the transforming growth factor-beta (TGF-β) superfamily, has established roles in vertebrate development. However, components of the Nodal signaling pathway are also expressed at the maternal-fetal interface and have been implicated in many processes of mammalian reproduction. Emerging evidence indicates that Nodal and its extracellular inhibitor Lefty are expressed in the uterus and complex interactions between the two proteins mediate menstruation, decidualization and embryo implantation. Furthermore, several studies have shown that Nodal from both fetal and maternal sources may regulate trophoblast cell fate and facilitate placentation as both embryonic and uterine-specific Nodal knockout mouse strains exhibit disrupted placenta morphology. Here we review the established and prospective roles of Nodal signaling in facilitating successful pregnancy, including recent evidence supporting a potential link to parturition and preterm birth. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Flavonoids and Wnt/β-Catenin Signaling: Potential Role in Colorectal Cancer Therapies

    Directory of Open Access Journals (Sweden)

    Nathália G. Amado

    2014-07-01

    Full Text Available It is now well documented that natural products have played an important role in anticancer therapy. Many studies focus on the ability of these natural compounds to modulate tumor-related signaling pathways and the relationship of these properties to an anticancer effect. According to the World Health Organization (WHO, colorectal cancer (CRC is the third most common cancer and the fourth leading cause of cancer death among men and women. Therefore, finding strategies to fight against CRC is an emergent health problem. CRC has a strong association with deregulation of Wnt/β-catenin signaling pathway. As some types of natural compounds are capable of modulating the Wnt/β-catenin signaling, one important question is whether they could counteract CRC. In this review, we discuss the role of flavonoids, a class of natural compounds, on Wnt/β-catenin regulation and its possible potential for therapeutic usage on colorectal cancer.

  14. The imidazopyridine derivative JK184 reveals dual roles for microtubules in Hedgehog signaling.

    Science.gov (United States)

    Cupido, Tommaso; Rack, Paul G; Firestone, Ari J; Hyman, Joel M; Han, Kyuho; Sinha, Surajit; Ocasio, Cory A; Chen, James K

    2009-01-01

    Eradicating hedgehogs: The title molecule has been previously identified as a potent inhibitor of the Hedgehog signaling pathway, which gives embryonic cells information needed to develop properly. This molecule is shown to modulate Hedgehog target gene expression by depolymerizing microtubules, thus revealing dual roles of the cytoskeleton in pathway regulation (see figure).

  15. Role asymmetry and code transmission in signaling games: an experimental and computational investigation.

    Science.gov (United States)

    Moreno, Maggie; Baggio, Giosuè

    2015-07-01

    In signaling games, a sender has private access to a state of affairs and uses a signal to inform a receiver about that state. If no common association of signals and states is initially available, sender and receiver must coordinate to develop one. How do players divide coordination labor? We show experimentally that, if players switch roles at each communication round, coordination labor is shared. However, in games with fixed roles, coordination labor is divided: Receivers adjust their mappings more frequently, whereas senders maintain the initial code, which is transmitted to receivers and becomes the common code. In a series of computer simulations, player and role asymmetry as observed experimentally were accounted for by a model in which the receiver in the first signaling round has a higher chance of adjusting its code than its partner. From this basic division of labor among players, certain properties of role asymmetry, in particular correlations with game complexity, are seen to follow. Copyright © 2014 Cognitive Science Society, Inc.

  16. The role of stop-signal probability and expectation in proactive inhibition

    NARCIS (Netherlands)

    Vink, Matthijs; Kaldewaij, Reinoud; Zandbelt, Bram B; Pas, Pascal; du Plessis, Stefan

    The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop-signal probability and the subjective

  17. Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

    Science.gov (United States)

    Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

    2015-01-01

    Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

  18. Role played by Disabled-2 in albumin induced MAP Kinase signalling

    International Nuclear Information System (INIS)

    Diwakar, Ramaswamy; Pearson, Alexander L.; Colville-Nash, Paul; Baines, Deborah L.; Dockrell, Mark E.C.

    2008-01-01

    Albumin has been shown to activate the mitogen activated protein kinase (MAPK) pathway in proximal tubular cells (PTECs) of the kidney. Megalin, the putative receptor for albumin has potential signalling properties. However, the mechanisms by which megalin signals are unclear. The adaptor phosphoprotein Disabled-2 (Dab2) is known to interact with the cytoplasmic tail of megalin and may be involved in albumin-mediated MAPK signalling. In this study, we investigated the role of Dab2 in albumin-mediated MAPK signalling and further studied the role of Dab2 in albumin-induced TGFβ-1 secretion, a MAPK dependent event. We used RNA interference to knockdown Dab2 protein abundance in HKC-8 cells a model of human PTECs. Albumin activated ERK1,2 and Elk-1 in a MEK-1 dependent manner and resulted in secretion of TGFβ-1. In the absence of albumin, knockdown of Dab2 resulted in a trend towards increase in pERK1,2 consistent with its putative role as an inhibitor of cell proliferation. However albumin-induced ERK1,2 activation was completely abolished by Dab2 knockdown. Dab2 knockdown did not however result in inhibition of albumin-induced TGFβ-1 secretion. These results suggest that Dab2 is a ligand dependent bi-directional regulator of ERK1,2 activity by demonstrating that in addition to its more traditional role as an inhibitor of ERK1,2 it may also activate ERK1,2

  19. Role of Notch-1 signaling in ethanol induced PC12 apoptosis | Li ...

    African Journals Online (AJOL)

    Chronic alcoholic dementia has crucial role in progress of neurodegenerative disease and affects a large portion of our aging population. Neuronal cell apoptosis may be a contributing factor of neurodegenerative disease (ND) and Alzheimer's disease (AD). Previous researches have indicated that Notch-1 signaling ...

  20. CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness.

    Science.gov (United States)

    Grass, G Daniel; Tolliver, Lauren B; Bratoeva, Momka; Toole, Bryan P

    2013-09-06

    The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.

  1. CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness*

    Science.gov (United States)

    Grass, G. Daniel; Tolliver, Lauren B.; Bratoeva, Momka; Toole, Bryan P.

    2013-01-01

    The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777–788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer. PMID:23888049

  2. Adaptive control of human action: The role of outcome representations and reward signals

    Directory of Open Access Journals (Sweden)

    Hans eMarien

    2013-09-01

    Full Text Available The present paper aims to advance the understanding of the control of human behavior by integrating two lines of literature that so far have led separate lives. First, one line of literature is concerned with the ideomotor principle of human behavior, according to which actions are represented in terms of their outcomes. The second line of literature mainly considers the role of reward signals in adaptive control. Here, we offer a combined perspective on how outcome representations and reward signals work together to modulate adaptive control processes. We propose that reward signals signify the value of outcome representations and facilitate the recruitment of control resources in situations where behavior needs to be maintained or adapted to attain the represented outcome. We discuss recent research demonstrating how adaptive control of goal-directed behavior may emerge when outcome representations are co-activated with positive reward signals.

  3. Cooperative strategies European perspectives

    CERN Document Server

    Killing, J Peter

    1997-01-01

    Cooperative Strategies: European Perspectives is one of three geographically targeted volumes in which the contributors present the most current research on topics such as advances in theories of cooperative strategies, the formation of cooperative alliances, the dynamics of partner relationships, and the role of information and knowledge in cooperative alliances. Blending conceptual insights with empirical analyses, the contributors highlight commonalities and differences across national, cultural, and trade zones. The chapters in this volume are anchored in a wide set of theoretical approaches, conceptual frameworks, and models, illustrating how rich the area of cooperative strategies is for scholarly inquiry.

  4. Exchange Rate Determination: A Model of the Decisive Role of Central Bank Cooperation and Conflict

    OpenAIRE

    Robin Pope; Reinhard Selten; Sebastian Kube; Johannes Kaiser; Jürgen von Hagen

    2007-01-01

    Opinion is divided on whether it is better to have a single world  money or variable exchange rates.  Pope, Selten and von Hagen (2003)  propose that fresh light would be shed via an analysis that allows  for seven complexity impacts on the exchange rate that are  underplayed (where not entirely absent) from current analyses: 1) the  role of official sector, including its central bank; 2) the numerous  official and private sector goals; 3) the disparate degrees of market  power of dif...

  5. Nuclear knowledge management - The role of the IAEA and its Technical Cooperation programme

    International Nuclear Information System (INIS)

    Ahmad, I.

    2004-01-01

    The paper presents the essentials of sound knowledge management, including NKM: capturing and storing relevant data; conversion of tacit knowledge to explicit knowledge; use information to develop knowledge; networking; building knowledge management culture. An overview is made of the various departments of the IAEA their role from the perspective of KM. It is stated that in addition to consolidating KM-related activities in the departments, there is a need to develop a central focal point, specially to devise strategies for meeting the expected shortages of young professionals and harmonizing and enhancing the training activities. Another area should be strengthening and modernizing INIS and national information services

  6. Cooperation Not Competition: Bihemispheric tDCS and fMRI Show Role for Ipsilateral Hemisphere in Motor Learning.

    Science.gov (United States)

    Waters, Sheena; Wiestler, Tobias; Diedrichsen, Jörn

    2017-08-02

    What is the role of ipsilateral motor and premotor areas in motor learning? One view is that ipsilateral activity suppresses contralateral motor cortex and, accordingly, that inhibiting ipsilateral regions can improve motor learning. Alternatively, the ipsilateral motor cortex may play an active role in the control and/or learning of unilateral hand movements. We approached this question by applying double-blind bihemispheric transcranial direct current stimulation (tDCS) over both contralateral and ipsilateral motor cortex in a between-group design during 4 d of unimanual explicit sequence training in human participants. Independently of whether the anode was placed over contralateral or ipsilateral motor cortex, bihemispheric stimulation yielded substantial performance gains relative to unihemispheric or sham stimulation. This performance advantage appeared to be supported by plastic changes in both hemispheres. First, we found that behavioral advantages generalized strongly to the untrained hand, suggesting that tDCS strengthened effector-independent representations. Second, functional imaging during speed-matched execution of trained sequences conducted 48 h after training revealed sustained, polarity-independent increases in activity in both motor cortices relative to the sham group. These results suggest a cooperative rather than competitive interaction of the two motor cortices during skill learning and suggest that bihemispheric brain stimulation during unimanual skill learning may be beneficial because it harnesses plasticity in the ipsilateral hemisphere. SIGNIFICANCE STATEMENT Many neurorehabilitation approaches are based on the idea that is beneficial to boost excitability in the contralateral hemisphere while attenuating that of the ipsilateral cortex to reduce interhemispheric inhibition. We observed that bihemispheric transcranial direct current stimulation (tDCS) with the excitatory anode either over contralateral or ipsilateral motor cortex

  7. O-Fucose Monosaccharide of Drosophila Notch Has a Temperature-sensitive Function and Cooperates with O-Glucose Glycan in Notch Transport and Notch Signaling Activation*

    Science.gov (United States)

    Ishio, Akira; Sasamura, Takeshi; Ayukawa, Tomonori; Kuroda, Junpei; Ishikawa, Hiroyuki O.; Aoyama, Naoki; Matsumoto, Kenjiroo; Gushiken, Takuma; Okajima, Tetsuya; Yamakawa, Tomoko; Matsuno, Kenji

    2015-01-01

    Notch (N) is a transmembrane receptor that mediates the cell-cell interactions necessary for many cell fate decisions. N has many epidermal growth factor-like repeats that are O-fucosylated by the protein O-fucosyltransferase 1 (O-Fut1), and the O-fut1 gene is essential for N signaling. However, the role of the monosaccharide O-fucose on N is unclear, because O-Fut1 also appears to have O-fucosyltransferase activity-independent functions, including as an N-specific chaperon. Such an enzymatic activity-independent function could account for the essential role of O-fut1 in N signaling. To evaluate the role of the monosaccharide O-fucose modification in N signaling, here we generated a knock-in mutant of O-fut1 (O-fut1R245A knock-in), which expresses a mutant protein that lacks O-fucosyltransferase activity but maintains the N-specific chaperon activity. Using O-fut1R245A knock-in and other gene mutations that abolish the O-fucosylation of N, we found that the monosaccharide O-fucose modification of N has a temperature-sensitive function that is essential for N signaling. The O-fucose monosaccharide and O-glucose glycan modification, catalyzed by Rumi, function redundantly in the activation of N signaling. We also showed that the redundant function of these two modifications is responsible for the presence of N at the cell surface. Our findings elucidate how different forms of glycosylation on a protein can influence the protein's functions. PMID:25378397

  8. US-Soviet cooperation in countering nuclear terrorism: the role of risk reduction centers

    International Nuclear Information System (INIS)

    Nunn, S.; Warner, J.W.

    1987-01-01

    Preventing nuclear terrorism should be high on the agenda of US-Soviet relations. Indeed, the specter of nuclear terrorism, more than any other factor originally prompted and has subsequently sustained the author's deep interest in US-Soviet agreements on establishment of US-Soviet Nuclear Risk Reduction Centers and other important risk-reduction measures. Such centers can play an invaluable role in facilitating discussions aimed at forestalling possible contingencies and in providing a mechanism for dampening escalatory dangers that might otherwise result from any future nuclear terrorism incident. In addition to these crucial substantive functions, the centers could serve to reassure anxious publics that the governments they have entrusted with command authority over tens of thousands of nuclear devices are giving the highest priority to reducing the risk that any of them will ever be used, whether by design or by accident. Nuclear risk Reduction Centers are an idea whose time has come

  9. Environmental Empowerment - the role of Co-operation between Civil Society, Universities and Science Shops

    DEFF Research Database (Denmark)

    Brodersen, Søsser; Jørgensen, Michael Søgaard; Hansen, Anne Grethe

    2006-01-01

    The University based Science Shops were established in the 1970s in the Netherlands, and in Denmark and other countries in the 1980s and 1990s. The aim was to give civil society organisations access to scientific knowledge and to empower citizen participation regarding environmental and social...... improvements. It has recently been suggested that the role of Science Shops should change as a consequence of the stated increasing professionalisation of the Non Governmental Organisations and Civil Society Organisations, and of industry’s increasing interest in introducing environmental management measures....... Increasing internationalisation of the environmental agenda has contributed to this as well as a general acceptance of environmental considerations in industry policy and strategy. However, with departure point in three different Science Shop projects, the article proposes that Science Shops are still...

  10. Interactions of Ras proteins with the plasma membrane and their roles in signaling.

    Science.gov (United States)

    Eisenberg, Sharon; Henis, Yoav I

    2008-01-01

    The complex dynamic structure of the plasma membrane plays critical roles in cellular signaling; interactions with the membrane lipid milieu, spatial segregation within and between cellular membranes and/or targeting to specific membrane-associated scaffolds are intimately involved in many signal transduction pathways. In this review, we focus on the membrane interactions of Ras proteins. These small GTPases play central roles in the regulation of cell growth and proliferation, and their excessive activation is commonly encountered in human tumors. Ras proteins associate with the membrane continuously via C-terminal lipidation and additional interactions in both their inactive and active forms; this association, as well as the targeting of specific Ras isoforms to plasma membrane microdomains and to intracellular organelles, have recently been implicated in Ras signaling and oncogenic potential. We discuss biochemical and biophysical evidence for the roles of specific domains of Ras proteins in mediating their association with the plasma membrane, and consider the potential effects of lateral segregation and interactions with membrane-associated protein assemblies on the signaling outcomes.

  11. The regulatory role of heparin on c-Met signaling in hepatocellular carcinoma cells.

    Science.gov (United States)

    İşcan, Evin; Güneş, Aysim; Korhan, Peyda; Yılmaz, Yeliz; Erdal, Esra; Atabey, Neşe

    2017-06-01

    The role of heparin as an anticoagulant is well defined; however, its role in tumorigenesis and tumor progression is not clear yet. Some studies have shown that anticoagulant treatment in cancer patients improve overall survival, however, recent clinical trials have not shown a survival benefit in cancer patients receiving heparin treatment. In our previous studies we have shown the inhibitory effects of heparin on Hepatocyte Growth Factor (HGF)-induced invasion and migration in hepatocellular carcinoma (HCC) cells. In this study, we showed the differential effects of heparin on the behaviors of HCC cells based on the presence or absence of HGF. In the absence of HGF, heparin activated HGF/c-Met signaling and promoted motility and invasion in HCC cells. Heparin treatment led to c-Met receptor dimerization and activated c-Met signaling in an HGF independent manner. Heparin-induced c-Met activation increased migration and invasion through ERK1/2, early growth response factor 1 (EGR1) and Matrix Metalloproteinases (MMP) axis. Interestingly, heparin modestly decreased the proliferation of HCC cells by inhibiting activatory phosphorylation of Akt. The inhibition of c-Met signaling reversed heparin-induced increase in motility and invasion and, proliferation inhibition. Our study provides a new perspective into the role of heparin on c-Met signaling in HCC.

  12. The Changing Role of International Cooperation in Developing Countries (as They Develop): A Case Study of Skills Development Policies in Peru

    Science.gov (United States)

    Jaramillo, Miguel

    2012-01-01

    A focus on the changes in the relationship between international cooperation and local actors in the skills development field in Peru as the country strengthened its financial position in the last two decades allows us to examine the role of the economic factor in these changes. The paper argues that indeed there is an association between the two.…

  13. The impact of social value orientation on affective commitment : The moderating role of work group cooperative climate, and of climate strength

    NARCIS (Netherlands)

    Bogaert, S.; Boone, Chr.; van Witteloostuijn, A.

    2012-01-01

    We investigate the moderating role of an individual's social value orientation (which refers to self- versus other-regarding preferences) and of climate strength (which refers to the extent of agreement among group members on group norms and values) on the relationship between work group cooperative

  14. AKT-independent PI3-K signaling in cancer – emerging role for SGK3

    Directory of Open Access Journals (Sweden)

    Bruhn MA

    2013-08-01

    Full Text Available Maressa A Bruhn,1,6 Richard B Pearson,1–4 Ross D Hannan,1–5 Karen E Sheppard1–3 1Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 2Sir Peter MacCallum Department of Oncology, 3Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia; 4Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; 5School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia; 6School of Biological Sciences, Flinders University, Bedford Park, South Australia, Australia Abstract: The phosphoinositide 3-kinase (PI3-K signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling. Keywords: SGK3, AKT, PI3-kinase, mTOR, cancer

  15. MicroRNA Roles in the NF-κB Signaling Pathway during Viral Infections

    Directory of Open Access Journals (Sweden)

    Zeqian Gao

    2014-01-01

    Full Text Available NF-κB signaling network is a crucial component of innate immunity. miRNAs are a subtype of small noncoding RNAs, involved in regulation of gene expression at the posttranscriptional level. Increasing evidence has emerged that miRNAs play an important role in regulation of NF-κB signaling pathway during viral infections. Both host and viral miRNAs are attributed to modulation of NF-κB activity, thus affecting viral infection and clearance. Understandings of the mechanisms of these miRNAs will open a direction for development of novel antivirus drugs.

  16. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    Energy Technology Data Exchange (ETDEWEB)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-15

    Effects of {gamma}-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following {gamma}-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by {gamma}-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by {gamma} -irradiation in all cell lines. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by {gamma}-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in {gamma}-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by {gamma} -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of {gamma}-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In {gamma}-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of {gamma}-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The

  17. Investigation on the role of IGF-1 signal transduction in the biological radiation responses

    International Nuclear Information System (INIS)

    Jung, U Hee; Jo, Sung Kee; Park, Hae Ran; Oh, Soo Jin; Cho, Eun Hee; Eom, Hyun Soo; Ju, Eun Jin

    2009-05-01

    Effects of γ-irradiation on the IGF-1 related gene expressions and activations in various cell lines - Various expression patterns of IGF-1 and IGF-1R following γ-irradiation were observed according to the cell lines - The increased expressions of IGF-1 and IGF-1R were observed in Balb/3T3 and NIH/3T3 cells - Among the IGF-1 downstream signaling molecules, the phosphorylated ERK5 were not changed by γ-irradiation in all three examined cell lines, whereas the phosphorylated p65 were increased by γ -irradiation in all cell lines. The role of IGF-1 and p38 signaling in γ-irradiated mouse embryonic fibroblast (MEF) cells - In MEF cells, IGF-1 signaling molecules were decreased and p21/phosphorylated p38 were increased by γ-irradiation - The experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 signaling is involved but not essential in radiation-induced cell growth arrest and senescence and that p38 MAP kinase play a important role in this cellular radiation response. The role of IGF-1 and p38 signaling in γ-irradiated mouse fibroblast (NIH/3T3) cell - In NIH/3T3 cells, IGF-1 signaling molecules and p21/phosphorylated p38 were increased by γ -irradiation. - However, the experiments with IGF-1R inhibitor (AG1024) and p38 inhibitor (SB203580) revealed that IGF-1 and p38 signaling do not play a crucial role in radiation-induced cell growth arrest and senescence in NIH/3T3 cells. Effects of γ-irradiation on the expressions and activations on the genes related to the IGF-1 signaling in mouse tissues - In γ-irradiated mice, the increased expressions of IGF-1 and IGF-1R were observed in the lung and kidney at 2 months after irradiation, and in all the tissues examined (lung, liver and kidney) at 6 months after irradiation. - In the lung of γ-irradiated mice at 6 months after irradiation, the increases of IGF-1R, phosphorylated FOXO3a, p65, p38, p21 were observed. - The patterns of altered expressions showed significant

  18. Redox modification of caveolar proteins in the cardiovascular system- role in cellular signalling and disease.

    Science.gov (United States)

    Bubb, Kristen J; Birgisdottir, Asa Birna; Tang, Owen; Hansen, Thomas; Figtree, Gemma A

    2017-08-01

    Rapid and coordinated release of a variety of reactive oxygen species (ROS) such as superoxide (O 2 .- ), hydrogen peroxide (H 2 O 2 ) and peroxynitrite, in specific microdomains, play a crucial role in cell signalling in the cardiovascular system. These reactions are mediated by reversible and functional modifications of a wide variety of key proteins. Dysregulation of this oxidative signalling occurs in almost all forms of cardiovascular disease (CVD), including at the very early phases. Despite the heavily publicized failure of "antioxidants" to improve CVD progression, pharmacotherapies such as those targeting the renin-angiotensin system, or statins, exert at least part of their large clinical benefit via modulating cellular redox signalling. Over 250 proteins, including receptors, ion channels and pumps, and signalling proteins are found in the caveolae. An increasing proportion of these are being recognized as redox regulated-proteins, that reside in the immediate vicinity of the two major cellular sources of ROS, nicotinamide adenine dinucleotide phosphate oxidase (Nox) and uncoupled endothelial nitric oxide synthase (eNOS). This review focuses on what is known about redox signalling within the caveolae, as well as endogenous protective mechanisms utilized by the cell, and new approaches to targeting dysregulated redox signalling in the caveolae as a therapeutic strategy in CVD. Copyright © 2017. Published by Elsevier Inc.

  19. The Role of Verbal and Nonverbal Communication in a Two-Person, Cooperative Manipulation Task

    Directory of Open Access Journals (Sweden)

    Sarangi P. Parikh

    2014-01-01

    Full Text Available Motivated by the differences between human and robot teams, we investigated the role of verbal communication between human teammates as they work together to move a large object to a series of target locations. Only one member of the group was told the target sequence by the experimenters, while the second teammate had no target knowledge. The two experimental conditions we compared were haptic-verbal (teammates are allowed to talk and haptic only (no talking allowed. The team’s trajectory was recorded and evaluated. In addition, participants completed a NASA TLX-style postexperimental survey which gauges workload along 6 different dimensions. In our initial experiment we found no significant difference in performance when verbal communication was added. In a follow-up experiment, using a different manipulation task, we did find that the addition of verbal communication significantly improved performance and reduced the perceived workload. In both experiments, for the haptic-only condition, we found that a remarkable number of groups independently improvised common haptic communication protocols (CHIPs. We speculate that such protocols can be substituted for verbal communication and that the performance difference between verbal and nonverbal communication may be related to how easy it is to distinguish the CHIPs from motions required for task completion.

  20. Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma

    Science.gov (United States)

    Qin, Z; Dai, L; Bratoeva, M; Slomiany, MG; Toole, BP; Parsons, C

    2013-01-01

    The Kaposi’s sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), for which cytotoxic chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these tumors to chemotherapy. The membrane-bound glycoprotein emmprin (CD147) enhances chemoresistance in tumors through effects on transporter expression, trafficking and interactions. Interactions between hyaluronan and hyaluronan receptors on the cell surface also facilitate emmprin-mediated chemoresistance. Whether emmprin or hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated malignancies is unknown. Using human PEL tumor cells, we found that PEL sensitivity to chemotherapy is directly proportional to expression of emmprin, the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and a drug transporter known as the breast cancer resistance protein/ABCG2 (BCRP), and that emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by chemotherapy. Finally, disruption of hyaluronan-receptor interactions using small hyaluronan oligosaccharides reduces expression of emmprin and BCRP while sensitizing PEL cells to chemotherapy. Collectively, these data support interdependent roles for emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL. PMID:21660043

  1. Cooperative role of calnexin and TigA in Aspergillus oryzae glycoprotein folding.

    Science.gov (United States)

    Wang, Ning; Seko, Akira; Takeda, Yoichi; Kikuma, Takashi; Ito, Yukishige

    2015-10-01

    Calnexin (CNX), known as a lectin chaperone located in the endoplasmic reticulum (ER), specifically recognizes G1M9GN2-proteins and facilitates their proper folding with the assistance of ERp57 in mammalian cells. However, it has been left unidentified how CNX works in Aspergillus oryzae, which is a filamentous fungus widely exploited in biotechnology. In this study, we found that a protein disulfide isomerase homolog TigA can bind with A. oryzae CNX (AoCNX), which was revealed to specifically recognize monoglucosylated glycans, similarly to CNX derived from other species, and accelerate the folding of G1M9GN2-ribonuclease (RNase) in vitro. For refolding experiments, a homogeneous monoglucosylated high-mannose-type glycoprotein G1M9GN2-RNase was chemoenzymatically synthesized from G1M9GN-oxazoline and GN-RNase. Denatured G1M9GN2-RNase was refolded with highest efficiency in the presence of both soluble form of AoCNX and TigA. TigA contains two thioredoxin domains with CGHC motif, mutation analysis of which revealed that the one in N-terminal regions is involved in binding to AoCNX, while the other in catalyzing protein refolding. The results suggested that in glycoprotein folding process of A. oryzae, TigA plays a similar role as ERp57 in mammalian cells, as a partner protein of AoCNX. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Role of Neurokinin 3 Receptor Signaling in Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Obata, Kyoichi; Shimo, Tsuyoshi; Okui, Tatsuo; Matsumoto, Kenichi; Takada, Hiroyuki; Takabatake, Kiyofumi; Kunisada, Yuki; Ibaragi, Soichiro; Yoshioka, Norie; Kishimoto, Koji; Nagatsuka, Hitoshi; Sasaki, Akira

    2017-11-01

    The neurokinin 3 receptor (NK-3R) is differentially expressed in the central nervous system including cases of human oral squamous cell carcinoma. However, the role of NK-3R signaling in oral squamous cell carcinoma is not well known. NK-3R expression in surgically resected oral squamous cell carcinoma was examined immunohistochemically and the strength of the expression was quantified. We evaluated the function of NK-3R signaling using NK-3R antagonist in human oral squamous cell carcinoma bone invasion mouse model. NK-3R was significantly expressed in tumor cells that had invaded the bone matrix compared to the oral side tumor cells. SB222200, a selective antagonist of NK-3R, significantly suppressed the radiographic osteolytic lesion and tumorigenesis. NK-3R signaling is a potential target for the treatment of oral squamous cell carcinoma in cases of bone destruction. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Role of Ubiquitylation in Controlling Suppressor of Cytokine Signalling 3 (SOCS3 Function and Expression

    Directory of Open Access Journals (Sweden)

    Jamie J. L. Williams

    2014-05-01

    Full Text Available The realisation that unregulated activation of the Janus kinase–signal transducer and activator of transcription (JAK–STAT pathway is a key driver of a wide range of diseases has identified its components as targets for therapeutic intervention by small molecule inhibitors and biologicals. In this review, we discuss JAK-STAT signalling pathway inhibition by the inducible inhibitor “suppressor of cytokine signaling 3 (SOCS3, its role in diseases such as myeloproliferative disorders, and its function as part of a multi-subunit E3 ubiquitin ligase complex. In addition, we highlight potential applications of these insights into SOCS3-based therapeutic strategies for management of conditions such as vascular re-stenosis associated with acute vascular injury, where there is strong evidence that multiple processes involved in disease progression could be attenuated by localized potentiation of SOCS3 expression levels.

  4. The role of Na,K-ATPase/Src-kinase signaling pathway in the vascular wall contaction

    DEFF Research Database (Denmark)

    Bouzinova, Elena

    Aim: Na,K-ATPase is essential for maintaining the transmembrane ion gradient and might initiate various intracellular signaling. These signals possibly act through a modification of the local ion concentrations or via Src-kinase activation. It is known that inhibition of the α-2 isoform of Na......,K-ATPase by ouabain elevates blood pressure. Consequently, ouabain was shown to potentiate arterial contraction in vitro. In contrast, we have demonstrated that siRNA-induced down-regulation of the α-2 isoform Na,K-ATPase expression reduced arterial sensitivity to agonist stimulation and prevented the effect......) phosphorylation assay. Down-regulation of the α-2 isoform Na,K-ATPase prevented the inhibitory effect of Src inhibitors on arterial contraction. Conclusions: The pro-contractile action of ouabain-sensitive Na,K-ATPase inhibition is associated with Src-kinase inhibition suggesting the role of this signaling...

  5. The role of MAPK signaling in patterning and establishing axial symmetry in the gastropod Haliotis asinina

    DEFF Research Database (Denmark)

    Koop, Demian; Richards, Gemma S; Wanninger, Andreas

    2007-01-01

    , the embryo begins to gastrulate and assumes a bilateral cleavage pattern. Here we inhibit MAPK activation in 3D with U0126 and examine its effect on the formation and patterning of the trochophore, using a suite of territory-specific markers. The head (pretrochal) region appears to maintain quadri...... (D) quadrant is intimately linked with body plan organization and in equally cleaving gastropods occurs when one of the vegetal macromeres makes contact with overlying micromeres and receives an inductive signal that activates a MAPK signaling cascade. Following the induction of the 3D macromere......-radial symmetry in U0126-treated embryos, supporting a role for MAPK signaling in 3D in establishing dorsoventral polarity in this region. Posterior (posttrochal) structures - larval musculature, shell and foot--fail to develop in MAPK inhibited trochophores. Inhibition of 3D specification by an alternative...

  6. The EBI2 signalling pathway plays a role in cellular crosstalk between astrocytes and macrophages.

    Science.gov (United States)

    Rutkowska, Aleksandra; O'Sullivan, Sinead A; Christen, Isabelle; Zhang, Juan; Sailer, Andreas W; Dev, Kumlesh K

    2016-05-11

    EBI2 is a G protein-coupled receptor activated by oxysterol 7α, 25-dihydroxycholesterol (7α25HC) and regulates T cell-dependant antibody response and B cell migration. We recently found EBI2 is expressed in human astrocytes, regulates intracellular signalling and modulates astrocyte migration. Here, we report that LPS treatment of mouse astrocytes alters mRNA levels of EBI2 and oxysterols suggesting that the EBI2 signalling pathway is sensitive to LPS-mediated immune challenge. We also find that conditioned media obtained from LPS-stimulated mouse astrocytes induces macrophage migration, which is inhibited by the EBI2 antagonist NIBR189. These results demonstrate a role for the EBI2 signalling pathway in astrocytes as a sensor for immune challenge and for communication with innate immune cells such as macrophages.

  7. Building visual identity of scientific and research units and the role of visualization in cooperation with business

    Directory of Open Access Journals (Sweden)

    Alfreda Kamińska

    2014-12-01

    Full Text Available The need for commercialization of scientific research leads to the necessity of changing the orientation of scientific-research units to marketing orientation, which is characterized by, among others, conducting research aimed at learning the clients’ needs and building better communication with the recipients. What is an important element of a unit’s marketing communication is its visual identity system, which the recipients use to build their opinion and their picture of the unit. The goal of this article is an attempt to define the key rules of designing visual identity of scientific and research institutions, as well as presenting the role of visualization in their cooperation with business. In the article the notions of image, identity, corporate identity and visual identity are subject to analysis. The article also presents the significance of visualization in the functioning of research and scientific units, elements of visual identity system and the rules of designing visual identity of scientific and research institutions. An analysis of chosen research-scientific units was carried out with regard to visualization.

  8. Role of cooperative groups and funding source in clinical trials supporting guidelines for systemic therapy of breast cancer.

    Science.gov (United States)

    Tibau, Ariadna; Anguera, Geòrgia; Andrés-Pretel, Fernando; Templeton, Arnoud J; Seruga, Bostjan; Barnadas, Agustí; Amir, Eitan; Ocana, Alberto

    2018-03-13

    Clinical research is conducted by academia, cooperative groups (CGs) or pharmaceutical industry. Here, we evaluate the role of CGs and funding sources in the development of guidelines for breast cancer therapies. We identified 94 studies. CGs were involved in 28 (30%) studies while industry either partially or fully sponsored 64 (68%) studies. The number of industry funded studies increased over time (from 0% in 1976 to 100% in 2014; p for trend = 0.048). Only 10 (11%) government or academic studies were identified. Studies conducted by GCs included a greater number of subjects (median 448 vs. 284; p = 0.015), were more common in the neo/adjuvant setting ( p funding was associated with higher likelihood of positive outcomes favoring the sponsored experimental arm ( p = 0.013) but this relationship was not seen for CG-sponsored trials ( p = 0.53). ASCO, ESMO, and NCCN guidelines were searched to identify systemic anti-cancer therapies for early-stage and metastatic breast cancer. Trial characteristics and outcomes were collected. We identified sponsors and/or the funding source(s) and determined whether CGs, industry, or government or academic institutions were involved. Chi-square tests were used for comparison between studies. Industry funding is present in the majority of studies providing the basis for which recommendations about treatment of breast cancer are made. Industry funding, but not CG-based funding, was associated with higher likelihood of positive outcomes in clinical studies supporting guidelines for systemic therapy.

  9. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

    International Nuclear Information System (INIS)

    Dontu, Gabriela; Jackson, Kyle W; McNicholas, Erin; Kawamura, Mari J; Abdallah, Wissam M; Wicha, Max S

    2004-01-01

    Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. These studies

  10. The Protective Role of Vitamin D Signaling in Non-Melanoma Skin Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bikle, Daniel D., E-mail: daniel.bikle@ucsf.edu; Jiang, Yan [Department of Medicine and Endocrine, Research Unit and Department of Dermatology, VA Medical Center, University of California San Francisco, 4150 Clement St (111N), San Francisco, CA 94121 (United States)

    2013-11-05

    Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation of keratinocytes, the major cell in the epidermis from which NMSC are derived, is well known. However, recent findings that mice lacking the VDR are predisposed to skin cancer has brought to the fore the question of how the VDR is protective. In this review we will look first at the role of vitamin D signaling in regulating the proliferation and differentiation of keratinocytes. We will examine two pathways, β-catenin (CTNNB) and hedgehog (HH), that are regulated by vitamin D signaling and may contribute to the dysregulated proliferation and differentiation in the absence of VDR. We will then examine the failure of VDR deficient keratinocytes to repair DNA damaged by UVB. Finally we will examine the change in long non-coding RNA (LncRNA) expression in VDR null keratinocytes that in other cells is associated with malignant transformation, a potential newly appreciated mechanism by which vitamin D signaling is protective against NMSC.

  11. The Protective Role of Vitamin D Signaling in Non-Melanoma Skin Cancer

    International Nuclear Information System (INIS)

    Bikle, Daniel D.; Jiang, Yan

    2013-01-01

    Although the epidemiologic evidence that adequate vitamin D nutrition protects against non-melanoma skin cancer (NMSC) is limited, recent evidence that the vitamin D receptor (VDR) is protective is compelling. The role of vitamin D signaling in limiting the proliferation while promoting the differentiation of keratinocytes, the major cell in the epidermis from which NMSC are derived, is well known. However, recent findings that mice lacking the VDR are predisposed to skin cancer has brought to the fore the question of how the VDR is protective. In this review we will look first at the role of vitamin D signaling in regulating the proliferation and differentiation of keratinocytes. We will examine two pathways, β-catenin (CTNNB) and hedgehog (HH), that are regulated by vitamin D signaling and may contribute to the dysregulated proliferation and differentiation in the absence of VDR. We will then examine the failure of VDR deficient keratinocytes to repair DNA damaged by UVB. Finally we will examine the change in long non-coding RNA (LncRNA) expression in VDR null keratinocytes that in other cells is associated with malignant transformation, a potential newly appreciated mechanism by which vitamin D signaling is protective against NMSC

  12. A role for nitric oxide-driven retrograde signaling in the consolidation of a fear memory

    Directory of Open Access Journals (Sweden)

    Kathie A Overeem

    2010-02-01

    Full Text Available In both invertebrate and vertebrate models of synaptic plasticity, signaling via the putative “retrograde messenger” nitric oxide (NO has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. However, while in vitro models of synaptic plasticity have consistently implicated NO signaling in linking postsynaptic induction mechanisms with accompanying presynaptic changes, a convincing role of such “retrograde signaling” in mammalian memory formation has remained elusive. Using auditory Pavlovian fear conditioning, we show that synaptic plasticity and NO signaling in the lateral nucleus of the amygdala (LA regulate the expression of the ERK-driven immediate early gene early growth response gene I (EGR-1 in regions of the auditory thalamus that are presynaptic to the LA. Further, antisense knockdown of EGR-1 in the auditory thalamus impairs both fear memory consolidation and the training-induced elevation of two presynaptically localized proteins in the LA. These findings indicate that synaptic plasticity and NO signaling in the LA during auditory fear conditioning promote alterations in ERK-driven gene expression in auditory thalamic neurons that are required for both fear memory consolidation as well as presynaptic correlates of fear memory formation in the LA, and provide general support for a role of NO as a “retrograde signal” in mammalian memory formation.

  13. Performance of Cooperative Learning Groups in a Postgraduate Education Research Methodology Course: The Role of Social Interdependence

    Science.gov (United States)

    Onwuegbuzie, Anthony J.; Collins, Kathleen M. T.; Jiao, Qun G.

    2009-01-01

    This study investigated the degree that social interdependence predicted the achievement of 26 cooperative learning groups. Social interdependence was assessed in terms of postgraduate students' individual orientation (that is, cooperative, competitive, and individualistic). Participants were 84 postgraduate students enrolled in an…

  14. Cooperative Group Performance in Graduate Research Methodology Courses: The Role of Study Coping and Examination-Taking Coping Strategies

    Science.gov (United States)

    Jiao, Qun G.; Collins, Kathleen M. T.; Onwuegbuzie, Anthony J.

    2013-01-01

    This study seeks to examine the extent to which cooperative group members' levels of coping strategies (study and examination-taking coping strategies) and the degree that heterogeneity (variability of study coping strategies and examination-taking coping strategies) predict cooperative groups' levels of achievement in research methodology…

  15. The role of cGMP signalling in regulating life cycle progression of Plasmodium.

    Science.gov (United States)

    Hopp, Christine S; Bowyer, Paul W; Baker, David A

    2012-08-01

    The 3'-5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) is the main mediator of cGMP signalling in the malaria parasite. This article reviews the role of PKG in Plasmodium falciparum during gametogenesis and blood stage schizont rupture, as well as the role of the Plasmodium berghei orthologue in ookinete differentiation and motility, and liver stage schizont development. The current views on potential effector proteins downstream of PKG and the mechanisms that may regulate cyclic nucleotide levels are presented. Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  16. Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

    OpenAIRE

    Lappano, Rosamaria; Rigiracciolo, Damiano; De Marco, Paola; Avino, Silvia; Cappello, Anna Rita; Rosano, Camillo; Maggiolini, Marcello; De Francesco, Ernestina Marianna

    2016-01-01

    G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GP...

  17. Role of Translocted Signals in Regulating Root Development and Nutrient Uptake in Legumes

    Energy Technology Data Exchange (ETDEWEB)

    Atkins, C. A. [School of Plant Biology, University of Western Australia, Crawley, WA (Australia)

    2013-11-15

    Uptake of nutrients is achieved through the expression and activity of specific carrier/transporter mechanisms localized in the root system and distributed as a consequence of the development of the architecture of the system. Both root system development and the nutrient transport mechanisms are responsive to environmental factors that include nutrient supply and availability, water supply, salinity, soil acidity and compaction together with a wide range of biotic stresses. The response to each may be regulated at the molecular level by both local and systemic signals. These signals include the classical plant growth regulators but also low molecular weight compounds such as sugars and amino acids as well as macromolecules, including peptides, proteins and nucleic acids. Among the latter, recent research has shown that small RNA species and especially small interfering RNAs (siRNA) and microRNAs (miRNA) are potent and effective regulators of gene expression which, in the context of root development as well as nutrient uptake, have central and critical roles. Systemic (translocated) signals that specifically regulate root development and function are less well defined but analyses of phloem exudate in species of lupin (Lupinus albus and L. angustifolius) and species of Brassica and cucurbits have demonstrated that a wide range of macromolecules, including miRNAs, are present and potentially translocated from source organs (principally leaves) to sinks (shoot apical meristems, developing fruits and seeds, roots and nodules). While specific signaling roles for many of these macromolecules are yet to be discovered there are some that have been documented and their regulatory activity in organ development and functioning, as well as in nutrition, confirmed. The following article provides an up to date review and presents the results of recent research using lupin with emphasis on the analysis of small RNAs and their likely role(s) in regulation of root development and

  18. The Role of Thyroid Hormone Signaling in the Prevention of Digestive System Cancers

    Directory of Open Access Journals (Sweden)

    Rosalia C. M. Simmen

    2013-08-01

    Full Text Available Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin αVβ3 receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals.

  19. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

    Directory of Open Access Journals (Sweden)

    Leilei Zhong

    2015-08-01

    Full Text Available Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA. Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP/Transforming growth factor-β (TGFβ, Parathyroid hormone-related peptide (PTHrP, Indian hedgehog (IHH, Fibroblast growth factor (FGF, Insulin like growth factor (IGF and Hypoxia-inducible factor (HIF. This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC repair, and improves understanding of the disease stages and cellular responses within an OA articular joint.

  20. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling.

    Science.gov (United States)

    Wang, Ying; Branicky, Robyn; Noë, Alycia; Hekimi, Siegfried

    2018-04-18

    Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling. © 2018 Wang et al.

  1. EphA4 Regulates the Balance between Self-Renewal and Differentiation of Radial Glial Cells and Intermediate Neuronal Precursors in Cooperation with FGF Signaling.

    Directory of Open Access Journals (Sweden)

    Qingfa Chen

    Full Text Available In mouse cerebral corticogenesis, neurons are generated from radial glial cells (RGCs or from their immediate progeny, intermediate neuronal precursors (INPs. The balance between self-renewal of these neuronal precursors and specification of cell fate is critical for proper cortical development, but the signaling mechanisms that regulate this progression are poorly understood. EphA4, a member of the receptor tyrosine kinase superfamily, is expressed in RGCs during embryogenesis. To illuminate the function of EphA4 in RGC cell fate determination during early corticogenesis, we deleted Epha4 in cortical cells at E11.5 or E13.5. Loss of EphA4 at both stages led to precocious in vivo RGC differentiation toward neurogenesis. Cortical cells isolated at E14.5 and E15.5 from both deletion mutants showed reduced capacity for neurosphere formation with greater differentiation toward neurons. They also exhibited lower phosphorylation of ERK and FRS2α in the presence of FGF. The size of the cerebral cortex at P0 was smaller than that of controls when Epha4 was deleted at E11.5 but not when it was deleted at E13.5, although the cortical layers were formed normally in both mutants. The number of PAX6-positive RGCs decreased at later developmental stages only in the E11.5 Epha4 deletion mutant. These results suggest that EphA4, in cooperation with an FGF signal, contributes to the maintenance of RGC self-renewal and repression of RGC differentiation through the neuronal lineage. This function of EphA4 is especially critical and uncompensated in early stages of corticogenesis, and thus deletion at E11.5 reduces the size of the neonatal cortex.

  2. A positive role of cadherin in Wnt/β-catenin signalling during epithelial-mesenchymal transition.

    Directory of Open Access Journals (Sweden)

    Sara Howard

    Full Text Available The Wnt/β-catenin signalling pathway shares a key component, β-catenin, with the cadherin-based adhesion system. The signalling function of β-catenin is conferred by a soluble cytoplasmic pool that is unstable in the absence of a Wnt signal, whilst the adhesion function is based on a cadherin-bound, stable pool at the membrane. The cadherin complex is dynamic, allowing for cell-cell rearrangements such as epithelial-mesenchymal transition (EMT, where the complex turns over through internalisation. Potential interplay between the two pools remains poorly understood, but cadherins are generally considered negative regulators of Wnt signalling because they sequester cytoplasmic β-catenin. Here we explore how cellular changes at EMT affect the signalling capacity of β-catenin using two models of EMT: hepatocyte growth factor (HGF treatment of MDCK cells, and gastrulation in embryonic development. We show that EMT not only provides a pool of signalling-competent β-catenin following internalisation of cadherin, but also significantly facilitates activation of the Wnt pathway in response to both Wnt signals and exogenous β-catenin. We further demonstrate that availability of β-catenin in the cytoplasm does not necessarily correlate with Wnt/β-catenin pathway activity, since blocking endocytosis or depleting endogenous cadherin abolishes pathway activation despite the presence of β-catenin in the cytoplasm. Lastly we present data suggesting that cadherins are required for augmented activation of the Wnt/β-catenin pathway in vivo. This suggests that cadherins play a crucial role in β-catenin-dependent transcription.

  3. International cooperation

    International Nuclear Information System (INIS)

    2008-01-01

    In this chapter international cooperation of the Division for Radiation Safety, NPP Decommissioning and Radwaste Management of the VUJE, a. s. is presented. Very important is cooperation with the International Atomic Energy Agency. This cooperation has various forms - national and regional projects of technical cooperation, coordinated research activities, participation of our experts in preparation of the IAEA documentation etc.

  4. An unexplored role for Peroxiredoxin in exercise-induced redox signalling?

    Directory of Open Access Journals (Sweden)

    Alex J. Wadley

    2016-08-01

    Full Text Available Peroxiredoxin (PRDX is a ubiquitous oxidoreductase protein with a conserved ionised thiol that permits catalysis of hydrogen peroxide (H2O2 up to a million times faster than any thiol-containing signalling protein. The increased production of H2O2 within active tissues during exercise is thought to oxidise conserved cysteine thiols, which may in turn facilitate a wide variety of physiological adaptations. The precise mechanisms linking H2O2 with the oxidation of signalling thiol proteins (phosphates, kinases and transcription factors are unclear due to these proteins' low reactivity with H2O2 relative to abundant thiol peroxidases such as PRDX. Recent work has shown that following exposure to H2O2 in vitro, the sulfenic acid of the PRDX cysteine can form mixed disulphides with transcription factors associated with cell survival. This implicates PRDX as an ‘active’ redox relay in transmitting the oxidising equivalent of H2O2 to downstream proteins. Furthermore, under oxidative stress, PRDX can form stable oxidised dimers that can be secreted into the extracellular space, potentially acting as an extracellular ‘stress’ signal. There is extensive literature assessing non-specific markers of oxidative stress in response to exercise, however the PRDX catalytic cycle may offer a more robust approach for measuring changes in redox balance following exercise. This review discusses studies assessing PRDX-mediated cellular signalling and integrates the recent advances in redox biology with investigations that have examined the role of PRDX during exercise in humans and animals. Future studies should explore the role of PRDX as a key regulator of peroxide mediated-signal transduction during exercise in humans.

  5. Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors

    Directory of Open Access Journals (Sweden)

    Antonio eLuchicchi

    2014-10-01

    Full Text Available Acetylcholine (ACh signaling underlies specific aspects of cognitive functions and behaviors, including attention, learning, memory and motivation. Alterations in ACh signaling are involved in the pathophysiology of multiple neuropsychiatric disorders. In the central nervous system, ACh transmission is mainly guaranteed by dense innervation of select cortical and subcortical regions from disperse groups of cholinergic neurons within the basal forebrain (e.g. diagonal band, medial septal, nucleus basalis and the pontine-mesencephalic nuclei, respectively. Despite the fundamental role of cholinergic signaling in the CNS and the long standing knowledge of the organization of cholinergic circuitry, remarkably little is known about precisely how ACh release modulates cortical and subcortical neural activity and the behaviors these circuits subserve. Growing interest in cholinergic signaling in the CNS focuses on the mechanism(s of action by which endogenously released ACh regulates cognitive functions, acting as a neuromodulator and /or as a direct transmitter via nicotinic and muscarinic receptors. The development of optogenetic techniques has provided a valuable toolbox with which we can address these questions, as it allows the selective manipulation of the excitability of cholinergic inputs to the diverse array of cholinergic target fields within cortical and subcortical domains. Here, we review recent papers that use the light-sensitive opsins in the cholinergic system to elucidate the role of ACh in circuits related to attention and emotionally salient behaviors. In particular, we highlight recent optogenetic studies which have tried to disentangle the precise role of ACh in the modulation of cortical-, hippocampal- and striatal-dependent functions.

  6. The Role of MAPK Modules and ABA during Abiotic Stress Signaling

    KAUST Repository

    Zélicourt, Axel de

    2016-05-01

    To respond to abiotic stresses, plants have developed specific mechanisms that allow them to rapidly perceive and respond to environmental changes. The phytohormone abscisic acid (ABA) was shown to be a pivotal regulator of abiotic stress responses in plants, triggering major changes in plant physiology. The ABA core signaling pathway largely relies on the activation of SnRK2 kinases to mediate several rapid responses, including gene regulation, stomatal closure, and plant growth modulation. Mitogen-activated protein kinases (MAPKs) have also been implicated in ABA signaling, but an entire ABA-activated MAPK module was uncovered only recently. In this review, we discuss the evidence for a role of MAPK modules in the context of different plant ABA signaling pathways. Abiotic stresses impact average yield in agriculture by more than 50% globally.Since ABA is a key regulator of abiotic stress responses, an understanding of its functioning at the molecular level is essential for plant breeding. Although the ABA core signaling pathway has been unraveled, several downstream events are still unclear.MAPKs are involved in most plant developmental stages and in response to stresses. Several members of the MAPK family were shown to be directly or indirectly activated by the ABA core signaling pathway.Recent evidence shows that the complete MAP3K17/18-MKK3-MPK1/2/7/14 module is under the control of ABA, whose members are under the transcriptional and post-translational control of the ABA core signaling pathway. © 2016 Elsevier Ltd.

  7. One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

    Directory of Open Access Journals (Sweden)

    Joshua M. Corbin

    2016-07-01

    Full Text Available Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR plays an essential role in the establishment and progression of prostate cancer (PCa, and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context.

  8. One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

    Science.gov (United States)

    Corbin, Joshua M.; Ruiz-Echevarría, Maria J.

    2016-01-01

    Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context. PMID:27472325

  9. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

    Directory of Open Access Journals (Sweden)

    Brian C. Shonesy

    2014-12-01

    Full Text Available Summary: Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.

  10. The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy.

    Science.gov (United States)

    Semba, Richard D; Huang, Hu; Lutty, Gerard A; Van Eyk, Jennifer E; Hart, Gerald W

    2014-04-01

    Diabetic retinopathy is a leading cause of blindness worldwide. Despite laser and surgical treatments, antiangiogenic and other therapies, and strict metabolic control, many patients progress to visual impairment and blindness. New insights are needed into the pathophysiology of diabetic retinopathy in order to develop new methods to improve the detection and treatment of disease and the prevention of blindness. Hyperglycemia and diabetes result in increased flux through the hexosamine biosynthetic pathway, which, in turn, results in increased PTM of Ser/Thr residues of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). O-GlcNAcylation is involved in regulation of many nuclear and cytoplasmic proteins in a manner similar to protein phosphorylation. Altered O-GlcNAc signaling has been implicated in the pathogenesis of diabetes and may play an important role in the pathogenesis of diabetic retinopathy. The goal of this review is to summarize the biology of the hexosamine biosynthesis pathway and O-GlcNAc signaling, to present the current evidence for the role of O-GlcNAc signaling in diabetes and diabetic retinopathy, and to discuss future directions for research on O-GlcNAc in the pathogenesis of diabetic retinopathy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Studies of transformational leadership in consumer service: leadership trust and the mediating-moderating role of cooperative conflict management.

    Science.gov (United States)

    Yang, Yi-Feng

    2012-02-01

    This is the third in a series of studies evaluating how transformational leadership is associated with related variables such as job satisfaction, change commitment, leadership trust, cooperative conflict management, and market orientation. The present paper evaluates the effects of transformational leadership and cooperative conflict management along with their mediating and moderating of leadership trust in the life insurance industry for two sample groups, sales managers and sales employees. The main effect of leadership trust was mediated and moderated by cooperative conflict management. Cooperative conflict management made a more important contribution than transformational leadership or the moderating effect (interaction), but these three together were the most important variables predicting highest leadership trust. Transformational leadership has an indirect influence on leadership trust. This work summarizes the specific contribution and importance of building successful leadership trust associations with employees in relation to leadership and satisfaction with change commitment.

  12. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    Energy Technology Data Exchange (ETDEWEB)

    Schaal, Courtney [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States); Padmanabhan, Jaya [Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave., Tampa, FL 33612 (United States); Chellappan, Srikumar, E-mail: Srikumar.Chellappan@moffitt.org [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States)

    2015-07-31

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

  13. Roles for gut vagal sensory signals in determining energy availability and energy expenditure.

    Science.gov (United States)

    Schwartz, Gary J

    2018-08-15

    The gut sensory vagus transmits a wide range of meal-related mechanical, chemical and gut peptide signals from gastrointestinal and hepatic tissues to the central nervous system at the level of the caudal brainstem. Results from studies using neurophysiological, behavioral physiological and metabolic approaches that challenge the integrity of this gut-brain axis support an important role for these gut signals in the negative feedback control of energy availability by limiting food intake during a meal. These experimental approaches have now been applied to identify important and unanticipated contributions of the vagal sensory gut-brain axis to the control of two additional effectors of overall energy balance: the feedback control of endogenous energy availability through hepatic glucose production and metabolism, and the control of energy expenditure through brown adipose tissue thermogenesis. Taken together, these studies reveal the pleiotropic influences of gut vagal meal-related signals on energy balance, and encourage experimental efforts aimed at understanding how the brainstem represents, organizes and coordinates gut vagal sensory signals with these three determinants of energy homeostasis. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    International Nuclear Information System (INIS)

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer

  15. IAEA's technical co-operation programme and its role in assisting member states in the safe utilisation of nuclear power

    International Nuclear Information System (INIS)

    Reed, J.

    2000-01-01

    In this contribution the author deals with the technical co-operation projects of the IAEA. The Agency's technical co-operation programme is a most welcome mechanism for the transfer of nuclear technology, and to developing countries it is certainly the most attractive side of the Agency, since it is through this programme that the IAEA can contribute to the solution of their problems through the provision of know-how, technology and training. (authors)

  16. The role of progesterone signaling in the pathogenesis of uterine leiomyoma

    Science.gov (United States)

    Kim, J. Julie; Sefton, Elizabeth C.

    2011-01-01

    Uterine leiomyomas are benign tumors that originate from the myometrium. Evidence points to ovarian steroid hormones, in particular, progesterone as major promoters of leiomyoma development and growth. While progesterone action in leiomyomas involves the classical nuclear receptor effects on gene regulation, there is growing evidence that signaling pathways are directly activated by the progesterone receptor (PR) and that PR can interact with growth factor signaling systems to promote proliferation and survival of leiomyomas. Studies investigating the genomic and non-genomic actions of PR and its role in leiomyoma growth are summarized here. Studies testing various selective progesterone receptor modulators for the treatment of leiomyomas are also highlighted. An increased understanding of the mechanisms associated with progesterone-driven growth of leiomyomas is critical in order to develop more efficient and targeted therapies for this prevalent disease. PMID:21672608

  17. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

    International Nuclear Information System (INIS)

    Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

    2008-01-01

    Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1

  18. Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis.

    Science.gov (United States)

    Wang, Weiye; Xu, Suowen; Yin, Meimei; Jin, Zheng Gen

    2015-02-15

    Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. The Role of Sexual Selection in the Evolution of Chemical Signals in Insects

    Directory of Open Access Journals (Sweden)

    Sandra Steiger

    2014-06-01

    Full Text Available Chemical communication is the most ancient and widespread form of communication. Yet we are only beginning to grasp the complexity of chemical signals and the role they play in sexual selection. Focusing on insects, we review here the recent progress in the field of olfactory-based sexual selection. We will show that there is mounting empirical evidence that sexual selection affects the evolution of chemical traits, but form and strength of selection differ between species. Studies indicate that some chemical signals are expressed in relation to an individual’s condition and depend, for example, on age, immunocompetence, fertility, body size or degree of inbreeding. Males or females might benefit by choosing based on those traits, gaining resources or “good genes”. Other chemical traits appear to reliably reflect an individual’s underlying genotype and are suitable to choose a mating partner that matches best the own genotype.

  20. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification.

    Science.gov (United States)

    Kramer, Ina; Sigrist, Markus; de Nooij, Joriene C; Taniuchi, Ichiro; Jessell, Thomas M; Arber, Silvia

    2006-02-02

    Subpopulations of sensory neurons in the dorsal root ganglion (DRG) can be characterized on the basis of sensory modalities that convey distinct peripheral stimuli, but the molecular mechanisms that underlie sensory neuronal diversification remain unclear. Here, we have used genetic manipulations in the mouse embryo to examine how Runx transcription factor signaling controls the acquisition of distinct DRG neuronal subtype identities. Runx3 acts to diversify an Ngn1-independent neuronal cohort by promoting the differentiation of proprioceptive sensory neurons through erosion of TrkB expression in prospective TrkC+ sensory neurons. In contrast, Runx1 controls neuronal diversification within Ngn1-dependent TrkA+ neurons by repression of neuropeptide CGRP expression and controlling the fine pattern of laminar termination in the dorsal spinal cord. Together, our findings suggest that Runx transcription factor signaling plays a key role in sensory neuron diversification.

  1. Functional studies on the role of Notch signaling in Hydractinia development.

    Science.gov (United States)

    Gahan, James M; Schnitzler, Christine E; DuBuc, Timothy Q; Doonan, Liam B; Kanska, Justyna; Gornik, Sebastian G; Barreira, Sofia; Thompson, Kerry; Schiffer, Philipp; Baxevanis, Andreas D; Frank, Uri

    2017-08-01

    The function of Notch signaling was previously studied in two cnidarians, Hydra and Nematostella, representing the lineages Hydrozoa and Anthozoa, respectively. Using pharmacological inhibition in Hydra and a combination of pharmacological and genetic approaches in Nematostella, it was shown in both animals that Notch is required for tentacle morphogenesis and for late stages of stinging cell maturation. Surprisingly, a role for Notch in neural development, which is well documented in bilaterians, was evident in embryonic Nematostella but not in adult Hydra. Adult neurogenesis in the latter seemed to be unaffected by DAPT, a drug that inhibits Notch signaling. To address this apparent discrepancy, we studied the role of Notch in Hydractinia echinata, an additional hydrozoan, in all life stages. Using CRISPR-Cas9 mediated mutagenesis, transgenesis, and pharmacological interference we show that Notch is dispensable for Hydractinia normal neurogenesis in all life stages but is required for the maturation of stinging cells and for tentacle morphogenesis. Our results are consistent with a conserved role for Notch in morphogenesis and nematogenesis across Cnidaria, and a lineage-specific loss of Notch dependence in neurogenesis in hydrozoans. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. DMPD: Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15546391 Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Watf...ord WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ. Immunol Rev. 2004 Dec;202:139-56. (.png) (.svg) (....html) (.csml) Show Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. PubmedID 15546391 T...itle Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Author...s Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJ. Publication Immunol Rev. 2004 Dec;202:139-56

  3. Zebrafish eda and edar mutants reveal conserved and ancestral roles of ectodysplasin signaling in vertebrates.

    Directory of Open Access Journals (Sweden)

    Matthew P Harris

    2008-10-01

    Full Text Available The genetic basis of the development and variation of adult form of vertebrates is not well understood. To address this problem, we performed a mutant screen to identify genes essential for the formation of adult skeletal structures of the zebrafish. Here, we describe the phenotypic and molecular characterization of a set of mutants showing loss of adult structures of the dermal skeleton, such as the rays of the fins and the scales, as well as the pharyngeal teeth. The mutations represent adult-viable, loss of function alleles in the ectodysplasin (eda and ectodysplasin receptor (edar genes. These genes are frequently mutated in the human hereditary disease hypohidrotic ectodermal dysplasia (HED; OMIM 224900, 305100 that affects the development of integumentary appendages such as hair and teeth. We find mutations in zebrafish edar that affect similar residues as mutated in human cases of HED and show similar phenotypic consequences. eda and edar are not required for early zebrafish development, but are rather specific for the development of adult skeletal and dental structures. We find that the defects of the fins and scales are due to the role of Eda signaling in organizing epidermal cells into discrete signaling centers of the scale epidermal placode and fin fold. Our genetic analysis demonstrates dose-sensitive and organ-specific response to alteration in levels of Eda signaling. In addition, we show substantial buffering of the effect of loss of edar function in different genetic backgrounds, suggesting canalization of this developmental system. We uncover a previously unknown role of Eda signaling in teleosts and show conservation of the developmental mechanisms involved in the formation and variation of both integumentary appendages and limbs. Lastly, our findings point to the utility of adult genetic screens in the zebrafish in identifying essential developmental processes involved in human disease and in morphological evolution.

  4. The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence

    Directory of Open Access Journals (Sweden)

    Khaled A. Selim

    2017-04-01

    Full Text Available Reactive oxygen species (ROS are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses. The oxidative stress of redundant free radicals production can lead to oxidative denaturation of cellular macromolecules including proteins, lipids and DNA. Moreover, oxidative damage is one of the major causes of DNA mutations, replication errors and genomic abnormalities which result in either inhibition or induction of transcription, and end with the disturbance of signal transduction pathways. Among affected signaling pathways are redox-sensitive kinases. The stimulation of these kinases induces several transcription factors through the phosphorylation of their module proteins. The activation of such pathways induces proliferation and cellular transformation. A diet rich in antioxidant compounds has potential health benefits, and there is a growing interest in the role of natural antioxidants in nutrition for prevention and cure of cancer diseases. A controversy has risen regarding the relation between antioxidants and the significant decrease in the risk of cancer incidence. In this review, we will focus on redox-sensitive kinases signaling pathways, highlighting the effects of dietary antioxidant on the prevention, incidence, prognosis or even treatment of human cancers. In addition, we will place emphasis on the chemical classes of pterocarpans as natural anti-oxidants/cancers as well as their underlying mechanisms of action, including their effects on MAPKs and topoisomerase activities.

  5. Zebrafish eda and edar Mutants Reveal Conserved and Ancestral Roles of Ectodysplasin Signaling in Vertebrates

    Science.gov (United States)

    Harris, Matthew P.; Rohner, Nicolas; Schwarz, Heinz; Perathoner, Simon; Konstantinidis, Peter; Nüsslein-Volhard, Christiane

    2008-01-01

    The genetic basis of the development and variation of adult form of vertebrates is not well understood. To address this problem, we performed a mutant screen to identify genes essential for the formation of adult skeletal structures of the zebrafish. Here, we describe the phenotypic and molecular characterization of a set of mutants showing loss of adult structures of the dermal skeleton, such as the rays of the fins and the scales, as well as the pharyngeal teeth. The mutations represent adult-viable, loss of function alleles in the ectodysplasin (eda) and ectodysplasin receptor (edar) genes. These genes are frequently mutated in the human hereditary disease hypohidrotic ectodermal dysplasia (HED; OMIM 224900, 305100) that affects the development of integumentary appendages such as hair and teeth. We find mutations in zebrafish edar that affect similar residues as mutated in human cases of HED and show similar phenotypic consequences. eda and edar are not required for early zebrafish development, but are rather specific for the development of adult skeletal and dental structures. We find that the defects of the fins and scales are due to the role of Eda signaling in organizing epidermal cells into discrete signaling centers of the scale epidermal placode and fin fold. Our genetic analysis demonstrates dose-sensitive and organ-specific response to alteration in levels of Eda signaling. In addition, we show substantial buffering of the effect of loss of edar function in different genetic backgrounds, suggesting canalization of this developmental system. We uncover a previously unknown role of Eda signaling in teleosts and show conservation of the developmental mechanisms involved in the formation and variation of both integumentary appendages and limbs. Lastly, our findings point to the utility of adult genetic screens in the zebrafish in identifying essential developmental processes involved in human disease and in morphological evolution. PMID:18833299

  6. Role of signaling lymphocytic activation molecule in T helper cell responses

    Directory of Open Access Journals (Sweden)

    Jan E. de Vries

    1998-01-01

    Full Text Available Signaling lymphocytic activation molecule (SLAM; CDw150 is a 70 kDa glycoprotein. Signaling lymphocytic activation molecule is constitutively expressed on memory T cells, CD56+ T cells, a subset of T cell receptor γδ+ cells, immature thymocytes and, at low levels, on a proportion of peripheral blood B cells. Signaling lymphocytic activation molecule is rapidly upregulated on all T and B cells after activation. Engagement of SLAM by F(ab’2 fragments of an anti-SLAM monoclonal antibody (mAb A12 enhances antigen-specific T cell proliferation. In addition, mAb A12 was directly mitogenic for T cell clones and activated T cells. T cell proliferation induced by mAb A12 is independent of interleukin (IL-2, IL-4, IL-12 and IL-15, but is cyclosporin A sensitive. Ligation of SLAM during antigen-specific T cell proliferation resulted in upregulation of interferon (IFN-γ production, even by allergen-specific T helper cell (Th 2 clones, whereas the levels of IL-4 and IL-5 production were only marginally affected. The mAb A12 was unable to induce IL-4 and IL-5 production by Th1 clones. Co-stimulation of skin-derived Der P1-specific Th2 cells from patients with atopic dermatitis via SLAM resulted in the generation of a population of IFN-γ-producing cells, thereby reverting their phenotype to a Th0 pattern. Signaling lymphocytic activation molecule is a high-affinity self ligand mediating homophilic cell interaction. In addition, soluble SLAM enhances both T and B cell proliferation. Collectively, these data indicate that SLAM molecules act both as receptors and ligands that are not only involved in T cell expansion but also drive the expanding T cells during immune responses into the Th0/Th1 pathway. This suggests that signaling through SLAM plays a role in directing Th0/Th1 development.

  7. Immune Homeostasis in Epithelial Cells: Evidence and Role of Inflammasome Signaling Reviewed.

    Science.gov (United States)

    Peeters, Paul M; Wouters, Emiel F; Reynaert, Niki L

    2015-01-01

    The epithelium regulates the interaction between the noxious xenogenous, as well as the microbial environment and the immune system, not only by providing a barrier but also by expressing a number of immunoregulatory membrane receptors, and intracellular danger sensors and their downstream effectors. Amongst these are a number of inflammasome sensor subtypes, which have been initially characterized in myeloid cells and described to be activated upon assembly into multiprotein complexes by microbial and environmental triggers. This review compiles a vast amount of literature that supports a pivotal role for inflammasomes in the various epithelial barriers of the human body as essential factors maintaining immune signaling and homeostasis.

  8. Wnt signalling via the epidermal growth factor receptor: a role in breast cancer?

    International Nuclear Information System (INIS)

    Musgrove, Elizabeth A

    2004-01-01

    Recent data have suggested the epidermal-growth-factor receptor (EGFR) as a point of convergence for several different classes of receptor. Civenni and colleagues have now demonstrated crosstalk between Wnt signalling and the EGFR, showing that in breast epithelial cells Wnts activate downstream targets of the EGFR, including cyclin D1. Given the role of members of these pathways in the aetiology of breast cancer and as markers of outcome and potential therapeutic targets in breast cancer, this observation has a number of potential implications important for both the basic biology of breast cancer and the clinical management of the disease

  9. Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Shi, Juan; Li, Feng; Luo, Meihui; Wei, Jun

    2017-01-01

    Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases. PMID:28588349

  10. THE ROLE OF SUPPORT GROUPS IN THE COOPERATION BETWEEN PARENTS OF PEOPLE WITH INTELLECTUAL DISABILITIES AND PROFESSIONAL STAFF

    Directory of Open Access Journals (Sweden)

    Metka NOVAK

    2014-09-01

    Full Text Available Introduction: One of the ways of building and developing a better cooperative relationship between parents of people with severe and profound intellectual disabilities and professional staff is the inclusion of parents in support groups for parents and staff in support groups for staff. Goal: To examine the correlation of the level of cooperative relationship between the parents of people with severe and profound intellectual disabilities and professional staff with the inclusion of parents in support groups for parents and staff in support groups for staff. Methodology: Respondents: parents (296 of people with severe and profound learning disabilities and staff (298 in five centres across Slovenia; Methods: descriptive statistics, test of homogeneity, the rankit method, one-way analysis of variance; Procedures: survey questionnaires for parents and staff. The data was processed using SPSS software for personal computers. Results: The difference between the variances of the groups (parent found is statistically significant (F = 6.16; p = 0.01. Staff included in support groups have a significantly lower level of cooperative relationship with parents (f=10; M = - 0.12 than staff not included in these groups (f = 191; M = 0.04. Conclusion:In contrast to theoretical findings the results indicated less successful cooperation for professional staff included in support groups. The results furthermore did not confirm any differences in the cooperative relationship of parents included in support groups and those who are not. We suggest an in-depth analysis of the workings of support groups.

  11. Conflictual cooperation

    DEFF Research Database (Denmark)

    Axel, Erik

    2011-01-01

    , cooperation appeared as the continuous reworking of contradictions in the local arrangement of societal con- ditions. Subjects were distributed and distributed themselves according to social privileges, resources, and dilemmas in cooperation. Here, the subjects’ activities and understandings took form from...

  12. Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

    International Nuclear Information System (INIS)

    Fujii, Hodaka

    2007-01-01

    Binding of interleukin-2 (IL-2) to its specific receptor induces activation of two members of Jak family protein tyrosine kinases, Jak1 and Jak3. An IL-2 receptor (IL-2R)-reconstituted NIH 3T3 fibroblast cell line proliferates in response to IL-2 only when hematopoietic lineage-specific Jak3 is ectopically expressed. However, the mechanism of Jak3-dependent proliferation in the fibroblast cell line is not known. Here, I showed that Jak3 expression is dispensable for IL-2-induced activation of Jak1 and Stat proteins and expression of nuclear proto-oncogenes in the IL-2R-reconstituted fibroblast cell line. Jak3 expression markedly enhanced these IL-2-induced signaling events. In contrast, Jak3 expression was essential for induction of cyclin genes involved in the G1-S transition. These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling

  13. Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction

    Science.gov (United States)

    Fujii, Hodaka

    2007-01-01

    Binding of IL-2 to its specific receptor induces activation of two members of Jak family protein tyrosine kinases, Jak1 and Jak3. An IL-2R-reconstituted NIH 3T3 fibroblast cell line proliferates in response to IL-2 only when hematopoietic lineage-specific Jak3 is ectopically expressed. However, the mechanism of Jak3-dependent proliferation in the fibroblast cell line is not known. Here, I showed that Jak3 expression is dispensable for IL-2-induced activation of Jak1 and Stat proteins and expression of nuclear proto-oncogenes in the IL-2R-reconstituted fibroblast cell line. However, Jak3 expression markedly enhanced these IL-2-induced signaling events. In contrast, Jak3 expression was essential for induction of cyclin genes involved in the G1-S transition. These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling. PMID:17266928

  14. Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria

    Science.gov (United States)

    Jauregui, Alexandra; Mintz, Daniel H; Mundel, Peter; Fornoni, Alessia

    2010-01-01

    Purpose of review In diabetic nephropathy (DN), insulin resistance and hyperinsulinemia correlate with the development of albuminuria. The possibility that altered insulin signaling in glomerular cells and particularly podocytes contributes to the development of DN will be discussed. Recent findings While normal podocytes uptake glucose in response to insulin, diabetic podocytes become insulin resistant in experimental DN prior to the development of significant albuminuria. Both clinical and experimental data suggest that insulin sensitizers may be renoprotective independently of their systemic effects on the metabolic control of diabetes. Summary We will review the clinical and experimental evidence that altered insulin signaling correlates with the development of DN in both type 1 and type 2 diabetes, and that insulin sensitizers may be superior to other hypoglycemic agents in the prevention of DN. We will then review potential mechanisms by which altered podocyte insulin signaling may contribute to the development of DN. Understanding the role of podocyte in glucose metabolism is important because it may lead to the discovery of novel pathogenetic mechanisms of DN, it may affect current strategies for prevention and treatment of DN, and it may allow for the identification of novel therapeutic targets. PMID:19724224

  15. Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B

    Science.gov (United States)

    Venkatesan, Balachandar; Ghosh-Choudhury, Nandini; Das, Falguni; Mahimainathan, Lenin; Kamat, Amrita; Kasinath, Balakuntalam S.; Abboud, Hanna E.; Choudhury, Goutam Ghosh

    2008-01-01

    Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC50 of 10 μM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.—Venkatesan, B., Ghosh-Choudhury, N., Das, F., Mahimainathan, L., Kamat, A., Kasinath, B. S., Abboud, H. E., Choudhury, G. G. Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B. PMID:18567737

  16. The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

    Science.gov (United States)

    Aoui, Chaker; Prigent, Antoine; Sut, Caroline; Tariket, Sofiane; Hamzeh-Cognasse, Hind; Pozzetto, Bruno; Richard, Yolande; Cognasse, Fabrice; Laradi, Sandrine; Garraud, Olivier

    2014-01-01

    The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors. PMID:25479079

  17. Role of TGF-β signaling in inherited and acquired myopathies

    Directory of Open Access Journals (Sweden)

    Burks Tyesha N

    2011-05-01

    Full Text Available Abstract The transforming growth factor-beta (TGF-β superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs, and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders.

  18. Plant phospholipase C family: Regulation and functional role in lipid signaling.

    Science.gov (United States)

    Singh, Amarjeet; Bhatnagar, Nikita; Pandey, Amita; Pandey, Girdhar K

    2015-08-01

    Phospholipase C (PLC), a major membrane phospholipid hydrolyzing enzyme generates signaling messengers such as diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) in animals, and their phosphorylated forms such as phosphatidic acid (PA) and inositol hexakisphosphate (IP6) are thought to regulate various cellular processes in plants. Based on substrate specificity, plant PLC family is sub-divided into phosphatidylinositol-PLC (PI-PLC) and phosphatidylcholine-PLC (PC-PLC) groups. The activity of plant PLCs is regulated by various factors and the major ones include, Ca(2+) concentration, phospholipid substrate, post-translational modifications and interacting proteins. Most of the PLC members have been localized at the plasma membrane, suited for their function of membrane lipid hydrolysis. Several PLC members have been implicated in various cellular processes and signaling networks, triggered in response to a number of environmental cues and developmental events in different plant species, which makes them potential candidates for genetically engineering the crop plants for stress tolerance and enhancing the crop productivity. In this review article, we are focusing mainly on the plant PLC signaling and regulation, potential cellular and physiological role in different abiotic and biotic stresses, nutrient deficiency, growth and development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer

    International Nuclear Information System (INIS)

    Bishop, Jennifer L.; Thaper, Daksh; Zoubeidi, Amina

    2014-01-01

    The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed

  20. Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy

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    Vito Cucchiara

    2017-01-01

    Full Text Available Androgen receptor (AR signaling remains the major oncogenic pathway in prostate cancer (PCa. Androgen-deprivation therapy (ADT is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC. Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles involved in AR expression and their possible role as therapeutic targets.

  1. Potential role of insulin signaling on vascular smooth muscle cell migration, proliferation, and inflammation pathways.

    Science.gov (United States)

    Cersosimo, Eugenio; Xu, Xiaojing; Musi, Nicolas

    2012-02-15

    To investigate the role of insulin signaling pathways in migration, proliferation, and inflammation of vascular smooth muscle cells (VSMCs), we examined the expression of active components of the phosphatidyl inositol 3 (PI-3) kinase (p-Akt) and mitogen-activated protein kinase (MAPK) (p-Erk) in primary cultures of VSMCs from human coronary arteries. VSMCs were treated in a dose-response manner with insulin (0, 1, 10, and 100 nM) for 20 min, and Akt and Erk phosphorylation were measured by Western blot analysis. In separate experiments, we evaluated the effect of 200 μM palmitate, in the presence and absence of 8 μM pioglitazone, on insulin-stimulated (100 nM for 20 min) Akt and Erk phosphorylation. The phosphorylation of Akt and Erk in VSMCs exhibited a dose dependency with a three- to fourfold increase, respectively, at the highest dose (100 nM). In the presence of palmitate, insulin-induced Akt phosphorylation was completely abolished, and there was a threefold increase in p-Erk. With addition of pioglitazone, the phosphorylation of Akt by insulin remained unchanged, whereas insulin-stimulated Erk phosphorylation was reduced by pioglitazone. These data in VSMCs indicate that high palmitate decreases insulin-stimulated Akt phosphorylation and stimulates MAPK, whereas preexposure peroxisome proliferator-activated receptor-γ agonist pioglitazone preserves Akt phosphorylation and simultaneously attenuates MAPK signaling. Our results suggest that metabolic and mitogenic insulin signals have different sensitivity, are independently regulated, and may play a role in arterial smooth muscle cells migration, proliferation, and inflammation in conditions of acute hyperinsulinemia.

  2. Role of JAK-STAT signaling in the pathogenesis of myeloproliferative disorders.

    Science.gov (United States)

    Levine, Ross L; Wernig, Gerlinde

    2006-01-01

    The identification of JAK2V617F mutations in polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) represents an important advance in our understanding of these myeloproliferative disorders (MPD). Most, if not all, patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling most efficiently when co-expressed with the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Data from murine models supports the central role of JAK2V617F in the pathogenesis of MPD, as expression of JAK2V617F in a bone marrow transplantation assay results in polycythemia and myelofibrosis in recipient mice. Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identification of the constitutively active MPLW515L allele in ET and MF. Small molecule inhibitors of JAK-STAT signaling are currently being developed, which offer potential for molecularly targeted therapy for patients with PV, ET, and MF. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical efficacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.

  3. Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors

    Science.gov (United States)

    Park, Tea Soon; Huo, Jeffrey S.; Peters, Ann; Talbot, C. Conover; Verma, Karan; Zimmerlin, Ludovic; Kaplan, Ian M.; Zambidis, Elias T.

    2012-01-01

    Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (∼0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ∼50% in purified episome-expressing cells. Lineage-committed CD33+CD45+CD34− myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG+TRA-1-81+ hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NFκB signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self

  4. Roles of NO signaling in long-term memory formation in visual learning in an insect.

    Directory of Open Access Journals (Sweden)

    Yukihisa Matsumoto

    Full Text Available Many insects exhibit excellent capability of visual learning, but the molecular and neural mechanisms are poorly understood. This is in contrast to accumulation of information on molecular and neural mechanisms of olfactory learning in insects. In olfactory learning in insects, it has been shown that cyclic AMP (cAMP signaling critically participates in the formation of protein synthesis-dependent long-term memory (LTM and, in some insects, nitric oxide (NO-cyclic GMP (cGMP signaling also plays roles in LTM formation. In this study, we examined the possible contribution of NO-cGMP signaling and cAMP signaling to LTM formation in visual pattern learning in crickets. Crickets that had been subjected to 8-trial conditioning to associate a visual pattern with water reward exhibited memory retention 1 day after conditioning, whereas those subjected to 4-trial conditioning exhibited 30-min memory retention but not 1-day retention. Injection of cycloheximide, a protein synthesis inhibitor, into the hemolymph prior to 8-trial conditioning blocked formation of 1-day memory, whereas it had no effect on 30-min memory formation, indicating that 1-day memory can be characterized as protein synthesis-dependent long-term memory (LTM. Injection of an inhibitor of the enzyme producing an NO or cAMP prior to 8-trial visual conditioning blocked LTM formation, whereas it had no effect on 30-min memory formation. Moreover, injection of an NO donor, cGMP analogue or cAMP analogue prior to 4-trial conditioning induced LTM. Induction of LTM by an NO donor was blocked by DDA, an inhibitor of adenylyl cyclase, an enzyme producing cAMP, but LTM induction by a cAMP analogue was not impaired by L-NAME, an inhibitor of NO synthase. The results indicate that cAMP signaling is downstream of NO signaling for visual LTM formation. We conclude that visual learning and olfactory learning share common biochemical cascades for LTM formation.

  5. The Role of Diet in Shaping the Chemical Signal Design of Lacertid Lizards.

    Science.gov (United States)

    Baeckens, Simon; García-Roa, Roberto; Martín, José; Van Damme, Raoul

    2017-09-01

    Lizards communicate with others via chemical signals, the composition of which may vary among species. Although the selective pressures and constraints affecting chemical signal diversity at the species level remain poorly understood, the possible role of diet has been largely neglected. The chemical signals of many lizards originate from the femoral glands that exude a mixture of semiochemicals, and may be used in a variety of contexts. We analyzed the lipophilic fraction of the glandular secretions of 45 species of lacertid lizard species by gas chromatography/mass spectrometry. The proportions of nine major chemical classes (alcohols, aldehydes, fatty acids, furanones, ketones, steroids, terpenoids, tocopherols and waxy esters), the relative contributions of these different classes ('chemical diversity'), and the total number of different lipophilic compounds ('chemical richness') varied greatly among species. We examined whether interspecific differences in these chemical variables could be coupled to interspecific variation in diet using data from the literature. In addition, we compared chemical signal composition among species that almost never, occasionally, or often eat plant material. We found little support for the hypothesis that the chemical profile of a given species' secretion depends on the type of food consumed. Diet breadth did not correlate with chemical diversity or richness. The amount of plants or ants consumed did not affect the relative contribution of any of the nine major chemical classes to the secretion. Chemical diversity did not differ among lizards with different levels of plant consumption; however, chemical richness was low in species with an exclusive arthropod diet, suggesting that incorporating plants in the diet enables lizards to increase the number of compounds allocated to secretions, likely because a (partly) herbivorous diet allows them to include compounds of plant origin that are unavailable in animal prey. Still, overall

  6. Towards a unified theory of cooperative breeding : The role of ecology and life history re-examined

    NARCIS (Netherlands)

    Pen, I.; Weissing, F.J.

    2000-01-01

    We present quantitative models that unify several adaptive hypotheses for the evolution of cooperative breeding in a single framework: the ecological constraints hypothesis, the life-history hypothesis and the benefits-of-philopatry hypothesis. Our goal is to explain interspecific variation in the

  7. The Role of Trust-building in Fostering Cooperation in the Eastern Nile Basin: A Case of Experimental Game Application

    Directory of Open Access Journals (Sweden)

    Mahsa Motlagh

    2017-09-01

    Full Text Available Escalating tension and a sense of mistrust currently prevail between downstream and upstream countries in the Nile Basin over Ethiopia's construction of the Grand Ethiopian Renaissance Dam (GERD. Striving for self-sufficiency in hydropower generation, Ethiopia has initiated a new series of upstream reservoir construction projects, with the GERD being the largest, and this may affect the water availability in downstream countries of Egypt and Sudan. This paper examines a set of compensation options to induce cooperation through trust-building, possibly minimizing uncertainties in water allocation decision-making and simplifying complex inter-relationships in the basin using laboratory game experiments. The game was developed and conducted using hydro-economic modeling of the basin with GAMS software, an expert survey with the SPSS program and Z-tree software to design and analyze the laboratory experiment. This paper presents the results of the laboratory game experiment where the Eastern Nile Basin scenario was modeled as a multi-round, adjusted trust game with non-binding deals among players. The results suggest that the "win for all" situation may be reached through a stable integrative, cooperative framework. Building the enabling environment, in particular, transparency, knowledge, trust, and confidence among riparian states is the first step in developing transboundary cooperation. Basin-wide cooperation requires a transparent environment including a variety of compensation options, institutional changes, and incentive-compatible considerations.

  8. The role of social capital on trust development and dynamics: Implications for cooperation, monitoring and team performance

    NARCIS (Netherlands)

    Costa, A.C.; Bijlsma-Frankema, K.M.; de Jong, B.A.

    2009-01-01

    This study examined the development and dynamics of trust in project teams and explored the relation with cooperation, monitoring and team performance. Two types of teams were distinguished at the start of the projects: low prior social-capital teams (teams composed of members that have no previous

  9. Features of the Phosphatidylinositol Cycle and its Role in Signal Transduction.

    Science.gov (United States)

    Epand, Richard M

    2017-08-01

    The phosphatidylinositol cycle (PI-cycle) has a central role in cell signaling. It is the major pathway for the synthesis of phosphatidylinositol and its phosphorylated forms. In addition, some lipid intermediates of the PI-cycle, including diacylglycerol and phosphatidic acid, are also important lipid signaling agents. The PI-cycle has some features that are important for the understanding of its role in the cell. As a cycle, the intermediates will be regenerated. The PI-cycle requires a large amount of metabolic energy. There are different steps of the cycle that occur in two different membranes, the plasma membrane and the endoplasmic reticulum. In order to complete the PI-cycle lipid must be transferred between the two membranes. The role of the Nir proteins in the process has recently been elucidated. The lipid intermediates of the PI-cycle are normally highly enriched with 1-stearoyl-2-arachidonoyl molecular species in mammals. This enrichment will be retained as long as the intermediates are segregated from other lipids of the cell. However, there is a significant fraction (>15 %) of lipids in the PI-cycle of normal cells that have other acyl chains. Phosphatidylinositol largely devoid of arachidonoyl chains are found in cancer cells. Phosphatidylinositol species with less unsaturation will not be as readily converted to phosphatidylinositol-3,4,5-trisphosphate, the lipid required for the activation of Akt with resulting effects on cell proliferation. Thus, the cyclical nature of the PI-cycle, its dependence on acyl chain composition and its requirement for lipid transfer between two membranes, explain many of the biological properties of this cycle.

  10. A Joint Less Ordinary: Intriguing Roles for Hedgehog Signalling in the Development of the Temporomandibular Synovial Joint

    Directory of Open Access Journals (Sweden)

    Malgorzata Kubiak

    2016-08-01

    Full Text Available This review highlights the essential role of Hedgehog (Hh signalling in the developmental steps of temporomandibular joint (TMJ formation. We review evidence for intra- and potentially inter-tissue Hh signaling as well as Glioma-Associated Oncogene Homolog (GLI dependent and independent functions. Morphogenesis and maturation of the TMJ’s individual components and the general landscape of Hh signalling is also covered. Comparison of the appendicular knee and axial TMJ also reveals interesting differences and similarities in their mechanisms of development, chondrogenesis and reliance on Hh signalling.

  11. A Joint Less Ordinary: Intriguing Roles for Hedgehog Signalling in the Development of the Temporomandibular Synovial Joint

    Science.gov (United States)

    Kubiak, Malgorzata; Ditzel, Mark

    2016-01-01

    This review highlights the essential role of Hedgehog (Hh) signalling in the developmental steps of temporomandibular joint (TMJ) formation. We review evidence for intra- and potentially inter-tissue Hh signaling as well as Glioma-Associated Oncogene Homolog (GLI) dependent and independent functions. Morphogenesis and maturation of the TMJ’s individual components and the general landscape of Hh signalling is also covered. Comparison of the appendicular knee and axial TMJ also reveals interesting differences and similarities in their mechanisms of development, chondrogenesis and reliance on Hh signalling. PMID:29615589

  12. Two MYB-related transcription factors play opposite roles in sugar signaling in Arabidopsis.

    Science.gov (United States)

    Chen, Yi-Shih; Chao, Yi-Chi; Tseng, Tzu-Wei; Huang, Chun-Kai; Lo, Pei-Ching; Lu, Chung-An

    2017-02-01

    Sugar regulation of gene expression has profound effects at all stages of the plant life cycle. Although regulation at the transcriptional level is one of the most prominent mechanisms by which gene expression is regulated, only a few transcription factors have been identified and demonstrated to be involved in the regulation of sugar-regulated gene expression. OsMYBS1, an R1/2-type MYB transcription factor, has been demonstrated to be involved in sugar- and hormone-regulated α-amylase gene expression in rice. Arabidopsis contains two OsMYBS1 homologs. In the present study, we investigate MYBS1 and MYBS2 in sugar signaling in Arabidopsis. Our results indicate that MYBS1 and MYBS2 play opposite roles in regulating glucose and ABA signaling in Arabidopsis during seed germination and early seedling development. MYB proteins have been classified into four subfamilies: R2R3-MYB, R1/2-MYB, 3R-MYB, and 4R-MYB. An R1/2-type MYB transcription factor, OsMYBS1, has been demonstrated to be involved in sugar- and hormone-regulated α-amylase genes expression in rice. In this study, two genes homologous to OsMYBS1, MYBS1 and MYBS2, were investigated in Arabidopsis. Subcellular localization analysis showed that MYBS1 and MYBS2 were localized in the nucleus. Rice embryo transient expression assays indicated that both MYBS1 and MYBS2 could recognize the sugar response element, TA-box, in the promoter and induced promoter activity. mybs1 mutant exhibited hypersensitivity to glucose, whereas mybs2 seedlings were hyposensitive to it. MYBS1 and MYBS2 are involved in the control of glucose-responsive gene expression, as the mybs1 mutant displayed increased expression of a hexokinase gene (HXK1), chlorophyll a/b-binding protein gene (CAB1), ADP-glucose pyrophosphorylase gene (APL3), and chalcone synthase gene (CHS), whereas the mybs2 mutant exhibited decreased expression of these genes. mybs1 also showed an enhanced response to abscisic acid (ABA) in the seed germination and seedling

  13. Conference RSIS (The role of science in the information society) - Contributions to Economic Development - Building 40 S2 - B01 - Mr. John Dryden, Chairman, Deputy Director, Organisation for Economic Cooperation and Development.

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    Maximilien Brice

    2003-01-01

    Conference RSIS (The role of science in the information society) - Contributions to Economic Development - Building 40 S2 - B01 - Mr. John Dryden, Chairman, Deputy Director, Organisation for Economic Cooperation and Development.

  14. AREB1, AREB2, and ABF3 are master transcription factors that cooperatively regulate ABRE-dependent ABA signaling involved in drought stress tolerance and require ABA for full activation.

    Science.gov (United States)

    Yoshida, Takuya; Fujita, Yasunari; Sayama, Hiroko; Kidokoro, Satoshi; Maruyama, Kyonoshin; Mizoi, Junya; Shinozaki, Kazuo; Yamaguchi-Shinozaki, Kazuko

    2010-02-01

    A myriad of drought stress-inducible genes have been reported, and many of these are activated by abscisic acid (ABA). In the promoter regions of such ABA-regulated genes, conserved cis-elements, designated ABA-responsive elements (ABREs), control gene expression via bZIP-type AREB/ABF transcription factors. Although all three members of the AREB/ABF subfamily, AREB1, AREB2, and ABF3, are upregulated by ABA and water stress, it remains unclear whether these are functional homologs. Here, we report that all three AREB/ABF transcription factors require ABA for full activation, can form hetero- or homodimers to function in nuclei, and can interact with SRK2D/SnRK2.2, an SnRK2 protein kinase that was identified as a regulator of AREB1. Along with the tissue-specific expression patterns of these genes and the subcellular localization of their encoded proteins, these findings clearly indicate that AREB1, AREB2, and ABF3 have largely overlapping functions. To elucidate the role of these AREB/ABF transcription factors, we generated an areb1 areb2 abf3 triple mutant. Large-scale transcriptome analysis, which showed that stress-responsive gene expression is remarkably impaired in the triple mutant, revealed novel AREB/ABF downstream genes in response to water stress, including many LEA class and group-Ab PP2C genes and transcription factors. The areb1 areb2 abf3 triple mutant is more resistant to ABA than are the other single and double mutants with respect to primary root growth, and it displays reduced drought tolerance. Thus, these results indicate that AREB1, AREB2, and ABF3 are master transcription factors that cooperatively regulate ABRE-dependent gene expression for ABA signaling under conditions of water stress.

  15. Insulin signaling disruption in male mice due to perinatal bisphenol A exposure: Role of insulin signaling in the brain.

    Science.gov (United States)

    Fang, Fangfang; Gao, Yue; Wang, Tingwei; Chen, Donglong; Liu, Jingli; Qian, Wenyi; Cheng, Jie; Gao, Rong; Wang, Jun; Xiao, Hang

    2016-03-14

    Bisphenol A (BPA), an environmental estrogenic endocrine disruptor, is widely used for producing polycarbonate plastics and epoxy resins. Available data have shown that perinatal exposure to BPA contributes to peripheral insulin resistance, while in the present study, we aimed to investigate the effects of perinatal BPA exposure on insulin signaling and glucose transport in the cortex of offspring mice. The pregnant mice were administrated either vehicle or BPA (100 μg/kg/day) at three perinatal stages. Stage I: from day 6 of gestation until parturition (P6-PND0 fetus exposure); Stage II: from lactation until delactation (PND0-PND21 newborn exposure) and Stage III: from day 6 of pregnancy until delactation (P6-PND21 fetus and newborn exposure). At 8 months of age for the offspring mice, the insulin signaling pathways and glucose transporters (GLUTs) were detected. Our data indicated that the insulin signaling including insulin, phosphorylated insulin receptor (IR), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated extracellular signal regulated protein kinase (p-ERK) were significantly decreased in the brain. In parallel, GLUTs (GLUT1/3/4) were obviously decreased as well in BPA-treated group in mice brain. Noteworthily, the phosphorylated tau (p-tau) and amyloid precursor protein (APP) were markedly up-regulated in all BPA-treated groups. These results, taken together, suggest the adverse effects of BPA on insulin signaling and GLUTs, which might subsequently contribute to the increment of p-tau and APP in the brain of adult offspring. Therefore, perinatal BPA exposure might be a risk factor for the long-term neurodegenerative changes in offspring male mice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. A conserved glutamine plays a central role in LOV domain signal transmission and duration

    Science.gov (United States)

    Nash, Abigail I.; Ko, Wen-Huang; Harper, Shannon M.; Gardner, Kevin H.

    2009-01-01

    Light is a key stimulus for plant biological functions, several of which are controlled by light-activated kinases known as phototropins, a group of kinases that contain two light-sensing domains (LOV, Light-Oxygen-Voltage domains) and a C-terminal serine/threonine kinase domain. The second sensory domain, LOV2, plays a key role in regulating kinase enzymatic activity via the photochemical formation of a covalent adduct between a LOV2 cysteine residue and an internally-bound flavin mononucleotide (FMN) chromophore. Subsequent conformational changes in LOV2 lead to the unfolding of a peripheral Jα helix, and ultimately, phototropin kinase activation. To date, the mechanism coupling bond formation and helix dissociation has remained unclear. Previous studies found that a conserved glutamine residue (Q513 in the Avena sativa phototropin 1 LOV2 (AsLOV2) domain) switches its hydrogen-bonding pattern with FMN upon light stimulation. Located in the immediate vicinity of the FMN binding site, this Gln residue is provided by the Iβ strand that interacts with the Jα helix, suggesting a route for signal propagation from the core of the LOV domain to its peripheral Jα helix. To test whether Q513 plays a key role in tuning the photochemical and transduction properties of AsLOV2, we designed two point mutations, Q513L and Q513N, and monitored the effects on the chromophore and protein using a combination of UV-visible absorbance and circular dichroism spectroscopy, limited proteolysis, and solution NMR. The results show that these mutations significantly dampen the changes between the dark and lit state AsLOV2 structures, leaving the protein in a pseudo-dark state (Q513L) or a pseudo-lit state (Q513N) conformation. Further, both mutations changed the photochemical properties of this receptor, particularly the lifetime of the photoexcited signaling states. Together, these data establish that this residue plays a central role in both spectral tuning and signal propagation from

  17. Role of Notch signalling pathway in cancer and its association with ...

    Indian Academy of Sciences (India)

    The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organ- ... Abnormal Notch signalling is seen in many cancers like T-cell acute ...... Morgan T. H. 1917 The theory of the gene.

  18. Efficacy of Mesenchymal Stem Cells in Suppression of Hepatocarcinorigenesis in Rats: Possible Role of Wnt Signaling

    LENUS (Irish Health Repository)

    Abdel Aziz, Mohamed T

    2011-05-05

    Abstract Background The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis. Methods Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl 4 , rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups. Results Histopathological examination of liver tissue from animals which received DENA-CCl4 only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect. Conclusions Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation

  19. Role of the MAPKs/TGF-β1/TRAF6 signaling pathway in postoperative atrial fibrillation.

    Directory of Open Access Journals (Sweden)

    Daoliang Zhang

    Full Text Available To explore the relationship between the MAPKs/TGF-β1/TRAF6 signaling pathway and atrial fibrosis in patients with rheumatic heart disease (RHD and its role in atrial fibrillation (AF after cardiac surgery on the basis of our previous animal study of the MAPKs/TGF-β1/TRAF6 signaling pathway in atrial fibrosis.A total of 57 patients with RHD without a history of AF consented to left atrial biopsy. Histopathology quantified the percentage of fibrosis, and real-time PCR and western blot assessed the mRNA and protein expression of TGF-β1, TRAF6, and connective tissue growth factor (CTGF, respectively. Western blot was also used to measure the protein expression of phosphorylated MAPKs and TGF-β-activated kinase 1 (TAK1. Serum angiotensin II (Ang II levels were assayed using enzyme-linked immunosorbent assay (ELISA.Eighteen patients developed AF, whereas 39 remained in sinus rhythm (SR. The severity of atrial fibrosis was significantly higher in patients who developed AF versus those who remained in SR; the mRNA and protein expression of TGF-β1, TRAF6 and CTGF were significantly higher in patients with AF. The protein expression of phosphorylated MAPKs and TAK1 was significantly increased in patients who developed AF compared with the patients who remained in SR. Serum Ang II levels were significantly higher in patients who developed AF versus those who remained in SR.The MAPKs/TGF-β1/TRAF6 signaling pathway is involved in atrial fibrosis in patients with RHD, which results in the occurrence of AF after cardiac surgery.

  20. Common and distinct roles of juvenile hormone signaling genes in metamorphosis of holometabolous and hemimetabolous insects.

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    Barbora Konopova

    Full Text Available Insect larvae metamorphose to winged and reproductive adults either directly (hemimetaboly or through an intermediary pupal stage (holometaboly. In either case juvenile hormone (JH prevents metamorphosis until a larva has attained an appropriate phase of development. In holometabolous insects, JH acts through its putative receptor Methoprene-tolerant (Met to regulate Krüppel-homolog 1 (Kr-h1 and Broad-Complex (BR-C genes. While Met and Kr-h1 prevent precocious metamorphosis in pre-final larval instars, BR-C specifies the pupal stage. How JH signaling operates in hemimetabolous insects is poorly understood. Here, we compare the function of Met, Kr-h1 and BR-C genes in the two types of insects. Using systemic RNAi in the hemimetabolous true bug, Pyrrhocoris apterus, we show that Met conveys the JH signal to prevent premature metamorphosis by maintaining high expression of Kr-h1. Knockdown of either Met or Kr-h1 (but not of BR-C in penultimate-instar Pyrrhocoris larvae causes precocious development of adult color pattern, wings and genitalia. A natural fall of Kr-h1 expression in the last larval instar normally permits adult development, and treatment with an exogenous JH mimic methoprene at this time requires both Met and Kr-h1 to block the adult program and induce an extra larval instar. Met and Kr-h1 therefore serve as JH-dependent repressors of deleterious precocious metamorphic changes in both hemimetabolous and holometabolous juveniles, whereas BR-C has been recruited for a new role in specifying the holometabolous pupa. These results show that despite considerable evolutionary distance, insects with diverse developmental strategies employ a common-core JH signaling pathway to commit to adult morphogenesis.

  1. The role of auxin and cytokinin signalling in specifying the root architecture of Arabidopsis thaliana

    KAUST Repository

    Muraro, Daniele

    2013-01-01

    Auxin and cytokinin are key hormonal signals that control the cellular architecture of the primary root and the initiation of new lateral root organs in the plant Arabidopsis thaliana. Both developmental processes are regulated by cross-talk between these hormones and their signalling pathways. In this paper, sub-cellular and multi-cellular mathematical models are developed to investigate how interactions between auxin and cytokinin influence the size and location of regions of division and differentiation within the primary root, and describe how their cross-regulation may cause periodic branching of lateral roots. We show how their joint activity may influence tissue-specific oscillations in gene expression, as shown in Moreno-Risueno et al. (2010) and commented upon in Traas and Vernoux (2010), and we propose mechanisms that may generate synchronisation of such periodic behaviours inside a cell and with its neighbours. Using a multi-cellular model, we also analyse the roles of cytokinin and auxin in specifying the three main regions of the primary root (elongation, transition and division zones), our simulation results being in good agreement with independent experimental observations. We then use our model to generate testable predictions concerning the effect of varying the concentrations of the auxin efflux transporters on the sizes of the different root regions. In particular, we predict that over-expression of the transporters will generate a longer root with a longer elongation zone and a smaller division zone than that of a wild type root. This root will contain fewer cells than its wild type counterpart. We conclude that our model can provide a useful tool for investigating the response of cell division and elongation to perturbations in hormonal signalling. © 2012 Elsevier Ltd.

  2. Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons.

    Science.gov (United States)

    Gill, Luther C; Gransee, Heather M; Sieck, Gary C; Mantilla, Carlos B

    2016-06-01

    Cervical spinal cord injury (SCI) interrupts descending neural drive to phrenic motoneurons causing diaphragm muscle (DIAm) paralysis. Recent studies using a well-established model of SCI, unilateral spinal hemisection of the C2 segment of the cervical spinal cord (SH), provide novel information regarding the molecular and cellular mechanisms of functional recovery after SCI. Over time post-SH, gradual recovery of rhythmic ipsilateral DIAm activity occurs. Recovery of ipsilateral DIAm electromyogram (EMG) activity following SH is enhanced by increasing brain-derived neurotrophic factor (BDNF) in the region of the phrenic motoneuron pool. Delivery of exogenous BDNF either via intrathecal infusion or via mesenchymal stem cells engineered to release BDNF similarly enhance recovery. Conversely, recovery after SH is blunted by quenching endogenous BDNF with the fusion-protein TrkB-Fc in the region of the phrenic motoneuron pool or by selective inhibition of TrkB kinase activity using a chemical-genetic approach in TrkB(F616A) mice. Furthermore, the importance of BDNF signaling via TrkB receptors at phrenic motoneurons is highlighted by the blunting of recovery by siRNA-mediated downregulation of TrkB receptor expression in phrenic motoneurons and by the enhancement of recovery evident following virally-induced increases in TrkB expression specifically in phrenic motoneurons. BDNF/TrkB signaling regulates synaptic plasticity in various neuronal systems, including glutamatergic pathways. Glutamatergic neurotransmission constitutes the main inspiratory-related, excitatory drive to motoneurons, and following SH, spontaneous neuroplasticity is associated with increased expression of ionotropic N-methyl-d-aspartate (NMDA) receptors in phrenic motoneurons. Evidence for the role of BDNF/TrkB and glutamatergic signaling in recovery of DIAm activity following cervical SCI is reviewed. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.

    Science.gov (United States)

    Yamasaki, Satoshi; Maeda, Motoi; Ohshima, Koichi; Kikuchi, Masahiro; Otsuka, Teruhisa; Harada, Mine

    2004-10-01

    Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.

  4. The Role of Head Movements and Signal Spectrum in an Auditory Front/Back Illusion

    Directory of Open Access Journals (Sweden)

    W Owen Brimijoin

    2012-04-01

    Full Text Available We used a dynamic auditory spatial illusion to investigate the role of self-motion and acoustics in shaping our spatial percept of the environment. Using motion capture, we smoothly moved a sound source around listeners as a function of their own head movements. A lowpass filtered sound behind a listener that moved in the direction it would have moved if it had been located in the front was perceived as statically located in front. The contrariwise effect occurred if the sound was in front but moved as if it were behind. The illusion was strongest for sounds lowpass filtered at 500 Hz and weakened as a function of increasing lowpass cutoff frequency. The signals with the most high frequency energy were often associated with an unstable location percept that flickered from front to back as self-motion cues and spectral cues for location came into conflict with one another.

  5. Role of HIF-1α signaling pathway in osteoarthritis: a systematic review

    Directory of Open Access Journals (Sweden)

    Javier Fernández-Torres

    Full Text Available Abstract Osteoarthritis (OA is the most common form of arthritis and is frequently diagnosed and managed in primary care; it is characterized by loss of articular hyaline cartilage, which is a unique connective tissue that physiologically lacks blood vessels. Articular cartilage survives in a microenvironment devoid of oxygen, which is regulated by hypoxia inducible factor (HIF-1α. HIF-1α is considered the main transcriptional regulator of cellular and developmental response to hypoxia. To date, the relevance of HIF-1α in the assessment of cartilage has increased since its participation is essential in the homeostasis of this tissue. Taking into account the new emerging insights of HIF-1α in the scientific literature in the last years, we focused the present review on the potential role of HIF-1α signaling pathway in OA development, especially in how some genetic factors may influence the maintenance or breakdown of articular cartilage.

  6. The pivotal role of abscisic acid signaling during transition from seed maturation to germination.

    Science.gov (United States)

    Yan, An; Chen, Zhong

    2017-05-01

    Seed maturation and germination are two continuous developmental processes that link two distinct generations in spermatophytes; the precise genetic control of these two processes is, therefore, crucially important for the survival of the next generation. Pieces of experimental evidence accumulated so far indicate that a concerted action of endogenous signals and environmental cues is required to govern these processes. Plant hormone abscisic acid (ABA) has been suggested to play a predominant role in directing seed maturation and maintaining seed dormancy under unfavorable environmental conditions until antagonized by gibberellins (GA) and certain environmental cues to allow the commencement of seed germination when environmental conditions are favorable; therefore, the balance of ABA and GA is a major determinant of the timing of seed germination. Due to the advent of new technologies and system biology approaches, molecular studies are beginning to draw a picture of the sophisticated genetic network that drives seed maturation during the past decade, though the picture is still incomplete and many details are missing. In this review, we summarize recent advances in ABA signaling pathway in the regulation of seed maturation as well as the transition from seed maturation to germination, and highlight the importance of system biology approaches in the study of seed maturation.

  7. The role of innate signaling in the homeostasis of tolerance and immunity in the intestine.

    Science.gov (United States)

    Wells, Jerry M; Loonen, Linda M P; Karczewski, Jurgen M

    2010-01-01

    In the intestine innate recognition of microbes is achieved through pattern recognition receptor (PRR) families expressed in immune cells and different cell lineages of the intestinal epithelium. Toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-like receptor (NLR) families are emerging as key mediators of immunity through their role as maturation factors of immune cells and triggers for the production of cytokines and chemokines and antimicrobial factors. At the mucosal surface chronic activation of the immune system is avoided through the epithelial production of a glycocalyx, steady-state production of antimicrobial factors as well as the selective expression and localization of PRRs. Additionally, the polarization of epithelial TLR signaling and suppression of NF-kappaB activation by luminal commensals appears to contribute to the homeostasis of tolerance and immunity. Several studies have demonstrated that TLR signaling in epithelial cells contributes to a range of homeostatic mechanisms including proliferation, wound healing, epithelial integrity, and regulation of mucosal immune functions. The intestinal epithelium appears to have uniquely evolved to maintain mucosal tolerance and immunity, and future efforts to further understand the molecular mechanisms of intestinal homeostasis may have a major impact on human health. Copyright 2009 Elsevier GmbH. All rights reserved.

  8. Streptozotocin induced activation of oxidative stress responsive splenic cell signaling pathways: Protective role of arjunolic acid

    International Nuclear Information System (INIS)

    Manna, Prasenjit; Ghosh, Jyotirmoy; Das, Joydeep; Sil, Parames C.

    2010-01-01

    Present study investigates the beneficial role of arjunolic acid (AA) against the alteration in the cytokine levels and simultaneous activation of oxidative stress responsive signaling pathways in spleen under hyperglycemic condition. Diabetes was induced by injection of streptozotocin (STZ) (at a dose of 70 mg/kg body weight, injected in the tail vain). STZ administration elevated the levels of IL-2 as well as IFN-γ and attenuated the level of TNF-α in the sera of diabetic animals. In addition, hyperglycemia is also associated with the increased production of intracellular reactive intermediates resulting with the elevation in lipid peroxidation, protein carbonylation and reduction in intracellular antioxidant defense. Investigating the oxidative stress responsive cell signaling pathways, increased expressions (immunoreactive concentrations) of phosphorylated p65 as well as its inhibitor protein phospho IκBα and phosphorylated mitogen activated protein kinases (MAPKs) have been observed in diabetic spleen tissue. Studies on isolated splenocytes revealed that hyperglycemia caused disruption of mitochondrial membrane potential, elevation in the concentration of cytosolic cytochrome c as well as activation of caspase 3 leading to apoptotic cell death. Histological examination revealed that diabetic induction depleted the white pulp scoring which is in agreement with the reduced immunological response. Treatment with AA prevented the hyperglycemia and its associated pathogenesis in spleen tissue. Results suggest that AA might act as an anti-diabetic and immunomodulatory agent against hyperglycemia.

  9. Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes.

    Directory of Open Access Journals (Sweden)

    Wai-Hong Tham

    2015-12-01

    Full Text Available The most severe form of malaria in humans is caused by the protozoan parasite Plasmodium falciparum. The invasive form of malaria parasites is termed a merozoite and it employs an array of parasite proteins that bind to the host cell to mediate invasion. In Plasmodium falciparum, the erythrocyte binding-like (EBL and reticulocyte binding-like (Rh protein families are responsible for binding to specific erythrocyte receptors for invasion and mediating signalling events that initiate active entry of the malaria parasite. Here we have addressed the role of the cytoplasmic tails of these proteins in activating merozoite invasion after receptor engagement. We show that the cytoplasmic domains of these type 1 membrane proteins are phosphorylated in vitro. Depletion of PfCK2, a kinase implicated to phosphorylate these cytoplasmic tails, blocks P. falciparum invasion of red blood cells. We identify the crucial residues within the PfRh4 cytoplasmic domain that are required for successful parasite invasion. Live cell imaging of merozoites from these transgenic mutants show they attach but do not penetrate erythrocytes implying the PfRh4 cytoplasmic tail conveys signals important for the successful completion of the invasion process.

  10. Roles of Wnt/β-catenin signaling in epithelial differentiation of mesenchymal stem cells

    International Nuclear Information System (INIS)

    Wang, Yajing; Sun, Zhaorui; Qiu, Xuefeng; Li, Yan; Qin, Jizheng; Han, Xiaodong

    2009-01-01

    Bone marrow-derived mesenchymal stem cells (MSCs) have been demonstrated to be able to differentiate into epithelial lineage, but the precise mechanisms controlling this process are unclear. Our aim is to explore the roles of Wnt/β-catenin in the epithelial differentiation of MSCs. Using indirect co-culture of rat MSCs with rat airway epithelial cells (RTE), MSCs expressed several airway epithelial markers (cytokeratin 18, tight junction protein occudin, cystic fibrosis transmembrance regulator). The protein levels of some important members in Wnt/β-catenin signaling were determined, suggested down-regulation of Wnt/β-catenin with epithelial differentiation of MSCs. Furthermore, Wnt3α can inhibit the epithelial differentiation of MSCs. A loss of β-catenin induced by Dickkopf-1 can enhance MSCs differentiation into epithelial cells. Lithium chloride transiently activated β-catenin expression and subsequently decreased β-catenin level and at last inhibited MSCs to differentiate into airway epithelium. Taken together, our study indicated that RTE cells can trigger epithelial differentiation of MSCs. Blocking Wnt/β-catenin signaling may promote MSCs to differentiate towards airway epithelial cells.

  11. A central role for TOR signalling in a yeast model for juvenile CLN3 disease

    Directory of Open Access Journals (Sweden)

    Michael E. Bond

    2015-11-01

    Full Text Available Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs or Batten disease in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases.

  12. Adult play fighting and potential role of tail signals in ringtailed lemurs (Lemur catta).

    Science.gov (United States)

    Palagi, Elisabetta

    2009-02-01

    Adult strepsirrhines have been completely neglected in the study of animal play. I focused on adult play fighting and the role of tail-play as a signal in ringtailed lemurs (Lemur catta). Tail-play is performed during play fighting, when lemurs anoint or, more rarely, wave their tails toward the playmate. During the prereproductive period, male and female lemurs engaged in play fighting with comparable frequencies, as was expected to occur in monomorphic species such as L. catta. The dyads showing low aggression rates engaged most frequently in play fighting, and polyadic play was frequently performed. Signals seem to be important in avoiding escalation to real aggression, especially when the playfulness of performers can be misunderstood by recipients. Tail-play was most frequent (a) in the dyads with low grooming rates (low familiarity degree) and (b) during the most risky play sessions (polyadic ones). Thus, tail-play can be considered as a useful tool for play communication in ringtailed lemurs. Copyright 2009 APA, all rights reserved.

  13. Physiological and Pathological Roles of CaMKII-PP1 Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Norifumi Shioda

    2017-12-01

    Full Text Available Ca2+/calmodulin (CaM-dependent protein kinase II (CaMKII, a multifunctional serine (Ser/threonine (Thr protein kinase, regulates diverse activities related to Ca2+-mediated neuronal plasticity in the brain, including synaptic activity and gene expression. Among its regulators, protein phosphatase-1 (PP1, a Ser/Thr phosphatase, appears to be critical in controlling CaMKII-dependent neuronal signaling. In postsynaptic densities (PSDs, CaMKII is required for hippocampal long-term potentiation (LTP, a cellular process correlated with learning and memory. In response to Ca2+ elevation during hippocampal LTP induction, CaMKIIα, an isoform that translocates from the cytosol to PSDs, is activated through autophosphorylation at Thr286, generating autonomous kinase activity and a prolonged Ca2+/CaM-bound state. Moreover, PP1 inhibition enhances Thr286 autophosphorylation of CaMKIIα during LTP induction. By contrast, CaMKII nuclear import is regulated by Ser332 phosphorylation state. CaMKIIδ3, a nuclear isoform, is dephosphorylated at Ser332 by PP1, promoting its nuclear translocation, where it regulates transcription. In this review, we summarize physio-pathological roles of CaMKII/PP1 signaling in neurons. CaMKII and PP1 crosstalk and regulation of gene expression is important for neuronal plasticity as well as survival and/or differentiation.

  14. Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

    Directory of Open Access Journals (Sweden)

    Masayo Aoki

    2016-01-01

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs and exported out of cells via transporters such as spinster homolog 2 (Spns2. S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs 1–5, through a process coined as “inside-out signaling.” The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing.

  15. Microtubule-Mediated Inositol Lipid Signaling Plays Critical Roles in Regulation of Blebbing.

    Directory of Open Access Journals (Sweden)

    Tatsuroh Sugiyama

    Full Text Available Cells migrate by extending pseudopods such as lamellipodia and blebs. Although the signals leading to lamellipodia extension have been extensively investigated, those for bleb extension remain unclear. Here, we investigated signals for blebbing in Dictyostelium cells using a newly developed assay to induce blebbing. When cells were cut into two pieces with a microneedle, the anucleate fragments vigorously extended blebs. This assay enabled us to induce blebbing reproducibly, and analyses of knockout mutants and specific inhibitors identified candidate molecules that regulate blebbing. Blebs were also induced in anucleate fragments of leukocytes, indicating that this assay is generally applicable to animal cells. After cutting, microtubules in the anucleate fragments promptly depolymerized, followed by the extension of blebs. Furthermore, when intact cells were treated with a microtubule inhibitor, they frequently extended blebs. The depolymerization of microtubules induced the delocalization of inositol lipid phosphatidylinositol 3,4,5-trisphosphate from the cell membrane. PI3 kinase-null cells frequently extended blebs, whereas PTEN-null cells extended fewer blebs. From these observations, we propose a model in which microtubules play a critical role in bleb regulation via inositol lipid metabolism.

  16. Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

    Directory of Open Access Journals (Sweden)

    Kenichiro Ishii

    2018-04-01

    Full Text Available Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.

  17. Opposing roles for interferon regulatory factor-3 (IRF-3 and type I interferon signaling during plague.

    Directory of Open Access Journals (Sweden)

    Ami A Patel

    Full Text Available Type I interferons (IFN-I broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.

  18. International cooperation

    International Nuclear Information System (INIS)

    Prieto, F.E.

    1984-01-01

    It looks doubtless that the need for an international cooperation to solve the worldwide energy problems is already a concern of individuals, institutions, and governments. This is an improvement. But there is something lacking. The author refers to the Atoms for Peace speech, the origin of the IAEA and of the subsequent spreading of the nuclear option. He also refers back to the call made by the Mexican government for a worldwide energy cooperation. He stresses the need for governments to cooperate, so that this international cooperation on energy can be put into operation for the benefit of mankind

  19. A novel role of sesamol in inhibiting NF-κB-mediated signaling in platelet activation

    Directory of Open Access Journals (Sweden)

    Chang Chao-Chien

    2011-12-01

    Full Text Available Abstract Background Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-κB-mediated platelet function. Methods Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study. Results NF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were markedly activated by collagen (1 μg/ml in washed human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM. Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 μM-mediated inhibitory effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA inhibitor, H89, also reversed sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB inhibitor, abolished IκBα degradation, phospholipase C (PLCγ2 phosphorylation, protein kinase C (PKC activation, [Ca2+]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca2+]i mobilization. Conclusions Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca2+]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-κB interferes with platelet function may

  20. Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol.

    Science.gov (United States)

    Glover, Elizabeth J; McDougle, Molly J; Siegel, Griffin S; Jhou, Thomas C; Chandler, L Judson

    2016-08-01

    While the rewarding effects of alcohol contribute significantly to its addictive potential, it is becoming increasingly appreciated that alcohol's aversive properties also play an important role in the propensity to drink. Despite this, the neurobiological mechanism for alcohol's aversive actions is not well understood. The rostromedial tegmental nucleus (RMTg) was recently characterized for its involvement in aversive signaling and has been shown to encode the aversive properties of cocaine, yet its involvement in alcohol's aversive actions have not been elucidated. Adult male and female Long-Evans rats underwent conditioned taste aversion (CTA) procedures where exposure to a novel saccharin solution was paired with intraperitoneal administration of saline, lithium chloride (LiCl), or ethanol (EtOH). Control rats underwent the same paradigm except that drug and saccharin exposure were explicitly unpaired. Saccharin consumption was measured on test day in the absence of drug administration, and rats were sacrificed 90 to 105 minutes following access to saccharin. Brains were subsequently harvested and processed for cFos immunohistochemistry. The number of cFos-labeled neurons was counted in the RMTg and the lateral habenula (LHb)-a region that sends prominent glutamatergic input to the RMTg. In rats that received paired drug and saccharin exposure, EtOH and LiCl induced significant CTA compared to saline to a similar degree in males and females. Both EtOH- and LiCl-induced CTA significantly enhanced cFos expression in the RMTg and LHb but not the hippocampus. Similar to behavioral measures, no significant effect of sex on CTA-induced cFos expression was observed. cFos expression in both the RMTg and LHb was significantly correlated with CTA magnitude with greater cFos being associated with more pronounced CTA. In addition, cFos expression in the RMTg was positively correlated with LHb cFos. These data suggest that the RMTg and LHb are involved in the expression of

  1. Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development

    Directory of Open Access Journals (Sweden)

    Lynda Elghazi

    2017-06-01

    Full Text Available Objective: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis. Method: Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors. Results: We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells. Conclusion: Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of

  2. Culture and Cooperation during the Interwar Period

    Directory of Open Access Journals (Sweden)

    Anişoara Popa

    2015-05-01

    Full Text Available Starting from the most important Publications of the International Institute for Intellectual Cooperation (1925-1946 we will explore the ideas concerning culture and personalities involved in the intellectual cooperation during the Interwar Period. Pointing out the role that the International Institute of Intellectual Cooperation had and the Romanian contribution to this cooperation is another purpose of this article.

  3. The Vicious Cycle of Myostatin Signaling in Sarcopenic Obesity: Myostatin Role in Skeletal Muscle Growth, Insulin Signaling and Implications for Clinical Trials.

    Science.gov (United States)

    Consitt, L A; Clark, B C

    2018-01-01

    The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.

  4. Comparative Phosphoproteomics Reveals an Important Role of MKK2 in Banana (Musa spp.) Cold Signal Network

    Science.gov (United States)

    Gao, Jie; Zhang, Sheng; He, Wei-Di; Shao, Xiu-Hong; Li, Chun-Yu; Wei, Yue-Rong; Deng, Gui-Ming; Kuang, Rui-Bin; Hu, Chun-Hua; Yi, Gan-Jun; Yang, Qiao-Song

    2017-01-01

    Low temperature is one of the key environmental stresses, which greatly affects global banana production. However, little is known about the global phosphoproteomes in Musa spp. and their regulatory roles in response to cold stress. In this study, we conducted a comparative phosphoproteomic profiling of cold-sensitive Cavendish Banana and relatively cold tolerant Dajiao under cold stress. Phosphopeptide abundances of five phosphoproteins involved in MKK2 interaction network, including MKK2, HY5, CaSR, STN7 and kinesin-like protein, show a remarkable difference between Cavendish Banana and Dajiao in response to cold stress. Western blotting of MKK2 protein and its T31 phosphorylated peptide verified the phosphoproteomic results of increased T31 phosphopeptide abundance with decreased MKK2 abundance in Daojiao for a time course of cold stress. Meanwhile increased expression of MKK2 with no detectable T31 phosphorylation was found in Cavendish Banana. These results suggest that the MKK2 pathway in Dajiao, along with other cold-specific phosphoproteins, appears to be associated with the molecular mechanisms of high tolerance to cold stress in Dajiao. The results also provide new evidence that the signaling pathway of cellular MKK2 phosphorylation plays an important role in abiotic stress tolerance that likely serves as a universal plant cold tolerance mechanism. PMID:28106078

  5. The role of aluminum sensing and signaling in plant aluminum resistance.

    Science.gov (United States)

    Liu, Jiping; Piñeros, Miguel A; Kochian, Leon V

    2014-03-01

    As researchers have gained a better understanding in recent years into the physiological, molecular, and genetic basis of how plants deal with aluminum (Al) toxicity in acid soils prevalent in the tropics and sub-tropics, it has become clear that an important component of these responses is the triggering and regulation of cellular pathways and processes by Al. In this review of plant Al signaling, we begin by summarizing the understanding of physiological mechanisms of Al resistance, which first led researchers to realize that Al stress induces gene expression and modifies protein function during the activation of Al resistance responses. Subsequently, an overview of Al resistance genes and their function provides verification that Al induction of gene expression plays a major role in Al resistance in many plant species. More recent research into the mechanistic basis for Al-induced transcriptional activation of resistance genes has led to the identification of several transcription factors as well as cis-elements in the promoters of Al resistance genes that play a role in greater Al-induced gene expression as well as higher constitutive expression of resistance genes in some plant species. Finally, the post-transcriptional and translational regulation of Al resistance proteins is addressed, where recent research has shown that Al can both directly bind to and alter activity of certain organic acid transporters, and also influence Al resistance proteins indirectly, via protein phosphorylation. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  6. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    Science.gov (United States)

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

  7. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer.

    Science.gov (United States)

    Pérez-Gómez, Eduardo; Andradas, Clara; Blasco-Benito, Sandra; Caffarel, María M; García-Taboada, Elena; Villa-Morales, María; Moreno, Estefanía; Hamann, Sigrid; Martín-Villar, Ester; Flores, Juana M; Wenners, Antonia; Alkatout, Ibrahim; Klapper, Wolfram; Röcken, Christoph; Bronsert, Peter; Stickeler, Elmar; Staebler, Annette; Bauer, Maret; Arnold, Norbert; Soriano, Joaquim; Pérez-Martínez, Manuel; Megías, Diego; Moreno-Bueno, Gema; Ortega-Gutiérrez, Silvia; Artola, Marta; Vázquez-Villa, Henar; Quintanilla, Miguel; Fernández-Piqueras, José; Canela, Enric I; McCormick, Peter J; Guzmán, Manuel; Sánchez, Cristina

    2015-06-01

    Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with

  8. Curcumin plays neuroprotective roles against traumatic brain injury partly via Nrf2 signaling.

    Science.gov (United States)

    Dong, Wenwen; Yang, Bei; Wang, Linlin; Li, Bingxuan; Guo, Xiangshen; Zhang, Miao; Jiang, Zhenfei; Fu, Jingqi; Pi, Jingbo; Guan, Dawei; Zhao, Rui

    2018-05-01

    Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide with no effective treatment. Curcumin has been shown to be beneficial for neuroprotection in vivo and in vitro, but the underlying mechanism remains unclear. This study determined whether the neuroprotective role of curcumin in mouse TBI is dependent on the NF-E2-related factor (Nrf2) pathway. The Feeney weight-drop contusion model was used to mimic TBI. Curcumin was administered intraperitoneally 15 min after TBI induction, and brains were collected at 24 h after TBI. The levels of Nrf2 and its downstream genes (Hmox-1, Nqo1, Gclm, and Gclc) were detected by Western blot and qRT-PCR at 24 h after TBI. In addition, edema, oxidative damage, cell apoptosis and inflammatory reactions were evaluated in wild type (WT) and Nrf2-knockout (Nrf2-KO) mice to explore the role of Nrf2 signaling after curcumin treatment. In wild type mice, curcumin treatment resulted in reduced ipsilateral cortex injury, neutrophil infiltration, and microglia activation, improving neuron survival against TBI-induced apoptosis and degeneration. These effects were accompanied by increased expression and nuclear translocation of Nrf2, and enhanced expression of antioxidant enzymes. However, Nrf2 deletion attenuated the neuroprotective effects of curcumin in Nrf2-KO mice after TBI. These findings demonstrated that curcumin effects on TBI are associated with the activation the Nrf2 pathway, providing novel insights into the neuroprotective role of Nrf2 and the potential therapeutic use of curcumin for TBI. Copyright © 2018. Published by Elsevier Inc.

  9. International cooperation

    International Nuclear Information System (INIS)

    1996-01-01

    In 1995, Nuclear Regulatory Authority of the Slovak Republic (NRA SR) ensured foreign cooperation particularly in the frame of the Slovak Republic is membership in the IAEA, as well as cooperation with the Nuclear Energy Agency of the Organization for Economic Cooperation and Development (OECD NEA), cooperation with European Union in the frame of PHARE programmes, and intergovernmental cooperation and cooperation among nuclear regulatory authorities. With respect to an international importance, prestige and a wide-scope possibilities of a technical assistance , either a direct one (expert assessments, technology supplies, work placement, scientific trips, training courses) or indirect one (participation at various conferences, seminars, technical committees, etc), the most important cooperation with the IAEA in Vienna. In 1994, the Slovak Republic, was elected to the Board Governors, the represent the group of Eastern European countries. The Slovak Government entrusted the NRA SR's Chairman with representing the Slovak Republic in the Board of Governors. Owing to a good name of Slovakia was elected to the one of two Vice-Chairmen of the Board of Governors at the 882-nd session on the Board. IAEA approved and developed 8 national projects for Slovakia in 1995. Generally, IAEA is contracting scientific contracts with research institutes, nuclear power plants and other organizations. Slovak organizations used these contracts as complementary funding of their tasks. In 1995, there were 12 scientific contracts in progress, or approved respectively. Other international activities of the NRA SR, international co-operations as well as foreign affairs are reported

  10. Pre-Service Teachers’ Experiences during Off-Campus Observation: Basis for Improving the Roles of Teacher Education Institutions and Cooperating Schools

    Directory of Open Access Journals (Sweden)

    Maripaz C. Abas

    2016-05-01

    Full Text Available Observing experienced teachers is an indispensable part of practicum studies in teacher education.  This paper examined the perceptions of pre-service teachers from five major fields of teacher education program on their experiences during off-campus observation in selected secondary schools. This used qualitative content analysis method in order to “subjectively interpret the content of text data through the systematic classification process of coding and identifying themes or patterns” (Hsieh & Shanon, 2005 p. 1278 . Data were taken from 136 pre-service teachers  through open-ended questions and two high school principals, 10 cooperating teachers, six student supervisors and 12 pre-service teachers through Focus Group Interview (FGI and Key Informant Interview (KII. Codes and emerging themes were derived using content analysis.  Results showed 18 themes for desirable experiences and 24 themes for undesirable experiences. Pre-service teachers’ experiences mostly focused on students’ attitudes and behaviors. Suggestions to improve off-campus observation from multi-level participants of the study concentrated on preparedness,  orientation programs, supervision and monitoring,  personal attributes and roles, values, attitudes and behaviors, deployment, post conferences,  supervisory plan, observation policies and guidelines,  required documents, seminars, time management, evaluation, coordination, and cultural diversity. To sustain the desirable experiences, both cooperating teachers and student supervisors believed that their roles were to serve as model, guide, leader, monitor, planner, and motivator. The varied experiences of pre-service teachers imply that Teacher Education Institutions (TEIs and cooperating schools should provide opportunities, develop competencies, take responsibilities and strengthen partnership to enhance off-campus observation.

  11. The Government's role in regulating, coordinating, and standardizing the response to Alzheimer's disease: Anticipated international cooperation in the area of intractable and rare diseases.

    Science.gov (United States)

    Tang, Qi; Song, Peipei; Xu, Lingzhong

    2016-11-01

    The World Health Organization (WHO) has emphasized that aging of the population is inextricably linked to many other global public health issues, such as universal health coverage, non-communicable diseases, and disability. However, Alzheimer's Disease International (ADI) estimates that 46.8 million elderly people worldwide were living with dementia in 2015. Alzheimer's disease (AD), the most common form of dementia, is one of the most common neurodegenerative diseases and is the main cause of cognitive impairment. AD will affect 5-7 out of every 100 older adults who are age 60 years or over. In response to the serious challenge posed by AD, governments are expected to play an important role in the prevention, diagnosis, and treatment of AD. As specific examples, i ) the Japanese Government has instituted and supported regulations to encourage the development of AD drugs in order to accelerate research and development of innovative drugs; ii ) the United States Government has cooperated with multiple partners such as non-governmental organizations in the response to AD; iii ) Chinese governmental measures have standardized clinical diagnosis and treatment as part of the response to AD, including eligible patients, diagnostic criteria, therapeutic schedules, drug selection, and required inspections; iv ) with political support from member governments, the European Union has issued guidelines and conducted clinical studies on medicines for the treatment of AD in order to ascertain the various stages of the disease and the relevance of biomarkers. AD is an intractable disease, so different countries need to share clinic trial information and cooperate in the conduct of those trials. International cooperation will play a key role in the response to other intractable and rare diseases.

  12. Ion Channels of Pituitary Gonadotrophs and Their Roles in Signaling and Secretion

    Directory of Open Access Journals (Sweden)

    Stanko S. Stojilkovic

    2017-06-01

    Full Text Available Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation-conducting, and chloride channels at their plasma membrane (PM. These cells also express the hyperpolarization-activated and cyclic nucleotide-gated cation channels at the PM, as well as GABAA, nicotinic, and purinergic P2X channels gated by γ-aminobutyric acid (GABA, acetylcholine (ACh, and ATP, respectively. Activation of these channels leads to initiation or amplification of the pacemaking activity, facilitation of calcium influx, and activation of the exocytic pathway. Gonadotrophs also express calcium-conducting channels at the endoplasmic reticulum membranes gated by inositol trisphosphate and intracellular calcium. These channels are activated potently by hypothalamic gonadotropin-releasing hormone (GnRH and less potently by several paracrine calcium-mobilizing agonists, including pituitary adenylate cyclase-activating peptides, endothelins, ACh, vasopressin, and oxytocin. Activation of these channels causes oscillatory calcium release and a rapid gonadotropin release, accompanied with a shift from tonic firing of single APs to periodic bursting type of electrical activity, which accounts for a sustained calcium signaling and gonadotropin secretion. This review summarizes our current understanding of ion channels as signaling molecules in gonadotrophs, the role of GnRH and paracrine agonists in their gating, and the cross talk among channels.

  13. Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Rommy eVon Bernhardi

    2015-10-01

    Full Text Available Aging is the main risk factor for Alzheimer’s disease (AD; being associated with conspicuous changes on microglia activation. Aged microglia exhibit an increased expression of cytokines, exacerbated reactivity to various stimuli, oxidative stress, and reduced phagocytosis of Aβ. Whereas normal inflammation is protective, it becomes dysregulated in the presence of a persistent stimulus, or in the context of an inflammatory environment, as observed in aging. Thus, neuroinflammation can be a self-perpetuating deleterious response, becoming a source of additional injury to host cells in neurodegenerative diseases. In aged individuals, although TGFβ is upregulated, its canonical Smad3 signaling is greatly reduced and neuroinflammation persists. This age-related Smad3 impairment reduces protective activation while facilitating cytotoxic activation of microglia through several cellular mechanisms, potentiating microglia-mediated neurodegeneration. Here, we critically discuss the role of TGFβ-Smad signaling on the cytotoxic activation of microglia and its relevance in the pathogenesis of AD. Other protective functions, such as phagocytosis, although observed in aged animals, are not further induced by inflammatory stimuli and TGFβ1. Analysis in silico revealed that increased expression of receptor SR-A, involved in Aβ uptake and cell activation, by microglia exposed to TGFβ, through a Smad3-dependent mechanism could be mediated by transcriptional co-factors Smad2/3 over the MSR1 gene. We discuss that changes of TGFβ-mediated regulation could at least partially mediate age-associated microglia changes, and, together with other changes on inflammatory response, could result in the reduction of protective activation and the potentiation of cytotoxicity of microglia, resulting in the promotion of neurodegenerative diseases.

  14. Role of CD137 signaling in dengue virus-mediated apoptosis

    International Nuclear Information System (INIS)

    Nagila, Amar; Netsawang, Janjuree; Srisawat, Chatchawan; Noisakran, Sansanee; Morchang, Atthapan; Yasamut, Umpa; Puttikhunt, Chunya; Kasinrerk, Watchara

    2011-01-01

    Highlights: → For the first time the role of CD137 in dengue virus (DENV) infection. → Induction of DENV-mediated apoptosis by CD137 signaling. → Sensitization to CD137-mediated apoptosis by dengue virus capsid protein (DENV C). → Nuclear localization of DENV C is required for CD137-mediated apoptosis. -- Abstract: Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137-mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis.

  15. Role of CD137 signaling in dengue virus-mediated apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Nagila, Amar [Medical Molecular Biology Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Netsawang, Janjuree [Faculty of Medical Technology, Rangsit University, Bangkok (Thailand); Srisawat, Chatchawan [Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Noisakran, Sansanee [Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok (Thailand); Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok (Thailand); Morchang, Atthapan; Yasamut, Umpa [Medical Molecular Biology Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Puttikhunt, Chunya [Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok (Thailand); Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok (Thailand); Kasinrerk, Watchara [Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai (Thailand); Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at Chiang Mai University, Chiang Mai (Thailand); and others

    2011-07-08

    Highlights: {yields} For the first time the role of CD137 in dengue virus (DENV) infection. {yields} Induction of DENV-mediated apoptosis by CD137 signaling. {yields} Sensitization to CD137-mediated apoptosis by dengue virus capsid protein (DENV C). {yields} Nuclear localization of DENV C is required for CD137-mediated apoptosis. -- Abstract: Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137-mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis.

  16. A Role for Bioelectric Effects in the Induction of Bystander Signals by Ionizing Radiation?

    Science.gov (United States)

    Mothersill, C.; Moran, G.; McNeill, F.; Gow, M.D.; Denbeigh, J.; Prestwich, W.; Seymour, C.B.

    2007-01-01

    The induction of “bystander effects” i.e. effects in cells which have not received an ionizing radiation track, is now accepted but the mechanisms are not completely clear. Bystander effects following high and low LET radiation exposure are accepted but mechanisms are still not understood. There is some evidence for a physical component to the signal. This paper tests the hypothesis that bioelectric or biomagnetic phenomena are involved. Human immortalized skin keratinocytes and primary explants of mouse bladder and fish skin, were exposed directly to ionizing radiation or treated in a variety of bystander protocols. Exposure of cells was conducted by shielding one group of flasks using lead, to reduce the dose below the threshold of 2mGy 60Cobalt gamma rays established for the bystander effect. The endpoint for the bystander effect in the reporter system used was reduction in cloning efficiency (RCE). The magnitude of the RCE was similar in shielded and unshielded flasks. When cells were placed in a Faraday cage the magnitude of the RCE was less but not eliminated. The results suggest that liquid media or cell-cell contact transmission of bystander factors may be only part of the bystander mechanism. Bioelectric or bio magnetic fields may have a role to play. To test this further, cells were placed in a Magnetic Resonance Imaging (MRI) machine for 10min using a typical head scan protocol. This treatment also induced a bystander response. Apart from the obvious clinical relevance, the MRI results further suggest that bystander effects may be produced by non-ionizing exposures. It is concluded that bioelectric or magnetic effects may be involved in producing bystander signaling cascades commonly seen following ionizing radiation exposure. PMID:18648606

  17. Role of necroptosis in autophagy signaling during hepatic ischemia and reperfusion

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Jeong-Min; Kim, Seok-Joo; Lee, Sun-Mee, E-mail: sunmee@skku.edu

    2016-10-01

    Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as “programmed necrosis” that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R. Male C57BL/6 mice were subjected to 60 min of ischemia followed by 3 h reperfusion. Necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.65 mg/kg) was administered intraperitoneally 5 min before reperfusion. Hepatic I/R significantly increased the level of RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome formation, which were attenuated by Nec-1. I/R also significantly increased serum levels of alanine aminotransferase, tumor necrosis factor-α, and interleukin-6, which were attenuated by Nec-1. Meanwhile, hepatic I/R activated autophagy and mitophagy, as evidenced by increased LC3-II, PINK1, and Parkin, and decreased sequestosome 1/p62 protein expression. Nec-1 attenuated these changes and attenuated the increased levels of autophagy-related protein (ATG) 3, ATG7, Rab7, and cathepsin B protein expression during hepatic I/R. Moreover, hepatic I/R activated the extracellular signal-regulated kinase (ERK) pathway, and Nec-1 attenuated this increase. Taken together, our findings suggest that necroptosis contributes to hepatic damage during I/R, which induces autophagy via ERK activation. - Highlights: • Hepatic I/R induces RIP1/RIP3-dependent necroptosis. • Necroptosis contributes to hepatic I/R injury. • Necroptosis activates autophagic flux via ERK activation during hepatic I/R.

  18. The role of NF-κB signaling in the maintenance of pluripotency of human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Osamu Takase

    Full Text Available NF-κB signaling plays an essential role in maintaining the undifferentiated state of embryonic stem (ES cells. However, opposing roles of NF-κB have been reported in mouse and human ES cells, and the role of NF-κB in human induced pluripotent stem (iPS cells has not yet been clarified. Here, we report the role of NF-κB signaling in maintaining the undifferentiated state of human iPS cells. Compared with differentiated cells, undifferentiated human iPS cells showed an augmentation of NF-κB activity. During differentiation induced by the removal of feeder cells and FGF2, we observed a reduction in NF-κB activity, the expression of the undifferentiation markers Oct3/4 and Nanog, and the up-regulation of the differentiated markers WT-1 and Pax-2. The specific knockdown of NF-κB signaling using p65 siRNA also reduced the expression of Oct3/4 and Nanog and up-regulated WT-1 and Pax-2 but did not change the ES-like colony formation. Our results show that the augmentation of NF-κB signaling maintains the undifferentiated state of human iPS and suggest the importance of this signaling pathway in maintenance of human iPS cells.

  19. The Cooperative and Interdependent Roles of GerA, GerK, and Ynd in Germination of Bacillus licheniformis Spores.

    Science.gov (United States)

    Borch-Pedersen, Kristina; Lindbäck, Toril; Madslien, Elisabeth H; Kidd, Shani W; O'Sullivan, Kristin; Granum, Per Einar; Aspholm, Marina

    2016-07-15

    When nutrients are scarce, Bacillus species form metabolically dormant and extremely resistant spores that enable survival over long periods of time under conditions not permitting growth. The presence of specific nutrients triggers spore germination through interaction with germinant receptors located in the spore's inner membrane. Bacillus licheniformis is a biotechnologically important species, but it is also associated with food spoilage and food-borne disease. The B. licheniformis ATCC 14580/DSM13 genome exhibits three gerA family operons (gerA, gerK, and ynd) encoding germinant receptors. We show that spores of B. licheniformis germinate efficiently in response to a range of different single l-amino acid germinants, in addition to a weak germination response seen with d-glucose. Mutational analyses revealed that the GerA and Ynd germination receptors function cooperatively in triggering an efficient germination response with single l-amino acid germinants, whereas the GerK germination receptor is essential for germination with d-glucose. Mutant spores expressing only GerA and GerK or only Ynd and GerK show reduced or severely impaired germination responses, respectively, with single l-amino acid germinants. Neither GerA nor Ynd could function alone in stimulating spore germination. Together, these results functionally characterize the germination receptor operons present in B. licheniformis We demonstrate the overlapping germinant recognition patterns of the GerA and Ynd germination receptors and the cooperative functionalities between GerA, Ynd, and GerK in inducing germination. To ensure safe food production and durable foods, there is an obvious need for more knowledge on spore-forming bacteria. It is the process of spore germination that ultimately leads to food spoilage and food poisoning. Bacillus licheniformis is a biotechnologically important species that is also associated with food spoilage and food-borne disease. Despite its importance, the

  20. The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism

    Directory of Open Access Journals (Sweden)

    Dietmar Fuchs

    2010-08-01

    Full Text Available Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC and the non-psychotropic cannabidiol (CBD modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC. The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO, suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.

  1. A role for chemokine signaling in neural crest cell migration and craniofacial development

    Science.gov (United States)

    Killian, Eugenia C. Olesnicky; Birkholz, Denise A.; Artinger, Kristin Bruk

    2009-01-01

    Neural crest cells (NCCs) are a unique population of multipotent cells that migrate along defined pathways throughout the embryo and give rise to many diverse cell types including pigment cells, craniofacial cartilage and the peripheral nervous system (PNS). Aberrant migration of NCCs results in a wide variety of congenital birth defects including craniofacial abnormalities. The chemokine Sdf1 and its receptors, Cxcr4 and Cxcr7, have been identified as key components in the regulation of cell migration in a variety of tissues. Here we describe a novel role for the zebrafish chemokine receptor Cxcr4a in the development and migration of cranial NCCs (CNCCs). We find that loss of Cxcr4a, but not Cxcr7b results in aberrant CNCC migration, defects in the neurocranium, as well as cranial ganglia dismorphogenesis. Moreover, overexpression of either Sdf1b or Cxcr4a causes aberrant CNCC migration and results in ectopic craniofacial cartilages. We propose a model in which Sdf1b signaling from the pharyngeal arch endoderm and optic stalk to Cxcr4a expressing CNCCs is important for both the proper condensation of the CNCCs into pharyngeal arches and the subsequent patterning and morphogenesis of the neural crest derived tissues. PMID:19576198

  2. Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles

    Directory of Open Access Journals (Sweden)

    Nunzio Iraci

    2016-02-01

    Full Text Available Extracellular vesicles (EVs are a heterogeneous population of secreted membrane vesicles, with distinct biogenesis routes, biophysical properties and different functions both in physiological conditions and in disease. The release of EVs is a widespread biological process, which is conserved across species. In recent years, numerous studies have demonstrated that several bioactive molecules are trafficked with(in EVs, such as microRNAs, mRNAs, proteins and lipids. The understanding of their final impact on the biology of specific target cells remains matter of intense debate in the field. Also, EVs have attracted great interest as potential novel cell-free therapeutics. Here we describe the proposed physiological and pathological functions of EVs, with a particular focus on their molecular content. Also, we discuss the advances in the knowledge of the mechanisms regulating the secretion of EV-associated molecules and the specific pathways activated upon interaction with the target cell, highlighting the role of EVs in the context of the immune system and as mediators of the intercellular signalling in the brain.

  3. Role of iNOS in Bystander Signaling Between Macrophages and Lymphoma Cells

    International Nuclear Information System (INIS)

    Ghosh, Somnath; Maurya, Dharmendra Kumar; Krishna, Malini

    2008-01-01

    Purpose: The present report describes the bystander effects of radiation between similar and dissimilar cells and the role of iNOS in such communication. Materials and Methods: EL-4 and RAW 264.7 cells were exposed to 5 Gy γ-irradiation. The medium from irradiated cells was transferred to unirradiated cells. Results: Irradiated EL-4 cells as well as those cultured in the presence of medium from γ-irradiated EL-4 cells showed an upregulation of NF-κB, iNOS, p53, and p21/waf1 genes. The directly irradiated and the bystander EL-4 cells showed an increase in DNA damage, apoptosis, and NO production. Bystander signaling was also found to exist between RAW 264.7 (macrophage) and EL-4 (lymphoma) cells. Unstimulated or irradiated RAW 264.7 cells did not induce bystander effect in unirradiated EL-4 cells, but LPS stimulated and irradiated RAW 264.7 cells induced an upregulation of NF-κB and iNOS genes and increased the DNA damage in bystander EL-4 cells. Treatment of EL-4 or RAW 264.7 cells with L-NAME significantly reduced the induction of gene expression and DNA damage in the bystander EL-4 cells, whereas treatment with cPTIO only partially reduced the induction of gene expression and DNA damage in the bystander EL-4 cells. Conclusions: It was concluded that active iNOS in the irradiated cells was essential for bystander response

  4. The role of fishing cooperatives on social – Economic and cultural development of rural areas of Bord Khun city of Bushehr, Iran

    Directory of Open Access Journals (Sweden)

    Masoud Samian

    2017-04-01

    Full Text Available The main purpose of this study was to determine the role of fishing cooperatives on the socio – economic development of and rural areas in the Bord Khun of Bushehr, Iran. This research, in terms of objective, was exploratory and in terms of data collection was descriptive (causal-comparative. The under study population were active fishing cooperatives of Bord Khun. To determine the validity of the questionnaire the content validity was used which was obtained through the views of teachers and specialists after several steps of revision. To identify the reliability of the questionnaire a pretest (30 questionnaires was administered in Abkesh Village, of Bushehr, Iran. Cronbach’s alpha coefficient was obtained (0.864–0.610 showing the validity of the questionnaire. The results showed that mean total economic for the registered villages was 1.57 (SD = 0.367 and for the non-registered villages was 1.51 (SD = 1.82. These figures indicated a very poor economic situation of registered villagers compared to non-registered members before implementing the plan. The total socio-cultural mean for the registered villagers was 2.122 (SD = 0.609 and for the non-registered members was 2.578(SD = 0.673. The figures indicated better socio-cultural situation of non-registered villagers compared to registered members before implementing the plan. It can be claimed that the fishing cooperatives had significant impact on rural areas.

  5. Deciphering the role of the Gag-Pol ribosomal frameshift signal in HIV-1 RNA genome packaging.

    Science.gov (United States)

    Nikolaitchik, Olga A; Hu, Wei-Shau

    2014-04-01

    A key step of retroviral replication is packaging of the viral RNA genome during virus assembly. Specific packaging is mediated by interactions between the viral protein Gag and elements in the viral RNA genome. In HIV-1, similar to most retroviruses, the packaging signal is located within the 5' untranslated region and extends into the gag-coding region. A recent study reported that a region including the Gag-Pol ribosomal frameshift signal plays an important role in HIV-1 RNA packaging; deletions or mutations that affect the RNA structure of this signal lead to drastic decreases (10- to 50-fold) in viral RNA packaging and virus titer. We examined here the role of the ribosomal frameshift signal in HIV-1 RNA packaging by studying the RNA packaging and virus titer in the context of proviruses. Three mutants with altered ribosomal frameshift signal, either through direct deletion of the signal, mutation of the 6U slippery sequence, or alterations of the secondary structure were examined. We found that RNAs from all three mutants were packaged efficiently, and they generate titers similar to that of a virus containing the wild-type ribosomal frameshift signal. We conclude that although the ribosomal frameshift signal plays an important role in regulating the replication cycle, this RNA element is not directly involved in regulating RNA encapsidation. To generate infectious viruses, HIV-1 must package viral RNA genome during virus assembly. The specific HIV-1 genome packaging is mediated by interactions between the structural protein Gag and elements near the 5' end of the viral RNA known as packaging signal. In this study, we examined whether the Gag-Pol ribosomal frameshift signal is important for HIV-1 RNA packaging as recently reported. Our results demonstrated that when Gag/Gag-Pol is supplied in trans, none of the tested ribosomal frameshift signal mutants has defects in RNA packaging or virus titer. These studies provide important information on how HIV-1

  6. Hypothalamic roles of mTOR complex I: Integration of nutrient and hormone signals to regulate energy homeostasis

    Science.gov (United States)

    Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight...

  7. Night/day changes in pineal expression of >600 genes: central role of adrenergic/cAMP signaling

    DEFF Research Database (Denmark)

    Bailey, Michael J; Coon, Steven L; Carter, John David

    2009-01-01

    The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip(R) technology to obtain a more complete description of pine...

  8. The role of multimodal signals in species recognition between tree-killing bark beetles in a narrow sympatric zone.

    Science.gov (United States)

    Deepa S. Pureswaran; Richard W. Hofstetter; Brian Sullivan; Kristen A. Potter

    2016-01-01

    When related species coexist, selection pressure should favor evolution of species recognition mechanisms to prevent interspecific pairing and wasteful reproductive encounters. We investigated the potential role of pheromone and acoustic signals in species recognition between two species of tree-killing bark beetles, the southern pine beetle, Dendroctonus frontalis...

  9. Biphasic Role of Chondroitin Sulfate in Cardiac Differentiation of Embryonic Stem Cells through Inhibition of Wnt/beta-Catenin Signaling

    NARCIS (Netherlands)

    Prinz, R.D.; Willis, C.M.; Kuppevelt, T.H. van; Kluppel, M.

    2014-01-01

    The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional

  10. The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

    DEFF Research Database (Denmark)

    Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder

    2013-01-01

    Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment...

  11. The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Verheij, M.; Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Blitterswijk, W.J. van; Fuks, Z.; Haimovitz-Friedman, A.

    1998-01-01

    Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  12. Quinolinic acid neurotoxicity: Differential roles of astrocytes and microglia via FGF-2-mediated signaling in redox-linked cytoskeletal changes.

    Science.gov (United States)

    Pierozan, Paula; Biasibetti, Helena; Schmitz, Felipe; Ávila, Helena; Parisi, Mariana M; Barbe-Tuana, Florencia; Wyse, Angela T S; Pessoa-Pureur, Regina

    2016-12-01

    QUIN is a glutamate agonist playing a role in the misregulation of the cytoskeleton, which is associated with neurodegeneration in rats. In this study, we focused on microglial activation, FGF2/Erk signaling, gap junctions (GJs), inflammatory parameters and redox imbalance acting on cytoskeletal dynamics of the in QUIN-treated neural cells of rat striatum. FGF-2/Erk signaling was not altered in QUIN-treated primary astrocytes or neurons, however cytoskeleton was disrupted. In co-cultured astrocytes and neurons, QUIN-activated FGF2/Erk signaling prevented the cytoskeleton from remodeling. In mixed cultures (astrocyte, neuron, microglia), QUIN-induced FGF-2 increased level failed to activate Erk and promoted cytoskeletal destabilization. The effects of QUIN in mixed cultures involved redox imbalance upstream of Erk activation. Decreased connexin 43 (Cx43) immunocontent and functional GJs, was also coincident with disruption of the cytoskeleton in primary astrocytes and mixed cultures. We postulate that in interacting astrocytes and neurons the cytoskeleton is preserved against the insult of QUIN by activation of FGF-2/Erk signaling and proper cell-cell interaction through GJs. In mixed cultures, the FGF-2/Erk signaling is blocked by the redox imbalance associated with microglial activation and disturbed cell communication, disrupting the cytoskeleton. Thus, QUIN signal activates differential mechanisms that could stabilize or destabilize the cytoskeleton of striatal astrocytes and neurons in culture, and glial cells play a pivotal role in these responses preserving or disrupting a combination of signaling pathways and cell-cell interactions. Taken together, our findings shed light into the complex role of the active interaction of astrocytes, neurons and microglia in the neurotoxicity of QUIN. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Regulation and regulatory role of WNT signaling in potentiating FSH action during bovine dominant follicle selection.

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    P S P Gupta

    Full Text Available Follicular development occurs in wave like patterns in monotocous species such as cattle and humans and is regulated by a complex interaction of gonadotropins with local intrafollicular regulatory molecules. To further elucidate potential mechanisms controlling dominant follicle selection, granulosa cell RNA harvested from F1 (largest and F2 (second largest follicles isolated at predeviation (PD and onset of diameter deviation (OD stages of the first follicular wave was subjected to preliminary RNA transcriptome analysis. Expression of numerous WNT system components was observed. Hence experiments were performed to test the hypothesis that WNT signaling modulates FSH action on granulosa cells during follicular waves. Abundance of mRNA for WNT pathway members was evaluated in granulosa cells harvested from follicles at emergence (EM, PD, OD and early dominance (ED stages of the first follicular wave. In F1 follicles, abundance of CTNNB1 and DVL1 mRNAs was higher and AXIN2 mRNA was lower at ED versus EM stages and DVL1 and FZD6 mRNAs were higher and AXIN2 mRNA was lower in F1 versus F2 follicle at the ED stage. Bovine granulosa cells were treated in vitro with increasing doses of the WNT inhibitor IWR-1+/- maximal stimulatory dose of FSH. IWR-1 treatment blocked the FSH-induced increase in granulosa cell numbers and reduced the FSH-induced increase in estradiol. Granulosa cells were also cultured in the presence or absence of FSH +/- IWR-1 and hormonal regulation of mRNA for WNT pathway members and known FSH targets determined. FSH treatment increased CYP19A1, CCND2, CTNNB1, AXIN2 and FZD6 mRNAs and the stimulatory effect on CYP19A1 mRNA was reduced by IWR-1. In contrast, FSH reduced CARTPT mRNA and IWR-1 partially reversed the inhibitory effect of FSH. Results support temporal and hormonal regulation and a potential role for WNT signaling in potentiating FSH action during dominant follicle selection.

  14. Retinoic acid signaling plays a restrictive role in zebrafish primitive myelopoiesis.

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    Dong Liang

    Full Text Available Retinoic acid (RA is known to regulate definitive myelopoiesis but its role in vertebrate primitive myelopoiesis remains unclear. Here we report that zebrafish primitive myelopoiesis is restricted by RA in a dose dependent manner mainly before 11 hpf (hours post fertilization when anterior hemangioblasts are initiated to form. RA treatment significantly reduces expressions of anterior hemangioblast markers scl, lmo2, gata2 and etsrp in the rostral end of ALPM (anterior lateral plate mesoderm of the embryos. The result indicates that RA restricts primitive myelopoiesis by suppressing formation of anterior hemangioblasts. Analyses of ALPM formation suggest that the defective primitive myelopoiesis resulting from RA treatment before late gastrulation may be secondary to global loss of cells for ALPM fate whereas the developmental defect resulting from RA treatment during 10-11 hpf should be due to ALPM patterning shift. Overexpressions of scl and lmo2 partially rescue the block of primitive myelopoiesis in the embryos treated with 250 nM RA during 10-11 hpf, suggesting RA acts upstream of scl to control primitive myelopoiesis. However, the RA treatment blocks the increased primitive myelopoiesis caused by overexpressing gata4/6 whereas the abolished primitive myelopoiesis in gata4/5/6 depleted embryos is well rescued by 4-diethylamino-benzaldehyde, a retinal dehydrogenase inhibitor, or partially rescued by knocking down aldh1a2, the major retinal dehydrogenase gene that is responsible for RA synthesis during early development. Consistently, overexpressing gata4/6 inhibits aldh1a2 expression whereas depleting gata4/5/6 increases aldh1a2 expression. The results reveal that RA signaling acts downstream of gata4/5/6 to control primitive myelopoiesis. But, 4-diethylamino-benzaldehyde fails to rescue the defective primitive myelopoiesis in either cloche embryos or lycat morphants. Taken together, our results demonstrate that RA signaling restricts

  15. Maize and Arabidopsis ARGOS Proteins Interact with Ethylene Receptor Signaling Complex, Supporting a Regulatory Role for ARGOS in Ethylene Signal Transduction[OPEN

    Science.gov (United States)

    Shi, Jinrui; Wang, Hongyu; Habben, Jeffrey E.

    2016-01-01

    The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown. Here, we demonstrate in Arabidopsis that ZmARGOS1, as well as the Arabidopsis ARGOS homolog ORGAN SIZE RELATED1, physically interacts with Arabidopsis REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1), an ethylene receptor interacting protein that regulates the activity of ETHYLENE RESPONSE1. The protein-protein interaction was also detected with the yeast split-ubiquitin two-hybrid system. Using the same yeast assay, we found that maize RTE1 homolog REVERSION-TO-ETHYLENE SENSITIVITY1 LIKE4 (ZmRTL4) and ZmRTL2 also interact with maize and Arabidopsis ARGOS proteins. Like AtRTE1 in Arabidopsis, ZmRTL4 and ZmRTL2 reduce ethylene responses when overexpressed in maize, indicating a similar mechanism for ARGOS regulating ethylene signaling in maize. A polypeptide fragment derived from ZmARGOS8, consisting of a Pro-rich motif flanked by two transmembrane helices that are conserved among members of the ARGOS family, can interact with AtRTE1 and maize RTL proteins in Arabidopsis. The conserved domain is necessary and sufficient to reduce ethylene sensitivity in Arabidopsis and maize. Overall, these results suggest a physical association between ARGOS and the ethylene receptor signaling complex via AtRTE1 and maize RTL proteins, supporting a role for ARGOS in regulating ethylene perception and the early steps of signal transduction in Arabidopsis and maize. PMID:27268962

  16. A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Xu, Wei; Deng, Chenguang; Xu, Shaoxin; Li, Fanghua; Wu, Yuejin; Wu, Lijun [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei 230031 (China); Bian, Po, E-mail: bianpo@ipp.ac.cn [Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei 230031 (China)

    2016-09-15

    Highlights: • The JA signal pathway plays a pivotal role in mediating radiation-induced bystander effects in Arabidopsis thaliana. • The JA signal pathway is involved in both the generation of bystander signals in irradiated roots and radiation responses in bystander aerial plants. • Over-accumulation of endogenous JA enhances the radiosensitivity of plants in terms of RIBE. - Abstract: Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX

  17. Progress of the radioactive waste management at the Dalat Nuclear Research Institute and the role of an IAEA technical co-operation project in this process

    International Nuclear Information System (INIS)

    Nang, N.T.; Ngoc, O.V.; Nhu Thuy, T.T.; Nghi, D.V.; Thu, N.T.

    2002-01-01

    At present, the main radioactive waste generator in Vietnam is the Dalat Nuclear Research Institute (DNRI). For safe management of radioactive waste generated from this nuclear center, in 1982 Soviet specialists newly constructed one combined technology system for low level radioactive waste management. The existing system consists of two main parts, a Liquid Radioactive Waste Treatment Station and a Storage/Disposal Facility. The liquid treatment station can in principle meet the needs for this nuclear center but disposal technology and storage/disposal facilities are not good enough both with respect to safety and economy, especially the storage/disposal facility placed in Dalat, the tourist city. In order to help DNRI and Vietnam to solve the radioactive waste management problem, the IAEA Technical Co-operation (TC) project VIE/9/007 was implemented in Vietnam. The facilities and IAEA experts provided under this project gradually help to develop radioactive waste management at DNRI, Vietnam. This paper outlines progress under way in the management of the radioactive waste at the Nuclear Research Institute (NRI), Dalat, Vietnam, and the role of the IAEA Technical Co-operation (TC) project in this process. (author)

  18. Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling.

    Science.gov (United States)

    Moon, Seungtae; Lee, Yong-Kyu; Lee, Sang-Wang; Um, Soo-Jong

    2017-10-07

    BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What is the Role of Competence?

    Science.gov (United States)

    Kiecker, Clemens; Graham, Anthony; Logan, Malcolm

    2016-01-01

    A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic. PMID:29615599

  20. Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What is the Role of Competence?

    Directory of Open Access Journals (Sweden)

    Clemens Kiecker

    2016-12-01

    Full Text Available A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic.

  1. An Oncogenic Role for Alternative NF-κB Signaling in DLBCL Revealed upon Deregulated BCL6 Expression

    Directory of Open Access Journals (Sweden)

    Baochun Zhang

    2015-05-01

    Full Text Available Diffuse large B cell lymphoma (DLBCL is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.

  2. Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells.

    Science.gov (United States)

    Ghosh, Somnath; Ghosh, Anu; Krishna, Malini

    2015-12-01

    The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in γ-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased γ-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. The signaling role for chloride in the bidirectional communication between neurons and astrocytes.

    Science.gov (United States)

    Wilson, Corinne S; Mongin, Alexander A

    2018-01-09

    It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl - ) fluxes via the inhibitory GABA A and glycine receptors. Here, we discuss the putative contribution of Cl - fluxes and intracellular Cl - to other forms of information transfer in the CNS, namely the bidirectional communication between neurons and astrocytes. The manuscript (i) summarizes the generic functions of Cl - in cellular physiology, (ii) recaps molecular identities and properties of Cl - transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl - in the modulation of neuroglial communication. The existing literature suggests that neurons can alter astrocytic Cl - levels in a number of ways; via (a) the release of neurotransmitters and activation of glial transporters that have intrinsic Cl - conductance, (b) the metabotropic receptor-driven changes in activity of the electroneutral cation-Cl - cotransporter NKCC1, and (c) the transient, activity-dependent changes in glial cell volume which open the volume-regulated Cl - /anion channel VRAC. Reciprocally, astrocytes are thought to alter neuronal [Cl - ] i through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABA A and glycine receptor/Cl - channels, or (b) the gliotransmitter-driven stimulation of NKCC1. The most important recent developments in this area are the identification of the molecular composition and functional heterogeneity of brain VRAC channels, and the discovery of a new cytosolic [Cl - ] sensor - the Wnk family protein kinases. With new work in the field, our understanding of the role of Cl - in information processing within the CNS is expected to be significantly updated. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. BIOLOGICAL ROLE OF ALDO-KETO REDUCTASES IN RETINOIC ACID BIOSYNTHESIS AND SIGNALING

    Directory of Open Access Journals (Sweden)

    F. Xavier eRuiz

    2012-04-01

    Full Text Available Several aldo-keto reductase (AKR enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3, as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance.

  5. AMPK signaling in skeletal muscle during exercise: Role of reactive oxygen and nitrogen species.

    Science.gov (United States)

    Morales-Alamo, David; Calbet, Jose A L

    2016-09-01

    Reactive oxygen and nitrogen species (RONS) are generated during exercise depending on intensity, duration and training status. A greater amount of RONS is released during repeated high-intensity sprint exercise and when the exercise is performed in hypoxia. By activating adenosine monophosphate-activated kinase (AMPK), RONS play a critical role in the regulation of muscle metabolism but also in the adaptive responses to exercise training. RONS may activate AMPK by direct an indirect mechanisms. Directly, RONS may activate or deactivate AMPK by modifying RONS-sensitive residues of the AMPK-α subunit. Indirectly, RONS may activate AMPK by reducing mitochondrial ATP synthesis, leading to an increased AMP:ATP ratio and subsequent Thr(172)-AMPK phosphorylation by the two main AMPK kinases: LKB1 and CaMKKβ. In presence of RONS the rate of Thr(172)-AMPK dephosphorylation is reduced. RONS may activate LKB1 through Sestrin2 and SIRT1 (NAD(+)/NADH.H(+)-dependent deacetylase). RONS may also activate CaMKKβ by direct modification of RONS sensitive motifs and, indirectly, by activating the ryanodine receptor (Ryr) to release Ca(2+). Both too high (hypoxia) and too low (ingestion of antioxidants) RONS levels may lead to Ser(485)-AMPKα1/Ser(491)-AMPKα2 phosphorylation causing inhibition of Thr(172)-AMPKα phosphorylation. Exercise training increases muscle antioxidant capacity. When the same high-intensity training is applied to arm and leg muscles, arm muscles show signs of increased oxidative stress and reduced mitochondrial biogenesis, which may be explained by differences in RONS-sensing mechanisms and basal antioxidant capacities between arm and leg muscles. Efficient adaptation to exercise training requires optimal exposure to pulses of RONS. Inappropriate training stimulus may lead to excessive RONS formation, oxidative inactivation of AMPK and reduced adaptation or even maladaptation. Theoretically, exercise programs should be designed taking into account the

  6. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism.

    Science.gov (United States)

    Gregory, L C; Gaston-Massuet, C; Andoniadou, C L; Carreno, G; Webb, E A; Kelberman, D; McCabe, M J; Panagiotakopoulos, L; Saldanha, J W; Spoudeas, H A; Torpiano, J; Rossi, M; Raine, J; Canham, N; Martinez-Barbera, J P; Dattani, M T

    2015-05-01

    The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicating involvement in pituitary development. We aimed to establish the role of the HH pathway in the aetiology of hypothalamo-pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in SHH, GLI2, Shh brain enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1). Two variants and a deletion of GLI2 were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA-binding domain, c.1552G > A [pE518K], was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A [p.R720H], was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26·6 Mb deletion, 2q12·3-q21·3, encompassing GLI2 and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characterisation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2 mutations. No mutations were identified in GAS1 or SBE2. A novel SHH variant, c.1295T>A [p.I432N], was identified in two siblings with variable midline defects but normal pituitary function. Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for CH. © 2014 John Wiley & Sons Ltd.

  7. Nucleoside adducts are formed by cooperative reaction of acetaldehyde and alcohols: Possible mechanism for the role of ethanol in carcinogenesis

    International Nuclear Information System (INIS)

    Fraenkel-Conrat, H.; Singer, B.

    1988-01-01

    The exocyclic amino groups of ribonucleosides and deoxyribonucleosides react rapidly at ambient temperature with acetaldehyde and alcohols to yield mixed acetals [-NH-CH(CH 3 )OR]. Nucleotides and nucleoside di- and triphosphates also react. Depending on the nucleoside used and on the relative amounts of aldehyde, alcohol, and water, preparative reactions reach equilibrium with yields up to 75% in a few house. The structures have been confirmed by fast atom bombardment MS and proton NMR. Half-lives at 37 degree C have been determined, and maximum stability is in the pH range of 7.5-9.5. In the absence of alcohol, acetaldehyde-nucleoside adducts could be isolated at 4 degree C, but these were too unstable to characterize except for their UV spectra, also at 4 degree C. Ethanol is often present in human blood and tissues, and acetaldehyde is its initial metabolic product, as well as being formed by many other metabolic processes. Both chemicals have separately been implicated in carcinogenic and other cytophathologic processes, but no cooperative mechanism has been proposed. The reactions reported here are of biological concern because they also occur in dilute aqueous solution. These finding supply a mechanism by which ethanol can be covalently bound to nucleic acids under physiological conditions

  8. Making Cooperative Learning Groups Work.

    Science.gov (United States)

    Hawley, James; De Jong, Cherie

    1995-01-01

    Discusses the use of cooperative-learning groups with middle school students. Describes cooperative-learning techniques, including group roles, peer evaluation, and observation and monitoring. Considers grouping options, including group size and configuration, dyads, the think-pair-share lecture, student teams achievement divisions, jigsaw groups,…

  9. International cooperation Brazil-Cuba-Haiti: the role of community radios in strengthening social mobilization in the public health context in Haiti.

    Science.gov (United States)

    Gomes, Renata Machado Dos Santos; Oliveira, Valdir de Castro

    2015-01-01

    The present article investigates the role of Haitian community radios in strengthening social mobilization, with the aim of supporting the actions undertaken in the field of public health in Haiti, based on the development of the Workshop for community radios, as part of the Tripartite Cooperation Brazil-Cuba-Haiti. The qualitative methodology is justified because of the study content, an analysis of documents and direct observation, through a case study presented at the Workshop held in the department of Hinches, in Haiti. This meeting was held in the context of the Working Group on Tripartite Communication, under the responsibility of the Health Channel/Fiocruz, in partnership with the Department for Health Promotion and Environmental Prevention of the Ministry of Health and Population of Haiti (DPSPE/MSPP/Haiti), with a proposal to better structure a network of multipliers in health promotion.

  10. Social power, conflict policing, and the role of subordination signals in rhesus macaque society.

    Science.gov (United States)

    Beisner, Brianne A; Hannibal, Darcy L; Finn, Kelly R; Fushing, Hsieh; McCowan, Brenda

    2016-05-01

    Policing is a conflict-limiting mechanism observed in many primate species. It is thought to require a skewed distribution of social power for some individuals to have sufficiently high social power to stop others' fights, yet social power has not been examined in most species with policing behavior. We examined networks of subordination signals as a source of social power that permits policing behavior in rhesus macaques. For each of seven captive groups of rhesus macaques, we (a) examined the structure of subordination signal networks and used GLMs to examine the relationship between (b) pairwise dominance certainty and subordination network pathways and (c) policing frequency and social power (group-level convergence in subordination signaling pathways). Networks of subordination signals had perfect linear transitivity, and pairs connected by both direct and indirect pathways of signals had more certain dominance relationships than pairs with no such network connection. Social power calculated using both direct and indirect network pathways showed a heavy-tailed distribution and positively predicted conflict policing. Our results empirically substantiate that subordination signaling is associated with greater dominance relationship certainty and further show that pairs who signal rarely (or not at all) may use information from others' signaling interactions to infer or reaffirm the relative certainty of their own relationships. We argue that the network of formal dominance relationships is central to societal stability because it is important for relationship stability and also supports the additional stabilizing mechanism of policing. © 2016 Wiley Periodicals, Inc.

  11. Role of Mitochondrial Reactive Oxygen Species in the Activation of Cellular Signals, Molecules, and Function

    DEFF Research Database (Denmark)

    Indo, Hiroko P.; Hawkins, Clare L; Nakanishi, Ikuo

    2017-01-01

    -κB) and GATA signaling pathways. We have also reviewed the effects of ROS on the activation of MMP and HIF. There is significant evidence to support the hypothesis that mitochondrial superoxide can initiate signaling pathways following transport into the cytosol. In this study, we provide evidence of TATA...

  12. DKWSLLL, a versatile DXXXLL-type signal with distinct roles in the Cu(+)-regulated trafficking of ATP7B.

    Science.gov (United States)

    Lalioti, Vasiliki; Hernandez-Tiedra, Sonia; Sandoval, Ignacio V

    2014-08-01

    In the liver, the P-type ATPase and membrane pump ATP7B plays a crucial role in Cu(+) donation to cuproenzymes and in the elimination of excess Cu(+). ATP7B is endowed with a COOH-cytoplasmic (DE)XXXLL-type traffic signal. We find that accessory (Lys -3, Trp -2, Ser -1 and Leu +2) and canonical (D -4, Leu 0 and Leu +1) residues confer the DKWSLLL signal with the versatility required for the Cu(+)-regulated cycling of ATP7B between the trans-Golgi network (TGN) and the plasma membrane (PM). The separate mutation of these residues caused a disruption of the signal, resulting in different ATP7B distribution phenotypes. These phenotypes indicate the key roles of specific residues at separate steps of ATP7B trafficking, including sorting at the TGN, transport from the TGN to the PM and its endocytosis, and recycling to the TGN and PM. The distinct roles of ATP7B in the TGN and PM and the variety of phenotypes caused by the mutation of the canonical and accessory residues of the DKWSLLL signal can explain the separate or joined presentation of Wilson's cuprotoxicosis and the dysfunction of the cuproenzymes that accept Cu(+) at the TGN. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. 454 Transcriptome sequencing suggests a role for two-component signalling in cellularization and differentiation of barley endosperm transfer cells.

    Science.gov (United States)

    Thiel, Johannes; Hollmann, Julien; Rutten, Twan; Weber, Hans; Scholz, Uwe; Weschke, Winfriede

    2012-01-01

    Cell specification and differentiation in the endosperm of cereals starts at the maternal-filial boundary and generates the endosperm transfer cells (ETCs). Besides the importance in assimilate transfer, ETCs are proposed to play an essential role in the regulation of endosperm differentiation by affecting development of proximate endosperm tissues. We attempted to identify signalling elements involved in early endosperm differentiation by using a combination of laser-assisted microdissection and 454 transcriptome sequencing. 454 sequencing of the differentiating ETC region from the syncytial state until functionality in transfer processes captured a high proportion of novel transcripts which are not available in existing barley EST databases. Intriguingly, the ETC-transcriptome showed a high abundance of elements of the two-component signalling (TCS) system suggesting an outstanding role in ETC differentiation. All components and subfamilies of the TCS, including distinct kinds of membrane-bound receptors, have been identified to be expressed in ETCs. The TCS system represents an ancient signal transduction system firstly discovered in bacteria and has previously been shown to be co-opted by eukaryotes, like fungi and plants, whereas in animals and humans this signalling route does not exist. Transcript profiling of TCS elements by qRT-PCR suggested pivotal roles for specific phosphorelays activated in a coordinated time flow during ETC cellularization and differentiation. ETC-specificity of transcriptionally activated TCS phosphorelays was assessed for early differentiation and cellularization contrasting to an extension of expression to other grain tissues at the beginning of ETC maturation. Features of candidate genes of distinct phosphorelays and transcriptional activation of genes putatively implicated in hormone signalling pathways hint at a crosstalk of hormonal influences, putatively ABA and ethylene, and TCS signalling. Our findings suggest an integral

  14. The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Fajardo, Alexandra M.; Piazza, Gary A. [Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Ave, Suite 3029, Mobile, AL 36604 (United States); Tinsley, Heather N., E-mail: htinsley@montevallo.edu [Department of Biology, Chemistry, and Mathematics, University of Montevallo, Station 6480, Montevallo, AL 35115 (United States)

    2014-02-26

    For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

  15. An Origin of Cooperative Oxygen Binding of Human Adult Hemoglobin: Different Roles of the α and β Subunits in the α2β2 Tetramer.

    Directory of Open Access Journals (Sweden)

    Shigenori Nagatomo

    Full Text Available Human hemoglobin (Hb, which is an α2β2 tetramer and binds four O2 molecules, changes its O2-affinity from low to high as an increase of bound O2, that is characterized by 'cooperativity'. This property is indispensable for its function of O2 transfer from a lung to tissues and is accounted for in terms of T/R quaternary structure change, assuming the presence of a strain on the Fe-histidine (His bond in the T state caused by the formation of hydrogen bonds at the subunit interfaces. However, the difference between the α and β subunits has been neglected. To investigate the different roles of the Fe-His(F8 bonds in the α and β subunits, we investigated cavity mutant Hbs in which the Fe-His(F8 in either α or β subunits was replaced by Fe-imidazole and F8-glycine. Thus, in cavity mutant Hbs, the movement of Fe upon O2-binding is detached from the movement of the F-helix, which is supposed to play a role of communication. Recombinant Hb (rHb(αH87G, in which only the Fe-His in the α subunits is replaced by Fe-imidazole, showed a biphasic O2-binding with no cooperativity, indicating the coexistence of two independent hemes with different O2-affinities. In contrast, rHb(βH92G, in which only the Fe-His in the β subunits is replaced by Fe-imidazole, gave a simple high-affinity O2-binding curve with no cooperativity. Resonance Raman, 1H NMR, and near-UV circular dichroism measurements revealed that the quaternary structure change did not occur upon O2-binding to rHb(αH87G, but it did partially occur with O2-binding to rHb(βH92G. The quaternary structure of rHb(αH87G appears to be frozen in T while its tertiary structure is changeable. Thus, the absence of the Fe-His bond in the α subunit inhibits the T to R quaternary structure change upon O2-binding, but its absence in the β subunit simply enhances the O2-affinity of α subunit.

  16. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: Implications in targeted cancer therapies

    Science.gov (United States)

    Yang, Ke; Wang, Xin; Zhang, Hongmei; Wang, Zhongliang; Nan, Guoxin; Li, Yasha; Zhang, Fugui; Mohammed, Maryam K.; Haydon, Rex C.; Luu, Hue H.; Bi, Yang; He, Tong-Chuan

    2015-01-01

    The canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the canonical pathway is the activation of β-catenin mediated transcriptional activity. Canonical WNTs control the β-catenin dynamics as the cytoplasmic level of β-catenin is tightly regulated via phosphorylation by the ‘destruction complex’, consisting of glycogen synthase kinase 3β (GSK3β), casein kinase 1α (CK1α), the scaffold protein AXIN, and the tumor suppressor adenomatous polyposis coli (APC). Aberrant regulation of this signaling cascade is associated with varieties of human diseases, especially cancers. Over the past decade, significant progress has been made in understanding the mechanisms of canonical WNT signaling. In this review, we focus on the current understanding of WNT signaling at the extracellular, cytoplasmic membrane, and intracellular/nuclear levels, including the emerging knowledge of crosstalk with other pathways. Recent progresses in developing novel WNT pathway-targeted therapies will also be reviewed. Thus, this review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway. PMID:26618721

  17. Lipid binding to cytoglobin leads to a change in haem co-ordination: a role for cytoglobin in lipid signalling of oxidative stress.

    Science.gov (United States)

    Reeder, Brandon J; Svistunenko, Dimitri A; Wilson, Michael T

    2011-03-15

    Cytoglobin is a recently discovered hexa-co-ordinate haemoglobin that does not appear to function as a classical oxygen-binding protein. Its function is unknown and studies on the effects of changes in its expression have not decisively determined its role within the cell. In the present paper, we report that the protein is transformed from hexa-co-ordinate to penta-co-ordinate on binding a lipid molecule. This transformation occurs with the ferric oxidation state of the protein, but not the ferrous state, indicating that this process only occurs under an oxidative environment and may thus be related to redox-linked cell signalling mechanisms. Oleate binds to the protein in a 1:1 stoichiometry and with high affinity (K(d)=0.7 μM); however, stopped-flow kinetic measurements yield a K(d) value of 110 μM. The discrepancy between these K(d) values may be rationalized by recognizing that cytoglobin is a disulfide-linked dimer and invoking co-operativity in oleate binding. The lipid-induced transformation of cytoglobin from hexa-co-ordinate to penta-co-ordinate does not occur with similar hexa-co-ordinate haemoglobins such as neuroglobin, and therefore appears to be a unique property of cytoglobin among the haemoglobin superfamily. The lipid-derived transformation may explain why cytoglobin has enhanced peroxidatic activity, converting lipids into various oxidized products, a property virtually absent from neuroglobin and much decreased in myoglobin. We propose that the binding of ferric cytoglobin to lipids and their subsequent transformation may be integral to the physiological function of cytoglobin, generating cell signalling lipid molecules under an oxidative environment.

  18. The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice

    Science.gov (United States)

    You, Jae-Sung; Anderson, Garrett B.; Dooley, Matthew S.; Hornberger, Troy A.

    2015-01-01

    ABSTRACT The maintenance of skeletal muscle mass contributes substantially to health and to issues associated with the quality of life. It has been well recognized that skeletal muscle mass is regulated by mechanically induced changes in protein synthesis, and that signaling by mTOR is necessary for an increase in protein synthesis and the hypertrophy that occurs in response to increased mechanical loading. However, the role of mTOR signaling in the regulation of protein synthesis and muscle mass during decreased mechanical loading remains largely undefined. In order to define the role of mTOR signaling, we employed a mouse model of hindlimb immobilization along with pharmacological, mechanical and genetic means to modulate mTOR signaling. The results first showed that immobilization induced a decrease in the global rates of protein synthesis and muscle mass. Interestingly, immobilization also induced an increase in mTOR signaling, eIF4F complex formation and cap-dependent translation. Blocking mTOR signaling during immobilization with rapamycin not only impaired the increase in eIF4F complex formation, but also augmented the decreases in global protein synthesis and muscle mass. On the other hand, stimulating immobilized muscles with isometric contractions enhanced mTOR signaling and rescued the immobilization-induced decrease in global protein synthesis through a rapamycin-sensitive mechanism that was independent of ribosome biogenesis. Unexpectedly, the effects of isometric contractions were also independent of eIF4F complex formation. Similar to isometric contractions, overexpression of Rheb in immobilized muscles enhanced mTOR signaling, cap-dependent translation and global protein synthesis, and prevented the reduction in fiber size. Therefore, we conclude that the activation of mTOR signaling is both necessary and sufficient to alleviate the decreases in protein synthesis and muscle mass that occur during immobilization. Furthermore, these results indicate

  19. Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

    Science.gov (United States)

    Pilorge, M; Fassier, C; Le Corronc, H; Potey, A; Bai, J; De Gois, S; Delaby, E; Assouline, B; Guinchat, V; Devillard, F; Delorme, R; Nygren, G; Råstam, M; Meier, J C; Otani, S; Cheval, H; James, V M; Topf, M; Dear, T N; Gillberg, C; Leboyer, M; Giros, B; Gautron, S; Hazan, J; Harvey, R J; Legendre, P; Betancur, C

    2016-07-01

    Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive

  20. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

    NARCIS (Netherlands)

    Zhong, Leilei; Huang, X; Karperien, Hermanus Bernardus Johannes; Post, Janine Nicole

    2015-01-01

    Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the

  1. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen C

    2006-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways which in turn results in the loss of growth control in prostate cancer cells...

  2. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2004-01-01

    .... The experiments proposed in this application are based upon the hypothesis that stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  3. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2002-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  4. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen C

    2005-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  5. The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

    National Research Council Canada - National Science Library

    Gao, Allen

    2003-01-01

    .... The experiments proposed in this application are based upon the hypothesis that Stat3 activation alters androgen receptor signaling pathways, that in turn results in the loss of growth control in prostate cancer cells...

  6. The role of auxin and cytokinin signalling in specifying the root architecture of Arabidopsis thaliana

    KAUST Repository

    Muraro, Daniele; Byrne, Helen; King, John; Bennett, Malcolm

    2013-01-01

    these hormones and their signalling pathways. In this paper, sub-cellular and multi-cellular mathematical models are developed to investigate how interactions between auxin and cytokinin influence the size and location of regions of division and differentiation

  7. Role of Ethylene and Its Cross Talk with Other Signaling Molecules in Plant Responses to Heavy Metal Stress1

    Science.gov (United States)

    Thao, Nguyen Phuong; Khan, M. Iqbal R.; Thu, Nguyen Binh Anh; Hoang, Xuan Lan Thi; Asgher, Mohd; Khan, Nafees A.; Tran, Lam-Son Phan

    2015-01-01

    Excessive heavy metals (HMs) in agricultural lands cause toxicities to plants, resulting in declines in crop productivity. Recent advances in ethylene biology research have established that ethylene is not only responsible for many important physiological activities in plants but also plays a pivotal role in HM stress tolerance. The manipulation of ethylene in plants to cope with HM stress through various approaches targeting either ethylene biosynthesis or the ethylene signaling pathway has brought promising outcomes. This review covers ethylene production and signal transduction in plant responses to HM stress, cross talk between ethylene and other signaling molecules under adverse HM stress conditions, and approaches to modify ethylene action to improve HM tolerance. From our current understanding about ethylene and its regulatory activities, it is believed that the optimization of endogenous ethylene levels in plants under HM stress would pave the way for developing transgenic crops with improved HM tolerance. PMID:26246451

  8. Role of Cytokine-Induced Glycosylation Changes in Regulating Cell Interactions and Cell Signaling in Inflammatory Diseases and Cancer

    Directory of Open Access Journals (Sweden)

    Justine H. Dewald

    2016-11-01

    Full Text Available Glycosylation is one of the most important modifications of proteins and lipids, and cell surface glycoconjugates are thought to play important roles in a variety of biological functions including cell-cell and cell-substrate interactions, bacterial adhesion, cell immunogenicity and cell signaling. Alterations of glycosylation are observed in number of diseases such as cancer and chronic inflammation. In that context, pro-inflammatory cytokines have been shown to modulate cell surface glycosylation by regulating the expression of glycosyltransferases involved in the biosynthesis of carbohydrate chains. These changes in cell surface glycosylation are also known to regulate cell signaling and could contribute to disease pathogenesis. This review summarizes our current knowledge of the glycosylation changes induced by pro-inflammatory cytokines, with a particular focus on cancer and cystic fibrosis, and their consequences on cell interactions and signaling.

  9. Na/K-ATPase Signaling and Salt Sensitivity: The Role of Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Jiang Liu

    2017-03-01

    Full Text Available Other than genetic regulation of salt sensitivity of blood pressure, many factors have been shown to regulate renal sodium handling which contributes to long-term blood pressure regulation and have been extensively reviewed. Here we present our progress on the Na/K-ATPase signaling mediated sodium reabsorption in renal proximal tubules, from cardiotonic steroids-mediated to reactive oxygen species (ROS-mediated Na/K-ATPase signaling that contributes to experimental salt sensitivity.

  10. Differential Cellular Responses to Hedgehog Signalling in Vertebrates—What is the Role of Competence?

    OpenAIRE

    Clemens Kiecker; Anthony Graham; Malcolm Logan

    2016-01-01

    A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in compete...

  11. The role of lossless systems in modern digital signal processing: a tutorial

    OpenAIRE

    Vaidyanathan, P. P.; Doğanata, Zinnur

    1989-01-01

    A self-contained discussion of discrete-time lossless systems and their properties and relevance in digital signal processing is presented. The basic concept of losslessness is introduced, and several algebraic properties of lossless systems are studied. An understanding of these properties is crucial in order to exploit the rich usefulness of lossless systems in digital signal processing. Since lossless systems typically have many input and output terminals, a brief review of multiinput mult...

  12. [The role of Smads and related transcription factors in the signal transduction of bone morphogenetic protein inducing bone formation].

    Science.gov (United States)

    Xu, Xiao-liang; Dai, Ke-rong; Tang, Ting-ting

    2003-09-01

    To clarify the mechanisms of the signal transduction of bone morphogenetic proteins (BMPs) inducing bone formation and to provide theoretical basis for basic and applying research of BMPs. We looked up the literature of the role of Smads and related transcription factors in the signal transduction of BMPs inducing bone formation. The signal transduction processes of BMPs included: 1. BMPs combined with type II and type I receptors; 2. the type I receptor phosphorylated Smads; and 3. Smads entered the cell nucleus, interacted with transcription factors and influenced the transcription of related proteins. Smads could be divided into receptor-regulated Smads (R-Smads: Smad1, Smad2, Smad3, Smad5, Smad8 and Smad9), common-mediator Smad (co-Smad: Smad4), and inhibitory Smads (I-Smads: Smad6 and Smad7). Smad1, Smad5, Smad8, and probable Smad9 were involved in the signal transduction of BMPs. Multiple kinases, such as focal adhesion kinase (FAK), Ras-extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and Akt serine/threonine kinase were related to Smads signal transduction. Smad1 and Smad5 related with transcription factors included core binding factor A1 (CBFA1), smad-interacting protein 1 (SIP1), ornithine decarboxylase antizyme (OAZ), activating protein-1 (AP-1), xenopus ventralizing homeobox protein-2 (Xvent-2), sandostatin (Ski), antiproliferative proteins (Tob), and homeodomain-containing transcriptian factor-8 (Hoxc-8), et al. CBFA1 could interact with Smad1, Smad2, Smad3, and Smad5, so it was involved in TGF-beta and BMP-2 signal transduction, and played an important role in the bone formation. Cleidocranial dysplasia (CCD) was thought to be caused by heterozygous mutations in CBFA1. The CBFA1 knockout mice showed no osteogenesis and had maturational disturbance of chondrocytes. Smads and related transcription factors, especially Smad1, Smad5, Smad8 and CBFA1, play an important role in the signal transduction of BMPs inducing bone

  13. The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1

    Science.gov (United States)

    Alvares, Stacy M.; Dunn, Clarence A.; Brown, Tod A.; Wayner, Elizabeth E.; Carter, William G.

    2008-01-01

    Cell adhesion to the extracellular matrix (ECM) via integrin adhesion receptors initiates signaling cascades leading to changes in cell behavior. While integrin clustering is necessary to initiate cell attachment to the matrix, additional membrane components are necessary to mediate the transmembrane signals and the cell adhesion response that alter downstream cell behavior. Many of these signaling components reside in glycosphingolipid-rich and cholesterol-rich membrane domains such as Tetraspanin Enriched Microdomains (TEMs)/Glycosynapse 3 and Detergent-Resistant Microdomains (DRMs), also known as lipid rafts. In the following article, we will review examples of how components in these membrane microdomains modulate integrin adhesion after initial attachment to the ECM. Additionally, we will present data on a novel adhesion-responsive transmembrane glycoprotein Gp140/CUB Domain Containing Protein 1, which clusters in epithelial cell-cell contacts. Gp140 can then be phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals- possibly through interactions involving the extracellular CUB domains. Data presented here suggests that outside-in signals through Gp140 in cell-cell contacts assemble membrane clusters that associate with membrane microdomains to recruit and activate SFKs. Active SFKs then mediate phosphorylation of Gp140, SFK and PKCδ with Gp140 acting as a transmembrane scaffold for these kinases. We propose that the clustering of Gp140 and signaling components in membrane microdomains in cell-cell contacts contributes to changes in cell behavior. PMID:18269919

  14. mTOR signaling and its roles in normal and abnormal brain development.

    Directory of Open Access Journals (Sweden)

    Nobuyuki eTakei

    2014-04-01

    Full Text Available Target of rapamycin (TOR was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mTOR (mammalian TOR. mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system (CNS, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.

  15. Review article: the many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease.

    Science.gov (United States)

    Coates, M D; Tekin, I; Vrana, K E; Mawe, G M

    2017-09-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of every major gut-related function. Recent investigations also suggest that 5-HT can influence the development and severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD). To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD. We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5-HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5-HT signalling elements within the gut. Inflammation appears to affect every major element of intestinal 5-HT signalling, including 5-HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5-HT 4 R and antagonism of 5-HT 3 R) or 5-HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner. Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting. © 2017 John Wiley & Sons Ltd.

  16. A role for hedgehog signaling in the differentiation of the insertion site of the patellar tendon in the mouse.

    Directory of Open Access Journals (Sweden)

    Chia-Feng Liu

    Full Text Available Tendons are typically composed of two histologically different regions: the midsubstance and insertion site. We previously showed that Gli1, a downstream effector of the hedgehog (Hh signaling pathway, is expressed only in the insertion site of the mouse patellar tendon during its differentiation. To test for a functional role of Hh signaling, we targeted the Smoothened (Smo gene in vivo using a Cre/Lox system. Constitutive activation of the Hh pathway in the mid-substance caused molecular markers of the insertion site, e.g. type II collagen, to be ectopically expressed or up-regulated in the midsubstance. This was confirmed using a novel organ culture method in vitro. Conversely, when Smo was excised in the scleraxis-positive cell population, the development of the fibrocartilaginous insertion site was affected. Whole transcriptome analysis revealed that the expression of genes involved in chondrogenesis and mineralization was down-regulated in the insertion site, and expression of insertion site markers was decreased. Biomechanical testing of murine adult patellar tendon, which developed in the absence of Hh signaling, showed impairment of tendon structural properties (lower linear stiffness and greater displacement and material properties (greater strain, although the linear modulus of the mutant group was not significantly lower than controls. These studies provide new insights into the role of Hh signaling during tendon development.

  17. Jelektrojenergeticheskaja kooperacija v Baltijskom regione i rol' v nej Rossii [Electric energy cooperation in the Baltic Sea region and the role of Russia in it

    Directory of Open Access Journals (Sweden)

    Zverev Yuri

    2013-01-01

    Full Text Available This article examines cooperation in the electric energy sector in the Baltic region. The author explores the existing undersea HVDC power exchange projects. It is emphasised that cooperation in the electric energy sector is concentrated largely in the EU member states despite earlier plans to establish the Baltic energy ring, which would also include Russia and Belarus. The author stresses that one of the most acute problems for the EU today is overcoming isolation of the energy systems of the Baltic States (Lithuania, Latvia, and Estonia from that of the major part of the EU. This task has become especially relevant after the closing of the Ignalina NPP (Lithuania, which used to be the primary energy source for the three Baltic States. The article examines key projects of the construction of new international power transmission lines in the framework of the Baltic Energy Market Interconnection Plan (BEMIP and the prospects of the Visaginas NPP (Lithuania in solving energy problems of the Baltic States. The author analyses Russia’s role in the electric energy market and focuses on a possible increase of the country’s energy market share following the construction of the Baltic NPP and the export of generated electric energy to Poland, Lithuania, Germany, and Sweden. The author concludes that the prospects of Russia’s energy export to the Baltic Sea region will be determined not only by technological, economic and market factors, but rather by the general state of relations between Russia and the EU. Moreover, a lot depends on Lithuania’s decision on the construction of the Visaginas NPP, as well as the way the EU and the Baltic States solve the problem of energy supply in case the NPP project is terminated.

  18. Key role of integrin α(IIb)β (3) signaling to Syk kinase in tissue factor-induced thrombin generation.

    Science.gov (United States)

    van der Meijden, Paola E J; Feijge, Marion A H; Swieringa, Frauke; Gilio, Karen; Nergiz-Unal, Reyhan; Hamulyák, Karly; Heemskerk, Johan W M

    2012-10-01

    The fibrin(ogen) receptor, integrin α(IIb)β(3), has a well-established role in platelet spreading, aggregation and clot retraction. How α(IIb)β(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used α(IIb)β(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca(2+) responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in α(IIb)β(3) signaling similarly enhances thrombin-induced Ca(2+) rises and PS exposure. These responses are reduced in α(IIb)β(3)-deficient platelets from patients with Glanzmann's thrombasthenia. Furthermore, the contribution of α(IIb)β(3) to tissue factor-induced platelet Ca(2+) rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on α(IIb)β(3) activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca(2+) signal generation, and furthermore that a considerable part of Syk activation relies on α(IIb)β(3) signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation.

  19. Biphasic role of chondroitin sulfate in cardiac differentiation of embryonic stem cells through inhibition of Wnt/β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Robert D Prinz

    Full Text Available The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.

  20. Biphasic role of chondroitin sulfate in cardiac differentiation of embryonic stem cells through inhibition of Wnt/β-catenin signaling.

    Science.gov (United States)

    Prinz, Robert D; Willis, Catherine M; van Kuppevelt, Toin H; Klüppel, Michael

    2014-01-01

    The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.

  1. Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis.

    Science.gov (United States)

    Hu, Fang; Xu, Yong; Liu, Feng

    2016-06-01

    Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight. mTOR integrates signals from a variety of "energy balancing" hormones such as leptin, insulin, and ghrelin, although its action varies in response to these distinct hormonal stimuli as well as across different neuronal populations. In this review, we summarize and highlight recent findings regarding the functional roles of mTOR complex 1 (mTORC1) in the hypothalamus specifically in its regulation of body weight, energy expenditure, and glucose/lipid homeostasis. Understanding the role and underlying mechanisms behind mTOR-related signaling in the brain will undoubtedly pave new avenues for future therapeutics and interventions that can combat obesity, insulin resistance, and diabetes. Copyright © 2016 the American Physiological Society.

  2. Dual role of BMP signaling in the regulation of Drosophila intestinal stem cell self-renewal.

    Science.gov (United States)

    Tian, Aiguo; Jiang, Jin

    2017-10-02

    Many adult organs including Drosophila adult midguts rely on resident stem cells to replenish damaged cells during tissue homeostasis and regeneration. Previous studies have shown that, upon injury, intestinal stem cells (ISCs) in the midguts can increase proliferation and lineage differentiation to meet the demand for tissue repair. Our recent study has demonstrated that, in response to certain injury, midguts can expand ISC population size as an additional regenerative mechanism. We found that injury elicited by bleomycin feeding or bacterial infection increased the production of two BMP ligands (Dpp and Gbb) in enterocytes (ECs), leading to elevated BMP signaling in progenitor cells that drove an expansion of ISCs by promoting their symmetric self-renewing division. Interestingly, we also found that BMP signaling in ECs inhibits the production of Dpp and Gbb, and that this negative feedback mechanism is required to reset ISC pool size to the homeostatic state. Our findings suggest that BMP signaling exerts two opposing influences on stem cell activity depending on where it acts: BMP signaling in progenitor cells promotes ISC self-renewal while BMP signaling in ECs restricts ISC self-renewal by preventing excessive production of BMP ligands. Our results further suggest that transient expansion of ISC population in conjunction with increasing ISC proliferation provides a more effective strategy for tissue regeneration.

  3. Role of type I interferon receptor signaling on NK cell development and functions.

    Directory of Open Access Journals (Sweden)

    Jean Guan

    Full Text Available Type I interferons (IFN are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27+CD11b+ double positive (DP compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-γ production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions.

  4. Role of Nutrient-Sensing Signals in the Pathogenesis of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Shinji Kume

    2014-01-01

    Full Text Available Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. The multipronged drug approach still fails to fully prevent the onset and progression of diabetic nephropathy. Therefore, a new therapeutic target to improve the prognosis of diabetic nephropathy is urgently required. Nutrient-sensing signals and their related intracellular machinery have evolved to combat prolonged periods of starvation in mammals; and these systems are conserved in the kidney. Recent studies have suggested that the activity of three nutrient-sensing signals, mTORC1, AMPK, and Sirt1, is altered in the diabetic kidney. Furthermore, autophagy activity, which is regulated by the above-mentioned nutrient-sensing signals, is also altered in both podocytes and proximal tubular cells under diabetic conditions. Under diabetic conditions, an altered nutritional state owing to nutrient excess may disturb cellular homeostasis regulated by nutrient-responsible systems, leading to exacerbation of organelle dysfunction and diabetic nephropathy. In this review, we discuss new findings showing relationships between nutrient-sensing signals, autophagy, and diabetic nephropathy and suggest the therapeutic potential of nutrient-sensing signals in diabetic nephropathy.

  5. Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents.

    Science.gov (United States)

    Hickman, M J; Samson, L D

    1999-09-14

    All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O(6)-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O(6)-methylguanine (O(6)MeG) and O(6)-chloroethylguanine (O(6)CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSalpha branch of the DNA mismatch repair pathway (but not the MutSbeta branch) is absolutely required for signaling the initiation of apoptosis in response to O(6)MeGs and is partially required for signaling apoptosis in response to O(6)CEGs. Further, O(6)MeG lesions signal the stabilization of the p53 tumor suppressor, and such signaling is also MutSalpha-dependent. Despite this, MutSalpha-dependent apoptosis can be executed in a p53-independent manner. DNA mismatch repair status did not influence the response of cells to other inducers of p53 and apoptosis. Thus, it appears that mismatch repair status, rather than p53 status, is a strong indicator of the susceptibility of cells to alkylation-induced apoptosis. This experimental system will allow dissection of the signal transduction events that couple a specific type of DNA base lesion with the final outcome of apoptotic cell death.

  6. Revisiting the fear of snakes in children: the role of aposematic signalling.

    Science.gov (United States)

    Souchet, Jérémie; Aubret, Fabien

    2016-11-25

    Why humans fear snakes is an old, yet unresolved debate. Its innate origin from evolutionary causes is debated against the powerful influence early experience, culture, media and religion may have on people's aversion to snakes. Here we show that the aversion to snakes in human beings may have been mistaken for an aversion to aposematic signals that are commonly displayed by snakes. A total of 635 children were asked to rate single item images as "nice" or "mean". Snakes, pets and smiley emoticon items were not rated as "mean" unless they displayed subtle aposematic signals in the form of triangular (rather than round) shapes. Another 722 children were shown images featuring two items and asked which item was "nice" and which item was "mean". This context dependent comparison triggered even sharper responses to aposematic signals. We hypothesise that early primates evolved an aversion for aposematic signals in the form of potentially harmful triangular shapes such as teeth, claws or spikes, not for snakes per se. Further, we hypothesise that this adaptation was in turn exploited by snakes in their anti-predatory threat display as a triangular head or dorsal zig-zag pattern, and is currently the basis for efficient international road-danger signalling.

  7. New insights into the organization of plasma membrane and its role in signal transduction.

    Science.gov (United States)

    Suzuki, Kenichi G N

    2015-01-01

    Plasma membranes have heterogeneous structures for efficient signal transduction, required to perform cell functions. Recent evidence indicates that the heterogeneous structures are produced by (1) compartmentalization by actin-based membrane skeleton, (2) raft domains, (3) receptor-receptor interactions, and (4) the binding of receptors to cytoskeletal proteins. This chapter provides an overview of recent studies on diffusion, clustering, raft association, actin binding, and signal transduction of membrane receptors, especially glycosylphosphatidylinositol (GPI)-anchored receptors. Studies on diffusion of GPI-anchored receptors suggest that rafts may be small and/or short-lived in plasma membranes. In steady state conditions, GPI-anchored receptors form transient homodimers, which may represent the "standby state" for the stable homodimers and oligomers upon ligation. Furthermore, It is proposed that upon ligation, the binding of GPI-anchored receptor clusters to cytoskeletal actin filaments produces a platform for downstream signaling, and that the pulse-like signaling easily maintains the stability of the overall signaling activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Latin American cooperation on nuclear energy

    International Nuclear Information System (INIS)

    Faria, N.M. de; Associacao Brasileira de Direito Nuclear, Rio de Janeiro)

    1984-01-01

    The cooperation between Latin American countries on nuclear matters in which Brazil should play a significant role is presented. The possible areas for cooperation, particularly the nuclear law, are focused. The cooperation should be developed on bilateral or multilateral basis, by governmental and non governmental entities. (Author) [pt

  9. Neurodegeneration in Alzheimer Disease: Role of Amyloid Precursor Protein and Presenilin 1 Intracellular Signaling

    Directory of Open Access Journals (Sweden)

    Mario Nizzari

    2012-01-01

    Full Text Available Alzheimer disease (AD is a heterogeneous neurodegenerative disorder characterized by (1 progressive loss of synapses and neurons, (2 intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3 amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP and presenilin 1 and 2 (PS1 and PS2. The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration.

  10. Connective Tissue Disorders and Cardiovascular Complications: The indomitable role of Transforming Growth Factor-beta signaling

    Science.gov (United States)

    Wheeler, Jason B.; Ikonomidis, John S.; Jones, Jeffrey A.

    2015-01-01

    Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system. PMID:24443024

  11. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

    Science.gov (United States)

    2012-10-01

    PI3K/ Akt and MAPK/Erk signaling. We identified the A-type cyclin, cyclin A1 as an important downstream target of PI3K/ Akt (59); 3) autocrine IL-6...DACH1 inhibits transforming growth factor-beta signaling through binding Smad4 . J Biol Chem. 2003; 278(51):51673- 84. 33. Le Grand F, Grifone R, Mourikis...androgen receptor. Endocr Relat Cancer. 2009; 16(1):155-69. 59. Wegiel B, Bjartell A, Culig Z, Persson JL. Interleukin-6 activates PI3K/ Akt pathway

  12. Role of the middle ear muscle apparatus in mechanisms of speech signal discrimination

    Science.gov (United States)

    Moroz, B. S.; Bazarov, V. G.; Sachenko, S. V.

    1980-01-01

    A method of impedance reflexometry was used to examine 101 students with hearing impairment in order to clarify the interrelation between speech discrimination and the state of the middle ear muscles. Ability to discriminate speech signals depends to some extent on the functional state of intraaural muscles. Speech discrimination was greatly impaired in the absence of stapedial muscle acoustic reflex, in the presence of low thresholds of stimulation and in very small values of reflex amplitude increase. Discrimination was not impeded in positive AR, high values of relative thresholds and normal increase of reflex amplitude in response to speech signals with augmenting intensity.

  13. The role of mechanical force and ROS in integrin-dependent signals.

    Directory of Open Access Journals (Sweden)

    Kathrin S Zeller

    Full Text Available Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced by integrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition of ROCK and myosin II activity, i.e. the reactions occurred independently of intracellular contractile force acting on the adhesion sites. The contraction-independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching of the adherent cells induced a robust phosphorylation only of ERK1/2 and the phosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via α5β1 or αvβ3 integrins were detected. The importance of mitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signals induced by cyclic cell stretching, it abolished the activation of AKT and reduced the actin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composed of separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and

  14. Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for Staphylococcus aureus cutaneous host defense.

    Directory of Open Access Journals (Sweden)

    Philip O Scumpia

    2017-07-01

    Full Text Available Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs by pathogen recognition receptors (PRRs to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways-the Toll-like receptor (TLR and Stimulator of Interferon Gene (STING pathways-were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed S. aureus. This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS. Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus. TLR signaling was required for host defense, with its absence reducing interleukin (IL-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by S. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus.

  15. Multi-tasking role of the mechanosensing protein Ankrd2 in the signaling network of striated muscle.

    Directory of Open Access Journals (Sweden)

    Anna Belgrano

    Full Text Available Ankrd2 (also known as Arpp together with Ankrd1/CARP and DARP are members of the MARP mechanosensing proteins that form a complex with titin (N2A/calpain 3 protease/myopalladin. In muscle, Ankrd2 is located in the I-band of the sarcomere and moves to the nucleus of adjacent myofibers on muscle injury. In myoblasts it is predominantly in the nucleus and on differentiation shifts from the nucleus to the cytoplasm. In agreement with its role as a sensor it interacts both with sarcomeric proteins and transcription factors.Expression profiling of endogenous Ankrd2 silenced in human myotubes was undertaken to elucidate its role as an intermediary in cell signaling pathways. Silencing Ankrd2 expression altered the expression of genes involved in both intercellular communication (cytokine-cytokine receptor interaction, endocytosis, focal adhesion, tight junction, gap junction and regulation of the actin cytoskeleton and intracellular communication (calcium, insulin, MAPK, p53, TGF-β and Wnt signaling. The significance of Ankrd2 in cell signaling was strengthened by the fact that we were able to show for the first time that Nkx2.5 and p53 are upstream effectors of the Ankrd2 gene and that Ankrd1/CARP, another MARP member, can modulate the transcriptional ability of MyoD on the Ankrd2 promoter. Another novel finding was the interaction between Ankrd2 and proteins with PDZ and SH3 domains, further supporting its role in signaling. It is noteworthy that we demonstrated that transcription factors PAX6, LHX2, NFIL3 and MECP2, were able to bind both the Ankrd2 protein and its promoter indicating the presence of a regulatory feedback loop mechanism.In conclusion we demonstrate that Ankrd2 is a potent regulator in muscle cells affecting a multitude of pathways and processes.

  16. Role of ERK/MAPK in endothelin receptor signaling in human aortic smooth muscle cells

    DEFF Research Database (Denmark)

    Chen, Qing-wen; Edvinsson, Lars; Xu, Cang-Bao

    2009-01-01

    muscle cells (VSMCs) through activation of endothelin type A (ETA) and type B (ETB) receptors. The extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein kinases (MAPK) are involved in ET-1-induced VSMC contraction and proliferation. This study was designed to investigat...

  17. Subdural to subgaleal EEG signal transmission: The role of distance, leakage and insulating affectors

    DEFF Research Database (Denmark)

    Duun-Henriksen, Jonas; Kjaer, Troels Wesenberg; Madsen, Rasmus Elsborg

    2013-01-01

    Objective To estimate the area of cortex affecting the extracranial EEG signal. MethodsThe coherence between intra- and extracranial EEG channels were evaluated on at least 10min of spontaneous, awake data from seven patients admitted for epilepsy surgery work up. Results Cortical electrodes show...

  18. Regulatory role of adenosine signalling in heamatopoiesis: mobilization and in vitro studies

    Czech Academy of Sciences Publication Activity Database

    Weiterová, Lenka; Hofer, Michal; Pospíšil, Milan; Znojil, V.

    2004-01-01

    Roč. 5, Suppl. 2 (2004), s. S65-S66 ISSN 1466-4860. [Congress of the European Hematology Association /9./. 10.06.2004-13.06.2004, Geneva] R&D Projects: GA ČR GP305/03/D050; GA ČR GA305/02/0423 Keywords : adenosine signalling * heamatopoiesis Subject RIV: BO - Biophysics

  19. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction

    NARCIS (Netherlands)

    Green, J.; Nusse, R.; van Amerongen, R.

    2014-01-01

    Receptor tyrosine kinases of the Ryk and Ror families were initially classified as orphan receptors because their ligands were unknown. They are now known to contain functional extracellular Wnt-binding domains and are implicated in Wnt-signal transduction in multiple species. Although their

  20. The Effect of Nonverbal Signals on Student Role-Play Evaluations

    Science.gov (United States)

    Taute, Harry A.; Heiser, Robert S.; McArthur, David N.

    2011-01-01

    Although salespeople have long been urged to recognize and adapt to customer needs and wants by observing communications style and other cues or signals by the buyer, nonverbal communications by the salesperson have received much less empirical scrutiny. However, nonverbal communications may be important in this context; research in several…

  1. Predict or classify: The deceptive role of time-locking in brain signal classification

    Science.gov (United States)

    Rusconi, Marco; Valleriani, Angelo

    2016-06-01

    Several experimental studies claim to be able to predict the outcome of simple decisions from brain signals measured before subjects are aware of their decision. Often, these studies use multivariate pattern recognition methods with the underlying assumption that the ability to classify the brain signal is equivalent to predict the decision itself. Here we show instead that it is possible to correctly classify a signal even if it does not contain any predictive information about the decision. We first define a simple stochastic model that mimics the random decision process between two equivalent alternatives, and generate a large number of independent trials that contain no choice-predictive information. The trials are first time-locked to the time point of the final event and then classified using standard machine-learning techniques. The resulting classification accuracy is above chance level long before the time point of time-locking. We then analyze the same trials using information theory. We demonstrate that the high classification accuracy is a consequence of time-locking and that its time behavior is simply related to the large relaxation time of the process. We conclude that when time-locking is a crucial step in the analysis of neural activity patterns, both the emergence and the timing of the classification accuracy are affected by structural properties of the network that generates the signal.

  2. Social referencing and child anxiety: the evolutionary based role of fathers' versus mothers' signals

    NARCIS (Netherlands)

    Möller, E.L.; Majdandžić, M.; Vriends, N.; Bögels, S.M.

    2014-01-01

    Children use signals from others to guide their behavior when confronted with potentially dangerous situations, so called social referencing. Due to evolutionary based different expertise of fathers and mothers, parents might be different social references for their children. The present study

  3. An Origin of Cooperative Oxygen Binding of Human Adult Hemoglobin: Different Roles of the α and β Subunits in the α2β2 Tetramer

    Science.gov (United States)

    Sakurai, Hiroshi; Imai, Kiyohiro; Mizusawa, Naoki; Ogura, Takashi

    2015-01-01

    Human hemoglobin (Hb), which is an α2β2 tetramer and binds four O2 molecules, changes its O2-affinity from low to high as an increase of bound O2, that is characterized by ‘cooperativity’. This property is indispensable for its function of O2 transfer from a lung to tissues and is accounted for in terms of T/R quaternary structure change, assuming the presence of a strain on the Fe-histidine (His) bond in the T state caused by the formation of hydrogen bonds at the subunit interfaces. However, the difference between the α and β subunits has been neglected. To investigate the different roles of the Fe-His(F8) bonds in the α and β subunits, we investigated cavity mutant Hbs in which the Fe-His(F8) in either α or β subunits was replaced by Fe-imidazole and F8-glycine. Thus, in cavity mutant Hbs, the movement of Fe upon O2-binding is detached from the movement of the F-helix, which is supposed to play a role of communication. Recombinant Hb (rHb)(αH87G), in which only the Fe-His in the α subunits is replaced by Fe-imidazole, showed a biphasic O2-binding with no cooperativity, indicating the coexistence of two independent hemes with different O2-affinities. In contrast, rHb(βH92G), in which only the Fe-His in the β subunits is replaced by Fe-imidazole, gave a simple high-affinity O2-binding curve with no cooperativity. Resonance Raman, 1H NMR, and near-UV circular dichroism measurements revealed that the quaternary structure change did not occur upon O2-binding to rHb(αH87G), but it did partially occur with O2-binding to rHb(βH92G). The quaternary structure of rHb(αH87G) appears to be frozen in T while its tertiary structure is changeable. Thus, the absence of the Fe-His bond in the α subunit inhibits the T to R quaternary structure change upon O2-binding, but its absence in the β subunit simply enhances the O2-affinity of α subunit. PMID:26244770

  4. A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana.

    Science.gov (United States)

    Wang, Ting; Xu, Wei; Deng, Chenguang; Xu, Shaoxin; Li, Fanghua; Wu, Yuejin; Wu, Lijun; Bian, Po

    Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX and allene oxide synthase (AOS) genes, inhibited RIBE-mediated expression of the AtRAD54 gene, but up-regulated expression of the AtKU70 and AtLIG4 genes in the non-homologous end joining (NHEJ) pathway. Considering that NHEJ is employed by plants with increased DNA damage, the switch from HR to NHEJ suggests that over-accumulation of endogenous JA might enhance the radiosensitivity of plants

  5. Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration.

    Science.gov (United States)

    Deochand, Chetram; Tong, Ming; Agarwal, Amit R; Cadenas, Enrique; de la Monte, Suzanne M

    2016-01-01

    Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer's disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery (CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312-IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased AβPP-Aβ, and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal.

  6. CACN-1/Cactin plays a role in Wnt signaling in C. elegans.

    Directory of Open Access Journals (Sweden)

    Melissa LaBonty

    Full Text Available Wnt signaling is tightly regulated during animal development and controls cell proliferation and differentiation. In C. elegans, activation of Wnt signaling alters the activity of the TCF/LEF transcription factor, POP-1, through activation of the Wnt/β-catenin or Wnt/β-catenin asymmetry pathways. In this study, we have identified CACN-1 as a potential regulator of POP-1 in C. elegans larval development. CACN-1/Cactin is a well-conserved protein of unknown molecular function previously implicated in the regulation of several developmental signaling pathways. Here we have used activation of POPTOP, a POP-1-responsive reporter construct, as a proxy for Wnt signaling. POPTOP requires POP-1 and SYS-1/β-catenin for activation in L4 uterine cells. RNAi depletion experiments show that CACN-1 is needed to prevent excessive activation of POPTOP and for proper levels and/or localization of POP-1. Surprisingly, high POPTOP expression correlates with increased levels of POP-1 in uterine nuclei, suggesting POPTOP may not mirror endogenous gene expression in all respects. Genetic interaction studies suggest that CACN-1 may act partially through LIT-1/NLK to alter POP-1 localization and POPTOP activation. Additionally, CACN-1 is required for proper proliferation of larval seam cells. Depletion of CACN-1 results in a loss of POP-1 asymmetry and reduction of terminal seam cell number, suggesting an adoption of the anterior, differentiated fate by the posterior daughter cells. These findings suggest CACN-1/Cactin modulates Wnt signaling during larval development.

  7. FIP1 Plays an Important Role in Nitrate Signaling and Regulates CIPK8 and CIPK23 Expression in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Chao Wang

    2018-05-01

    Full Text Available Unraveling the molecular mechanisms of nitrate regulation and deciphering the underlying genetic network is vital for elucidating nitrate uptake and utilization in plants. Such knowledge could lead to the improvement of nitrogen-use efficiency in agriculture. Here, we report that the FIP1 gene (factor interacting with poly(A polymerase 1 plays an important role in nitrate signaling in Arabidopsis thaliana. FIP1 encodes a putative core component of the polyadenylation factor complex. We found that FIP1 interacts with the cleavage and polyadenylation specificity factor 30-L (CPSF30-L, which is also an essential player in nitrate signaling. The induction of nitrate-responsive genes following nitrate treatment was inhibited in the fip1 mutant. The nitrate content was also reduced in fip1 seedlings due to their decreased nitrate uptake activity. Furthermore, the nitrate content was higher in the roots but lower in the roots of fip1, which may result from the downregulation of NRT1.8 and the upregulation of the nitrate assimilation genes. In addition, qPCR analyses revealed that FIP1 negatively regulated the expression of CIPK8 and CIPK23, two protein kinases involved in nitrate signaling. In the fip1 mutant, the increased expression of CIPK23 may affect nitrate uptake, resulting in its lower nitrate content. Genetic and molecular evidence suggests that FIP1 and CPSF30-L function in the same nitrate-signaling pathway, with FIP1 mediating signaling through its interaction with CPSF30-L and its regulation of CIPK8 and CIPK23. Analysis of the 3′-UTR of NRT1.1 showed that the pattern of polyadenylation sites was altered in the fip1 mutant. These findings add a novel component to the nitrate regulation network and enhance our understanding of the underlying mechanisms for nitrate signaling.

  8. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity

    Institute of Scientific and Technical Information of China (English)

    Hui Wang; Rui-Yun Peng

    2016-01-01

    With key roles in essential brain functions ranging from the long-term potentiation (LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor (NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca2+,postsynaptic density 95 (PSD-95),calcium/calmodulin-dependent protein kinase Ⅱ (CaMK Ⅱ),protein kinase A (PKA),mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.

  9. Memo has a novel role in S1P signaling and is [corrected] crucial for vascular development.

    Science.gov (United States)

    Kondo, Shunya; Bottos, Alessia; Allegood, Jeremy C; Masson, Regis; Maurer, Francisca G; Genoud, Christel; Kaeser, Patrick; Huwiler, Andrea; Murakami, Masato; Spiegel, Sarah; Hynes, Nancy E

    2014-01-01

    Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.

  10. Role of JAK/STAT signaling in neuroepithelial stem cell maintenance and proliferation in the Drosophila optic lobe

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wei; Li, Yonggang; Zhou, Liya; Yue, Haitao [School of Life Sciences, Tsinghua University, Beijing 100084 (China); Luo, Hong, E-mail: luohong@mail.tsinghua.edu.cn [School of Life Sciences, Tsinghua University, Beijing 100084 (China)

    2011-07-15

    Highlights: {yields} JAK/STAT activity is graded in the Drosophila optic lobe neuroepithelium. {yields} Inactivation of JAK signaling causes disintegration of the optic lobe neuroepithelium and depletion of the neuroepithelial stem cells. {yields} JAK pathway overactivation promotes neuroepithelial overgrowth. {yields} Notch signaling acts downstream of JAK/STAT to promote neuroepithelial growth and expansion. -- Abstract: During Drosophila optic lobe development, proliferation and differentiation must be tightly modulated to reach its normal size for proper functioning. The JAK/STAT pathway plays pleiotropic roles in Drosophila development and in the larval brain, has been shown to inhibit medulla neuroblast formation. In this study, we find that JAK/STAT activity is required for the maintenance and proliferation of the neuroepithelial stem cells in the optic lobe. In loss-of-function JAK/STAT mutant brains, the neuroepithelial cells lose epithelial cell characters and differentiate prematurely while ectopic activation of this pathway is sufficient to induce neuroepithelial overgrowth in the optic lobe. We further show that Notch signaling acts downstream of JAK/STAT to control the maintenance and growth of the optic lobe neuroepithelium. Thus, in addition to its role in suppression of neuroblast formation, the JAK/STAT pathway is necessary and sufficient for optic lobe neuroepithelial growth.

  11. Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine.

    Science.gov (United States)

    Biswas, Amlan; Wilmanski, Jeanette; Forsman, Huamei; Hrncir, Tomas; Hao, Liming; Tlaskalova-Hogenova, Helena; Kobayashi, Koichi S

    2011-01-01

    A healthy intestinal tract is characterized by controlled homeostasis due to the balanced interaction between commensal bacteria and the host mucosal immune system. Human and animal model studies have supported the hypothesis that breakdown of this homeostasis may underlie the pathogenesis of inflammatory bowel diseases. However, it is not well understood how intestinal microflora stimulate the intestinal mucosal immune system and how such activation is regulated. Using a spontaneous, commensal bacteria-dependent colitis model in IL-10-deficient mice, we investigated the role of TLR and their negative regulation in intestinal homeostasis. In addition to IL-10(-/-) MyD88(-/-) mice, IL-10(-/-) TLR4(-/-) mice exhibited reduced colitis compared to IL-10(-/-) mice, indicating that TLR4 signaling plays an important role in inducing colitis. Interestingly, the expression of IRAK-M, a negative regulator of TLR signaling, is dependent on intestinal commensal flora, as IRAK-M expression was reduced in mice re-derived into a germ-free environment, and introduction of commensal bacteria into germ-free mice induced IRAK-M expression. IL-10(-/-) IRAK-M(-/-) mice exhibited exacerbated colitis with increased inflammatory cytokine gene expression. Therefore, this study indicates that intestinal microflora stimulate the colitogenic immune system through TLR and negative regulation of TLR signaling is essential in maintaining intestinal homeostasis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Role of Nuclear Factor (Erythroid-Derived 2-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Anna Hammer

    2017-12-01

    Full Text Available To date, the intracellular signaling pathways involved in dendritic cell (DC function are poorly understood. The antioxidative transcription factor nuclear factor (erythroid-derived 2-like 2 (Nrf2 has been shown to affect maturation, function, and subsequent DC-mediated T cell responses of murine and human DCs. In experimental autoimmune encephalomyelitis (EAE, as prototype animal model for a T helper cell-mediated autoimmune disease, antigen presentation, cytokine production, and costimulation by DCs play a major role. We explore the role of Nrf2 in DC function, and DC-mediated T cell responses during T cell-mediated autoimmunity of the central nervous system using genetic ablation and pharmacological activation in mice and men to corroborate our data in a translational setting. In murine and human DCs, monomethyl fumarate induced Nrf2 signaling inhibits DC maturation and DC-mediated T cell proliferation by reducing inflammatory cytokine production and expression of costimulatory molecules. In contrast, Nrf2-deficient DCs generate more activated T helper cells (Th1/Th17 but fewer regulatory T cells and foster T cell proliferation. Transfer of DCs with Nrf2 activation during active EAE reduces disease severity and T cell infiltration. Our data demonstrate that Nrf2 signaling modulates autoimmunity in murine and human systems via inhibiting DC maturation and function thus shedding further light on the mechanism of action of antioxidative stress pathways in antigen-presenting cells.

  13. Liver Inflammation and Metabolic Signaling in ApcMin/+ Mice: The Role of Cachexia Progression

    Science.gov (United States)

    Narsale, Aditi A.; Enos, Reilly T.; Puppa, Melissa J.; Chatterjee, Saurabh; Murphy, E. Angela; Fayad, Raja; Pena, Majorette O’; Durstine, J. Larry; Carson, James A.

    2015-01-01

    The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer

  14. Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.

    Directory of Open Access Journals (Sweden)

    Aditi A Narsale

    Full Text Available The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein, IRE-1α (endoplasmic reticulum to nucleus signaling 1, and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3. While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3. Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin, despite a suppression of Akt (thymoma viral proto-oncogene 1 and S6 (ribosomal protein S6 phosphorylation. Thus

  15. [Social cooperatives in Italy].

    Science.gov (United States)

    Villotti, P; Zaniboni, S; Fraccaroli, F

    2014-06-01

    This paper describes the role of social cooperatives in Italy as a type of economic, non-profit organization and their role in contributing to the economic and social growth of the country. The purpose of this paper is to learn more about the experience of the Italian social cooperatives in promoting the work integration process of disadvantaged workers, especially those suffering from mental disorders, from a theoretical and an empirical point of view. Social enterprise is the most popular and consolidated legal and organizational model for social enterprises in Italy, introduced by Law 381/91. Developed during the early 1980s, and formally recognized by law in the early 1990s, social cooperatives aim at pursuing the general interest of the community to promote the human needs and social inclusion of citizens. They are orientated towards aims that go beyond the interest of the business owners, the primary beneficiary of their activities is the community, or groups of disadvantaged people. In Italy, Law 381/91 distinguishes between two categories of social cooperatives, those producing goods of social utility, such as culture, welfare and educational services (A-type), and those providing economic activities for the integration of disadvantaged people into employment (B-type). The main purpose of B-type social cooperatives is to integrate disadvantaged people into the open labour market. This goal is reached after a period of training and working experience inside the firm, during which the staff works to improve both the social and professional abilities of disadvantaged people. During the years, B-type social co-ops acquired a particular relevance in the care of people with mental disorders by offering them with job opportunities. Having a job is central in the recovery process of people suffering from mental diseases, meaning that B-type social co-ops in Italy play an important rehabilitative and integrative role for this vulnerable population of workers. The

  16. The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats

    Directory of Open Access Journals (Sweden)

    Xinjing Yang

    2017-01-01

    Full Text Available Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20 and Yintang (GV29 was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored.

  17. Unfolding Role of a Danger Molecule Adenosine Signaling in Modulation of Microbial Infection and Host Cell Response

    Directory of Open Access Journals (Sweden)

    Jaden S. Lee

    2018-01-01

    Full Text Available Ectonucleotidases CD39 and CD73, specific nucleotide metabolizing enzymes located on the surface of the host, can convert a pro-inflammatory environment driven by a danger molecule extracellular-ATP to an adenosine-mediated anti-inflammatory milieu. Accordingly, CD39/CD73 signaling has been strongly implicated in modulating the intensity, duration, and composition of purinergic danger signals delivered to host. Recent studies have eluted potential roles for CD39 and CD73 in selective triggering of a variety of host immune cells and molecules in the presence of pathogenic microorganisms or microbial virulence molecules. Growing evidence also suggests that CD39 and CD73 present complimentary, but likely differential, actions against pathogens to shape the course and severity of microbial infection as well as the associated immune response. Similarly, adenosine receptors A2A and A2B have been proposed to be major immunomodulators of adenosine signaling during chronic inflammatory conditions induced by opportunistic pathogens, such as oral colonizer Porphyromonas gingivalis. Therefore, we here review the recent studies that demonstrate how complex network of molecules in the extracellular adenosine signaling machinery and their interactions can reshape immune responses and may also be targeted by opportunistic pathogens to establish successful colonization in human mucosal tissues and modulate the host immune response.

  18. The Role Dafachronic Acid Signaling in Development and Longevity in Caenorhabditis elegans: Digging Deeper Using Cutting Edge Analytical Chemistry

    Directory of Open Access Journals (Sweden)

    Hugo eAguilaniu

    2016-02-01

    Full Text Available Steroid hormones regulate physiological processes in species ranging from plants to humans. A wide range of steroid hormones exist, and their contributions to processes such as growth, reproduction, development, and aging, is almost always complex. Understanding the biosynthetic pathways that generate steroid hormones and the signaling pathways that mediate their effects is thus of fundamental importance. In this work, we review recent advances in (i the biological role of steroid hormones in the roundworm Caenorhabditis elegans and (ii the development of novel methods to facilitate the detection and identification of these molecules. Our current understanding of steroid signaling in this simple organism serves to illustrate the challenges we face moving forward. First, it seems clear that we have not yet identified all of the enzymes responsible for steroid biosynthesis and/or degradation. Second, perturbation of steroid signaling affects a wide range of phenotypes, and subtly different steroid molecules can have distinct effects. Finally, steroid hormone levels are critically important, and minute variations in quantity can profoundly impact a phenotype. Thus, it is imperative that we develop innovative analytical tools and combine them with cutting-edge approaches such as comprehensive and highly selective liquid chromatography coupled to mass spectrometry (LC-MS based or new methods such as supercritical fluid chromatography coupled to mass spectrometry (SFC-MS if we are to obtain a better understanding of the biological functions of steroid signaling.

  19. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction

    International Nuclear Information System (INIS)

    Dupont, Sirio

    2016-01-01

    Signalling from the extracellular matrix (ECM) is a fundamental cellular input that sustains proliferation, opposes cell death and regulates differentiation. Through integrins, cells perceive both the chemical composition and physical properties of the ECM. In particular, cell behaviour is profoundly influenced by the mechanical elasticity or stiffness of the ECM, which regulates the ability of cells to develop forces through their contractile actomyosin cytoskeleton and to mature focal adhesions. This mechanosensing ability affects fundamental cellular functions, such that alterations of ECM stiffness is nowadays considered not a simple consequence of pathology, but a causative input driving aberrant cell behaviours. We here discuss recent advances on how mechanical signals intersect nuclear transcription and in particular the activity of YAP/TAZ transcriptional coactivators, known downstream transducers of the Hippo pathway and important effectors of ECM mechanical cues.

  20. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction

    Energy Technology Data Exchange (ETDEWEB)

    Dupont, Sirio, E-mail: sirio.dupont@unipd.it

    2016-04-10

    Signalling from the extracellular matrix (ECM) is a fundamental cellular input that sustains proliferation, opposes cell death and regulates differentiation. Through integrins, cells perceive both the chemical composition and physical properties of the ECM. In particular, cell behaviour is profoundly influenced by the mechanical elasticity or stiffness of the ECM, which regulates the ability of cells to develop forces through their contractile actomyosin cytoskeleton and to mature focal adhesions. This mechanosensing ability affects fundamental cellular functions, such that alterations of ECM stiffness is nowadays considered not a simple consequence of pathology, but a causative input driving aberrant cell behaviours. We here discuss recent advances on how mechanical signals intersect nuclear transcription and in particular the activity of YAP/TAZ transcriptional coactivators, known downstream transducers of the Hippo pathway and important effectors of ECM mechanical cues.

  1. Role of Cbl-associated protein/ponsin in receptor tyrosine kinase signaling and cell adhesion

    Directory of Open Access Journals (Sweden)

    Ritva Tikkanen

    2012-10-01

    Full Text Available The Cbl-associated protein/ponsin (CAP is an adaptor protein that contains a so-called Sorbin homology (SoHo domain and three Src homology 3 (SH3 domains which are engaged in diverse protein-protein interactions. CAP has been shown to function in the regulation of the actin cytoskeleton and cell adhesion and to be involved in the differentiation of muscle cells and adipocytes. In addition, it participates in signaling pathways through several receptor tyrosine kinases such as insulin and neurotrophin receptors. In the last couple of years, several studies have shed light on the details of these processes and identified novel interaction partners of CAP. In this review, we summarize these recent findings and provide an overview on the function of CAP especially in cell adhesion and membrane receptor signaling.

  2. Nuclear energy and international cooperation

    International Nuclear Information System (INIS)

    Oshima, Keiichi

    1981-01-01

    There is no need to emphasize that nuclear energy cannot be developed without international cooperation at either the industrial or the academic level. In the meanwhile, there have been some marked political, economic and social changes in recent years which are posing constraints to the international cooperation in nuclear energy. The problems and constraints impeding nuclear power programs cannot be overcome by only one nation; international cooperation with common efforts to solve the problems is essential. Nuclear energy is different from fossil energy resources in that it is highly technology-intensive while others are resource-intensive. International cooperation in technology has an entirely different importance in the field of nuclear energy. Educational institutions will play a role in a new era of the international cooperation. (Mori, K.)

  3. Distinct transcriptional networks in quiescent myoblasts: a role for Wnt signaling in reversible vs. irreversible arrest.

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    Sindhu Subramaniam

    Full Text Available Most cells in adult mammals are non-dividing: differentiated cells exit the cell cycle permanently, but stem cells exist in a state of reversible arrest called quiescence. In damaged skeletal muscle, quiescent satellite stem cells re-enter the cell cycle, proliferate and subsequently execute divergent programs to regenerate both post-mitotic myofibers and quiescent stem cells. The molecular basis for these alternative programs of arrest is poorly understood. In this study, we used an established myogenic culture model (C2C12 myoblasts to generate cells in alternative states of arrest and investigate their global transcriptional profiles. Using cDNA microarrays, we compared G0 myoblasts with post-mitotic myotubes. Our findings define the transcriptional program of quiescent myoblasts in culture and establish that distinct gene expression profiles, especially of tumour suppressor genes and inhibitors of differentiation characterize reversible arrest, distinguishing this state from irreversibly arrested myotubes. We also reveal the existence of a tissue-specific quiescence program by comparing G0 C2C12 myoblasts to isogenic G0 fibroblasts (10T1/2. Intriguingly, in myoblasts but not fibroblasts, quiescence is associated with a signature of Wnt pathway genes. We provide evidence that different levels of signaling via the canonical Wnt pathway characterize distinct cellular states (proliferation vs. quiescence vs. differentiation. Moderate induction of Wnt signaling in quiescence is associated with critical properties such as clonogenic self-renewal. Exogenous Wnt treatment subverts the quiescence program and negatively affects clonogenicity. Finally, we identify two new quiescence-induced regulators of canonical Wnt signaling, Rgs2 and Dkk3, whose induction in G0 is required for clonogenic self-renewal. These results support the concept that active signal-mediated regulation of quiescence contributes to stem cell properties, and have implications for

  4. Distinct transcriptional networks in quiescent myoblasts: a role for Wnt signaling in reversible vs. irreversible arrest.

    Science.gov (United States)

    Subramaniam, Sindhu; Sreenivas, Prethish; Cheedipudi, Sirisha; Reddy, Vatrapu Rami; Shashidhara, Lingadahalli Subrahmanya; Chilukoti, Ravi Kumar; Mylavarapu, Madhavi; Dhawan, Jyotsna

    2014-01-01

    Most cells in adult mammals are non-dividing: differentiated cells exit the cell cycle permanently, but stem cells exist in a state of reversible arrest called quiescence. In damaged skeletal muscle, quiescent satellite stem cells re-enter the cell cycle, proliferate and subsequently execute divergent programs to regenerate both post-mitotic myofibers and quiescent stem cells. The molecular basis for these alternative programs of arrest is poorly understood. In this study, we used an established myogenic culture model (C2C12 myoblasts) to generate cells in alternative states of arrest and investigate their global transcriptional profiles. Using cDNA microarrays, we compared G0 myoblasts with post-mitotic myotubes. Our findings define the transcriptional program of quiescent myoblasts in culture and establish that distinct gene expression profiles, especially of tumour suppressor genes and inhibitors of differentiation characterize reversible arrest, distinguishing this state from irreversibly arrested myotubes. We also reveal the existence of a tissue-specific quiescence program by comparing G0 C2C12 myoblasts to isogenic G0 fibroblasts (10T1/2). Intriguingly, in myoblasts but not fibroblasts, quiescence is associated with a signature of Wnt pathway genes. We provide evidence that different levels of signaling via the canonical Wnt pathway characterize distinct cellular states (proliferation vs. quiescence vs. differentiation). Moderate induction of Wnt signaling in quiescence is associated with critical properties such as clonogenic self-renewal. Exogenous Wnt treatment subverts the quiescence program and negatively affects clonogenicity. Finally, we identify two new quiescence-induced regulators of canonical Wnt signaling, Rgs2 and Dkk3, whose induction in G0 is required for clonogenic self-renewal. These results support the concept that active signal-mediated regulation of quiescence contributes to stem cell properties, and have implications for pathological

  5. Pannexin 1 channels play essential roles in urothelial mechanotransduction and intercellular signaling.

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    Hiromitsu Negoro

    Full Text Available Urothelial cells respond to bladder distension with ATP release, and ATP signaling within the bladder and from the bladder to the CNS is essential for proper bladder function. In other cell types, pannexin 1 (Panx1 channels provide a pathway for mechanically-induced ATP efflux and for ATP-induced ATP release through interaction with P2X7 receptors (P2X7Rs. We report that Panx1 and P2X7R are functionally expressed in the bladder mucosa and in immortalized human urothelial cells (TRT-HU1, and participate in urothelial ATP release and signaling. ATP release from isolated rat bladders induced by distention was reduced by the Panx1 channel blocker mefloquine (MFQ and was blunted in mice lacking Panx1 or P2X7R expression. Hypoosmotic shock induced YoPro dye uptake was inhibited by MFQ and the P2X7R blocker A438079 in TRT-HU1 cells, and was also blunted in primary urothelial cells derived from mice lacking Panx1 or P2X7R expression. Rinsing-induced mechanical stimulation of TRT-HU1 cells triggered ATP release, which was reduced by MFQ and potentiated in low divalent cation solution (LDPBS, a condition known to enhance P2X7R activation. ATP signaling evaluated as intercellular Ca2+ wave radius was significantly larger in LDPBS, reduced by MFQ and by apyrase (ATP scavenger. These findings indicate that Panx1 participates in urothelial mechanotransduction and signaling by providing a direct pathway for mechanically-induced ATP release and by functionally interacting with P2X7Rs.

  6. The role of ethylene and wound signaling in resistance of tomato to Botrytis cinerea

    NARCIS (Netherlands)

    Díaz, J.; Have, ten A.; Kan, van J.A.L.

    2002-01-01

    Ethylene, jasmonate, and salicylate play important roles in plant defense responses to pathogens. To investigate the contributions of these compounds in resistance of tomato (Lycopersicon esculentum) to the fungal pathogen Botrytis cinerea, three types of experiments were conducted: (a) quantitative

  7. The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Hutchinson, John

    2002-01-01

    ...) and its downstream target Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we generated transgenic mice that express an activated Akt (Akt-DD...

  8. The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Hutchinson, John

    2001-01-01

    ...) and its downstream targets such as the Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we have generated transgenic mice that express an activated Akt (Akt-DD...

  9. E3 ligase Hei10: a multifaceted structure-based signaling molecule with roles within and beyond meiosis

    Science.gov (United States)

    De Muyt, Arnaud; Zhang, Liangran; Piolot, Tristan; Kleckner, Nancy; Espagne, Eric; Zickler, Denise

    2014-01-01

    Human enhancer of invasion-10 (Hei10) mediates meiotic recombination and also plays roles in cell proliferation. Here we explore Hei10’s roles throughout the sexual cycle of the fungus Sordaria with respect to localization and effects of null, RING-binding, and putative cyclin-binding (RXL) domain mutations. Hei10 makes three successive types of foci. Early foci form along synaptonemal complex (SC) central regions. At some of these positions, depending on its RING and RXL domains, Hei10 mediates development and turnover of two sequential types of recombination complexes, each demarked by characteristic amplified Hei10 foci. Integration with ultrastructural data for recombination nodules further reveals that recombination complexes differentiate into three types, one of which corresponds to crossover recombination events during or prior to SC formation. Finally, Hei10 positively and negatively modulates SUMO localization along SCs by its RING and RXL domains, respectively. The presented findings suggest that Hei10 integrates signals from the SC, associated recombination complexes, and the cell cycle to mediate both the development and programmed turnover/evolution of recombination complexes via SUMOylation/ubiquitination. Analogous cell cycle-linked assembly/disassembly switching could underlie localization and roles for Hei10 in centrosome/spindle pole body dynamics and associated nuclear trafficking. We suggest that Hei10 is a unique type of structure-based signal transduction protein. PMID:24831702

  10. Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

    Science.gov (United States)

    Deep, Gagan; Panigrahi, Gati K.

    2017-01-01

    Prostate cancer (PCA) is the leading malignancy in men and the second leading cause of cancer-related deaths. Hypoxia (low O2 condition) is considered an early event in prostate carcinogenesis associated with an aggressive phenotype. In fact, clinically, hypoxia and hypoxia-related biomarkers are associated with treatment failure and disease progression. Hypoxia-inducible factor 1 (HIF-1) is the key factor that is activated under hypoxia, and mediates adaptation of cells to hypoxic conditions through regulating the expression of genes associated with angiogenesis, epithelial-to-mesenchymal transition (EMT), metastasis, survival, proliferation, metabolism, stemness, hormone-refractory progression, and therapeutic resistance. Besides HIF-1, several other signaling pathways including PI3K/Akt/mTOR, NADPH oxidase (NOX), Wnt/β-catenin, and Hedgehog are activated in cancer cells under hypoxic conditions, and also contribute in hypoxia-induced biological effects in HIF-1-dependent and -independent manners. Hypoxic cancer cells cause extensive changes in the tumor microenvironment both local and distant, and recent studies have provided ample evidence supporting the crucial role of nanosized vesicles “exosomes” in mediating hypoxia-induced tumor microenvironment remodeling. Exosomes’ role has been reported in hypoxia-induced angiogenesis, stemness, activation of cancer-associated fibroblasts (CAFs), and EMT. Together, existing literature suggests that hypoxia plays a predominant role in PCA growth and progression, and PCA could be effectively prevented and treated via targeting hypoxia/hypoxia-related signaling pathways. PMID:27279239

  11. Genetic and proteomic evidence for roles of Drosophila SUMO in cell cycle control, Ras signaling, and early pattern formation.

    Directory of Open Access Journals (Sweden)

    Minghua Nie

    2009-06-01

    Full Text Available SUMO is a protein modifier that is vital for multicellular development. Here we present the first system-wide analysis, combining multiple approaches, to correlate the sumoylated proteome (SUMO-ome in a multicellular organism with the developmental roles of SUMO. Using mass-spectrometry-based protein identification, we found over 140 largely novel SUMO conjugates in the early Drosophila embryo. Enriched functional groups include proteins involved in Ras signaling, cell cycle, and pattern formation. In support of the functional significance of these findings, sumo germline clone embryos exhibited phenotypes indicative of defects in these same three processes. Our cell culture and immunolocalization studies further substantiate roles for SUMO in Ras signaling and cell cycle regulation. For example, we found that SUMO is required for efficient Ras-mediated MAP kinase activation upstream or at the level of Ras activation. We further found that SUMO is dynamically localized during mitosis to the condensed chromosomes, and later also to the midbody. Polo kinase, a SUMO substrate found in our screen, partially colocalizes with SUMO at both sites. These studies show that SUMO coordinates multiple regulatory processes during oogenesis and early embryogenesis. In addition, our database of sumoylated proteins provides a valuable resource for those studying the roles of SUMO in development.

  12. Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory.

    Science.gov (United States)

    Shen, Fang; Li, Yi-Jing; Shou, Xiao-Jing; Cui, Cai-Lian

    2012-09-01

    Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7-NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Role of Extracellular RNA and TLR3‐Trif Signaling in Myocardial Ischemia–Reperfusion Injury

    Science.gov (United States)

    Chen, Chan; Feng, Yan; Zou, Lin; Wang, Larry; Chen, Howard H.; Cai, Jia‐Yan; Xu, Jun‐Mei; Sosnovik, David E.; Chao, Wei

    2014-01-01

    Background Toll‐like receptor 3 (TLR3) was originally identified as the receptor for viral RNA and represents a major host antiviral defense mechanism. TLR3 may also recognize extracellular RNA (exRNA) released from injured tissues under certain stress conditions. However, a role for exRNA and TLR3 in the pathogenesis of myocardial ischemic injury has not been tested. This study examined the role of exRNA and TLR3 signaling in myocardial infarction (MI), apoptosis, inflammation, and cardiac dysfunction during ischemia‐reperfusion (I/R) injury. Methods and Results Wild‐type (WT), TLR3−/−, Trif−/−, and interferon (IFN) α/β receptor‐1 deficient (IFNAR1−/−) mice were subjected to 45 minutes of coronary artery occlusion and 24 hours of reperfusion. Compared with WT, TLR3−/− or Trif−/− mice had smaller MI and better preserved cardiac function. Surprisingly, unlike TLR(2/4)‐MyD88 signaling, lack of TLR3‐Trif signaling had no impact on myocardial cytokines or neutrophil recruitment after I/R, but myocardial apoptosis was significantly attenuated in Trif−/− mice. Deletion of the downstream IFNAR1 had no effect on infarct size. Importantly, hypoxia and I/R led to release of RNA including microRNA from injured cardiomyocytes and ischemic heart, respectively. Necrotic cardiomyocytes induced a robust and dose‐dependent cytokine response in cultured cardiomyocytes, which was markedly reduced by RNase but not DNase, and partially blocked in TLR3‐deficient cardiomyocytes. In vivo, RNase administration reduced serum RNA level, attenuated myocardial cytokine production, leukocytes infiltration and apoptosis, and conferred cardiac protection against I/R injury. Conclusion TLR3‐Trif signaling represents an injurious pathway during I/R. Extracellular RNA released during I/R may contribute to myocardial inflammation and infarction. PMID:24390148

  14. Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Besma Aouar

    Full Text Available Crosslinking of regulatory immunoreceptors (RR, such as BDCA-2 (CD303 or ILT7 (CD85g, of plasmacytoid dendritic cells (pDCs efficiently suppresses production of type-I interferon (IFN-α/β and other cytokines in response to Toll-like receptor (TLR 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs. Novel highly specific Syk inhibitor AB8779 suppressed IFN-α, TNF-α and IL-6 production induced by TLR7/9 agonists in primary pDCs and in the pDC cell line GEN2.2. Triggering of TLR9 or RR signaling induced a differential kinetics of phosphorylation at Y352 and Y525/526 of Syk and a differential sensitivity to AB8779. Consistent with the different roles of Syk in TLR7/9 and RR signaling, a concentration of AB8779 insufficient to block TLR7/9 signaling still released the block of IFN-α production triggered via the RR pathway, including that induced by hepatitis B and C viruses. Thus, pharmacological targeting of Syk partially restored the main pDC function-IFN-α production. Opposing roles of Syk in TLR7/9 and RR pathways may regulate the innate immune response to weaken inflammation reaction.

  15. Possible role of glutamine synthetase in the NO signaling response in root nodules by contributing to the antioxidant defenses

    Directory of Open Access Journals (Sweden)

    Liliana Santos Silva

    2013-09-01

    Full Text Available Nitric oxide (NO is emerging as an important regulatory player in the Rhizobium-legume symbiosis. The occurrence of NO during several steps of the symbiotic interaction suggests an important, but yet unknown, signaling role of this molecule for root nodule formation and functioning. The identification of the molecular targets of NO is key for the assembly of the signal transduction cascade that will ultimately help to unravel NO function. We have recently shown that the key nitrogen assimilatory enzyme Glutamine Synthetase (GS is a molecular target of NO in root nodules of Medicago truncatula, being post-translationally regulated by tyrosine nitration in relation to nitrogen fixation. In functional nodules of M. truncatula NO formation has been located in the bacteroid containing cells of the fixation zone, where the ammonium generated by bacterial nitrogenase is released to the plant cytosol and assimilated into the organic pools by plant GS. We propose that the NO-mediated GS post-translational inactivation is connected to nitrogenase inhibition induced by NO and is related to metabolite channeling to boost the nodule antioxidant defenses. Glutamate, a substrate for GS activity is also the precursor for the synthesis of glutathione (GSH, which is highly abundant in root nodules of several plant species and known to play a major role in the antioxidant defense participating in the ascorbate/GSH cycle. Existing evidence suggests that upon NO-mediated GS inhibition, glutamate could be channeled for the synthesis of GSH. According to this hypothesis, GS would be involved in the NO-signaling responses in root nodules and the NO-signaling events would meet the nodule metabolic pathways to provide an adaptive response to the inhibition of symbiotic nitrogen fixation by reactive nitrogen species (RNS.

  16. The unique and cooperative roles of the Grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity.

    Science.gov (United States)

    Boglev, Yeliz; Wilanowski, Tomasz; Caddy, Jacinta; Parekh, Vishwas; Auden, Alana; Darido, Charbel; Hislop, Nikki R; Cangkrama, Michael; Ting, Stephen B; Jane, Stephen M

    2011-01-15

    The Grainy head-like 3 (Grhl3) gene encodes a transcription factor that plays essential roles in epidermal morphogenesis during embryonic development, with deficient mice exhibiting failed skin barrier formation, defective wound repair, and loss of eyelid fusion. Despite sharing significant sequence homology, overlapping expression patterns, and an identical core consensus DNA binding site, the other members of the Grhl family (Grhl1 and -2) fail to compensate for the loss of Grhl3 in these processes. Here, we have employed diverse genetic models, coupled with biochemical studies, to define the inter-relationships of the Grhl factors in epidermal development. We show that Grhl1 and Grhl3 have evolved complete functional independence, as evidenced by a lack of genetic interactions in embryos carrying combinations of targeted alleles of these genes. In contrast, compound heterozygous Grhl2/Grhl3 embryos displayed failed wound repair, and loss of a single Grhl2 allele in Grhl3-null embryos results in fully penetrant eyes open at birth. Expression of Grhl2 from the Grhl3 locus in homozygous knock-in mice corrects the wound repair defect, but these embryos still display a complete failure of skin barrier formation. This functional dissociation is due to unexpected differences in target gene specificity, as both GRHL2 and GRHL3 bind to and regulate expression of the wound repair gene Rho GEF 19, but regulation of the barrier forming gene, Transglutaminase 1 (TGase1), is unique to GRHL3. Our findings define the mechanisms underpinning the unique and cooperative roles of the Grhl genes in epidermal development. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance

    Science.gov (United States)

    Mohammed, Maryam K.; Shao, Connie; Wang, Jing; Wei, Qiang; Wang, Xin; Collier, Zachary; Tang, Shengli; Liu, Hao; Zhang, Fugui; Huang, Jiayi; Guo, Dan; Lu, Minpeng; Liu, Feng; Liu, Jianxiang; Ma, Chao; Shi, Lewis L.; Athiviraham, Aravind; He, Tong-Chuan; Lee, Michael J.

    2016-01-01

    Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in control of cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best characterized among the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of many cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance. PMID:27077077

  18. Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling

    International Nuclear Information System (INIS)

    Singhal, Sharad S.; Singh, Sharda P.; Singhal, Preeti; Horne, David; Singhal, Jyotsana; Awasthi, Sanjay

    2015-01-01

    4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes — higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article. - Highlights: • GSTs are the major

  19. Role of Activin-A and Myostatin and Their Signaling Pathway in Human Myometrial and Leiomyoma Cell Function

    Science.gov (United States)

    Islam, Md Soriful; Catherino, William H.; Protic, Olga; Janjusevic, Milijana; Gray, Peter Clarke; Giannubilo, Stefano Raffaele; Ciavattini, Andrea; Lamanna, Pasquale; Tranquilli, Andrea Luigi; Petraglia, Felice

    2014-01-01

    Context: Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. Objective: The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. Design: This was a laboratory study. Setting: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. Patients: The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Interventions: Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. Results: We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. Conclusions: This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling. PMID:24606069

  20. Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors.

    Science.gov (United States)

    Haugen, Martin; Dammen, Rikard; Svejda, Bernhard; Gustafsson, Bjorn I; Pfragner, Roswitha; Modlin, Irvin; Kidd, Mark

    2012-11-15

    The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O(2). Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O(2) would reduce 5-HT production and secretion. Isolated normal EC cells as well as the well-characterized EC cell model KRJ-I were used to examine HIF signaling (luciferase-assays), hypoxia transcriptional response element (HRE)-mediated transcription (PCR), signaling pathways (Western blot), and 5-HT release (ELISA) during exposure to different oxygen levels. Normal EC cells and KRJ-I cells express HIF-1α, and transient transfection with Renilla luciferase under HRE control identified a hypoxia-mediated pathway in these cells. PCR confirmed activation of HIF-downstream targets, GLUT1, IGF2, and VEGF under reduced O(2) levels (0.5%). Reducing O(2) also elevated 5-HT secretion (2-3.2-fold) as well as protein levels of HIF-1α (1.7-3-fold). Increasing O(2) to 100% inhibited HRE-mediated signaling, transcription, reduced 5-HT secretion, and significantly lowered HIF-1α levels (∼75% of control). NF-κB signaling was also elevated during hypoxia (1.2-1.6-fold), but no significant changes were noted in PKA/cAMP. We concluded that gut EC cells are oxygen responsive, and alterations in O(2) levels differentially activate HIF-1α and tryptophan hydroxylase 1, as well as NF-κB signaling. This results in alterations in 5-HT production and secretion and identifies that the chemomechanosensory role of EC cells extends to oxygen sensing.

  1. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

    Science.gov (United States)

    Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

    2011-01-01

    The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

  2. The Role of Peroxiredoxins in the Transduction of H2O2 Signals.

    Science.gov (United States)

    Rhee, Sue Goo; Woo, Hyun Ae; Kang, Dongmin

    2018-03-01

    Hydrogen peroxide (H 2 O 2 ) is produced on stimulation of many cell surface receptors and serves as an intracellular messenger in the regulation of diverse physiological events, mostly by oxidizing cysteine residues of effector proteins. Mammalian cells express multiple H 2 O 2 -eliminating enzymes, including catalase, glutathione peroxidase (GPx), and peroxiredoxin (Prx). A conserved cysteine in Prx family members is the site of oxidation by H 2 O 2 . Peroxiredoxins possess a high-affinity binding site for H 2 O 2 that is lacking in catalase and GPx and which renders the catalytic cysteine highly susceptible to oxidation, with a rate constant several orders of magnitude greater than that for oxidation of cysteine in most H 2 O 2 effector proteins. Moreover, Prxs are abundant and present in all subcellular compartments. The cysteines of most H 2 O 2 effectors are therefore at a competitive disadvantage for reaction with H 2 O 2 . Recent Advances: Here we review intracellular sources of H 2 O 2 as well as H 2 O 2 target proteins classified according to biochemical and cellular function. We then highlight two strategies implemented by cells to overcome the kinetic disadvantage of most target proteins with regard to H 2 O 2 -mediated oxidation: transient inactivation of local Prx molecules via phosphorylation, and indirect oxidation of target cysteines via oxidized Prx. Critical Issues and Future Directions: Recent studies suggest that only a small fraction of the total pools of Prxs and H 2 O 2 effector proteins localized in specific subcellular compartments participates in H 2 O 2 signaling. Development of sensitive tools to selectively detect phosphorylated Prxs and oxidized effector proteins is needed to provide further insight into H 2 O 2 signaling. Antioxid. Redox Signal. 28, 537-557.

  3. A role of TDIF peptide signaling in vascular cell differentiation is conserved among euphyllophytes

    Directory of Open Access Journals (Sweden)

    Yuki eHirakawa

    2015-11-01

    Full Text Available Peptide signals mediate a variety of cell-to-cell communication crucial for plant growth and development. During Arabidopsis thaliana vascular development, a CLE (CLAVATA3/EMBRYO SURROUNDING REGION-related family peptide hormone, TDIF (tracheary element differentiation inhibitory factor, regulates procambial cell fate by its inhibitory activity on xylem differentiation. To address if this activity is conserved among vascular plants, we performed comparative analyses of TDIF signaling in non-flowering vascular plants (gymnosperms, monilophytes and lycophytes. We identified orthologs of TDIF/CLE as well as its receptor TDR/PXY (TDIF RECEPTOR/PHLOEM INTERCALATED WITH XYLEM in Ginkgo biloba, Adiantum aethiopicum and Selaginella kraussiana by RACE-PCR. The predicted TDIF peptide sequences in seed plants and monilophytes were identical to that of A. thaliana TDIF. We examined the effects of exogenous CLE peptide-motif sequences of TDIF in these species. We found that liquid culturing of dissected leaves or shoots was useful for examining TDIF activity during vascular development. TDIF treatment suppressed xylem/tracheary element differentiation of procambial cells in G. bioloba and A. aethiopicum leaves. In contrast, neither TDIF nor putative endogenous TDIF inhibited xylem differentiation in developing shoots and rhizophores of S. kraussiana. These data suggest that activity of TDIF in vascular development is conserved among extant euphyllophytes. In addition to the conserved function, via liquid culturing of its bulbils, we found a novel inhibitory activity on root growth in the monilophyte Asplenium x lucrosum suggesting lineage-specific co-option of peptide signaling occurred during the evolution of vascular plant organs.

  4. Bang-bang control of feeding: role of hypothalamic and satiety signals.

    Directory of Open Access Journals (Sweden)

    B Silvano Zanutto

    2007-05-01

    Full Text Available Rats, people, and many other omnivores eat in meals rather than continuously. We show by experimental test that eating in meals is regulated by a simple bang-bang control system, an idea foreshadowed by Le Magnen and many others, shown by us to account for a wide range of behavioral data, but never explicitly tested or tied to neurophysiological facts. The hypothesis is simply that the tendency to eat rises with time at a rate determined by satiety signals. When these signals fall below a set point, eating begins, in on-off fashion. The delayed sequelae of eating increment the satiety signals, which eventually turn eating off. Thus, under free conditions, the organism eats in bouts separated by noneating activities. We report an experiment with rats to test novel predictions about meal patterns that are not explained by existing homeostatic approaches. Access to food was systematically but unpredictably interrupted just as the animal tried to start a new meal. A simple bang-bang model fits the resulting meal-pattern data well, and its elements can be identified with neurophysiological processes. Hypothalamic inputs can provide the set point for longer-term regulation carried out by a comparator in the hindbrain. Delayed gustatory and gastrointestinal aftereffects of eating act via the nucleus of the solitary tract and other hindbrain regions as neural feedback governing short-term regulation. In this way, the model forges real links between a functioning feedback mechanism, neuro-hormonal data, and both short-term (meals and long-term (eating-rate regulation behavioral data.

  5. Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction

    DEFF Research Database (Denmark)

    Frödin, M; Gammeltoft, S

    1999-01-01

    ), which were among the first substrates of ERK to be discovered and which has proven to be a ubiquitous and versatile mediator of ERK signal transduction. RSK is composed of two functional kinase domains that are activated in a sequential manner by a series of phosphorylations. Recently, a family of RSK......-related kinases that are activated by ERK as well as p38 MAPK were discovered and named mitogen- and stress-activated protein kinases (MSK). A number of cellular functions of RSK have been proposed. (1) Regulation of gene expression via association and phosphorylation of transcriptional regulators including c...

  6. Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents

    OpenAIRE

    Hickman, Mark J.; Samson, Leona D.

    1999-01-01

    All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O6-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O6-methylguanine (O6MeG) and O6-chloroethylguanine (O6CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSα branch of the DNA mismatch repair pathway (but not the MutSβ branch) is absolutely required for signaling the ...

  7. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

    Science.gov (United States)

    2013-10-01

    Wu K, Wang L, Jiao X, Ju X, Li Z, Ertel A, Addya S, McCue P, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. Androgen therapy resistant...Li Z, Hu J, Chen K, Wu J, Pestell RG. DACH1 inhibited prostate cancer cellular proliferation and Interleukon-6 signaling. AACR 103rd Annual Meeting...March 31 – April 4, 2012, Chicago, IL.  Wang J, Cai S, Chen K, Sun Y, Li S, Pestell RG, Wu K. Regulation of AR transcriptional activity and

  8. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenes

    Science.gov (United States)

    2015-12-01

    S, Zhang W, Zhou J, Wang J, Ertel A, Li Z, Rui H, Quong A, Lisanti MP, Tozeren A, Tanes C, Addya S, Gormley M, Wang C, McMahon SB, Pestell RG...MP, Wang C, Pestell RG. Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer. Oncotarget...MP, Quong A, Ertel A, Pestell RG. Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation. Cancer Res. 2014;74(3):829

  9. The role of muscarinic cholinergic signaling in cost-benefit decision making

    Science.gov (United States)

    Fobbs, Wambura

    Animals regularly face decisions that affect both their immediate success and long term survival. Such decisions typically involve some form of cost-benefit analysis and engage a number of high level cognitive processes, including learning, memory and motivational influences. While decision making has been a focus of study for over a century, it's only in the last 20 years that researchers have begun to identify functional neural circuits that subserve different forms of cost-benefit decision making. Even though the cholinergic system is both functionally and anatomically positioned to modulate cost-benefit decision circuits, the contribution of the cholinergic system to decision making has been little studied. In this thesis, I investigated the cognitive and neural contribution of muscarinic cholinergic signaling to cost-benefit decision making. I, first, re-examined the effects of systemic administration of 0.3 mg/kg atropine on delay and probability discounting tasks and found that blockade of muscarinic acetylcholine receptors by atropine induced suboptimal choices (impulsive and risky) in both tasks. Since the effect on delay discounting was restricted to the No Cue version of the delay discounting task, I concluded that muscarinic cholinergic signaling mediates both forms of cost-benefit decision making and is selectively engaged when decisions require valuation of reward options whose costs are not externally signified. Second, I assessed the impact of inactivating the nucleus basalis (NBM) on both forms decision making and the effect of injecting atropine locally into the orbitofrontal cortex (OFC), basolateral amygdala (BLA), or nucleus accumbens (NAc) core during the No Cue version of the delay discounting task. I discovered that although NBM inactivation failed to affect delay discounting, it induced risk aversion in the probability discounting task; and blockade of intra- NAc core, but not intra-OFC or intra-BLA, muscarinic cholinergic signaling lead to

  10. Living without insulin: the role of leptin signaling in the hypothalamus

    Directory of Open Access Journals (Sweden)

    Teppei eFujikawa

    2015-03-01

    Full Text Available Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS regulates glucose metabolism in an insulin-independent manner.

  11. The role of protease-activated receptor type 2 in nociceptive signaling and pain

    Czech Academy of Sciences Publication Activity Database

    Mrózková, Petra; Paleček, Jiří; Špicarová, Diana

    2016-01-01

    Roč. 65, č. 3 (2016), s. 357-367 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LH12058; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA15-11138S; GA MŠk(CZ) LH15279; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : protease-activated receptor (PAR2) * signaling pathways * nociception * pain * spinal cord Subject RIV: FH - Neurology Impact factor: 1.461, year: 2016

  12. Transboundary cooperation

    International Nuclear Information System (INIS)

    Rauber, D.

    2006-01-01

    The operation of nuclear power plants near national borders requires a close bilateral co-operation to cope with accidents having off-site radiological impacts. For example in 1978 such an agreement was signed by the German and Swiss government. The accident at the Chernobyl NPP changed the international co-operation in the framework of international consequence management. International conventions were agreed to insure a timely notification and international assistance in case of an accident with transboundary effects. In order to fulfill these conventions several procedures were introduced. In addition, bilateral agreements were signed also with countries which are not operating nuclear power plants near national borders. Since then no accident took place that would have required any notification. However, following the experience the expectations to these networks have changed considerably and hence sustainable development is required to cope with new challenges such as long term consequences management, new radiological threats, faster international assistance, media and public concerns, and technical evolution of communications systems. (author)

  13. Role of CBFs as Integrators of Chloroplast Redox, Phytochrome and Plant Hormone Signaling during Cold Acclimation

    Directory of Open Access Journals (Sweden)

    Norman P. A. Hüner

    2013-06-01

    Full Text Available Cold acclimation of winter cereals and other winter hardy species is a prerequisite to increase subsequent freezing tolerance. Low temperatures upregulate the expression of C-repeat/dehydration-responsive element binding transcription factors (CBF/DREB1 which in turn induce the expression of COLD-REGULATED (COR genes. We summarize evidence which indicates that the integration of these interactions is responsible for the dwarf phenotype and enhanced photosynthetic performance associated with cold-acclimated and CBF-overexpressing plants. Plants overexpressing CBFs but grown at warm temperatures mimic the cold-tolerant, dwarf, compact phenotype; increased photosynthetic performance; and biomass accumulation typically associated with cold-acclimated plants. In this review, we propose a model whereby the cold acclimation signal is perceived by plants through an integration of low temperature and changes in light intensity, as well as changes in light quality. Such integration leads to the activation of the CBF-regulon and subsequent upregulation of COR gene and GA 2-oxidase (GA2ox expression which results in a dwarf phenotype coupled with increased freezing tolerance and enhanced photosynthetic performance. We conclude that, due to their photoautotrophic nature, plants do not rely on a single low temperature sensor, but integrate changes in light intensity, light quality, and membrane viscosity in order to establish the cold-acclimated state. CBFs appear to act as master regulators of these interconnecting sensing/signaling pathways.

  14. The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing [Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (United States); Yang, Haifeng, E-mail: qing_zhang@dfci.harvard.edu [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH (United States); Haifeng Yang, E-mail: yangh2@ccf.org [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, NB-40, 9500 Euclid Avenue, Cleveland, OH 44195 (United States)

    2012-04-12

    The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL’s tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.

  15. Role of dihydrotestosterone (DHT) on TGF-β1 signaling pathway in epithelial ovarian cancer cells.

    Science.gov (United States)

    Kohan-Ivani, Karla; Gabler, Fernando; Selman, Alberto; Vega, Margarita; Romero, Carmen

    2016-01-01

    One of the hypotheses regarding the genesis of epithelial ovarian cancer involves the action of androgens on the proliferation of epithelial ovarian cells, as well as inclusion cysts. The purpose of the present study was to evaluate whether DHT causes changes in the TGF-β1 pathway that might modify the anti-proliferative effect of the latter. The levels of TGF-β1 protein, of its receptors (TGFBR1 and TGFBR2), of Smad2/3 (canonical signaling pathway protein) and of p21 (cell cycle protein) were assessed in ovarian tissues, epithelial ovarian cancer cell lines (A27