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Sample records for response regulator irr

  1. Differential control of Bradyrhizobium japonicum iron stimulon genes through variable affinity of the iron response regulator (Irr) for target gene promoters and selective loss of activator function.

    Science.gov (United States)

    Jaggavarapu, Siddharth; O'Brian, Mark R

    2014-05-01

    Bradyrhizobium japonicum Irr is a conditionally stable transcriptional activator and repressor that accumulates in cells under iron-limited, manganese-replete conditions, but degrades in a haem-dependent manner under high iron conditions, manganese limitation or upon exposure to H2 O2 . Here, we identified Irr-regulated genes that were relatively unresponsive to factors that promote Irr degradation. The promoters of those genes bound Irr with at least 200-fold greater affinity than promoters of the responsive genes, resulting in maintenance of promoter occupancy over a wide cellular Irr concentration range. For Irr-repressible genes, promoter occupancy correlated with transcriptional repression, resulting in differential levels of expression based on Irr affinity for target promoters. However, inactivation of positively controlled genes required neither promoter vacancy nor loss of DNA-binding activity by Irr. Thus, activation and repression functions of Irr may be uncoupled from each other under certain conditions. Abrogation of Irr activation function was haem-dependent, thus haem has two functionally separable roles in modulating Irr activity. The findings imply a greater complexity of control by Irr than can be achieved by conditional stability alone. We suggest that these regulatory mechanisms accommodate the differing needs for Irr regulon genes in response to the prevailing metabolic state of the cell.

  2. Role of the Irr protein in the regulation of iron metabolism in Rhodobacter sphaeroides.

    Directory of Open Access Journals (Sweden)

    Verena Peuser

    Full Text Available In Rhizobia the Irr protein is an important regulator for iron-dependent gene expression. We studied the role of the Irr homolog RSP_3179 in the photosynthetic alpha-proteobacterium Rhodobacter sphaeroides. While Irr had little effect on growth under iron-limiting or non-limiting conditions its deletion resulted in increased resistance to hydrogen peroxide and singlet oxygen. This correlates with an elevated expression of katE for catalase in the Irr mutant compared to the wild type under non-stress conditions. Transcriptome studies revealed that Irr affects the expression of genes for iron metabolism, but also has some influence on genes involved in stress response, citric acid cycle, oxidative phosphorylation, transport, and photosynthesis. Most genes showed higher expression levels in the wild type than in the mutant under normal growth conditions indicating an activator function of Irr. Irr was however not required to activate genes of the iron metabolism in response to iron limitation, which showed even stronger induction in the absence of Irr. This was also true for genes mbfA and ccpA, which were verified as direct targets for Irr. Our results suggest that in R. sphaeroides Irr diminishes the strong induction of genes for iron metabolism under iron starvation.

  3. IrrE, a global regulator of extreme radiation resistance in Deinococcus radiodurans, enhances salt tolerance in Escherichia coli and Brassica napus.

    Directory of Open Access Journals (Sweden)

    Jie Pan

    Full Text Available BACKGROUND: Globally, about 20% of cultivated land is now affected by salinity. Salt tolerance is a trait of importance to all crops in saline soils. Previous efforts to improve salt tolerance in crop plants have met with only limited success. Bacteria of the genus Deinococcus are known for their ability to survive highly stressful conditions, and therefore possess a unique pool of genes conferring extreme resistance. In Deinococcus radiodurans, the irrE gene encodes a global regulator responsible for extreme radioresistance. METHODOLOGY/PRINCIPAL FINDINGS: Using plate assays, we showed that IrrE protected E. coli cells against salt shock and other abiotic stresses such as oxidative, osmotic and thermal shocks. Comparative proteomic analysis revealed that IrrE functions as a switch to regulate different sets of proteins such as stress responsive proteins, protein kinases, glycerol-degrading enzymes, detoxification proteins, and growth-related proteins in E. coli. We also used quantitative RT-PCR to investigate expression of nine selected stress-responsive genes in transgenic and wild-type Brassica napus plants. Transgenic B. napus plants expressing the IrrE protein can tolerate 350 mM NaCl, a concentration that inhibits the growth of almost all crop plants. CONCLUSIONS: Expression of IrrE, a global regulator for extreme radiation resistance in D. radiodurans, confers significantly enhanced salt tolerance in both E. coli and B. napus. We thus propose that the irrE gene might be used as a potentially promising transgene to improve abiotic stress tolerances in crop plants.

  4. Research Progress of the Global Regulator IrrE in Deinococcus radiodurans%耐辐射异常球菌全局调控蛋白IrrE的研究进展

    Institute of Scientific and Technical Information of China (English)

    陈震; 周正富; 张维; 陈明; 宋渊; 林敏

    2013-01-01

      全局调控蛋白 IrrE 是异常球菌属中所特有的一种 DNA 损伤修复调节因子,可以显著提高细胞受到损伤时各修复基因的表达。在目前已经完成测序的异常球菌中共发现7种不同来源的 IrrE 蛋白,经序列比对与同源建模,发现其氨基酸序列相似性较高且具有相同的保守结构域,这可能预示了其功能上的相似性。此外,irrE 在大肠杆菌及油菜中表达后,能明显增强宿主的耐盐性,体现了较高应用价值。本综述介绍了异常球菌属及其全局调控蛋白 IrrE 的发现、结构与相关功能,分析与展望了该调控蛋白潜在的应用前景。%  The unique global regulator IrrE, found in Deinococcus, can up-regulate the expression of DNA repair genes in response to DNA damage. Seven types of IrrE protein had been identified in different strains of Deinococcus, the results of sequence alignment and homology modeling suggest that they share a high identity in amino acid sequence and have the same conserved protein regions, which may indicate the similarity in their functions. Besides, when gene irrE expressed in E. coli and B. napus, the salt tolerance of both hosts can be significantly enhanced, which show a very promising future in application. This review introduced the basic traits of Deinococcus and the discovery, structure and related functions of the global regulator IrrE, then we analyzed and prospected its potential application.

  5. Significant rewiring of the transcriptome and proteome of an Escherichia coli strain harboring a tailored exogenous global regulator IrrE.

    Directory of Open Access Journals (Sweden)

    Tingjian Chen

    Full Text Available Cell reprogramming for microorganisms via engineered or artificial transcription factors and RNA polymerase mutants has presented a powerful tool for eliciting complex traits that are practically useful particularly for industrial strains, and for understanding at the global level the regulatory network of gene transcription. We previously further showed that an exogenous global regulator IrrE (derived from the extreme radiation-resistant bacterium Deinococcus radiodurans can be tailored to confer Escherichia coli (E. coli with significantly enhanced tolerances to different stresses. In this work, based on comparative transcriptomic and proteomic analyses of the representative strains E1 and E0, harboring the ethanol-tolerant IrrE mutant E1 and the ethanol-intolerant wild type IrrE, respectively, we found that the transcriptome and proteome of E. coli were extensively rewired by the tailored IrrE protein. Overall, 1196 genes (or approximately 27% of E. coli genes were significantly altered at the transcriptomic level, including notably genes in the nitrate-nitrite-nitric oxide (NO pathway, and genes for non-coding RNAs. The proteomic profile revealed significant up- or downregulation of several proteins associated with syntheses of the cell membrane and cell wall. Analyses of the intracellular NO level and cell growth under reduced temperature supported a close correlation between NO and ethanol tolerance, and also suggests a role for membrane fluidity. The significantly different omic profiles of strain E1 indicate that IrrE functions as a global regulator in E. coli, and that IrrE may be evolved for other cellular tolerances. In this sense, it will provide synthetic biology with a practical and evolvable regulatory "part" that operates at a higher level of complexity than local regulators. This work also suggests a possibility of introducing and engineering other exogenous global regulators to rewire the genomes of microorganism cells.

  6. The Site-Directed A184S Mutation in the HTH Domain of the Global Regulator IrrE Enhances Deinococcus radiodurans R1 Tolerance to UV Radiation and MMC Shock.

    Science.gov (United States)

    Zhang, Chen; Zhou, Zhengfu; Zhang, Wei; Chen, Zhen; Song, Yuan; Lu, Wei; Lin, Min; Chen, Ming

    2015-12-28

    IrrE is a highly conserved global regulator in the Deinococcus genus and contributes to survival from high doses of UV radiation, ionizing radiation, and desiccation. Drad-IrrE and Dgob-IrrE from Deinococcus radiodurans and Deinococcus gobiensis I-0 each share 66% sequence identity. However, Dgob-IrrE showed a stronger protection phenotype against UV radiation than Drad- IrrE in the D. radiodurans irrE-deletion mutant (ΔirrE), which may be due to amino acid residues differences around the DNA-binding HTH domain. Site-directed mutagenesis was used to generate a Drad-IrrE A184S single mutant, which has been characterized and compared with the ΔirrE mutant complemented strain with Drad-irrE, designated ΔirrE-E. The effects of the A184S mutation following UV radiation and mitomycin C (MMC) shock were determined. The A184S mutant displayed significantly increased resistance to UV radiation and MMC shock. The corresponding A184 site in Dgob-IrrE was inversely mutated, generating the S131A mutant, which exhibited a loss of resistance against UV radiation, MMC shock, and desiccation. qPCR analysis revealed that critical genes in the DNA repair system, such as recA, pprA, uvrA, and ddrB, were remarkably induced after UV radiation and MMC shock in the ΔirrE-IE and A184S mutants. These data suggested that A184S improves the ability against UV radiation and MMC shock, providing new insights into the modification of IrrE. We speculated that the serine residue may determine the efficiency of DNA binding, leading to the increased expression of IrrE-dependent genes important for protection against DNA damage.

  7. The tolerant responses to NaCl Stress in IrrE-transgenic Brassica napus%转IrrE基因甘蓝型油菜对NaCl胁迫的耐受性应答

    Institute of Scientific and Technical Information of China (English)

    奉斌; 代其林; 刘婷婷; 田霞; 龚元亚; 孙英坤; 杜世章; 王劲

    2011-01-01

    The tolerant responses to NaC1 stress in IrrE-transgenic Brassica napus were studied. The results showed that the activity of peroxidas (POD), superoxide dismutase (SOD) and catalase (CAT) in transgenic Brassica napus was gradually increased under 200 mmol/L NaCl during 0~48 h, but the activity of POD, SOD and CAT in non-transgenic Brassica napus was increased during 0~24 h and subsequently decreased after 24 h. The content of proline and the dissoluble proein in transgenic Brassica hapus was higher than non-transgenic Brassica napus, but the content of malonaldehyde(MDA) in transgenie Brassica napus was lower than non-transgenic Brassica napus. Therefore, IrrE gene enhanced the activities of three antioxidant enzymes in transgenic Brassica napus, and then enhanced the tolerance of Brassica napus against NaCl stress.%以转IrrE基因甘蓝型油菜为材料,研究了转IrrE基因甘蓝型油菜幼苗对NaCl胁迫的耐受性应答情况.在200mmol/L NaCl胁迫下,随着胁迫时间的延长,转IrrE基因和野生型油菜的POD、SOD和CAT三种抗氧化酶活性均增加,其中野生型油菜的三种抗氧化酶在24h后达到峰值,随后逐渐下降,而转IrrE基因油菜的三种抗氧化酶活性却持续增加,并在相同的胁迫时间内均高于野生型油菜的酶活性;同时转IrrE基因油菜的脯氨酸和可溶性蛋白质含量均比野生型油菜的高,但其丙二醛(MDA)的含量比野生型油菜的低.结果表明,IrrE基因作为一种转录因子可能广泛参与了油菜幼苗对NaCl胁迫的耐受性应答过程,从而提高了植物对NaCl胁迫的耐受能力.

  8. IRRS: The CSN under the microscope; Mision IRRS: el CSN bajo el microscopio

    Energy Technology Data Exchange (ETDEWEB)

    Salome, M.

    2008-07-01

    Throughout the two weeks from January 28th to February 8th an international team of experts, appointed by the IAEA and led by Ulrich Schmocker from Switzerland, carried out a detailed study of the CSN. The objective of the IRRS mission, which was performed in response to a request from the Council itself, was to analyse the structure and operation of the Spanish regulatory body in order to determine its strengths and weaknesses and to suggest measures to improve its management. (Author)

  9. The IRRS follow-up mission to the Nuclear Safety Council; La mision follow-up de la IRRS al Consejo de Seguridad Nuclear

    Energy Technology Data Exchange (ETDEWEB)

    Gurgi Ferrer, A. P.; Collet Campo, D.

    2011-07-01

    The IRRS follow-up mission to the Nuclear Safety Council. From January 25th to February 1st last the CSN headquarters hosted a follow-up to the IAEA Integrated Regulatory Review Service (IRRS) mission carried out in January 2008. The objective of this follow-up has been to check the extent to which the suggestions and recommendations made by the original IRRS mission have been adopted by the audited regulator and, as a result, to verify its degree of adherence to the strictest international standards. (Author)

  10. Mission IRRS to Spain. First mission of this type realised in the world; Mision IRRS a Espana. Primera mision de este tipo realizada en el mundo

    Energy Technology Data Exchange (ETDEWEB)

    Lentijo, J. C.; Mellado, I.

    2008-07-01

    The IRRS (Integrated Regulatory Review Service) mission to the Spanish Nuclear Safety Council (CSN), which took place from January 28 until February 8, has been the first integrated review of a regulatory body that includes all the aspects on nuclear safety radiation protection and security of all the facilities and activities under CSN responsibility. The review team was composed of eighteen experts from fifteen member sates, two observers, three IAEA officers and an administrative assistant, which have performed an exhaustive analysis of the Spanish regulatory system, including the legal and governmental infrastructure, the functions, responsibilities an organization of the CSN, the regulations and standards, and the assessment and inspection activities. The team members have interviewed different stake holders (public administrations, technical support organizations and licensees) and have observed several CSN inspections to different facilities as well. From the CSN point of view, the results of the IRRS mission are very positive. The relevant efforts devoted to prepare it, mainly the self-assessment process and the action plan established for implementing the improvement opportunities, have benefited the whole regulatory system and practices, being not the least the updating of the regulations and standards and the development of a CSN management system according to the IAEA requirement GS-R-3. (Author)

  11. US Forest Service Integrated Resource Restoration (IRR)

    Data.gov (United States)

    US Forest Service, Department of Agriculture — A map service on the www depicting activities funded through the Integrated Resource Restoration (IRR) NFRR Budget Line Item and reported through the U.S. Forest...

  12. What Does an IRR (or Two) Mean?

    Science.gov (United States)

    Johnstone, David

    2008-01-01

    Defined mathematically, the internal rate of return (IRR) of a cash-flow stream is the discount rate at which its net present value is 0. What is the significance or meaning of such a measure? Using simple example problems and illustrative calculations, the author explains a technically correct but, at the same time, intuitively meaningful…

  13. How the IRR drives bias in energy investment decisions

    DEFF Research Database (Denmark)

    Groth, Tanja

    The project evaluation tool known as the IRR will often provide misleading or meaningless estimations of renewable energy investments......The project evaluation tool known as the IRR will often provide misleading or meaningless estimations of renewable energy investments...

  14. The irre cell recognition module (IRM) proteins.

    Science.gov (United States)

    Fischbach, Karl-Friedrich; Linneweber, Gerit Arne; Andlauer, Till Felix Malte; Hertenstein, Alexander; Bonengel, Bernhard; Chaudhary, Kokil

    2009-01-01

    One of the most challenging problems in developmental neurosciences is to understand the establishment and maintenance of specific membrane contacts between axonal, dendritic, and glial processes in the neuropils, which eventually secure neuronal connectivity. However, underlying cell recognition events are pivotal in other tissues as well. This brief review focuses on the pleiotropic functions of a small, evolutionarily conserved group of proteins of the immunoglobulin superfamily involved in cell recognition. In Drosophila, this protein family comprises Irregular chiasm C/Roughest (IrreC/Rst), Kin of irre (Kirre), and their interacting protein partners, Sticks and stones (SNS) and Hibris (Hbs). For simplicity, we propose to name this ensemble of proteins the irre cell recognition module (IRM) after the first identified member of this family. Here, we summarize evidence that the IRM proteins function together in various cellular interactions, including myoblast fusion, cell sorting, axonal pathfinding, and target recognition in the optic neuropils of Drosophila. Understanding IRM protein function will help to unravel the epigenetic rules by which the intricate neurite networks in sensory neuropils are formed.

  15. Irr(G|N) and Solvability%Irr(G|N)与群的可解性

    Institute of Scientific and Technical Information of China (English)

    孙光洪

    2003-01-01

    主要讨论了不可约特征标集Irr(G|N)在限制条件下对正规子群N的可解性的影响,然后讨论了关于N的一些简单结构. 得到了下面一些主要结果:定理1 设NG. 若Irr(G|N)中每特征标S单项,则N为S群.定理2 设NG. 若Irr(G|N)中每特征标χ,存在H≤G,λ∈Irr(H)使χ=λG,H/Ker λ可解,则N可解.定理6 设S为素数阶群的集合,NG,a=max(cd(G|N)),若任意χ∈Irr(G|N),χ(1)<a均有χ为S单项特征标,则N可解.定理8 假设G为整群,NG,p为一素数,若Irrm(G|N)中的所有特征标χ,p|χ(1),则N有正规p补,且N可解.

  16. Irr(G|N)的一些性质%Properties of Irr(G|N)

    Institute of Scientific and Technical Information of China (English)

    孙光洪

    2001-01-01

    在给定了Irr(G|N)的某些条件下, 讨论了导长dl(N)与|cd(G|N)|的关系, 并给出了群N的一些结构, 即定理1 若NG且N可解, 则dl(N)≤|Irr(G|N)|. 定理2 若NG, Irr(G|N)中所有特征标单项, 则dl(N)≤|cd(G|N)|且N可解. 定理3 若NG, Irr(G|N)中每特征标维数不同且G可解, 则下列情形之一成立: (i) N有特征子群序列N=N0>N1>…>Nk-1>Nk=1使Ni+1为Ni的正规pi补; (ii) N为Abel群; (iii) N为超特殊2群; (iv) N为2可迁Frobenius群, 且Frobenius补循环; (v) N为72阶2可迁Frobenius群, 且Frobenius补为四元数群;在(ii)-(iv)中, N为偶阶群或N=1.

  17. 25 CFR 170.800 - Who owns IRR transportation facilities?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Who owns IRR transportation facilities? 170.800 Section 170.800 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.800 Who owns IRR transportation facilities? Public...

  18. 25 CFR 170.442 - What is the IRR Inventory?

    Science.gov (United States)

    2010-04-01

    ... PROGRAM Planning, Design, and Construction of Indian Reservation Roads Program Facilities Irr Inventory... transportation facilities eligible for IRR Program funding by tribe, reservation, BIA agency and region... Distribution Factor. BIA or tribes can also use the inventory to assist in transportation and project planning...

  19. 25 CFR 170.622 - What IRR programs, functions, services, and activities are subject to the self-governance...

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false What IRR programs, functions, services, and activities are subject to the self-governance construction regulations? 170.622 Section 170.622 Indians BUREAU OF..., functions, services, and activities are subject to the self-governance construction regulations? All...

  20. Nickel-responsive transcriptional regulators.

    Science.gov (United States)

    Musiani, Francesco; Zambelli, Barbara; Bazzani, Micaela; Mazzei, Luca; Ciurli, Stefano

    2015-09-01

    Nickel is an essential micronutrient for a large number of living organisms, but it is also a toxic metal ion when it accumulates beyond the sustainable level as it may result if and when its cellular trafficking is not properly governed. Therefore, the homeostasis and metabolism of nickel is tightly regulated through metal-specific protein networks that respond to the available Ni(II) concentration. These are directed by specific nickel sensors, able to couple Ni(II) binding to a change in their DNA binding affinity and/or specificity, thus translating the cellular level of Ni(II) into a modification of the expression of the proteins devoted to modulating nickel uptake, efflux and cellular utilization. This review describes the Ni(II)-dependent transcriptional regulators discovered so far, focusing on their structural features, metal coordination modes and metal binding thermodynamics. Understanding these properties is essential to comprehend how these sensors correlate nickel availability to metal coordination and functional responses. A broad and comparative study, described here, reveals some general traits that characterize the binding stoichiometry and Ni(II) affinity of these metallo-sensors.

  1. Leptin Regulation of Immune Responses.

    Science.gov (United States)

    Naylor, Caitlin; Petri, William A

    2016-02-01

    Leptin is a regulatory hormone with multiple roles in the immune system. We favor the concept that leptin signaling 'licenses' various immune cells to engage in immune responses and/or to differentiate. Leptin is an inflammatory molecule that is capable of activating both adaptive and innate immunity. It can also 'enhance' immune functions, including inflammatory cytokine production in macrophages, granulocyte chemotaxis, and increased Th17 proliferation. Leptin can also 'inhibit' cells; CD4(+) T cells are inhibited from differentiating into regulatory T cells in the presence of elevated leptin, while NK cells can exhibit impaired cytotoxicity under the same circumstances. Consequently, understanding the effect of leptin signaling is important to appreciate various aspects of immune dysregulation observed in malnutrition, obesity, and autoimmunity.

  2. 78 FR 2443 - Criminal Justice Interview Room Recording System (IRRS) Standard, Supplier's Declaration of...

    Science.gov (United States)

    2013-01-11

    ... From the Federal Register Online via the Government Publishing Office ] DEPARTMENT OF JUSTICE Office of Justice Programs Criminal Justice Interview Room Recording System (IRRS) Standard, Supplier's... Criminal Justice IRRS Supplier's Declaration of Conformity Requirements 3. Draft Criminal Justice...

  3. The Construction of Recombinant Escherichia coli by IrrE and Cell Performance Analysis%IrrE重组大肠杆菌的构建和性能分析

    Institute of Scientific and Technical Information of China (English)

    骆健美; 郑媛媛; 王敏

    2015-01-01

    The heterologous expression of irrE,from Deinococcus radiodurans R1,in E. coli BL21(DE3)was carried out using the vector pET-28a(+). The optimal protein expression conditions of IrrE were as follows.The final concentration of IPTG was 2,mmol/L,and the induction temperature and time were 37,℃and 6,h,respectively. The influence of IrrE on cell growth and tolerance was further investigated. The results indicated that IrrE could enhance the growth rate and produce more final biomass of Escherichia coli under normal conditions,and improve the survival ability of the cell under stress shock to different extent,especially the tolerance to osmotic shock. The growth rate was higher and significantly more final biomasses of the recombinant strain containing pET-28a(+)-irrE under stress were found than in the control strain(harboring the empty vector pET-28a(+)). It can be concluded that the expression of IrrE could enhance the tolerance of E. coli to stress.%利用 pET-28a(+)质粒将来源于耐辐射异常球菌(Deinococcus radiodurans)R1的 irrE 基因在大肠杆菌(Escherichia coli)BL21(DE3)中进行异源表达,在IPTG终浓度2,mmol/L、诱导温度37,℃、诱导培养6,h条件下进行了蛋白诱导。进一步考察 IrrE 异源表达对大肠杆菌生长性能和耐受能力的影响,结果表明:IrrE 的表达能够提高大肠杆菌正常条件下的生长速率和最终生物量;同时,能够不同程度提高大肠杆菌在压力冲击下的存活能力,其中,高渗条件下存活能力的提高最为明显。而重组菌株在压力冲击下的生长速率和最终生物量均明显高于对照菌株。这说明 IrrE在提高大肠杆菌的压力耐受性方面表现出良好的效果。

  4. 25 CFR 170.806 - What is an IRR Transportation Facilities Maintenance Management System?

    Science.gov (United States)

    2010-04-01

    ... AND WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.806 What is an IRR Transportation Facilities Maintenance Management System? An IRR Transportation Facilities Maintenance Management... 25 Indians 1 2010-04-01 2010-04-01 false What is an IRR Transportation Facilities...

  5. 25 CFR 170.300 - May tribes use flexible financing to finance IRR transportation projects?

    Science.gov (United States)

    2010-04-01

    ... Financing § 170.300 May tribes use flexible financing to finance IRR transportation projects? Yes. Tribes may use flexible financing in the same manner as States to finance IRR transportation projects, unless... or bonds to finance IRR projects. Upon the request of a tribe, a BIA region will provide necessary...

  6. 25 CFR 170.444 - How is the IRR Inventory updated?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false How is the IRR Inventory updated? 170.444 Section 170.444 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS... § 170.444 How is the IRR Inventory updated? The IRR Inventory data for a tribe is updated on an...

  7. 23 CFR 661.55 - How are BIA and Tribal owned IRR bridges inspected?

    Science.gov (United States)

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false How are BIA and Tribal owned IRR bridges inspected? 661... AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.55 How are BIA and Tribal owned IRR bridges inspected? BIA and Tribally owned IRR bridges are inspected in accordance with 25 CFR...

  8. Arginine methylation regulates the p53 response

    DEFF Research Database (Denmark)

    Jansson, Martin; Durant, Stephen T; Cho, Er-Chieh;

    2008-01-01

    Activation of the p53 tumour suppressor protein in response to DNA damage leads to apoptosis or cell-cycle arrest. Enzymatic modifications are widely believed to affect and regulate p53 activity. We describe here a level of post-translational control that has an important functional consequence o...

  9. Regulation of intestinal IgA responses

    Science.gov (United States)

    Xiong, Na; Hu, Shaomin

    2015-01-01

    The intestine harbors enormous numbers of commensal bacteria and is under frequent attack from food-borne pathogens and toxins. A properly regulated immune response is critical for homeostatic maintenance of commensals and for protection against infection and toxins in the intestine. IgA isotype antibodies function specifically in mucosal sites such as the intestines to help maintain intestinal health by binding to and regulating commensal microbiota, pathogens and toxins. IgA antibodies are produced by intestinal IgA antibody-secreting plasma cells generated in gut-associated lymphoid tissues from naïve B cells in response to stimulations of the intestinal bacteria and components. Research on generation, migration, and maintenance of IgA-secreting cells is important in our effort to understand the biology of IgA responses and to help better design vaccines against intestinal infections. PMID:25837997

  10. Les paradoxes du terme "irréel"

    Directory of Open Access Journals (Sweden)

    Hounhouayenou-Toffa, Ernest

    2016-07-01

    Full Text Available This article analyses the term unreality (Irréel in French and its status in some grammars of the English language, with a special focus on Anglophone ones. Irréel is a well-established term in French grammatical taxonomy (DUBOIS ET AL. [1994] 2012: 258, but a polymorphic one in Anglophone grammars. One may come across irrealis (KRUISINGA & ERADES 1947: 200; GIVÓN 1994: 275; HUDDLESTON & PULLUM 2002: 149, irreality (LANGACKER 2008: 302 or unreality (JOOS 1964: 122, the latter being rarely labeled as a semantic category in Anglophone grammars. It will be argued that this multi-faceted feature points to the equivocal semantic perimeter of this notion. What is at stake is the usefulness of the term unreality in English grammar.

  11. The screening of functional proteins interacting with IrrE by the yeast two-hybrid system%利用酵母双杂交系统筛选IrrE相互作用蛋白

    Institute of Scientific and Technical Information of China (English)

    田霞; 代其林; 龚元亚; 孙英坤; 谢琳; 杨娟; 王劲

    2012-01-01

    IrrE was constructed as the bait protein and then interacted with functional proteins from the Arabidopsis cDNA library by yeast two-hybrid system. The result showed that there was one interacting protein from all the positive clones which had high identity (as high identical to 98%) with the LEA14 protein (Late Embryogenesis Abundant protein 14) encoded by Arabidopsis thaliana gene Atlg01470. It was inferred that IrrE protein may play an important role in improving the tolerance to salt stress in trans-gene plants.%本研究通过酵母双杂交技术,构建了IrrE蛋白为诱饵载体,从拟南芥cDNA文库中筛选与IrrE诱饵蛋白相互作用的功能蛋白.研究结果表明,在所获得的阳性克隆中,发现了一个与拟南芥基因Atlg01470所编码的蛋白有较高同源性的蛋白,即LEA14蛋白(晚期胚胎发育富集蛋白),同源性高达98%.推测IrrE转录因子在提高植物耐盐性的过程中起了重要作用.

  12. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    Directory of Open Access Journals (Sweden)

    Michal Amit Rahat

    2011-09-01

    Full Text Available Monocytes and Macrophages (Mo/Mϕ exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mϕ, combating invading pathogens and tumor cells (classically activated or M1 Mo/Mϕ, orchestrating wound healing (alternatively activated or M2 Mo/Mϕ, and restoring homeostasis after an inflammatory response (resolution Mϕ. Hypoxia is an important factor in the Mϕ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mϕ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mϕ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators HIF-1 and NF-κB, as well as other transcription factors (e.g. AP-1, Erg-1, but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mϕ pro-angiogenic mediators, suppress M1 Mϕ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mϕ into an activation state which approximate the alternatively activated or resolution Mϕ.

  13. Alkaline pH induces IRR-mediated phosphorylation of IRS-1 and actin cytoskeleton remodeling in a pancreatic beta cell line.

    Science.gov (United States)

    Deyev, Igor E; Popova, Nadezhda V; Serova, Oxana V; Zhenilo, Svetlana V; Regoli, Marì; Bertelli, Eugenio; Petrenko, Alexander G

    2017-07-01

    Secretion of mildly alkaline (pH 8.0-8.5) juice to intestines is one of the key functions of the pancreas. Recent reports indicate that the pancreatic duct system containing the alkaline juice may adjoin the endocrine cells of pancreatic islets. We have previously identified the insulin receptor-related receptor (IRR) that is expressed in islets as a sensor of mildly alkaline extracellular media. In this study, we show that those islet cells that are in contact with the excretory ducts are also IRR-expressing cells. We further analyzed the effects of alkaline media on pancreatic beta cell line MIN6. Activation of endogenous IRR but not of the insulin receptor was detected that could be inhibited with linsitinib. The IRR autophosphorylation correlated with pH-dependent linsitinib-sensitive activation of insulin receptor substrate 1 (IRS-1), the primary adaptor in the insulin signaling pathway. However, in contrast with insulin stimulation, no protein kinase B (Akt/PKB) phosphorylation was detected as a result of alkali treatment. We observed overexpression of several early response genes (EGR2, IER2, FOSB, EGR1 and NPAS4) upon alkali treatment of MIN6 cells but those were IRR-independent. The alkaline medium but not insulin also triggered actin cytoskeleton remodeling that was blocked by pre-incubation with linsitinib. We propose that the activation of IRR by alkali might be part of a local loop of signaling between the exocrine and endocrine parts of the pancreas where alkalinization of the juice facilitate insulin release that increases the volume of secreted juice to control its pH and bicabonate content. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  14. Regulation of oxidative stress response by CosR, an essential response regulator in Campylobacter jejuni.

    Directory of Open Access Journals (Sweden)

    Sunyoung Hwang

    Full Text Available CosR (Campylobacter oxidative stress regulator; Cj0355c is an OmpR-type response regulator essential for the viability of Campylobacter jejuni, a leading foodborne pathogen causing human gastroenteritis worldwide. Despite importance, the function of CosR remains completely unknown mainly because of cell death caused by its knockout mutation. To overcome this technical limitation, in this study, antisense technology was used to investigate the regulatory function of CosR by modulating the level of CosR expression. Two-dimensional gel electrophoresis (2DGE was performed to identify the CosR regulon either by suppressing CosR expression with antisense peptide nucleic acid (PNA or by overexpressing CosR in C. jejuni. According to the results of 2DGE, CosR regulated 32 proteins involved in various cellular processes. Notably, CosR negatively regulated a few key proteins of the oxidative stress response of C. jejuni, such as SodB, Dps, Rrc and LuxS, whereas CosR positively controlled AhpC. Electrophoretic mobility shift assay showed that CosR directly bound to the promoter region of the oxidative stress genes. DNase I footprinting assays identified 21-bp CosR binding sequences in the sodB and ahpC promoters, suggesting CosR specifically recognizes and binds to the regulated genes. Interestingly, the level of CosR protein was significantly reduced by paraquat (a superoxide generator but not by hydrogen peroxide. Consistent with the overall negative regulation of oxidative stress defense proteins by CosR, the CosR knockdown by antisense rendered C. jejuni more resistant to oxidative stress compared to the wild type. Overall, this study reveals the important role played by the essential response regulator CosR in the oxidative stress defense of C. jejuni.

  15. Hantavirus Regulation of Type I Interferon Responses

    Directory of Open Access Journals (Sweden)

    Valery Matthys

    2012-01-01

    Full Text Available Hantaviruses primarily infect human endothelial cells (ECs and cause two highly lethal human diseases. Early addition of Type I interferon (IFN to ECs blocks hantavirus replication and thus for hantaviruses to be pathogenic they need to prevent early interferon induction. PHV replication is blocked in human ECs, but not inhibited in IFN deficient VeroE6 cells and consistent with this, infecting ECs with PHV results in the early induction of IFNβ and an array of interferon stimulated genes (ISGs. In contrast, ANDV, HTNV, NY-1V and TULV hantaviruses, inhibit early ISG induction and successfully replicate within human ECs. Hantavirus inhibition of IFN responses has been attributed to several viral proteins including regulation by the Gn proteins cytoplasmic tail (Gn-T. The Gn-T interferes with the formation of STING-TBK1-TRAF3 complexes required for IRF3 activation and IFN induction, while the PHV Gn-T fails to alter this complex or regulate IFN induction. These findings indicate that interfering with early IFN induction is necessary for hantaviruses to replicate in human ECs, and suggest that additional determinants are required for hantaviruses to be pathogenic. The mechanism by which Gn-Ts disrupt IFN signaling is likely to reveal potential therapeutic interventions and suggest protein targets for attenuating hantaviruses.

  16. Importins and exportins regulating allergic immune responses.

    Science.gov (United States)

    Aggarwal, Ankita; Agrawal, Devendra K

    2014-01-01

    Nucleocytoplasmic shuttling of macromolecules is a well-controlled process involving importins and exportins. These karyopherins recognize and bind to receptor-mediated intracellular signals through specific signal sequences that are present on cargo proteins and transport into and out of the nucleus through nuclear pore complexes. Nuclear localization signals (NLS) present on cargo molecules to be imported while nuclear export signals (NES) on the molecules to be exported are recognized by importins and exportins, respectively. The classical NLS are found on many transcription factors and molecules that are involved in the pathogenesis of allergic diseases. In addition, several immune modulators, including corticosteroids and vitamin D, elicit their cellular responses by regulating the expression and activity of importin molecules. In this review article, we provide a comprehensive list of importin and exportin molecules and their specific cargo that shuttled between cytoplasm and the nucleus. We also critically review the role and regulation of specific importin and exportin involved in the transport of activated transcription factors in allergic diseases, the underlying molecular mechanisms, and the potential target sites for developing better therapeutic approaches.

  17. Importins and Exportins Regulating Allergic Immune Responses

    Directory of Open Access Journals (Sweden)

    Ankita Aggarwal

    2014-01-01

    Full Text Available Nucleocytoplasmic shuttling of macromolecules is a well-controlled process involving importins and exportins. These karyopherins recognize and bind to receptor-mediated intracellular signals through specific signal sequences that are present on cargo proteins and transport into and out of the nucleus through nuclear pore complexes. Nuclear localization signals (NLS present on cargo molecules to be imported while nuclear export signals (NES on the molecules to be exported are recognized by importins and exportins, respectively. The classical NLS are found on many transcription factors and molecules that are involved in the pathogenesis of allergic diseases. In addition, several immune modulators, including corticosteroids and vitamin D, elicit their cellular responses by regulating the expression and activity of importin molecules. In this review article, we provide a comprehensive list of importin and exportin molecules and their specific cargo that shuttled between cytoplasm and the nucleus. We also critically review the role and regulation of specific importin and exportin involved in the transport of activated transcription factors in allergic diseases, the underlying molecular mechanisms, and the potential target sites for developing better therapeutic approaches.

  18. 25 CFR 170.804 - How is BIA's Road Maintenance Program related to the IRR Program?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false How is BIA's Road Maintenance Program related to the IRR... WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.804 How is BIA's Road Maintenance Program related to the IRR Program? The following chart illustrates how BIA's Road Maintenance Program...

  19. 25 CFR 170.436 - How are public hearings for IRR planning and projects funded?

    Science.gov (United States)

    2010-04-01

    ... WATER INDIAN RESERVATION ROADS PROGRAM Planning, Design, and Construction of Indian Reservation Roads Program Facilities Public Hearings § 170.436 How are public hearings for IRR planning and projects funded... 25 Indians 1 2010-04-01 2010-04-01 false How are public hearings for IRR planning and projects...

  20. 25 CFR 170.605 - When may BIA use force account methods in the IRR Program?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false When may BIA use force account methods in the IRR Program... § 170.605 When may BIA use force account methods in the IRR Program? BIA may use force account methods... before using a force account under this situation. The applicable FAR and Federal law apply to BIA...

  1. Regulation of Neurotransmitter Responses in the Central Nervous System.

    Science.gov (United States)

    1987-05-01

    Phinucol. E-rp. flier. 230. ison of the effects of clonidine on ir-r. and postsvniaptic 31-323. adrenoceptors in the rapnit pulmonar \\ arter\\. .\\iinvn...E. (1982) J. Cell. Physiol. 112:42-50. 22. Jaken, S., Tashjian A.H. and Blumberg, P.M. (1981) Cancer Res. 41:2175-2181. 23. Niedel. J.E., Kuhn, LJ

  2. 25 CFR 170.301 - Can a tribe use IRR Program funds to leverage other funds or pay back loans?

    Science.gov (United States)

    2010-04-01

    ... or pay back loans? 170.301 Section 170.301 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... Financing § 170.301 Can a tribe use IRR Program funds to leverage other funds or pay back loans? (a) A tribe can use IRR Program funds to leverage other funds. (b) A tribe can use IRR Program funds to pay...

  3. Pellino-1 Selectively Regulates Epithelial Cell Responses to Rhinovirus

    NARCIS (Netherlands)

    Bennett, Julie A; Prince, Lynne R; Parker, Lisa C; Stokes, Clare A; de Bruin, Harold G; van den Berge, Maarten; Heijink, Irene H; Whyte, Moira K; Sabroe, Ian

    2012-01-01

    Pellino-1 has recently been identified as a regulator of interleukin-1 (IL-1) signaling, but its roles in regulation of responses of human cells to human pathogens are unknown. We investigated the potential roles of Pellino-1 in the airways. We show for the first time that Pellino-1 regulates respon

  4. Pellino-1 selectively regulates epithelial cell responses to rhinovirus

    NARCIS (Netherlands)

    Bennett, Julie A; Prince, Lynne R; Parker, Lisa C; Stokes, Clare A; de Bruin, Harold G; van den Berge, Maarten; Heijink, Irene H; Whyte, Moira K; Sabroe, Ian

    2012-01-01

    Pellino-1 has recently been identified as a regulator of interleukin-1 (IL-1) signaling, but its roles in regulation of responses of human cells to human pathogens are unknown. We investigated the potential roles of Pellino-1 in the airways. We show for the first time that Pellino-1 regulates respon

  5. Collide@CERN: Horizons Irrésolus

    CERN Multimedia

    2016-01-01

    Sound Installation by Collide@CERN Geneva artists Rudy Decelière and Vincent Hänni in collaboration with physicists Diego Blas and Robert Kieffer, for the Electron Festival 25-27th March, 2016 (see here).   Horizons irrésolus is a sound installation that follows on the artistic residency Collide@CERN 2014.    Registration is absolutely required. Each guest will have to have registered using their own name. Guests without having registered will not be able to come into CERN. Free entrance: Book here  A shuttle will be available every 15 minutes from 6 p.m. until 9 p.m. from CERN Reception (in front of CERN Globe) to the sound art installation. Access from Geneva to CERN Reception by tram 18, end of the line. With the support from The Republic and Canton of Geneva and The City of Geneva. Find out more on the artists and their Geneva 2...

  6. 25 CFR 170.2 - What is the IRR Program and BIA Road Maintenance Program policy?

    Science.gov (United States)

    2010-04-01

    .... The Secretary of the Interior will afford Indian tribes the flexibility, information, and discretion... organizational level within the Department of the Interior that carries out these functions. Including IRR...

  7. 23 CFR 661.35 - What percentage of IRRBP funding is available for use on BIA and Tribally owned IRR bridges, and...

    Science.gov (United States)

    2010-04-01

    ... BIA and Tribally owned IRR bridges, and non-BIA owned IRR bridges? 661.35 Section 661.35 Highways... RESERVATION ROAD BRIDGE PROGRAM § 661.35 What percentage of IRRBP funding is available for use on BIA and Tribally owned IRR bridges, and non-BIA owned IRR bridges? (a) Up to 80 percent of the available...

  8. Transcriptional responses and regulations to deficient phosphorus in plants

    Institute of Scientific and Technical Information of China (English)

    Jinxiang BAO; Shuhua ZHANG; Wenjing LU; Chengjin GUO; Juntao GU; Kai XIAO

    2009-01-01

    Significant progress has been made over the past several years in the understanding of phosphorus (Pi)-starvation responses in plants and their regulation. The transcriptional changes that occur in response to Pi starvation are beginning to be revealed, although much is left to understand about their significance. In this paper, the recent progresses on the gene expression changes under deficient-Pi, cis-regulatory elements involved in response to deficient-Pi, the transcriptional control of Pi-starvation responses in eukaryotes, transcription factors involved in response to Pi-starvation, the role of MicroRNA on regulation of phosphate homeostasis, and phosphate sensing and signal transduction in plants have been summarized. The purpose of this review is to provide some basis for further elucidation of the transcriptional responses and regulations, and the networks of Pi sensing and signal transduction under deficient-Pi in plants in the future.

  9. Linking maternal warmth and responsiveness to children's self-regulation

    OpenAIRE

    2011-01-01

    Abstract The present study demonstrated that a more differentiated view of positive parenting practices is necessary in the study of children?s acquisition of self-regulation. Here, the unique contributions of maternal warmth and responsiveness to distress to children?s self-regulation were tested in a sample of 102 German mothers and their kindergarten children (51 girls and 51 boys). Behavior regulation and internalization of rules of conduct were examined as specific components ...

  10. Linking maternal warmth and responsiveness to children's self-regulation

    OpenAIRE

    von Suchodoletz, Antje; Trommsdorff, Gisela; Heikamp, Tobias

    2011-01-01

    International audience; The present study demonstrated that a more differentiated view of positive parenting practices is necessary in the study of children's acquisition of self-regulation. Here, the unique contributions of maternal warmth and responsiveness to distress to children's self-regulation were tested in a sample of 102 German mothers and their kindergarten children (51 girls and 51 boys). Behavior regulation and internalization of rules of conduct were examined as specific compone...

  11. Hepato-cardiovascular response and its regulation

    Institute of Scientific and Technical Information of China (English)

    Xiang-Nong Li; Irving S Benjamin; Barry Alexander

    2005-01-01

    AIM: To determine the possible existence of a hepatocardiovascular response and its regulatory mechanism in normal rats.METHODS: Systemic hemodynamic changes following intraportal injection of latex microspheres were studied in two modified rat models of hepatic circulation, in which the extrahepatic splanchnic circulation was excluded by evisceration and the liver was perfused by systemic blood via either the portal vein (model 1) or hepatic artery(model 2)in vivo.RFSULTS: In model 1, intraportal injection of two sized microspheres (15-μm and 8O-μm) induced a similar decrease in mean arterial pressure, while extrahepatic portal venous occlusion induced an immediate increase in mean arterial pressure. In model 2, microsphere injection again induced a significant reduction in mean arterial pressure, aortic blood flow and aortic resistance. There were no significant differences in these parameters between liver-innervated rats and liver-denervated rats.The degrees of microsphere-induced reduction in mean arterial pressure (-38.1±1.9% in liver-innervated rats and -35.4±2.1% in liver-denervated rats, respectively)were similar to those obtained by withdrawal of 2.0 mL of blood via the jugular vein (-33.3±2.1%) (P>0.05).Injection of 2.0 mL Haemaccel in microsphere-treated rats, to compensate for the reduced effective circulating blood volume, led to a hyperdynamic state which, as compared with basal values and unlike control rats, was characterised by increased aortic blood flow (+21.6±3.3%),decreased aortic resistance (-38.1±3.5%) and reduced mean arterial pressure (-9.7±2.8%).CONCLUSION: A hepato-cardiovascular response exists in normal rats. It acts through a humoral mechanism leading to systemic vasodilatation, and may be involved in the hemodynamic disturbances associated with acute and chronic liver diseases.

  12. The circadian clock regulates auxin signaling and responses in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Michael F Covington

    2007-08-01

    Full Text Available The circadian clock plays a pervasive role in the temporal regulation of plant physiology, environmental responsiveness, and development. In contrast, the phytohormone auxin plays a similarly far-reaching role in the spatial regulation of plant growth and development. Went and Thimann noted 70 years ago that plant sensitivity to auxin varied according to the time of day, an observation that they could not explain. Here we present work that explains this puzzle, demonstrating that the circadian clock regulates auxin signal transduction. Using genome-wide transcriptional profiling, we found many auxin-induced genes are under clock regulation. We verified that endogenous auxin signaling is clock regulated with a luciferase-based assay. Exogenous auxin has only modest effects on the plant clock, but the clock controls plant sensitivity to applied auxin. Notably, we found both transcriptional and growth responses to exogenous auxin are gated by the clock. Thus the circadian clock regulates some, and perhaps all, auxin responses. Consequently, many aspects of plant physiology not previously thought to be under circadian control may show time-of-day-specific sensitivity, with likely important consequences for plant growth and environmental responses.

  13. Reconstructing a Network of Stress-Response Regulators via Dynamic System Modeling of Gene Regulation

    Directory of Open Access Journals (Sweden)

    Wei-Sheng Wu

    2008-01-01

    Full Text Available Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene’s expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specifi c stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably suffi cient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  14. Reconstructing a network of stress-response regulators via dynamic system modeling of gene regulation.

    Science.gov (United States)

    Wu, Wei-Sheng; Li, Wen-Hsiung; Chen, Bor-Sen

    2008-02-10

    Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs) that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene's expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA) to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions.

  15. Regulation of abiotic and biotic stress responses by plant hormones

    DEFF Research Database (Denmark)

    Grosskinsky, Dominik Kilian; van der Graaff, Eric; Roitsch, Thomas Georg

    2016-01-01

    Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights into ...... through ubiquitination. The wide range of biotic and abiotic stresses that affect crop plants limits agricultural production.......Plant hormones (phytohormones) are signal molecules produced within the plant, and occur in very low concentrations. In the present chapter, the current knowledge on the regulation of biotic and biotic stress responses by plant hormones is summarized with special focus on the novel insights...

  16. The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast.

    Science.gov (United States)

    Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A

    2014-05-01

    This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed.

  17. IrrE基因酵母双杂交体系诱饵载体的构建

    Institute of Scientific and Technical Information of China (English)

    杜世章; 奉斌; 代其林; 王劲

    2010-01-01

    耐辐射奇球菌中的IrrE基因能增强转IrrE基因油菜的盐胁迫耐受性.为了进一步筛选植物体内与IrrE相互作用蛋白,从而加深对盐胁迫耐受性分子调控网络的认识,根据IrrE基因的开放阅读框设计引物,从PBI121-IrrE上扩增该基因的编码区,将其克隆到酵母表达载体pGBKT7中,获得IrrE的酵母表达载体pGBKT7-IrrE,测序结果表明:pGBKT7-IrrE载体构建成功,可用于后续的酵母双杂交文库的筛选工作.

  18. 23 CFR 661.49 - Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges?

    Science.gov (United States)

    2010-04-01

    ..., and Toll Road IRR bridges? 661.49 Section 661.49 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION ENGINEERING AND TRAFFIC OPERATIONS INDIAN RESERVATION ROAD BRIDGE PROGRAM § 661.49 Can IRRBP funds be spent on Interstate, State Highway, and Toll Road IRR bridges? Yes....

  19. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false How are IRR Program projects and activities included in a self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance...

  20. 25 CFR 170.810 - To what standards must an IRR transportation facility be maintained?

    Science.gov (United States)

    2010-04-01

    ... WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.810 To what standards must an IRR... standards; (b) AASHTO road and bridge maintenance manuals, latest edition; or (c) Other applicable Federal, State, tribal, or local government maintenance standards as may be negotiated in an ISDEAA...

  1. 25 CFR 170.813 - When can access to IRR transportation facilities be restricted?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false When can access to IRR transportation facilities be restricted? 170.813 Section 170.813 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.813 When can access to...

  2. 25 CFR Appendix B to Subpart D - Design Standards for the IRR Program

    Science.gov (United States)

    2010-04-01

    ... Transportation Landscape and Environmental Design. 3. AASHTO Roadside Design Guide, latest edition. 4. AASHTO... 25 Indians 1 2010-04-01 2010-04-01 false Design Standards for the IRR Program B Appendix B to... ROADS PROGRAM Planning, Design, and Construction of Indian Reservation Roads Program Facilities Pt. 170...

  3. 25 CFR 170.403 - What IRR Program funds can be used for transportation planning?

    Science.gov (United States)

    2010-04-01

    ... planning? 170.403 Section 170.403 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Planning, Design, and Construction of Indian Reservation Roads Program Facilities Transportation Planning § 170.403 What IRR Program funds can be used for transportation...

  4. Ezrin Inhibition Up-regulates Stress Response Gene Expression*

    Science.gov (United States)

    Çelik, Haydar; Bulut, Gülay; Han, Jenny; Graham, Garrett T.; Minas, Tsion Z.; Conn, Erin J.; Hong, Sung-Hyeok; Pauly, Gary T.; Hayran, Mutlu; Li, Xin; Özdemirli, Metin; Ayhan, Ayşe; Rudek, Michelle A.; Toretsky, Jeffrey A.; Üren, Aykut

    2016-01-01

    Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes. PMID:27137931

  5. 17 CFR 450.1 - Scope of regulations; office responsible.

    Science.gov (United States)

    2010-04-01

    ... responsible. 450.1 Section 450.1 Commodity and Securities Exchanges DEPARTMENT OF THE TREASURY REGULATIONS UNDER TITLE II OF THE GOVERNMENT SECURITIES ACT OF 1986 CUSTODIAL HOLDINGS OF GOVERNMENT SECURITIES BY... institutions that hold government securities as fiduciary, custodian, or otherwise for the account of...

  6. VENTROMEDIAL HYPOTHALAMIC REGULATION OF HORMONAL AND METABOLIC RESPONSES TO EXERCISE

    NARCIS (Netherlands)

    Vissing, John; Wallace, Jo L.; Scheurink, Anton J.W.; Galbo, Henrik; Steffens, Anton B.

    1989-01-01

    Recent studies have indicated a neural regulation of hormonal and metabolic responses to exercise. Studies on the ventromedial hypothalamus (VMH) suggest that the VMH might be involved in neural control of exercise metabolism. We therefore studied 25 rats with or without Marcain-anesthetized VMH (Ma

  7. Enhancing forest tenure reforms through more responsive regulations

    Directory of Open Access Journals (Sweden)

    Anne M Larson

    2012-01-01

    Full Text Available Forest tenure reforms have offered new opportunities for communities to obtain formal rights to forests and forest benefits, but at the same time a variety of limitations are placed on livelihood options. This article draws on several case studies of reforms in Africa, Asia and Latin America to analyse the regulations accompanying reforms. It identifies three types of regulations, namely rules that limit areas available to local communities; rules that delineate conservation areas and impose related limits on use; and bureaucratic requirements for permits and management plans, which restrict the commercial use and marketing of valuable forest products. It discusses problems with these regulations, and proposes a simple framework for identifying ways to promote regulations that work for forest conservation but are more responsive to the needs of communities and forests.

  8. Arabidopsis YAK1 regulates abscisic acid response and drought resistance

    KAUST Repository

    Kim, Dongjin

    2016-06-06

    Abscisic acid (ABA) is an important phytohormone that controls several plant processes such as seed germination, seedling growth, and abiotic stress response. Here, we report that AtYak1 plays an important role in ABA signaling and postgermination growth in Arabidopsis. AtYak1 knockout mutant plants were hyposensitive to ABA inhibition of seed germination, cotyledon greening, seedling growth, and stomatal movement. atyak1-1 mutant plants display reduced drought stress resistance, as evidenced by water loss rate and survival rate. Molecular genetic analysis revealed that AtYak1 deficiency led to elevated expression of stomatal-related gene, MYB60, and down-regulation of several stress-responsive genes. Altogether, these results indicate that AtYak1 plays a role as a positive regulator in ABA-mediated drought response in Arabidopsis. © 2016 Federation of European Biochemical Societies.

  9. MicroRNAs as regulators in plant metal toxicity response

    Directory of Open Access Journals (Sweden)

    Ana Belen Mendoza-Soto

    2012-05-01

    Full Text Available Metal toxicity is a major stress affecting crop production. This includes metals that are essential for plants (copper, iron, zinc, manganese, and non-essential metals (cadmium, aluminum, cobalt, mercury. A primary common effect of high concentrations of metals such as aluminum, cooper, cadmium or mercury, is root growth inhibition. Metal toxicity triggers the accumulation of reactive oxygen species leading to damage of lipids, proteins and DNA. The plants response to metal toxicity involves several biological processes that require fine and precise regulation at transcriptional and post-transcriptional levels. MicroRNAs (miRNAs are 21 nucleotides non-coding RNAs that regulate gene expression at the post-transcriptional level. A miRNA, incorporated into a RNA induced silencing complex, promotes cleavage of its target mRNA that is recognized by an almost perfect base complementarity. In plants miRNA regulation has been involved in development and also in biotic and abiotic stress responses. We review novel advances in identifying miRNAs related to metal toxicity responses and their potential role according to their targets. Most of the targets for plant metal-responsive miRNAs are transcription factors. Information about metal-responsive miRNAs in different plants points to important regulatory roles of miR319, miR390, miR393 and miR398. The target of miR319 is the TCP transcription factor, implicated in growth control. MiR390 exerts its action through the biogenesis of trans-acting small interference RNAs that, in turn, regulate auxin responsive factors. MiR393 targets the auxin receptors TIR1/AFBs and a bHLH transcription factor. Increasing evidence points to the crucial role of miR398 and its targets Cu/Zn superoxide dismutases in the control of the oxidative stress generated after high metal copper or iron exposure.

  10. lncRNA-mediated regulation of the interferon response.

    Science.gov (United States)

    Valadkhan, Saba; Gunawardane, Lalith S

    2016-01-01

    The interferon (IFN) response is a critical arm of the innate immune response and a major host defense mechanism against viral infections. Following microbial encounter, a series of signaling events lead to transcriptional activation of the IFN genes, which in turn leads to significant changes in the cellular transcriptome by altering the expression of hundreds of target genes. Emerging evidence suggests that long non-coding RNAs (lncRNAs) constitute a major subgroup of the IFN target genes, and further, that the IFN response is subject to regulation by a large number of host- and pathogen-derived lncRNAs. While the vast majority of lncRNAs with potential roles in the IFN response remain unstudied, analysis of a very small subset provides a glimpse of the regulatory impact of this class of RNAs on IFN response.

  11. SOS response and its regulation on the fluoroquinolone resistance.

    Science.gov (United States)

    Qin, Ting-Ting; Kang, Hai-Quan; Ma, Ping; Li, Peng-Peng; Huang, Lin-Yan; Gu, Bing

    2015-12-01

    Bacteria can survive fluoroquinolone antibiotics (FQs) treatment by becoming resistant through a genetic change-mutation or gene acquisition. The SOS response is widespread among bacteria and exhibits considerable variation in its composition and regulation, which is repressed by LexA protein and derepressed by RecA protein. Here, we take a comprehensive review of the SOS gene network and its regulation on the fluoroquinolone resistance. As a unique survival mechanism, SOS may be an important factor influencing the outcome of antibiotic therapy in vivo.

  12. Regulation of inflammatory responses by IL-17F

    Science.gov (United States)

    Yang, Xuexian O.; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S.; Broaddus, Russell R.; Zhu, Zhou; Dong, Chen

    2008-01-01

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  13. Structural basis of response regulator dephosphorylation by Rap phosphatases.

    Science.gov (United States)

    Parashar, Vijay; Mirouze, Nicolas; Dubnau, David A; Neiditch, Matthew B

    2011-02-08

    Bacterial Rap family proteins have been most extensively studied in Bacillus subtilis, where they regulate activities including sporulation, genetic competence, antibiotic expression, and the movement of the ICEBs1 transposon. One subset of Rap proteins consists of phosphatases that control B. subtilis and B. anthracis sporulation by dephosphorylating the response regulator Spo0F. The mechanistic basis of Rap phosphatase activity was unknown. Here we present the RapH-Spo0F X-ray crystal structure, which shows that Rap proteins consist of a 3-helix bundle and a tetratricopeptide repeat domain. Extensive biochemical and genetic functional studies reveal the importance of the observed RapH-Spo0F interactions, including the catalytic role of a glutamine in the RapH 3-helix bundle that inserts into the Spo0F active site. We show that in addition to dephosphorylating Spo0F, RapH can antagonize sporulation by sterically blocking phosphoryl transfer to and from Spo0F. Our structure-function analysis of the RapH-Spo0F interaction identified Rap protein residues critical for Spo0F phosphatase activity. This information enabled us to assign Spo0F phosphatase activity to a Rap protein based on sequence alone, which was not previously possible. Finally, as the ultimate test of our newfound understanding of the structural requirements for Rap phosphatase function, a non-phosphatase Rap protein that inhibits the binding of the response regulator ComA to DNA was rationally engineered to dephosphorylate Spo0F. In addition to revealing the mechanistic basis of response regulator dephosphorylation by Rap proteins, our studies support the previously proposed T-loop-Y allostery model of receiver domain regulation that restricts the aromatic "switch" residue to an internal position when the β4-α4 loop adopts an active-site proximal conformation.

  14. Pleiotropic regulations of neutrophil receptors response to sepsis.

    Science.gov (United States)

    Zhang, Huafeng; Sun, Bingwei

    2017-03-01

    Sepsis is a complex clinical condition that causes a high mortality rate worldwide. Numerous studies on the pathophysiology of sepsis have revealed an imbalance in the inflammatory network, thus leading to tissue damage, organ failure, and ultimately death. The impairment of neu-trophil migration is associated with the outcome of sepsis. Literature review was performed on the roles of neutrophil recruitment and neutrophil receptors as pleiotropic regulators during sepsis. Additionally, we systematically classify neutrophil receptors with regard to the neutrophil response during sepsis and discuss the clinical implications of these receptors for the treatment of sepsis. Increasing evidence suggests that there is significant dysfunction in neutrophil recruitment during sepsis, characterized by the failure to migrate to the site of infection. Neutrophil receptors, as pleiotropic regulators, play important roles in the neutrophil response during sepsis. Neutrophil receptors play key roles in chemotactic neutrophil migration and may prove to be suitable targets in future pharmacological therapies for sepsis.

  15. The light responsive transcriptome of the zebrafish: function and regulation.

    Directory of Open Access Journals (Sweden)

    Benjamin D Weger

    Full Text Available Most organisms possess circadian clocks that are able to anticipate the day/night cycle and are reset or "entrained" by the ambient light. In the zebrafish, many organs and even cultured cell lines are directly light responsive, allowing for direct entrainment of the clock by light. Here, we have characterized light induced gene transcription in the zebrafish at several organizational levels. Larvae, heart organ cultures and cell cultures were exposed to 1- or 3-hour light pulses, and changes in gene expression were compared with controls kept in the dark. We identified 117 light regulated genes, with the majority being induced and some repressed by light. Cluster analysis groups the genes into five major classes that show regulation at all levels of organization or in different subset combinations. The regulated genes cover a variety of functions, and the analysis of gene ontology categories reveals an enrichment of genes involved in circadian rhythms, stress response and DNA repair, consistent with the exposure to visible wavelengths of light priming cells for UV-induced damage repair. Promoter analysis of the induced genes shows an enrichment of various short sequence motifs, including E- and D-box enhancers that have previously been implicated in light regulation of the zebrafish period2 gene. Heterologous reporter constructs with sequences matching these motifs reveal light regulation of D-box elements in both cells and larvae. Morpholino-mediated knock-down studies of two homologues of the D-box binding factor Tef indicate that these are differentially involved in the cell autonomous light induction in a gene-specific manner. These findings suggest that the mechanisms involved in period2 regulation might represent a more general pathway leading to light induced gene expression.

  16. Enzyme action in the regulation of plant hormone responses.

    Science.gov (United States)

    Westfall, Corey S; Muehler, Ashley M; Jez, Joseph M

    2013-07-05

    Plants synthesize a chemically diverse range of hormones that regulate growth, development, and responses to environmental stresses. The major classes of plant hormones are specialized metabolites with exquisitely tailored perception and signaling systems, but equally important are the enzymes that control the dose and exposure to the bioactive forms of these molecules. Here, we review new insights into the role of enzyme families, including the SABATH methyltransferases, the methylesterases, the GH3 acyl acid-amido synthetases, and the hormone peptidyl hydrolases, in controlling the biosynthesis and modifications of plant hormones and how these enzymes contribute to the network of chemical signals responsible for plant growth, development, and environmental adaptation.

  17. Regulation of Neurotransmitter Responses in the Central Nervous System

    Science.gov (United States)

    1990-02-05

    accordance with DoD 5200.1 -R, Information Security Program Regulation. Chapter V1 Section 2, V"-apaph 4-200. clasification markings are to be stamped...through pharmacologically distinct reports. Finally, the augmenting response does not appear to be mediated through protein kinase C. However, BAC...may facilitate second messenger production by altering the coupling of catecholamine receptor to C- proteins involved in the cAMP cascade. (( ( CONTRACT

  18. Adaptive Immune Responses Regulate the Pathophysiology of Lymphedema

    Science.gov (United States)

    2012-09-01

    Pathophysiology of Lymphedema PRINCIPAL INVESTIGATOR: Jamie Zampell, M.D. CONTRACTING ORGANIZATION: Sloan-Kettering Institute for...Immune Responses Regulate the Pathophysiology of Lymphedema 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0495 5c. PROGRAM ELEMENT... Lymphedema is a debilitating disorder affecting as many as 1 in 8 cancer survivors. Despite wide prevalence, limited understanding of disease

  19. MOF maintains transcriptional programs regulating cellular stress response.

    Science.gov (United States)

    Sheikh, B N; Bechtel-Walz, W; Lucci, J; Karpiuk, O; Hild, I; Hartleben, B; Vornweg, J; Helmstädter, M; Sahyoun, A H; Bhardwaj, V; Stehle, T; Diehl, S; Kretz, O; Voss, A K; Thomas, T; Manke, T; Huber, T B; Akhtar, A

    2016-05-01

    MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes.

  20. The genetic regulation of infant immune responses to vaccination

    Directory of Open Access Journals (Sweden)

    Melanie eNewport

    2015-02-01

    Full Text Available A number of factors are recognised to influence immune responses to vaccinations including age, gender, the dose and quality of the antigen used, the number of doses given, the route of administration and the nutritional status of the recipient. Additionally, several immunogenetic studies have identified associations between polymorphisms in genes encoding immune response proteins, both innate and adaptive, and variation in responses to vaccines. Variants in the genes encoding Toll-like receptors, HLA molecules, cytokines, cytokine receptors have associated with heterogeneity of responses to a wide range of vaccines including measles, hepatitis B, influenza A, BCG, Haemophilus influenzae type b and certain Neisseria meningitidis serotypes, amongst others. However, the vast majority of these studies have been conducted in older children and adults and there are very few data available from studies conducted in infants. This paper reviews the evidence to date that host genes influencing vaccines responses in these older population and identifies a large gap in our understanding of the genetic regulation of responses in early life. . Given the high mortality from infection in early life and the challenges of developing vaccines that generate effective immune responses in the context of the developing immune system further research on infant populations is required.

  1. VLDL hydrolysis by hepatic lipase regulates PPARδ transcriptional responses.

    Directory of Open Access Journals (Sweden)

    Jonathan D Brown

    Full Text Available BACKGROUND: PPARs (α,γ,δ are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL, an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown. METHODS/PRINCIPAL FINDINGS: Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL≫LDL, IDL to activate PPARδ preferentially over PPARα or PPARγ, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARδ in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARδ target genes, including adipocyte differentiation related protein (ADRP, angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARδ activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARδ activation and ADRP gene regulation in vitro. CONCLUSIONS: These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARδ through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight

  2. Analisis Strategi Bisnis NPV, IRR, PI dan DPB pada Golden Restaurant Jakarta

    OpenAIRE

    Kriswanto Kriswanto

    2011-01-01

    Golden Restaurant is located in Senayan, South Jakarta. Because of intense competition and a lack of good economic growth in Indonesia, the restaurant sales dropped sharply and having some problems in operation. The measures is to do effective business strategies to improve business performance by conducting research, create a budget to analyze and predict the financial performance, and formulate an effective working capital structure. Formulation of the problem discussed is NPV and IRR of re...

  3. Analisis Strategi Bisnis NPV, IRR, PI dan DPB Pada Golden Restaurant Jakarta

    Directory of Open Access Journals (Sweden)

    Kriswanto

    2011-04-01

    sales to 90% per year and provide a significant positive NPV and IRR of almost 20% which is higher than the original expectation of 15% and reach breakeven point within 4 to 7 years. From the results of this analysis also shows the business is sensitive to increased sales, operating expenses and cost of sales. In addition to inflation and economic conditions affect the performance of sensitive business.

  4. Supply chain carbon footprinting and responsibility allocation under emission regulations.

    Science.gov (United States)

    Chen, Jin-Xiao; Chen, Jian

    2017-03-01

    Reduction of greenhouse gas emissions has become an enormous challenge for any single enterprise and its supply chain because of the increasing concern on global warming. This paper investigates carbon footprinting and responsibility allocation for supply chains involved in joint production. Our study is conducted from the perspective of a social planner who aims to achieve social value optimization. The carbon footprinting model is based on operational activities rather than on firms because joint production blurs the organizational boundaries of footprints. A general model is proposed for responsibility allocation among firms who seek to maximize individual profits. This study looks into ways for the decentralized supply chain to achieve centralized optimality of social value under two emission regulations. Given a balanced allocation for the entire supply chain, we examine the necessity of over-allocation to certain firms under specific situations and find opportunities for the firms to avoid over-allocation. The comparison of the two regulations reveals that setting an emission standard per unit of product will motivate firms to follow the standard and improve their emission efficiencies. Hence, a more efficient and promising policy is needed in contrast to existing regulations on total production.

  5. Arabidopsis type B cytokinin response regulators ARR1, ARR10, and ARR12 negatively regulate plant responses to drought.

    Science.gov (United States)

    Nguyen, Kien Huu; Ha, Chien Van; Nishiyama, Rie; Watanabe, Yasuko; Leyva-González, Marco Antonio; Fujita, Yasunari; Tran, Uven Thi; Li, Weiqiang; Tanaka, Maho; Seki, Motoaki; Schaller, G Eric; Herrera-Estrella, Luis; Tran, L S

    2016-03-15

    In this study, we used a loss-of-function approach to elucidate the functions of three Arabidopsis type B response regulators (ARRs)--namely ARR1, ARR10, and ARR12--in regulating the Arabidopsis plant responses to drought. The arr1,10,12 triple mutant showed a significant increase in drought tolerance versus WT plants, as indicated by its higher relative water content and survival rate on drying soil. This enhanced drought tolerance of arr1,10,12 plants can be attributed to enhanced cell membrane integrity, increased anthocyanin biosynthesis, abscisic acid (ABA) hypersensitivity, and reduced stomatal aperture, but not to altered stomatal density. Further drought-tolerance tests of lower-order double and single mutants indicated that ARR1, ARR10, and ARR12 negatively and redundantly control plant responses to drought, with ARR1 appearing to bear the most critical function among the three proteins. In agreement with these findings, a comparative genome-wide analysis of the leaves of arr1,10,12 and WT plants under both normal and dehydration conditions suggested a cytokinin (CK) signaling-mediated network controlling plant adaptation to drought via many dehydration/drought- and/or ABA-responsive genes that can provide osmotic adjustment and protection to cellular and membrane structures. Expression of all three ARR genes was repressed by dehydration and ABA treatments, inferring that plants down-regulate these genes as an adaptive mechanism to survive drought. Collectively, our results demonstrate that repression of CK response, and thus CK signaling, is one of the strategies plants use to cope with water deficit, providing novel insight for the design of drought-tolerant plants by genetic engineering.

  6. Luminosity-Metallicity Relation for dIrr Galaxies in the Near-Infrared

    CERN Document Server

    Saviane, Ivo; Held, Enrico V; Alloin, Danielle; Rich, R Michael; Bresolin, Fabio; Rizzi, Luca

    2008-01-01

    (abridged) The present work is a first step to collect homogeneous abundances and near-infrared (NIR) luminosities for a sample of dwarf irregular (dIrr) galaxies, located in nearby groups. The use of NIR luminosities is intended to provide a better proxy to mass than the blue luminosities commonly used in the literature; in addition, selecting group members reduces the impact of uncertain distances. Accurate abundances are derived to assess the galaxy metallicity. Optical spectra are collected for Hii regions in the dIrrs, allowing the determination of oxygen abundances by means of the temperature-sensitive method. For each dIrr galaxy H-band imaging is performed and the total magnitudes are measured via surface photometry. This high-quality database allows us to build a well-defined luminosity-metallicity relation in the range -13 >= M(H) >= -20. The scatter around its linear fit is reduced to 0.11 dex, the lowest of all relations currently available. There might exist a difference between the relation for ...

  7. Analisis Strategi Bisnis NPV, IRR, PI dan DPB pada Golden Restaurant Jakarta

    Directory of Open Access Journals (Sweden)

    Kriswanto Kriswanto

    2011-05-01

    Full Text Available Golden Restaurant is located in Senayan, South Jakarta. Because of intense competition and a lack of good economic growth in Indonesia, the restaurant sales dropped sharply and having some problems in operation. The measures is to do effective business strategies to improve business performance by conducting research, create a budget to analyze and predict the financial performance, and formulate an effective working capital structure. Formulation of the problem discussed is NPV and IRR of restaurant sales for the feasibility of an investment, securities of the PI and IBA restaurant on the return on investment and analysis NPV, IRR, PI and IBA on strategy formulation restaurant. From the analysis of simple direct study expected an increase in sales to 90% per year and provide a significant positive NPV and IRR of almost 20% which is higher than the original expectation of 15% and reach breakeven point within 4 to 7 years. From the results of this analysis also shows the business is sensitive to increased sales, operating expenses and cost of sales. In addition to inflation and economic conditions affect the performance of sensitive business. 

  8. 25 CFR 170.412 - How is the tribal IRR long-range transportation plan developed and approved?

    Science.gov (United States)

    2010-04-01

    ... LAND AND WATER INDIAN RESERVATION ROADS PROGRAM Planning, Design, and Construction of Indian Reservation Roads Program Facilities Long-Range Transportation Planning § 170.412 How is the tribal IRR long...

  9. Glucocorticoids and the Brain: Neural Mechanisms Regulating the Stress Response.

    Science.gov (United States)

    Shirazi, Shawn N; Friedman, Aaron R; Kaufer, Daniela; Sakhai, Samuel A

    2015-01-01

    In this chapter, we describe the central role of the brain in the glucocorticoid mediated stress response. We describe the mechanisms by which the brain gauges the severity of stress, mechanisms of hypothalamic-pituitary-adrenal axis (HPA) regulation, and how various sub-systems of the brain respond to glucocorticoid (GC) signaling to regulate stress behavior. In particular, we focus on the hippocampus, pre-frontal cortex, and amygdala, where GCs can induce a series of changes. Finally, we briefly discuss an apparent paradox in GC signaling: while exposure to glucocorticoids promotes the survival of an organism during acute stress, these same hormones in chronic excess can also cause damage and promote illness.

  10. Circadian clock-regulated physiological outputs: dynamic responses in nature.

    Science.gov (United States)

    Kinmonth-Schultz, Hannah A; Golembeski, Greg S; Imaizumi, Takato

    2013-05-01

    The plant circadian clock is involved in the regulation of numerous processes. It serves as a timekeeper to ensure that the onset of key developmental events coincides with the appropriate conditions. Although internal oscillating clock mechanisms likely evolved in response to the earth's predictable day and night cycles, organisms must integrate a range of external and internal cues to adjust development and physiology. Here we introduce three different clock outputs to illustrate the complexity of clock control. Clock-regulated diurnal growth is altered by environmental stimuli. The complexity of the photoperiodic flowering pathway highlights numerous nodes through which plants may integrate information to modulate the timing of flowering. Comparative analyses among ecotypes that differ in flowering response reveal additional environmental cues and molecular processes that have developed to influence flowering. We also explore the process of cold acclimation, where circadian inputs, light quality, and stress responses converge to improve freezing tolerance in anticipation of colder temperatures. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. The tumor suppressor ARF regulates innate immune responses in mice.

    Science.gov (United States)

    Través, Paqui G; López-Fontal, Raquel; Luque, Alfonso; Hortelano, Sonsoles

    2011-12-15

    The innate immune system is the first line of defense against invading organisms, and TLRs are the main sensors of microbial components, initiating signaling pathways that induce the production of proinflammatory cytokines and type I IFNs. An antiviral action for the tumor suppressor alternative reading frame (ARF) has been reported; however, the precise role of ARF in innate immunity is unknown. In this study, we show that ARF plays an important role in regulation of inflammatory responses. In peritoneal macrophages and bone marrow-derived macrophages from ARF-deficient animals, the induction of proinflammatory cytokines and chemokines by TLR ligands was severely impaired. The altered responses of ARF(-/-) cells to TLR ligands result from aberrant activation of intracellular signaling molecules including MAPKs, IκBα degradation, and NF-κB activation. Additionally, animals lacking ARF were resistant to LPS-induced endotoxic shock. This impaired activation of inflammation in ARF(-/-) mice was not restricted to TLRs, as it was also shown in response to non-TLR signaling pathways. Thus, ARF(-/-) mice were also unable to trigger a proper inflammatory response in experimental peritonitis or in 12-O-tetradecanoylphorbol-13-acetate-induced edema. Overexpression of ARF, but not its downstream target p53, rescued the ARF-deficient phenotype, increasing TLR4 levels and restoring inflammatory reaction. An increase in the E2F1 protein levels observed in ARF(-/-) macrophages at basal condition and after LPS stimulation may be involved in the impaired response in this system, as E2F1 has been described as an inflammatory suppressor. These results indicate that tumor suppressor ARF is a new regulator of inflammatory cell signaling.

  12. Molecular Responses to Small Regulating Molecules against Huanglongbing Disease

    Science.gov (United States)

    Martinelli, Federico; Dolan, David; Fileccia, Veronica; Reagan, Russell L.; Phu, My; Spann, Timothy M.; McCollum, Thomas G.; Dandekar, Abhaya M.

    2016-01-01

    Huanglongbing (HLB; citrus greening) is the most devastating disease of citrus worldwide. No cure is yet available for this disease and infected trees generally decline after several months. Disease management depends on early detection of symptoms and chemical control of insect vectors. In this work, different combinations of organic compounds were tested for the ability to modulate citrus molecular responses to HLB disease beneficially. Three small-molecule regulating compounds were tested: 1) L-arginine, 2) 6-benzyl-adenine combined with gibberellins, and 3) sucrose combined with atrazine. Each treatment contained K-phite mineral solution and was tested at two different concentrations. Two trials were conducted: one in the greenhouse and the other in the orchard. In the greenhouse study, responses of 42 key genes involved in sugar and starch metabolism, hormone-related pathways, biotic stress responses, and secondary metabolism in treated and untreated mature leaves were analyzed. TGA5 was significantly induced by arginine. Benzyladenine and gibberellins enhanced two important genes involved in biotic stress responses: WRKY54 and WRKY59. Sucrose combined with atrazine mainly upregulated key genes involved in carbohydrate metabolism such as sucrose-phosphate synthase, sucrose synthase, starch synthase, and α-amylase. Atrazine also affected expression of some key genes involved in systemic acquired resistance such as EDS1, TGA6, WRKY33, and MYC2. Several treatments upregulated HSP82, which might help protect protein folding and integrity. A subset of key genes was chosen as biomarkers for molecular responses to treatments under field conditions. GPT2 was downregulated by all small-molecule treatments. Arginine-induced genes involved in systemic acquired resistance included PR1, WRKY70, and EDS1. These molecular data encourage long-term application of treatments that combine these regulating molecules in field trials. PMID:27459099

  13. Molecular Responses to Small Regulating Molecules against Huanglongbing Disease.

    Science.gov (United States)

    Martinelli, Federico; Dolan, David; Fileccia, Veronica; Reagan, Russell L; Phu, My; Spann, Timothy M; McCollum, Thomas G; Dandekar, Abhaya M

    2016-01-01

    Huanglongbing (HLB; citrus greening) is the most devastating disease of citrus worldwide. No cure is yet available for this disease and infected trees generally decline after several months. Disease management depends on early detection of symptoms and chemical control of insect vectors. In this work, different combinations of organic compounds were tested for the ability to modulate citrus molecular responses to HLB disease beneficially. Three small-molecule regulating compounds were tested: 1) L-arginine, 2) 6-benzyl-adenine combined with gibberellins, and 3) sucrose combined with atrazine. Each treatment contained K-phite mineral solution and was tested at two different concentrations. Two trials were conducted: one in the greenhouse and the other in the orchard. In the greenhouse study, responses of 42 key genes involved in sugar and starch metabolism, hormone-related pathways, biotic stress responses, and secondary metabolism in treated and untreated mature leaves were analyzed. TGA5 was significantly induced by arginine. Benzyladenine and gibberellins enhanced two important genes involved in biotic stress responses: WRKY54 and WRKY59. Sucrose combined with atrazine mainly upregulated key genes involved in carbohydrate metabolism such as sucrose-phosphate synthase, sucrose synthase, starch synthase, and α-amylase. Atrazine also affected expression of some key genes involved in systemic acquired resistance such as EDS1, TGA6, WRKY33, and MYC2. Several treatments upregulated HSP82, which might help protect protein folding and integrity. A subset of key genes was chosen as biomarkers for molecular responses to treatments under field conditions. GPT2 was downregulated by all small-molecule treatments. Arginine-induced genes involved in systemic acquired resistance included PR1, WRKY70, and EDS1. These molecular data encourage long-term application of treatments that combine these regulating molecules in field trials.

  14. Molecular Responses to Small Regulating Molecules against Huanglongbing Disease.

    Directory of Open Access Journals (Sweden)

    Federico Martinelli

    Full Text Available Huanglongbing (HLB; citrus greening is the most devastating disease of citrus worldwide. No cure is yet available for this disease and infected trees generally decline after several months. Disease management depends on early detection of symptoms and chemical control of insect vectors. In this work, different combinations of organic compounds were tested for the ability to modulate citrus molecular responses to HLB disease beneficially. Three small-molecule regulating compounds were tested: 1 L-arginine, 2 6-benzyl-adenine combined with gibberellins, and 3 sucrose combined with atrazine. Each treatment contained K-phite mineral solution and was tested at two different concentrations. Two trials were conducted: one in the greenhouse and the other in the orchard. In the greenhouse study, responses of 42 key genes involved in sugar and starch metabolism, hormone-related pathways, biotic stress responses, and secondary metabolism in treated and untreated mature leaves were analyzed. TGA5 was significantly induced by arginine. Benzyladenine and gibberellins enhanced two important genes involved in biotic stress responses: WRKY54 and WRKY59. Sucrose combined with atrazine mainly upregulated key genes involved in carbohydrate metabolism such as sucrose-phosphate synthase, sucrose synthase, starch synthase, and α-amylase. Atrazine also affected expression of some key genes involved in systemic acquired resistance such as EDS1, TGA6, WRKY33, and MYC2. Several treatments upregulated HSP82, which might help protect protein folding and integrity. A subset of key genes was chosen as biomarkers for molecular responses to treatments under field conditions. GPT2 was downregulated by all small-molecule treatments. Arginine-induced genes involved in systemic acquired resistance included PR1, WRKY70, and EDS1. These molecular data encourage long-term application of treatments that combine these regulating molecules in field trials.

  15. Regulation of cardiac microRNAs by serum response factor

    Directory of Open Access Journals (Sweden)

    Wei Jeanne Y

    2011-02-01

    Full Text Available Abstract Serum response factor (SRF regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg led to altered expression of a number of microRNAs. Interestingly, downregulation of miR-1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF-Tg resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis.

  16. Large-signal transient response of a switching regulator

    Science.gov (United States)

    Harada, K.; Nabeshima, T.

    Analytical and experimental considerations on the large-signal transient-responses of the buck-type switching regulator are described. The behaviour under the large-signal operation is different from the case of small signal because of the saturation characteristics of the PWM feedback controller. The effect of this nonlinearity is analyzed by dividing its operation into three modes. As a result, the maximum peak values of the inrush current and output voltage are obtained analytically both for the start-up and for the step change of the load current.

  17. Copper response regulator1-dependent and -independent responses of the Chlamydomonas reinhardtii transcriptome to dark anoxia.

    Science.gov (United States)

    Hemschemeier, Anja; Casero, David; Liu, Bensheng; Benning, Christoph; Pellegrini, Matteo; Happe, Thomas; Merchant, Sabeeha S

    2013-09-01

    Anaerobiosis is a stress condition for aerobic organisms and requires extensive acclimation responses. We used RNA-Seq for a whole-genome view of the acclimation of Chlamydomonas reinhardtii to anoxic conditions imposed simultaneously with transfer to the dark. Nearly 1.4 × 10(3) genes were affected by hypoxia. Comparing transcript profiles from early (hypoxic) with those from late (anoxic) time points indicated that cells activate oxidative energy generation pathways before employing fermentation. Probable substrates include amino acids and fatty acids (FAs). Lipid profiling of the C. reinhardtii cells revealed that they degraded FAs but also accumulated triacylglycerols (TAGs). In contrast with N-deprived cells, the TAGs in hypoxic cells were enriched in desaturated FAs, suggesting a distinct pathway for TAG accumulation. To distinguish transcriptional responses dependent on copper response regulator1 (CRR1), which is also involved in hypoxic gene regulation, we compared the transcriptomes of crr1 mutants and complemented strains. In crr1 mutants, ~40 genes were aberrantly regulated, reaffirming the importance of CRR1 for the hypoxic response, but indicating also the contribution of additional signaling strategies to account for the remaining differentially regulated transcripts. Based on transcript patterns and previous results, we conclude that nitric oxide-dependent signaling cascades operate in anoxic C. reinhardtii cells.

  18. Histamine regulates the inflammatory response of the tunicate Styela plicata.

    Science.gov (United States)

    García-García, Erick; Gómez-González, Nuria E; Meseguer, José; García-Ayala, Alfonsa; Mulero, Victoriano

    2014-10-01

    Histamine is stored inside hemocytes of the tunicate Styela plicata (Chordata, Tunicata, Ascidiacea), but no evidence on its role in the regulation of the immune response of this species has been reported. We examined whether histamine participated in the regulation of inflammation and host defense in S. plicata. The presence of histamine inside S. plicata hemocytes was confirmed by flow cytometry, and histamine release was detected by ELISA, after in vitro hemocyte stimulation with different PAMPs. In vitro hemocyte treatment with histamine, or specific histamine-receptor agonists, reduced their phagocytic ability. Injection of histamine into the tunic recruited hemocytes to the site of injection. Systemic injection of histamine, or the histamine-releasing agent compound 48/80, decreased the phagocytic ability of hemocytes. Histamine promoted the constriction of tunic hemolymph vessels in vivo, having a direct effect on vasoconstriction in tunic explants. These results provide for the first time clear evidence for the involvement of histamine in the regulation of inflammation and host defense in tunicates.

  19. Systemic inflammation regulates microglial responses to tissue damage in vivo

    Science.gov (United States)

    Gyoneva, Stefka; Davalos, Dimitrios; Biswas, Dipankar; Swanger, Sharon A.; Garnier-Amblard, Ethel; Loth, Francis; Akassoglou, Katerina; Traynelis, Stephen F.

    2015-01-01

    Microglia, the resident immune cells of the central nervous system, exist in either a “resting” state associated with physiological tissue surveillance or an “activated” state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under pro-inflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. PMID:24807189

  20. Hydrodynamic regulation of monocyte inflammatory response to an intracellular pathogen.

    Directory of Open Access Journals (Sweden)

    Shankar J Evani

    Full Text Available Systemic bacterial infections elicit inflammatory response that promotes acute or chronic complications such as sepsis, arthritis or atherosclerosis. Of interest, cells in circulation experience hydrodynamic shear forces, which have been shown to be a potent regulator of cellular function in the vasculature and play an important role in maintaining tissue homeostasis. In this study, we have examined the effect of shear forces due to blood flow in modulating the inflammatory response of cells to infection. Using an in vitro model, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with chlamydia, an intracellular pathogen which causes bronchitis and is implicated in the development of atherosclerosis. We found that chlamydial infection alters the morphology of monocytes and trigger the release of pro-inflammatory cytokines TNF-α, IL-8, IL-1β and IL-6. We also found that the exposure of chlamydia-infected monocytes to short durations of arterial shear stress significantly enhances the secretion of cytokines in a time-dependent manner and the expression of surface adhesion molecule ICAM-1. As a functional consequence, infection and shear stress increased monocyte adhesion to endothelial cells under flow and in the activation and aggregation of platelets. Overall, our study demonstrates that shear stress enhances the inflammatory response of monocytes to infection, suggesting that mechanical forces may contribute to disease pathophysiology. These results provide a novel perspective on our understanding of systemic infection and inflammation.

  1. Gene regulation in the immediate-early response process.

    Science.gov (United States)

    Bahrami, Shahram; Drabløs, Finn

    2016-09-01

    Immediate-early genes (IEGs) can be activated and transcribed within minutes after stimulation, without the need for de novo protein synthesis, and they are stimulated in response to both cell-extrinsic and cell-intrinsic signals. Extracellular signals are transduced from the cell surface, through receptors activating a chain of proteins in the cell, in particular extracellular-signal-regulated kinases (ERKs), mitogen-activated protein kinases (MAPKs) and members of the RhoA-actin pathway. These communicate through a signaling cascade by adding phosphate groups to neighboring proteins, and this will eventually activate and translocate TFs to the nucleus and thereby induce gene expression. The gene activation also involves proximal and distal enhancers that interact with promoters to simulate gene expression. The immediate-early genes have essential biological roles, in particular in stress response, like the immune system, and in differentiation. Therefore they also have important roles in various diseases, including cancer development. In this paper we summarize some recent advances on key aspects of the activation and regulation of immediate-early genes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Understanding the Posttranscriptional Regulation of Plant Responses to Abiotic Stress

    KAUST Repository

    AlShareef, Sahar A.

    2017-06-01

    Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and biotic and abiotic stresses. Recent work showed that AS is pervasive across plant species, with more than 60% of intron-containing genes producing different isoforms. Mammalian cell-based assays have discovered various AS small-molecule inhibitors that perturb splicing and thereby provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. Here, I show that the macrolide Pladienolide B (PB) and herboxidiene (GEX1A) inhibits both constitutive and alternative splicing, mimics an abiotic stress signal, and activates the abscisic acid (ABA) pathway in plants. Moreover, PB and GEX1A activate genome-wide transcriptional patterns involved in abiotic stress responses in plants. PB and GEX1A treatment triggered the ABA signaling pathway, activated ABA-inducible promoters, and led to stomatal closure. Interestingly, PB and GEX1A elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. This work establishes PB and GEX1A as potent splicing inhibitors in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications.

  3. Transcriptional regulation of the stress response by mTOR.

    Science.gov (United States)

    Aramburu, Jose; Ortells, M Carmen; Tejedor, Sonia; Buxadé, Maria; López-Rodríguez, Cristina

    2014-07-01

    The kinase mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation that integrates inputs from growth factor receptors, nutrient availability, intracellular ATP (adenosine 5'-triphosphate), and a variety of stressors. Since early works in the mid-1990s uncovered the role of mTOR in stimulating protein translation, this kinase has emerged as a rather multifaceted regulator of numerous processes. Whereas mTOR is generally activated by growth- and proliferation-stimulating signals, its activity can be reduced and even suppressed when cells are exposed to a variety of stress conditions. However, cells can also adapt to stress while maintaining their growth capacity and mTOR function. Despite knowledge accumulated on how stress represses mTOR, less is known about mTOR influencing stress responses. In this review, we discuss the capability of mTOR, in particular mTOR complex 1 (mTORC1), to activate stress-responsive transcription factors, and we outline open questions for future investigation.

  4. Transcriptional Regulation of Arabidopsis in Response to Salt Stress

    Institute of Scientific and Technical Information of China (English)

    Zhulong Chan

    2012-01-01

    Salt stress is a major factor limiting agricultural productivity worldwide.Adaptations to salt stress include avoidance by reduced sodium uptake,sequestration of toxic sodium ions away from the cytoplasm,or production of compatible solutes or osmoprotectants to reduce molecular disruption.Approaches to engineer salt stress resistance have included regulation of ion transport through introduction of Na+/H+ antiporter; synthesis of compatible solutes; or the introduction of transcription factors regulating expression of stress-responsive genes.On the other hand,naturally occurring variation among wild-type populations of plants also can be used to understand plant adaptive responses to their environments.In this study,we compared phenotypic and transcriptomic effects of constitutive expression of genes intended to confer salt stress tolerance by three different mechanisms:a transcription factor,CBF3/DREB1a; a metabolic gene,M6PR,for mannitol biosynthesis; and the Na+/H+ antiporter,SOS1.In the absence of salt,M6PR and SOS1 lines performed comparably with wild type; CBF3 lines exhibited dwarfing as reported previously.All three transgenes conferred fitness advantage when subjected to 100 mmol/L NaCI in the growth chamber.CBF3 and M6PR affected transcription of numerous abiotic stress-related genes as measured by Affymetrix microarray analysis.M6PR additionally modified expression of biotic stress and oxidative stress genes.Transcriptional effects of SOS1 were smaller and primarily limited to redox-related genes.In addition,we compared natural variations in salt tolerance between Ler and Sha ecotypes based on their responses to salt treatments and the results indicated that Ler was salt-sensitive,but Sha,which obtained a truncated RAS1 protein,was salt-tolerant.Transcriptome analysis revealed that many genes involved in secondary metabolism,photosynthesis,and protein synthesis were mainly down-regulated by salinity effects,while transposable element genes,microRNA and

  5. DMPD: Innate immune responses: crosstalk of signaling and regulation of genetranscription. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16753195 Innate immune responses: crosstalk of signaling and regulation of genetran...l) (.csml) Show Innate immune responses: crosstalk of signaling and regulation of genetranscription. PubmedI...D 16753195 Title Innate immune responses: crosstalk of signaling and regulation o

  6. DNA-responsive inflammasomes and their regulators in autoimmunity.

    Science.gov (United States)

    Choubey, Divaker

    2012-03-01

    Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to generate active forms. However, upon sensing cytosolic DNA, the IFI16 protein recruits STING to induce the expression of type I IFN. Recognition of self DNA by innate immune cells contributes to the production of increased levels of type I IFN. Given that the type I IFNs modulate the expression of inflammasome proteins and that the IFN-inducible proteins inhibit the activity of DNA-responsive inflammasomes, an improved understanding of the molecular mechanisms that regulate the activity of DNA-responsive inflammasomes is likely to identify new therapeutic targets to treat autoimmune diseases.

  7. Bmp indicator mice reveal dynamic regulation of transcriptional response.

    Directory of Open Access Journals (Sweden)

    Anna L Javier

    Full Text Available Cellular responses to Bmp ligands are regulated at multiple levels, both extracellularly and intracellularly. Therefore, the presence of these growth factors is not an accurate indicator of Bmp signaling activity. While a common approach to detect Bmp signaling activity is to determine the presence of phosphorylated forms of Smad1, 5 and 8 by immunostaining, this approach is time consuming and not quantitative. In order to provide a simpler readout system to examine the presence of Bmp signaling in developing animals, we developed BRE-gal mouse embryonic stem cells and a transgenic mouse line that specifically respond to Bmp ligand stimulation. Our reporter identifies specific transcriptional responses that are mediated by Smad1 and Smad4 with the Schnurri transcription factor complex binding to a conserved Bmp-Responsive Element (BRE, originally identified among Drosophila, Xenopus and human Bmp targets. Our BRE-gal mES cells specifically respond to Bmp ligands at concentrations as low as 5 ng/ml; and BRE-gal reporter mice, derived from the BRE-gal mES cells, show dynamic activity in many cellular sites, including extraembryonic structures and mammary glands, thereby making this a useful scientific tool.

  8. Listeria monocytogenes response regulators important for stress tolerance and pathogenesis

    DEFF Research Database (Denmark)

    Kallipolitis, B H; Ingmer, H

    2001-01-01

    Environmental sensing by two-component signal transduction systems is likely to play a role for growth and survival of Listeria monocytogenes both during transmission in food products and within a host organism. Two-component systems typically consist of a membrane-associated sensor histidine...... kinase and a gene regulatory protein, the response regulator (RR). We have identified seven putative RR genes in L. monocytogenes LO28 by PCR using degenerate oligonucleotide primers. By insertional inactivation we obtained data suggesting that three of the putative RRs contribute to the pathogenicity...... of L. monocytogenes in mice. Strikingly, the mutants that were attenuated in virulence also had a decreased ability to grow in the presence of various stress conditions potentially encountered in an infection process. Thus, our data point to a connection between the ability of the putative two...

  9. Quorum sensing regulates the osmotic stress response in Vibrio harveyi.

    Science.gov (United States)

    van Kessel, Julia C; Rutherford, Steven T; Cong, Jian-Ping; Quinodoz, Sofia; Healy, James; Bassler, Bonnie L

    2015-01-01

    Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress.

  10. Flexible parasympathetic responses to sadness facilitate spontaneous affect regulation.

    Science.gov (United States)

    Stange, Jonathan P; Hamilton, Jessica L; Fresco, David M; Alloy, Lauren B

    2017-07-01

    The ability of the parasympathetic nervous system to flexibly adapt to changes in environmental context is thought to serve as a physiological indicator of self-regulatory capacity, and deficits in parasympathetic flexibility appear to characterize affective disorders such as depression. However, whether parasympathetic flexibility (vagal withdrawal to emotional or environmental challenges such as sadness, and vagal augmentation during recovery from sadness) could facilitate the effectiveness of adaptive affect regulation strategies is not known. In a study of 178 undergraduate students, we evaluated whether parasympathetic flexibility in response to a sad film involving loss would enhance the effectiveness of regulatory strategies (reappraisal, distraction, and suppression) spontaneously employed to reduce negative affect during a 2-min uninstructed recovery period following the induction. Parasympathetic reactivity and recovery were indexed by fluctuations in respiratory sinus arrhythmia and high-frequency heart rate variability. Cognitive reappraisal and distraction were more effective in attenuating negative affect among individuals with more parasympathetic flexibility, particularly greater vagal augmentation during recovery, relative to individuals with less parasympathetic flexibility. In contrast, suppression was associated with less attenuation of negative affect, but only among individuals who also had less vagal withdrawal during the sad film. Alternative models provided partial support for reversed directionality, with reappraisal predicting greater parasympathetic recovery, but only when individuals also experienced greater reductions in negative affect. These results suggest that contextually appropriate parasympathetic reactivity and recovery may facilitate the success of affect regulation. Impairments in parasympathetic flexibility could confer risk for affective disorders due to attenuated capacity for effective self-regulation. © 2017 Society for

  11. Ozone promotes regeneration by regulating the inflammatory response in zebrafish.

    Science.gov (United States)

    Hao, Kenan; Li, Yanhao; Feng, Jianyu; Zhang, Wenqing; Zhang, Yiyue; Ma, Ning; Zeng, Qingle; Pang, Huajin; Wang, Chunyan; Xiao, Lijun; He, Xiaofeng

    2015-09-01

    Ozone is thought to advance wound healing by inhibiting inflammation, but the mechanism of this phenomenon has not been determined. Although the zebrafish is often used in regeneration experiments, there has been no report of zebrafish treated with ozonated water. We successfully established a zebrafish model of ozonated water treatment and demonstrate that ozonated water stimulates the regeneration of the zebrafish caudal fin, its mechanism, and time dependence. The growth rate of the caudal fin and the number of neutrophils migrating to the caudal fin wound after resection were higher in the experimental (ozonated) group than in the control group, preliminarily confirming that ozone-promoted regeneration is related to the stimulation of an early inflammatory response by ozone. Ozone modulated the expression of tumor necrosis factor-α (TNF-α) in two ways by regulating interleukin 10 (IL-10) expression. Therefore, ozone promotes tissue regeneration by regulating the inflammatory pathways. This effect of ozone in an experimental zebrafish model is demonstrated for the first time, confirming its promotion of wound healing and the mechanism of its effect in tissue regeneration. These results will open up new directions for ozone and regeneration research.

  12. Magnitude-dependent response of osteoblasts regulated by compressive stress

    Science.gov (United States)

    Shen, Xiao-qing; Geng, Yuan-ming; Liu, Ping; Huang, Xiang-yu; Li, Shu-yi; Liu, Chun-dong; Zhou, Zheng; Xu, Ping-ping

    2017-01-01

    The present study aimed to investigate the role of magnitude in adaptive response of osteoblasts exposed to compressive stress. Murine primary osteoblasts and MC3T3-E1 cells were exposed to compressive stress (0, 1, 2, 3, 4, and 5 g/cm2) in 3D culture. Cell viability was evaluated, and expression levels of Runx2, Alp, Ocn, Rankl, and Opg were examined. ALP activity in osteoblasts and TRAP activity in RAW264.7 cells co-cultured with MC3T3-E1 cells were assayed. Results showed that compressive stress within 5.0 g/cm2 did not influence cell viability. Both osteoblastic and osteoblast-regulated osteoclastic differentiation were enhanced at 2 g/cm2. An increase in stress above 2 g/cm2 did not enhance osteoblastic differentiation further but significantly inhibited osteoblast-regualted osteoclastic differentiation. This study suggested that compressive stress regulates osteoblastic and osteoclastic differentiation through osteoblasts in a magnitude-dependent manner. PMID:28317941

  13. Testosterone regulates tight junction proteins and influences prostatic autoimmune responses.

    Science.gov (United States)

    Meng, Jing; Mostaghel, Elahe A; Vakar-Lopez, Funda; Montgomery, Bruce; True, Larry; Nelson, Peter S

    2011-06-01

    Testosterone and inflammation have been linked to the development of common age-associated diseases affecting the prostate gland including prostate cancer, prostatitis, and benign prostatic hypertrophy. We hypothesized that testosterone regulates components of prostate tight junctions which serve as a barrier to inflammation, thus providing a connection between age- and treatment-associated testosterone declines and prostatic pathology. We examined the expression and distribution of tight junction proteins in prostate biospecimens from mouse models and a clinical study of chemical castration, using transcript profiling, immunohistochemistry, and electron microscopy. We determined that low serum testosterone is associated with reduced transcript and protein levels of Claudin 4 and Claudin 8, resulting in defective tight junction ultrastructure in benign prostate glands. Expression of Claudin 4 and Claudin 8 was negatively correlated with the mononuclear inflammatory infiltrate caused by testosterone deprivation. Testosterone suppression also induced an autoimmune humoral response directed toward prostatic proteins. Testosterone supplementation in castrate mice resulted in re-expression of tight junction components in prostate epithelium and significantly reduced prostate inflammatory cell numbers. These data demonstrate that tight junction architecture in the prostate is related to changes in serum testosterone levels, and identify an androgen-regulated mechanism that potentially contributes to the development of prostate inflammation and consequent pathology.

  14. TRPV1 Regulates Stress Responses through HDAC2

    Directory of Open Access Journals (Sweden)

    Sung Eun Wang

    2017-04-01

    Full Text Available Stress causes changes in neurotransmission in the brain, thereby influencing stress-induced behaviors. However, it is unclear how neurotransmission systems orchestrate stress responses at the molecular and cellular levels. Transient receptor potential vanilloid 1 (TRPV1, a non-selective cation channel involved mainly in pain sensation, affects mood and neuroplasticity in the brain, where its role is poorly understood. Here, we show that Trpv1-deficient (Trpv1−/− mice are more stress resilient than control mice after chronic unpredictable stress. We also found that glucocorticoid receptor (GR-mediated histone deacetylase 2 (HDAC 2 expression and activity are reduced in the Trpv1−/− mice and that HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered. Hippocampal knockdown of TRPV1 had similar effects, and its behavioral effects were blocked by HDAC2 overexpression. Collectively, our findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses.

  15. Metabolic Context Regulates Distinct Hypothalamic Transcriptional Responses to Antiaging Interventions

    Directory of Open Access Journals (Sweden)

    Alexis M. Stranahan

    2012-01-01

    Full Text Available The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic (db/db and nondiabetic wild-type (C57/Bl/6 animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non-diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds.

  16. Mitochondrial DNA in the regulation of innate immune responses

    Directory of Open Access Journals (Sweden)

    Chunju Fang

    2015-10-01

    Full Text Available Abstract Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.

  17. Btk regulates macrophage polarization in response to lipopolysaccharide.

    Directory of Open Access Journals (Sweden)

    Joan Ní Gabhann

    Full Text Available Bacterial Lipopolysaccharide (LPS is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (-\\- mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(-/- macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-κB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-κB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(-/- macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(-/- macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (-/- mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation.

  18. 转耐辐射球菌irrE基因提高拟南芥盐胁迫耐受性的表型分析%Expression of irrE in Deinococcus radiodurans can Enhance Salt Tolerance of Arabidopsis thaliana

    Institute of Scientific and Technical Information of China (English)

    童仕波; 文国琴; 林敏; 杨毅; 李旭锋

    2010-01-01

    耐辐射球菌中的irrE基因作为一种全局性调节因子,在抵御极端辐射照射时起着至关重要的作用.利用农杆菌介导的花序浸染法,将irrE基因转化拟南芥,筛选和鉴定出表达irrE的植株,并分析了转基因植株的盐胁迫耐受能力.结果显示,转irrE拟南芥表现出对盐胁迫的耐受性提高;在盐胁迫下,转基因拟南芥体内脯氨酸含量比野生型有明显的提高.RNA半定量分析显示转基因植株中AtNHX1表达水平升高.因此推测irrE基因在转基因拟南芥中调控了AtNHX1的表达,引起了植株的盐胁迫耐受性提高.

  19. Methane dynamics regulated by microbial community response to permafrost thaw.

    Science.gov (United States)

    McCalley, Carmody K; Woodcroft, Ben J; Hodgkins, Suzanne B; Wehr, Richard A; Kim, Eun-Hae; Mondav, Rhiannon; Crill, Patrick M; Chanton, Jeffrey P; Rich, Virginia I; Tyson, Gene W; Saleska, Scott R

    2014-10-23

    Permafrost contains about 50% of the global soil carbon. It is thought that the thawing of permafrost can lead to a loss of soil carbon in the form of methane and carbon dioxide emissions. The magnitude of the resulting positive climate feedback of such greenhouse gas emissions is still unknown and may to a large extent depend on the poorly understood role of microbial community composition in regulating the metabolic processes that drive such ecosystem-scale greenhouse gas fluxes. Here we show that changes in vegetation and increasing methane emissions with permafrost thaw are associated with a switch from hydrogenotrophic to partly acetoclastic methanogenesis, resulting in a large shift in the δ(13)C signature (10-15‰) of emitted methane. We used a natural landscape gradient of permafrost thaw in northern Sweden as a model to investigate the role of microbial communities in regulating methane cycling, and to test whether a knowledge of community dynamics could improve predictions of carbon emissions under loss of permafrost. Abundance of the methanogen Candidatus 'Methanoflorens stordalenmirensis' is a key predictor of the shifts in methane isotopes, which in turn predicts the proportions of carbon emitted as methane and as carbon dioxide, an important factor for simulating the climate feedback associated with permafrost thaw in global models. By showing that the abundance of key microbial lineages can be used to predict atmospherically relevant patterns in methane isotopes and the proportion of carbon metabolized to methane during permafrost thaw, we establish a basis for scaling changing microbial communities to ecosystem isotope dynamics. Our findings indicate that microbial ecology may be important in ecosystem-scale responses to global change.

  20. Global SUMO proteome responses guide gene regulation, mRNA biogenesis, and plant stress responses

    Directory of Open Access Journals (Sweden)

    Magdalena eMazur

    2012-09-01

    Full Text Available Small-ubiquitin-like MOdifier (SUMO is a key regulator of abiotic stress, disease resistance and development in plants. The identification of >350 plant SUMO targets has revealed many processes modulated by SUMO and potential consequences of SUMO on its targets. Importantly, highly related proteins are SUMO-modified in plants, yeast, and metazoans. Overlapping SUMO targets include heat-shock proteins, transcription regulators, histones, histone-modifying enzymes, proteins involved in DNA damage repair, but also proteins involved in mRNA biogenesis and nucleo-cytoplasmic transport. Proteomics studies indicate key roles for SUMO in gene repression by controlling histone (deacetylation activity at genomic loci. The responsible heavily sumoylated transcriptional repressor complexes are recruited by EAR (Ethylene-responsive element binding factor [ERF]-associated Amphiphilic Repression-motif containing transcription factors in plants. These transcription factors are not necessarily themselves a SUMO target. Conversely, SUMO acetylation prevents binding of downstream partners by preventing binding of SIMs (SUMO-interaction peptide motifs presents in these partners, while SUMO acetylation has emerged as mechanism to recruit specifically bromodomains; bromodomain are generally linked with gene activation. These findings strengthen the idea of a bidirectional sumo-/acetylation switch in gene regulation. Quantitative proteomics has highlighted that global sumoylation provides a dynamic response to protein damage involving SUMO chain-mediated protein degradation, but also SUMO E3 ligase-dependent transcription of HSP (Heat-shock protein genes. With these insights in SUMO function and novel technical advancements, we can now study SUMO dynamics in responses to (abiotic stress in plants.

  1. IrrE基因甘蓝型油菜农艺性状的分析

    Institute of Scientific and Technical Information of China (English)

    奉斌; 代其林; 刘婷婷; 田霞; 龚元亚; 孙英坤; 王劲

    2010-01-01

    文章主要研究了转IrrE基因T1代甘蓝型油菜在自然条件与Nacl盐胁迫条件下的农艺性状,结果表明:以自然条件下的野生型油菜为对照,自然条件下的转IrrE基因油菜在株高、主花序长度、全株有效角果数差异极显著,而分枝部位高度和分枝个数差异不显著.300mM NaCl高盐胁迫条件下的转IrrE基因油菜,株高、主花序长度、全株有效角果数差异极显著,分枝数差异不显著.

  2. Vibrio cholerae Response Regulator VxrB Controls Colonization and Regulates the Type VI Secretion System.

    Directory of Open Access Journals (Sweden)

    Andrew T Cheng

    2015-05-01

    Full Text Available Two-component signal transduction systems (TCS are used by bacteria to sense and respond to their environment. TCS are typically composed of a sensor histidine kinase (HK and a response regulator (RR. The Vibrio cholerae genome encodes 52 RR, but the role of these RRs in V. cholerae pathogenesis is largely unknown. To identify RRs that control V. cholerae colonization, in-frame deletions of each RR were generated and the resulting mutants analyzed using an infant mouse intestine colonization assay. We found that 12 of the 52 RR were involved in intestinal colonization. Mutants lacking one previously uncharacterized RR, VCA0566 (renamed VxrB, displayed a significant colonization defect. Further experiments showed that VxrB phosphorylation state on the predicted conserved aspartate contributes to intestine colonization. The VxrB regulon was determined using whole genome expression analysis. It consists of several genes, including those genes that create the type VI secretion system (T6SS. We determined that VxrB is required for T6SS expression using several in vitro assays and bacterial killing assays, and furthermore that the T6SS is required for intestinal colonization. vxrB is encoded in a four gene operon and the other vxr operon members also modulate intestinal colonization. Lastly, though ΔvxrB exhibited a defect in single-strain intestinal colonization, the ΔvxrB strain did not show any in vitro growth defect. Overall, our work revealed that a small set of RRs is required for intestinal colonization and one of these regulators, VxrB affects colonization at least in part through its regulation of T6SS genes.

  3. Vibrio cholerae Response Regulator VxrB Controls Colonization and Regulates the Type VI Secretion System.

    Science.gov (United States)

    Cheng, Andrew T; Ottemann, Karen M; Yildiz, Fitnat H

    2015-05-01

    Two-component signal transduction systems (TCS) are used by bacteria to sense and respond to their environment. TCS are typically composed of a sensor histidine kinase (HK) and a response regulator (RR). The Vibrio cholerae genome encodes 52 RR, but the role of these RRs in V. cholerae pathogenesis is largely unknown. To identify RRs that control V. cholerae colonization, in-frame deletions of each RR were generated and the resulting mutants analyzed using an infant mouse intestine colonization assay. We found that 12 of the 52 RR were involved in intestinal colonization. Mutants lacking one previously uncharacterized RR, VCA0566 (renamed VxrB), displayed a significant colonization defect. Further experiments showed that VxrB phosphorylation state on the predicted conserved aspartate contributes to intestine colonization. The VxrB regulon was determined using whole genome expression analysis. It consists of several genes, including those genes that create the type VI secretion system (T6SS). We determined that VxrB is required for T6SS expression using several in vitro assays and bacterial killing assays, and furthermore that the T6SS is required for intestinal colonization. vxrB is encoded in a four gene operon and the other vxr operon members also modulate intestinal colonization. Lastly, though ΔvxrB exhibited a defect in single-strain intestinal colonization, the ΔvxrB strain did not show any in vitro growth defect. Overall, our work revealed that a small set of RRs is required for intestinal colonization and one of these regulators, VxrB affects colonization at least in part through its regulation of T6SS genes.

  4. Somatostatin Negatively Regulates Parasite Burden and Granulomatous Responses in Cysticercosis

    Directory of Open Access Journals (Sweden)

    Mitra Khumbatta

    2014-01-01

    Full Text Available Cysticercosis is an infection of tissues with the larval cysts of the cestode, Taenia  solium. While live parasites elicit little or no inflammation, dying parasites initiate a granulomatous reaction presenting as painful muscle nodules or seizures when cysts are located in the brain. We previously showed in the T. crassiceps murine model of cysticercosis that substance P (SP, a neuropeptide, was detected in early granulomas and was responsible for promoting granuloma formation, while somatostatin (SOM, another neuropeptide and immunomodulatory hormone, was detected in late granulomas; SOM’s contribution to granuloma formation was not examined. In the current studies, we used somatostatin knockout (SOM−/− mice to examine the hypothesis that SOM downmodulates granulomatous inflammation in cysticercosis, thereby promoting parasite growth. Our results demonstrated that parasite burden was reduced 5.9-fold in SOM−/− mice compared to WT mice (P<0.05. This reduction in parasite burden in SOM−/− mice was accompanied by a 95% increase in size of their granulomas (P<0.05, which contained a 1.5-fold increase in levels of IFN-γ and a 26-fold decrease in levels of IL-1β (P<0.05 for both compared to granulomas from WT mice. Thus, SOM regulates both parasite burden and granulomatous inflammation perhaps through modulating granuloma production of IFN-γ and IL-1β.

  5. Phosphorylation-independent activity of atypical response regulators of Helicobacter pylori.

    Science.gov (United States)

    Schär, Jennifer; Sickmann, Albert; Beier, Dagmar

    2005-05-01

    The genome of the gastric pathogen Helicobacter pylori harbors a remarkably low number of regulatory genes, including three and five open reading frames encoding two-component histidine kinases and response regulators, respectively, which are putatively involved in transcriptional regulation. Two of the response regulator genes, hp1043 and hp166, proved to be essential for cell growth, and inactivation of the response regulator gene hp1021 resulted in a severe growth defect, as indicated by a small-colony phenotype. The sequences of the receiver domains of response regulators HP1043 and HP1021 differ from the consensus sequence of the acidic pocket of the receiver domain which is involved in the phosphotransfer reaction from the histidine kinase to the response regulator. Using a genetic complementation system, we demonstrated that the function of response regulator HP166, which is essential for cell growth, can be provided by a mutated derivative carrying a D52N substitution at the site of phosphorylation. We found that the atypical receiver sequences of HP1043 and HP1021 are not crucial for the function of these response regulators. Phosphorylation of the receiver domains of HP1043 and HP1021 is not needed for response regulator function and may not occur at all. Thus, the phosphorylation-independent action of these regulators differs from the well-established two-component paradigm.

  6. A CMOS image-rejection mixer with 58-dB IRR for DTV receivers

    Institute of Scientific and Technical Information of China (English)

    Yuan Shuai; Li Zhiqun; Huang Jing; Wang Zhigong

    2009-01-01

    The design, implementation, and characterization of an image-rejection double quadrature conversion mixer based on RC asymmetric polyphase filters (PPF) are presented. The mixer consists of three sets of PPFs and a mixer core for quadrature down conversion. Two sets of PPFs are used for the quadrature generation and the other one is used for the IF signal selection to reject the unwanted image band. Realized in 0.18-μm CMOS technology as a part of the DVB-T receiver chip, the mixer exhibits a high image rejection ratio (IRR) of 58 dB, a power consumption of 11 mW, and a 1-dB gain compression point of -15 dBm.

  7. Quality Costs (IRR Impact on Lot Size Considering Work in Process Inventory

    Directory of Open Access Journals (Sweden)

    Misbah Ullaha

    2014-06-01

    Full Text Available Economic order quantity model and production quantity model assume that production processes are error free. However, variations exist in processes which result in imperfection particularly in high machining environments. Processes variations result in nonconformities that increase quality costs in the form of rework, rejects and quality control techniques implementations to ensure quality product delivery. This paper is an attempt towards development of inventory model which incorporate inspection, rework, and rejection (IRR quality costs in optimum lot size calculation focusing work in process inventory. Mathematical model is derived for optimum lot size based on minimum average cost function using analytical approach. This new developed model (GTOQIRR assume an imperfect production environment. Numerical examples are used to visualize the significant effect of quality cost in the proposed model in comparison to the previously developed models. The proposed model is highly recommendable for quality based high machining manufacturing environments considering work in process inventories.

  8. 25 CFR 170.808 - Can BIA Road Maintenance Program funds be used to improve IRR transportation facilities?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Can BIA Road Maintenance Program funds be used to improve... THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.808 Can BIA Road Maintenance Program funds be used to improve IRR transportation facilities? No. BIA...

  9. 25 CFR 170.807 - What must BIA include when it develops an IRR Transportation Facilities Maintenance Management...

    Science.gov (United States)

    2010-04-01

    ... Transportation Facilities Maintenance Management System? 170.807 Section 170.807 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER INDIAN RESERVATION ROADS PROGRAM BIA Road Maintenance § 170.807 What must BIA include when it develops an IRR Transportation Facilities Maintenance Management...

  10. Hydraulic response and nitrogen retention in bioretention mesocosms with regulated outlets: part I--hydraulic response.

    Science.gov (United States)

    Lucas, William C; Greenway, Margaret

    2011-08-01

    In bioretention systems used for stormwater treatment, runoff interception improves with increased infiltration rates. However, nitrogen retention improves with increased retention time or decreasing infiltration rates. These contrasting responses were analyzed in 240-L experimental mesocosms using a variety of media treatments. The mesocosms were vegetated, except for one barren control. Dual-stage outlets were installed to extend retention time and equalize hydraulic responses. One unregulated treatment was free-draining. This part 1 paper presents the media properties and hydraulic responses. The highly aggregated media had saturated hydraulic conductivities ranging from 20.7 to 59.6 cm/h in August 2008 (austral winter), which increased to 42.8 to 110.6 cm/h in March 2009 (austral summer). The outlet regulated mesocosms provided retention over 8 times longer than the free-draining mesocosms, while still being able to capture large events. The outlets provide adaptive management for bioretention design to improve both runoff capture and nitrogen retention.

  11. Strigolactones and the Regulation of Pea Symbioses in Response to Nitrate and Phosphate Deficiency

    Institute of Scientific and Technical Information of China (English)

    Eloise Foo; Kaori Yoneyama; Cassandra J. Hugill; Laura J. Quittenden; James B. Reid

    2013-01-01

    New roles for the recently identified group of plant hormones,the strigolactones,are currently under active investigation.One of their key roles is to regulate plant symbioses.These compounds act as a rhizosphere signal in arbuscular mycorrhizal symbioses and as a positive regulator of nodulation in legumes.The phosphorous and nitrogen status of the soil has emerged as a powerful regulator of strigolactone production.However,until now,the potential role of strigolactones in regulating mycorrhizal development and nodulation in response to nutrient deficiency has not been proven.In this paper,the role of strigolactone synthesis and response in regulating these symbioses is examined in pea (Pisum sativum L.).Pea is well suited to this study,since there is a range of well-characterized strigolactone biosynthesis and response mutants that is unique amongst legumes.Evidence is provided for a novel endogenous role for strigolactone response within the root during mycorrhizal development,in addition to the action of strigolactones on the fungal partner.The strigolactone response pathway that regulates mycorrhizal development also appears to differ somewhat from the response pathway that regulates nodulation.Finally,studies with strigolactone-deficient pea mutants indicate that,despite strong regulation of strigolactone production by both nitrogen and phosphate,strigolactones are not required to regulate these symbioses in response to nutrient deficiency.

  12. 5 CFR 875.107 - What are OPM's responsibilities as regulator under this Program?

    Science.gov (United States)

    2010-01-01

    ... MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) FEDERAL LONG TERM CARE INSURANCE PROGRAM Administration and General Provisions § 875.107 What are OPM's responsibilities as regulator under this Program... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false What are OPM's responsibilities...

  13. Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin's lymphoma

    NARCIS (Netherlands)

    Plattel, Wouter J.; van den Berg, Anke; Visser, Lydia; van der Graaf, Anne-Marijn; Pruim, Jan; Vos, Hans; Hepkema, Bouke; Diepstra, Arjan; van Imhoff, Gustaaf W.

    2012-01-01

    BACKGROUND: Plasma thymus and activation-regulated chemokine is a potential biomarker for classical Hodgkin's lymphoma. To define its value as a marker to monitor treatment response, we correlated serial plasma thymus and activation-regulated chemokine levels with clinical response in newly diagnose

  14. DMPD: The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 10669111 The Lps locus: genetic regulation of host responses to bacteriallipopolysa...ccharide. Qureshi ST, Gros P, Malo D. Inflamm Res. 1999 Dec;48(12):613-20. (.png) (.svg) (.html) (.csml) Show The... Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. PubmedID 10669111 Title The

  15. Negative Regulation of IRF7 Activation by ATF4 Suggests a Cross Regulation Between the Interferon Responses and the Cellular Integrated Stress Responses

    OpenAIRE

    Liang, Qiming; Deng, Hongying; Sun, Chiao-Wang; Tim M. Townes; Zhu, Fanxiu

    2010-01-01

    Cells react to viral infection by exhibiting interferon (IFN)-based innate immune responses and integrated stress responses, but little is known about the interrelationships between the two. We here report a linkage between these two host protective cellular mechanisms. We found that IRF7, the master regulator of type I IFN gene expression, interacts with ATF4, a key component of the integrated stress responses whose translation is induced by viral infection and various stresses. We have demo...

  16. Regulation of Stress Responses and Translational Control by Coronavirus

    Science.gov (United States)

    Fung, To Sing; Liao, Ying; Liu, Ding Xiang

    2016-01-01

    Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER) results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed. PMID:27384577

  17. Regulation of Stress Responses and Translational Control by Coronavirus

    Directory of Open Access Journals (Sweden)

    To Sing Fung

    2016-07-01

    Full Text Available Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed.

  18. The Porphyromonas gingivalis ferric uptake regulator orthologue binds hemin and regulates hemin-responsive biofilm development.

    Directory of Open Access Journals (Sweden)

    Catherine A Butler

    Full Text Available Porphyromonas gingivalis is a Gram-negative pathogen associated with the biofilm-mediated disease chronic periodontitis. P. gingivalis biofilm formation is dependent on environmental heme for which P. gingivalis has an obligate requirement as it is unable to synthesize protoporphyrin IX de novo, hence P. gingivalis transports iron and heme liberated from the human host. Homeostasis of a variety of transition metal ions is often mediated in Gram-negative bacteria at the transcriptional level by members of the Ferric Uptake Regulator (Fur superfamily. P. gingivalis has a single predicted Fur superfamily orthologue which we have designated Har (heme associated regulator. Recombinant Har formed dimers in the presence of Zn2+ and bound one hemin molecule per monomer with high affinity (Kd of 0.23 µM. The binding of hemin resulted in conformational changes of Zn(IIHar and residue 97Cys was involved in hemin binding as part of a predicted -97C-98P-99L- hemin binding motif. The expression of 35 genes was down-regulated and 9 up-regulated in a Har mutant (ECR455 relative to wild-type. Twenty six of the down-regulated genes were previously found to be up-regulated in P. gingivalis grown as a biofilm and 11 were up-regulated under hemin limitation. A truncated Zn(IIHar bound the promoter region of dnaA (PGN_0001, one of the up-regulated genes in the ECR455 mutant. This binding decreased as hemin concentration increased which was consistent with gene expression being regulated by hemin availability. ECR455 formed significantly less biofilm than the wild-type and unlike wild-type biofilm formation was independent of hemin availability. P. gingivalis possesses a hemin-binding Fur orthologue that regulates hemin-dependent biofilm formation.

  19. Cell identity regulators link development and stress responses in the Arabidopsis root.

    Science.gov (United States)

    Iyer-Pascuzzi, Anjali S; Jackson, Terry; Cui, Hongchang; Petricka, Jalean J; Busch, Wolfgang; Tsukagoshi, Hironaka; Benfey, Philip N

    2011-10-18

    Stress responses in plants are tightly coordinated with developmental processes, but interaction of these pathways is poorly understood. We used genome-wide assays at high spatiotemporal resolution to understand the processes that link development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. However, common stress responses appear to exist with many showing cell type specificity. Common stress responses may be mediated by cell identity regulators because mutations in these genes resulted in altered responses to stress. Evidence for a direct role for cell identity regulators came from genome-wide binding profiling of the key regulator SCARECROW, which showed binding to regulatory regions of stress-responsive genes. Coexpression in response to stress was used to identify genes involved in specific developmental processes. These results reveal surprising linkages between stress and development at cellular resolution, and show the power of multiple genome-wide data sets to elucidate biological processes.

  20. Bio-responsive polymer hydrogels homeostatically regulate blood coagulation

    Science.gov (United States)

    Maitz, Manfred F.; Freudenberg, Uwe; Tsurkan, Mikhail V.; Fischer, Marion; Beyrich, Theresa; Werner, Carsten

    2013-01-01

    Bio-responsive polymer architectures can empower medical therapies by engaging molecular feedback-response mechanisms resembling the homeostatic adaptation of living tissues to varying environmental constraints. Here we show that a blood coagulation-responsive hydrogel system can deliver heparin in amounts triggered by the environmental levels of thrombin, the key enzyme of the coagulation cascade, which—in turn—becomes inactivated due to released heparin. The bio-responsive hydrogel quantitatively quenches blood coagulation over several hours in the presence of pro-coagulant stimuli and during repeated incubation with fresh, non-anticoagulated blood. These features enable the introduced material to provide sustainable, autoregulated anticoagulation, addressing a key challenge of many medical therapies. Beyond that, the explored concept may facilitate the development of materials that allow the effective and controlled application of drugs and biomolecules. PMID:23868446

  1. How antibodies use complement to regulate antibody responses.

    Science.gov (United States)

    Sörman, Anna; Zhang, Lu; Ding, Zhoujie; Heyman, Birgitta

    2014-10-01

    Antibodies, forming immune complexes with their specific antigen, can cause complete suppression or several 100-fold enhancement of the antibody response. Immune complexes containing IgG and IgM may activate complement and in such situations also complement components will be part of the immune complex. Here, we review experimental data on how antibodies via the complement system upregulate specific antibody responses. Current data suggest that murine IgG1, IgG2a, and IgG2b upregulate antibody responses primarily via Fc-receptors and not via complement. In contrast, IgM and IgG3 act via complement and require the presence of complement receptors 1 and 2 (CR1/2) expressed on both B cells and follicular dendritic cells. Complement plays a crucial role for antibody responses not only to antigen complexed to antibodies, but also to antigen administered alone. Lack of C1q, but not of Factor B or MBL, severely impairs antibody responses suggesting involvement of the classical pathway. In spite of this, normal antibody responses are found in mice lacking several activators of the classical pathway (complement activating natural IgM, serum amyloid P component (SAP), specific intracellular adhesion molecule-grabbing non-integrin R1 (SIGN-R1) or C-reactive protein. Possible explanations to these observations will be discussed.

  2. Mechanisms regulating osteoblast response to surface microtopography and vitamin D

    Science.gov (United States)

    Bell, Bryan Frederick, Jr.

    A comprehensive understanding of the interactions between orthopaedic and dental implant surfaces with the surrounding host tissue is essential in the design of advanced biomaterials that better promote bone growth and osseointegration of implants. Dental implants with roughened surfaces and high surface energy are well known to promote osteoblast differentiation in vitro and promote increased bone-to-implant contact in vivo. In addition, increased surface roughness increases osteoblasts response to the vitamin D metabolite 1alpha,25(OH)2D3. However, the exact mechanisms mediating cell response to surface properties and 1alpha,25(OH)2D3 are still being elucidated. The central aim of the thesis is to investigate whether integrin signaling in response to rough surface microtopography enhances osteoblast differentiation and responsiveness to 1alpha,25(OH)2D3. The hypothesis is that the integrin alpha5beta1 plays a role in osteoblast response to surface microtopography and that 1alpha,25(OH) 2D3 acts through VDR-independent pathways involving caveolae to synergistically enhance osteoblast response to surface roughness and 1alpha,25(OH) 2D3. To test this hypothesis the objectives of the studies performed in this thesis were: (1) to determine if alpha5beta 1 signaling is required for osteoblast response to surface microstructure; (2) to determine if increased responsiveness to 1alpha,25(OH)2D 3 requires the vitamin D receptor, (3) to determine if rough titanium surfaces functionalized with the peptides targeting integrins (RGD) and transmembrane proteoglycans (KRSR) will enhance both osteoblast proliferation and differentiation, and (4) to determine whether caveolae, which are associated with integrin and 1alpha,25(OH)2D3 signaling, are required for enhance osteogenic response to surface microstructure and 1alpha,25(OH)2D 3. The results demonstrate that integrins, VDR, and caveolae play important roles in mediating osteoblast response to surface properties and 1alpha,25

  3. Dietary methyl content regulates opioid responses in mice

    Directory of Open Access Journals (Sweden)

    Liang DY

    2013-03-01

    Full Text Available De-Yong Liang,1,2 Yuan Sun,1,2 J David Clark1,2 1Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, 2Stanford University School of Medicine, Stanford, CA, USA Background: Large interindividual differences in clinical responses to opioids and the variable susceptibility to abuse of this class of drugs make their use problematic. We lack a full understanding of the factors responsible for these differences. Dietary factors including methyl donor content have been noted to alter multiple physiological and behavioral characteristics of laboratory animals. The purpose of this research was to determine the effects of dietary methyl donor content on opioid responses in mice. Methods: Groups of male C57BL/6J mice were treated with high and low methyl donor diets either in the perinatal period or after weaning. Analgesic responses to morphine, as well as tolerance, opioid-induced hyperalgesia, and physical dependence were assessed. Results: Mice fed high and low methyl donor diets showed equal weight gain over the course of the experiments. Exposure to a high methyl donor diet in the perinatal period enhanced physical dependence. Dietary methyl donor content also altered analgesic responses to low doses of morphine when the dietary treatments were given to the mice after weaning. Opioid-induced hyperalgesia was unaltered by dietary methyl donor content. Conclusion: High and low methyl donor diet treatment has selective effects on opioid responses depending on the timing of exposure. These findings suggest that examination of DNA methylation patterns in specific brain regions linked to opioid analgesia and dependence may provide specific explanations for dietary effects on opioid responses. Keywords: opioid, methylation, tolerance, hyperalgesia, dependence

  4. Economic Analysis of Cikaso Mini Hydro Power Plant as a CDM Project for Increasing IRR

    Directory of Open Access Journals (Sweden)

    Irhan Febijanto

    2013-12-01

    Full Text Available Renewable energy fueled power generations are few developed by private sector in Indonesia. High-cost investment and low electricity selling price to PT PLN as a single buyer is main barriers for private sector to involve in the development of renewable energy fueled power generations. In this project, the economic feasibility of Mini Hydro Power Plant of Cikaso with capacity of 5.3 MW, located at Sukabumi Regency, West Java province was assessed. This project utilized revenue generated from carbon market to increase the economic feasibility. Procedure to register the project to United Nation for Climate Change Convention (UNFCCC as a Clean Development Mechanism project was explained in detail. Approved Consolidation Methodology (ACM 0002 Version 12.3.0 was used to calculate grid emission factor in Jawa-Bali-Madura the grid electricity system. It was calculated that the grid emission factor is 0.833 (t-CO2/MWh, and the carbon emission reduction generated for this project is 21,982 ton/year. From the analysis result, it can be proven that the additional revenue from carbon credit could increase the project IRR from 10.28% to 13.52%.

  5. Regulation of mat responses by a differentiation MAPK pathway in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Sheelarani Karunanithi

    Full Text Available Fungal species exhibit diverse behaviors when presented with extracellular challenges. Pathogenic fungi can undergo cell differentiation and biofilm formation in response to fluctuating nutrient levels, and these responses are required for virulence. In the model fungal eukaryote Saccharomyces cerevisiae, nutrient limitation induces filamentous growth and biofilm/mat formation. Both responses require the same signal transduction (MAPK pathway and the same cell adhesion molecule (Flo11 but have been studied under different conditions. We found that filamentous growth and mat formation are aspects of a related response that is regulated by the MAPK pathway. Cells in yeast-form mats differentiated into pseudohyphae in response to nutrient limitation. The MAPK pathway regulated mat expansion (in the plane of the XY-axis and substrate invasion (downward in the plane of the Z-axis, which optimized the mat's response to extracellular nutrient levels. The MAPK pathway also regulated an upward growth pattern (in the plane of the Z-axis in response to nutrient limitation and changes in surface rigidity. Upward growth allowed for another level of mat responsiveness and resembled a type of colonial chemorepulsion. Together our results show that signaling pathways play critical roles in regulating social behaviors in which fungal cells participate. Signaling pathways may regulate similar processes in pathogens, whose highly nuanced responses are required for virulence.

  6. An asymmetric heterodomain interface stabilizes a response regulator-DNA complex

    Energy Technology Data Exchange (ETDEWEB)

    Narayanan, Anoop; Kumar, Shivesh; Evrard, Amanda N.; Paul, Lake N.; Yernool, Dinesh A. [Purdue; (Duke-MED)

    2014-02-14

    Two-component signal transduction systems consist of pairs of histidine kinases and response regulators, which mediate adaptive responses to environmental cues. Most activated response regulators regulate transcription by binding tightly to promoter DNA via a phosphorylation-triggered inactive-to-active transition. The molecular basis for formation of stable response regulator–DNA complexes that precede the assembly of RNA polymerases is unclear. Here, we present structures of DNA complexed with the response regulator KdpE, a member of the OmpR/PhoB family. The distinctively asymmetric complex in an active-like conformation reveals a unique intramolecular interface between the receiver domain (RD) and the DNA-binding domain (DBD) of only one of the two response regulators in the complex. Structure–function studies show that this RD–DBD interface is necessary to form stable complexes that support gene expression. The conservation of sequence and structure suggests that these findings extend to a large group of response regulators that act as transcription factors.

  7. Concurrent and lasting effects of emotion regulation on amygdala response in adolescence and young adulthood.

    Science.gov (United States)

    Silvers, Jennifer A; Shu, Jocelyn; Hubbard, Alexa D; Weber, Jochen; Ochsner, Kevin N

    2015-09-01

    This study used functional MRI (fMRI) to examine a novel aspect of emotion regulation in adolescent development: whether age predicts differences in both the concurrent and lasting effects of emotion regulation on amygdala response. In the first, active regulation, phase of the testing session, fMRI data were collected while 56 healthy individuals (age range: 10.50-22.92 years) reappraised aversive stimuli so as to diminish negative responses to them. After a short delay, the second, re-presentation, phase involved passively viewing the aversive images from the reappraisal task. During active regulation, older individuals showed greater drops in negative affect and inverse rostrolateral prefrontal-amygdala connectivity. During re-presentation, older individuals continued to show lasting reductions in the amygdala response to aversive stimuli they had previously reappraised, an effect mediated by rostrolateral PFC. These data suggest that one source of heightened emotionality in adolescence is a diminished ability to cognitively down-regulate aversive reactions.

  8. Vitamin d-directed rheostatic regulation of monocyte antibacterial responses

    DEFF Research Database (Denmark)

    Adams, John S; Ren, Songyang; Liu, Philip T

    2009-01-01

    The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized...

  9. Development and regulation of response properties in spinal cord motoneurons

    DEFF Research Database (Denmark)

    Perrier, J F; Hounsgaard, J

    2000-01-01

    vertebrates in terms of both phylogeny and ontogeny. Spinal motoneurons in adults are remarkably similar in many respects ranging from the resting membrane potential to pacemaker properties. Apart from the axolotls, spinal motoneurons from all species investigated have latent intrinsic response properties...

  10. NaCl胁迫对转IrrE基因烟草抗氧化酶活性的影响

    Institute of Scientific and Technical Information of China (English)

    奉斌; 代其林; 刘婷婷; 田霞; 龚元亚; 孙英坤; 王劲

    2010-01-01

    文章主要研究了转IrrE基因烟草幼苗对NaCl胁迫的耐受性应答情况.结果表明,在200mmol/L NaCl胁迫下,其中野生型烟草随着胁迫时间的延长,POD、SOD、CAT三种抗氧化酶活性和可溶性蛋白的含量逐渐升高,处理24 h后达到一个峰值,然后又逐渐降低,叶片的相对含水量一直逐渐降低,而转IrrE基因烟草幼苗三种抗氧化酶活性和可溶性蛋白持续上升,相对含水量先有所降低然后逐渐升高,5个生理指标均高于野生型烟草.因此,IrrE基因作为一种转录因子可能调控了盐胁迫相关基因的表达,从而提高了植物对NaCl胁迫的耐受能力.

  11. IrrE基因转化甘蓝型油菜及其分子检测

    Institute of Scientific and Technical Information of China (English)

    杜世章; 代其林; 谢林; 杨娟

    2010-01-01

    为提高油菜的盐胁迫的耐受性,文章以甘蓝型油菜(Brassica napus L.)下胚轴为转化材料,通过农杆菌介导法将耐辐射球菌(Deiriococcus radiodurans,DR)的IrrE基因导入甘蓝型油菜84100-18(玻里马细胞质雄性不育恢复系)中,经过卡那霉素的筛选培养,获得了抗卡那霉素的再生植株,对抗性植株进行PCR和实时荧光定量PCR检测.结果表明:部分抗性植株多次重复检测显示为阳性植株,初步证实了IrrE已整合到油菜基因组中并且IrrE基因已经在这些植株中进行mRNA水平的转录.

  12. Sleep Moderates the Association Between Response Inhibition and Self-Regulation in Early Childhood.

    Science.gov (United States)

    Schumacher, Allyson M; Miller, Alison L; Watamura, Sarah E; Kurth, Salome; Lassonde, Jonathan M; LeBourgeois, Monique K

    2017-01-01

    Early childhood is a time of rapid developmental changes in sleep, cognitive control processes, and the regulation of emotion and behavior. This experimental study examined sleep-dependent effects on response inhibition and self-regulation, as well as whether acute sleep restriction moderated the association between these processes. Preschool children (N = 19; 45.6 ± 2.2 months; 11 female) followed a strict sleep schedule for at least 3 days before each of 2 morning behavior assessments: baseline (habitual nap/night sleep) and sleep restriction (missed nap/delayed bedtime). Response inhibition was evaluated via a go/no-go task. Twelve self-regulation strategies were coded from videotapes of children while attempting an unsolvable puzzle. We then created composite variables representing adaptive and maladaptive self-regulation strategies. Although we found no sleep-dependent effects on response inhibition or self-regulation measures, linear mixed-effects regression showed that acute sleep restriction moderated the relationship between these processes. At baseline, children with better response inhibition were more likely to use adaptive self-regulation strategies (e.g., self-talk, alternate strategies), and those with poorer response inhibition showed increased use of maladaptive self-regulation strategies (e.g., perseveration, fidgeting); however, response inhibition was not related to self-regulation strategies following sleep restriction. Our results showing a sleep-dependent effect on the associations between response inhibition and self-regulation strategies indicate that adequate sleep facilitates synergy between processes supporting optimal social-emotional functioning in early childhood. Although replication studies are needed, findings suggest that sleep may alter connections between maturing emotional and cognitive systems, which have important implications for understanding risk for or resilience to developmental psychopathology.

  13. Exploring car manufacturers' responses to technology-forcing regulation : The case of California's ZEV mandate

    NARCIS (Netherlands)

    Wesseling, Joeri; Farla, J. C M; Hekkert, M. P.

    2015-01-01

    The ability of firms to influence environmental regulation has largely been overlooked in transition studies. We study how car manufacturers combine and change their innovation and political influence strategies in response to a technology-forcing regulation. We apply a conceptual framework on corpo

  14. A Capacitor-Free, Fast Transient Response Linear Voltage Regulator In a 180nm CMOS

    DEFF Research Database (Denmark)

    Deleuran, Alexander N.; Lindbjerg, Nicklas; Pedersen, Martin K.;

    2015-01-01

    A 1.8 V capacitor-free linear regulator with fast transient response based on a new topology with a fast and slow regulation loop is presented. The design has been laid out and simulated in a 0.18 µm CMOS process. The design has a low component count and is tailored for system-on-chip integration...

  15. 76 FR 72327 - NASA Federal Acquisition Regulation Supplement; Responsibility, Suspension and Debarment

    Science.gov (United States)

    2011-11-23

    ... [Federal Register Volume 76, Number 226 (Wednesday, November 23, 2011)] [Rules and Regulations] [Pages 72327-72328] [FR Doc No: 2011-30148] NATIONAL AERONAUTICS AND SPACE ADMINISTRATION 48 CFR Part 1809 RIN 2700-AD54 NASA Federal Acquisition Regulation Supplement; Responsibility, Suspension and...

  16. Exploring car manufacturers' responses to technology-forcing regulation : The case of California's ZEV mandate

    NARCIS (Netherlands)

    Wesseling, Joeri|info:eu-repo/dai/nl/357536320; Farla, J. C M|info:eu-repo/dai/nl/106857576; Hekkert, M. P.|info:eu-repo/dai/nl/143777629

    2015-01-01

    The ability of firms to influence environmental regulation has largely been overlooked in transition studies. We study how car manufacturers combine and change their innovation and political influence strategies in response to a technology-forcing regulation. We apply a conceptual framework on

  17. Translation Control: A Multifaceted Regulator of Inflammatory Response

    Science.gov (United States)

    Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

    2010-01-01

    A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxicshock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation. PMID:20304832

  18. Gene regulation in response to protein disulphide isomerase deficiency

    DEFF Research Database (Denmark)

    Nørgaard, Per; Tachibana, Christine; Bruun, Anette W

    2003-01-01

    We have examined the activities of promoters of a number of yeast genes encoding resident endoplasmic reticulum proteins, and found increased expression in a strain with severe protein disulphide isomerase deficiency. Serial deletion in the promoter of the MPD1 gene, which encodes a PDI1-homologue...... element. The sequence (GACACG) does not resemble the unfolded protein response element. It is present in the upstream regions of the MPD1, MPD2, KAR2, PDI1 and ERO1 genes....

  19. Neural regulation of the stress response: glucocorticoid feedback mechanisms

    Directory of Open Access Journals (Sweden)

    J.P. Herman

    2012-04-01

    Full Text Available The mammalian stress response is an integrated physiological and psychological reaction to real or perceived adversity. Glucocorticoids are an important component of this response, acting to redistribute energy resources to both optimize survival in the face of challenge and to restore homeostasis after the immediate challenge has subsided. Release of glucocorticoids is mediated by the hypothalamo-pituitary-adrenal (HPA axis, driven by a neural signal originating in the paraventricular nucleus (PVN. Stress levels of glucocorticoids bind to glucocorticoid receptors in multiple body compartments, including the brain, and consequently have wide-reaching actions. For this reason, glucocorticoids serve a vital function in negative feedback inhibition of their own secretion. Negative feedback inhibition is mediated by a diverse collection of mechanisms, including fast, non-genomic feedback at the level of the PVN, stress-shut-off at the level of the limbic system, and attenuation of ascending excitatory input through destabilization of mRNAs encoding neuropeptide drivers of the HPA axis. In addition, there is evidence that glucocorticoids participate in stress activation via feed-forward mechanisms at the level of the amygdala. Feedback deficits are associated with numerous disease states, underscoring the necessity for adequate control of glucocorticoid homeostasis. Thus, rather than having a single, defined feedback ‘switch’, control of the stress response requires a wide-reaching feedback ‘network’ that coordinates HPA activity to suit the overall needs of multiple body systems.

  20. The Plant Heat Stress Transcription Factors (HSFs): Structure, Regulation, and Function in Response to Abiotic Stresses.

    Science.gov (United States)

    Guo, Meng; Liu, Jin-Hong; Ma, Xiao; Luo, De-Xu; Gong, Zhen-Hui; Lu, Ming-Hui

    2016-01-01

    Abiotic stresses such as high temperature, salinity, and drought adversely affect the survival, growth, and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological, and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  1. The plant heat stress transcription factors (HSFs: structure, regulation and function in response to abiotic stresses

    Directory of Open Access Journals (Sweden)

    Meng eGuo

    2016-02-01

    Full Text Available Abiotic stresses such as high temperature, salinity and drought adversely affect the survival, growth and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs, including heat stress transcription factors (HSFs. HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps. In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

  2. Bifidobacterium infantis attenuates colitis by regulating T cell subset responses

    Science.gov (United States)

    Zuo, Li; Yuan, Kai-Tao; Yu, Li; Meng, Qing-Hong; Chung, Peter Chee-Keung; Yang, Ding-Hua

    2014-01-01

    AIM: to investigate the effect of Bifidobacterium infantis (B. infantis) on the T cell subsets and in attenuating the severity of experimental colitis in mice. METHODS: Normal BALB/c mice were fed different doses of B. infantis for 3 wk, and T cell subsets and related cytokine profiles in mesenteric lymph nodes (MLNs) were detected by flow cytometry and real-time RT-PCR. Colitis was induced by administration of trinitrobenzene sulfonic acid (TNBS) in mice. Before colitis induction, mice were fed high dose B. infantis for 3 wk. Cytokine profiles in MLNs and histological changes of colonic tissue were examined 6 d after colitis induction. RESULTS: No significant change in cytokine profiles was observed in normal mice fed low dose B. infantis. However, Th1-related cytokines (IL-2, IFN-γ, IL-12p40), Th17-related transcription factor and cytokines (RORγt, IL-21, IL-23), regulatory T cell (Treg)-related transcription factor and cytokines (Foxp3, IL-10) were increased in normal mice fed high dose B. infantis. Furthermore, flow cytometry assay showed B. infantis increased the numbers of CD4+Foxp3+ Tregs and Th17 cells in MLNs. Colitis was successfully induced by TNBS in mice, characterized by colonic inflammation and aberrant Th1 and Th17 responses. Feeding high dose B. infantis for 3 wk before colitis induction decreased the inflammatory cell infiltration and goblet cell depletion and restored the intestinal epithelium. In addition, B. infantis feeding reduced Th1-related cytokines (T-bet, IL-2 and IFN-γ) and Th17-related cytokines (IL-12p40, RORγt, IL-17A, IL-21 and IL-23), and increased Treg-related molecules (Foxp3, IL-10 and TGF-β) in colitis mice. CONCLUSION: B. infantis effectively attenuates TNBS-induced colitis by decreasing Th1 and Th17 responses and increasing Foxp3+ Treg response in the colonic mucosa. PMID:25561798

  3. DNA-responsive inflammasomes and their regulators in autoimmunity

    OpenAIRE

    2011-01-01

    Upon sensing microbial and self-derived DNA, DNA sensors initiate innate immune responses. These sensors include the interferon (IFN)-inducible Toll-like receptor 9 (TLR9) and PYHIN proteins. Upon sensing DNA, cytosolic (murine Aim2 and human AIM2) and nuclear (IFI16) PYHIN proteins recruit an adaptor protein (ASC) and pro-caspase-1 to form an inflammasome, which activates caspase-1. The activated caspase-1 cleaves pro-IL-1β and pro-IL-18 to generate active forms. However, upon sensing cytoso...

  4. Ethylene regulates the susceptible response to pathogen infection in tomato.

    Science.gov (United States)

    Lund, S T; Stall, R E; Klee, H J

    1998-03-01

    Ethylene evolution occurs concomitantly with the progression of disease symptoms in response to many virulent pathogen infections in plants. A tomato mutant impaired in ethylene perception-Never ripe-exhibited a significant reduction in disease symptoms in comparison to the wild type after inoculations of both genotypes with virulent bacterial (Xanthomonas campestris pv vesicatoria and Pseudomonas syringae pv tomato) and fungal (Fusarium oxysporum f sp lycopersici) pathogens. Bacterial spot disease symptoms were also reduced in tomato genotypes impaired in ethylene synthesis (1-aminocyclopropane-1-carboxylic acid deaminase) and perception (14893), thereby corroborating a reducing effect for ethylene insensitivity on foliar disease development. The reduction in foliar disease symptoms in Never ripe plants was a specific effect of ethylene insensitivity and was not due to reductions in bacterial populations or decreased ethylene synthesis. PR-1B1 mRNA accumulation in response to X. c. vesicatoria infection was not affected by ethylene insensitivity, indicating that ethylene is not required for defense gene induction. Our findings suggest that broad tolerance of diverse vegetative diseases may be achieved via engineering of ethylene insensitivity in tomato.

  5. Ancillary-service details: regulation, load following, and generator response

    Energy Technology Data Exchange (ETDEWEB)

    Hirst, E.; Kirby, B.

    1996-09-01

    The purpose of this report is to examine empirically these intrahour and interhour load changes and the responses of a utility`s generating resources to those load changes. We analyze data, primarily from one control area, to see how it maintains ACE close to zero in an effort to meet the A1 and A2 criteria. Overall, we estimate that load following costs US electric utilities over one billion dollars a year. We first test alternative ways to identify trends over multihour periods using both regression analysis and rolling averages. Then, we consider several metrics for intrahour load following. Next we examine characteristics of load following for different time-averaging periods and compare the dynamics of loads and load following generation across these time periods. Finally, we consider the contribution of each load to the total load following requirements of the control area.

  6. TRAF-mediated regulation of immune and inflammatory responses

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The tumor necrosis factor (TNF) receptor-associated factor (TRAF) family consists of six mammalian members,and is shown to participate in signal transduction of a large number of receptor families including TNF receptor family (TNFR) and Toll-like receptors-interleukin-1 receptors (TLR-IL-1R) family.Upon receptor activation,TRAFs are directly or indirectly recruited to the intracellular domains of these receptors.They subsequently engage other signaling proteins to activate inhibitor of κB kinase (IKK) complex,TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) and inducible I κB kinase (IKK-i) (also known as IKKε),ultimately leading to activation of transcription factors such as NF-κB and interferon-regulatory factor (IRF) to induce immune and inflammatory responses.

  7. Chloride regulates afferent arteriolar contraction in response to depolarization

    DEFF Research Database (Denmark)

    Hansen, P B; Jensen, B L; Skott, O

    1998-01-01

    . The results show that K+-induced contraction of smooth muscle cells in the afferent arteriole is highly sensitive to chloride, whereas neurotransmitter release and ensuing contraction is not dependent on chloride. Thus, there are different activation pathways for depolarizing vasoconstrictors......-Renal vascular reactivity is influenced by the level of dietary salt intake. Recent in vitro data suggest that afferent arteriolar contractility is modulated by extracellular chloride. In the present study, we assessed the influence of chloride on K+-induced contraction in isolated perfused rabbit...... afferent arterioles. In 70% of vessels examined, K+-induced contraction was abolished by acute substitution of bath chloride. Consecutive addition of Cl- (30, 60, 80, 100, 110, and 117 mmol/L) restored the sensitivity to K+, and half-maximal response was observed at 82 mmol/L chloride. The calcium channel...

  8. GITR Activation Positively Regulates Immune Responses against Toxoplasma gondii

    Science.gov (United States)

    Costa, Frederico R. C.; Mota, Caroline M.; Santiago, Fernanda M.; Silva, Murilo V.; Ferreira, Marcela D.; Fonseca, Denise M.; Silva, João S.; Mineo, José R.; Mineo, Tiago W. P.

    2016-01-01

    Toxoplasma gondii is a widespread parasite responsible for causing clinical diseases especially in pregnant and immunosuppressed individuals. Glucocorticoid-induced TNF receptor (GITR), which is also known as TNFRS18 and belongs to the TNF receptor superfamily, is found to be expressed in various cell types of the immune system and provides an important costimulatory signal for T cells and myeloid cells. However, the precise role of this receptor in the context of T. gondii infection remains elusive. Therefore, the current study investigated the role of GITR activation in the immunoregulation mechanisms induced during the experimental infection of mice with T. gondii. Our data show that T. gondii infection slightly upregulates GITR expression in Treg cells and B cells, but the most robust increment in expression was observed in macrophages and dendritic cells. Interestingly, mice infected and treated with an agonistic antibody anti-GITR (DTA-1) presented a robust increase in pro-inflammatory cytokine production at preferential sites of parasite replication, which was associated with the decrease in latent brain parasitism of mice under treatment with DTA-1. Several in vivo and in vitro analysis were performed to identify the cellular mechanisms involved in GITR activation upon infection, however no clear alterations were detected in the phenotype/function of macrophages, Tregs and B cells under treatment with DTA-1. Therefore, GITR appears as a potential target for intervention during infection by the parasite Toxoplasma gondii, even though further studies are still necessary to better characterize the immune response triggered by GITR activation during T. gondii infection. PMID:27027302

  9. Violation regulation of financial services authority (FSA, financial performance, and corporate social responsibility disclosure

    Directory of Open Access Journals (Sweden)

    Habib Muhammad Shahib

    2016-07-01

    Full Text Available So far, there has been a bureaucracy reform and implementation of new regulations for good governance capital markets. However, policy violations are still frequent. For example, cases of violation of financial regulations leading to fraudulent financial reporting occurred in several companies listed on the Indonesia Stock Exchange. This study aims to examine the empirical facts related to the legitimacy theory with-in the scope of violation of financial regulation, financial performance and social responsibility disclosure of non-financial companies in Indonesia Stock Exchange. The data were obtained from the Indonesia Stock Exchange. There were 24 non-financial violator-companies of financial regulation chosen as the sample. These data, in relation to the research hypotheses, were analyzed by using a path analysis test. The result showed there were no significant effect of the violations of financial regulations on financial performance and the level of corporate social responsibility disclosure. Therefore, this study confirms legitimacy theory in different forms.

  10. The relation between emotion regulation strategies and physiological stress responses in middle childhood

    NARCIS (Netherlands)

    Veld, D.M.J. de; Riksen-Walraven, J.M.A.; Weerth, C. de

    2012-01-01

    The current study sought to examine whether children's spontaneous use of the emotion regulation strategies suppression and reappraisal during a psychosocial stress task was related to their cortisol and alpha-amylase responses to that task. Salivary cortisol and alpha-amylase responses to a

  11. Characterizing human skin blood flow regulation in response to different local skin temperature perturbations

    NARCIS (Netherlands)

    Wu, Y.; M.D. Nieuwenhoff (Mariska D.); F.J.P.M. Huygen (Frank); F.C.T. van der Helm (Frans C.); S.P. Niehof (Sjoerd); A.C. Schouten (A.)

    2017-01-01

    textabstractSmall nerve fibers regulate local skin blood flow in response to local thermal perturbations. Small nerve fiber function is difficult to assess with classical neurophysiological tests. In this study, a vasomotor response model in combination with a heating protocol was developed to

  12. Specific microRNAs Regulate Heat Stress Responses in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Nehammer, Camilla; Podolska, Agnieszka; Mackowiak, Sebastian D

    2015-01-01

    The ability of animals to sense and respond to elevated temperature is essential for survival. Transcriptional control of the heat stress response has been much studied, whereas its posttranscriptional regulation by microRNAs (miRNAs) is not well understood. Here we analyzed the miRNA response...... signaling that enables animals to robustly respond to the changing environment....

  13. Regulation of HuR by DNA Damage Response Kinases

    Directory of Open Access Journals (Sweden)

    Hyeon Ho Kim

    2010-01-01

    Full Text Available As many DNA-damaging conditions repress transcription, posttranscriptional processes critically influence gene expression during the genotoxic stress response. The RNA-binding protein HuR robustly influences gene expression following DNA damage. HuR function is controlled in two principal ways: (1 by mobilizing HuR from the nucleus to the cytoplasm, where it modulates the stability and translation of target mRNAs and (2 by altering its association with target mRNAs. Here, we review evidence that two main effectors of ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR, the checkpoint kinases Chk1 and Chk2, jointly influence HuR function. Chk1 affects HuR localization by phosphorylating (hence inactivating Cdk1, a kinase that phosphorylates HuR and thereby blocks HuR's cytoplasmic export. Chk2 modulates HuR binding to target mRNAs by phosphorylating HuR's RNA-recognition motifs (RRM1 and RRM2. We discuss how HuR phosphorylation by kinases including Chk1/Cdk1 and Chk2 impacts upon gene expression patterns, cell proliferation, and survival following genotoxic injury.

  14. Regulation of intestinal IgA responses by dietary palmitic acid and its metabolism.

    Science.gov (United States)

    Kunisawa, Jun; Hashimoto, Eri; Inoue, Asuka; Nagasawa, Risa; Suzuki, Yuji; Ishikawa, Izumi; Shikata, Shiori; Arita, Makoto; Aoki, Junken; Kiyono, Hiroshi

    2014-08-15

    Enhancement of intestinal IgA responses is a primary strategy in the development of oral vaccine. Dietary fatty acids are known to regulate host immune responses. In this study, we show that dietary palmitic acid (PA) and its metabolites enhance intestinal IgA responses. Intestinal IgA production was increased in mice maintained on a PA-enriched diet. These mice also showed increased intestinal IgA responses against orally immunized Ag, without any effect on serum Ab responses. We found that PA directly stimulates plasma cells to produce Ab. In addition, mice receiving a PA-enriched diet had increased numbers of IgA-producing plasma cells in the large intestine; this effect was abolished when serine palmitoyltransferase was inhibited. These findings suggest that dietary PA regulates intestinal IgA responses and has the potential to be a diet-derived mucosal adjuvant.

  15. Regulation of Toll-like receptors-dependent inflammatory response 

    Directory of Open Access Journals (Sweden)

    Ewa Kowalczyk

    2013-03-01

    Full Text Available Toll-like receptors (TLRs are a pivotal part of our innate immune response. They recognize a wide variety of pathogens and instigate an immune response, thus facilitating the removal of the disease-causing agent. Due to the intense nature of this response its strict control is of keyimportance, as a prolonged inflammatory signal leads to carcinogenesis and autoimmune disorders. The signaling cascade initiated by the activated TLR is complex and consists of multiple stages. It involves a variety of adaptor proteins, protein kinases and effector transcription factors. The number of stages in this process enables many possible checkpoints and ways of regulation. Signal modulation involves differentiated expression of TLRs, splicing variants of their adaptorproteins, enzymes modifying proteins engaged in the cascade and many more. This review focuses on endogenous factors responsible for controlling the TLR-dependent inflammatory response as well as on pharmacological therapies designed for regulating the innate immune response.  

  16. Vitamin A in regulation of insulin responsiveness: mini review.

    Science.gov (United States)

    Noy, Noa

    2016-05-01

    Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples 'sensing' of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases.

  17. Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction

    Science.gov (United States)

    Baker, Anna W.; Satyshur, Kenneth A.; Moreno Morales, Neydis

    2016-01-01

    ABSTRACT Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis. RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRRmon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. IMPORTANCE BphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these

  18. Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction.

    Science.gov (United States)

    Baker, Anna W; Satyshur, Kenneth A; Moreno Morales, Neydis; Forest, Katrina T

    2016-04-01

    Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRRmon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. BphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these proteins, rather than

  19. The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses

    Directory of Open Access Journals (Sweden)

    Yusuke Kanamaru

    2012-01-01

    Full Text Available To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide cellular energy but also integrate stress response signaling pathways, including those regulating cell death. Several lines of evidence suggest that the mitochondrial proteins that function in this process, such as Bcl-2 family proteins in apoptosis and phosphoglycerate mutase family member 5 (PGAM5 in necroptosis, are regulated by several kinases. It has also been suggested that the phosphorylation-dependent regulation of mitochondrial fission machinery, dynamin-related protein 1 (Drp1, facilitates appropriate cellular stress responses. However, mitochondria themselves are also damaged by various stresses. To avoid the deleterious effects exerted by damaged mitochondria, cells remove these mitochondria in a selective autophagic degradation process called mitophagy. Interestingly, several kinases, such as PTEN-induced putative kinase 1 (PINK1 in mammals and stress-responsive mitogen-activated protein (MAP kinases in yeast, have recently been shown to be involved in mitophagy. In this paper, we focus on the phosphorylation-dependent regulation of mitochondrial proteins and discuss the roles of this regulation in the mitochondrial and cellular stress responses.

  20. Ethylene participates in the regulation of Fe deficiency responses in Strategy I plants and in rice

    Directory of Open Access Journals (Sweden)

    Carlos eLucena

    2015-11-01

    Full Text Available Iron (Fe is very abundant in most soils but its availability for plants is low, especially in calcareous soils. Plants have been divided into Strategy I and Strategy II species to acquire Fe from soils. Strategy I species apply a reduction-based uptake system which includes all higher plants except the Poaceae. Strategy II species apply a chelation-based uptake system which includes the Poaceae. To cope with Fe deficiency both type of species activate several Fe deficiency responses, mainly in their roots. These responses need to be tightly regulated to avoid Fe toxicity and to conserve energy. Their regulation is not totally understood but some hormones and signaling substances have been implicated. Several years ago it was suggested that ethylene could participate in the regulation of Fe deficiency responses in Strategy I species. In Strategy II species, the role of hormones and signaling substances has been less studied. However, in rice, traditionally considered a Strategy II species but that possesses some characteristics of Strategy I species, it has been recently shown that ethylene can also play a role in the regulation of some of its Fe deficiency responses. Here, we will review and discuss the data supporting a role for ethylene in the regulation of Fe deficiency responses in both Strategy I species and rice. In addition, we will review the data about ethylene and Fe responses related to Strategy II species. We will also discuss the results supporting the action of ethylene through different transduction pathways and its interaction with other signals, such as certain Fe-related repressive signals occurring in the phloem sap. Finally, the possible implication of ethylene in the interactions among Fe deficiency responses and the responses to other nutrient deficiencies in the plant will be addressed.

  1. Tomato NAC transcription factor SlSRN1 positively regulates defense response against biotic stress but negatively regulates abiotic stress response.

    Directory of Open Access Journals (Sweden)

    Bo Liu

    Full Text Available Biotic and abiotic stresses are major unfavorable factors that affect crop productivity worldwide. NAC proteins comprise a large family of transcription factors that play important roles in plant growth and development as well as in responses to biotic and abiotic stresses. In a virus-induced gene silencing-based screening to identify genes that are involved in defense response against Botrytis cinerea, we identified a tomato NAC gene SlSRN1 (Solanum lycopersicum Stress-related NAC1. SlSRN1 is a plasma membrane-localized protein with transactivation activity in yeast. Expression of SlSRN1 was significantly induced by infection with B. cinerea or Pseudomonas syringae pv. tomato (Pst DC3000, leading to 6-8 folds higher than that in the mock-inoculated plants. Expression of SlSRN1 was also induced by salicylic acid, jasmonic acid and 1-amino cyclopropane-1-carboxylic acid and by drought stress. Silencing of SlSRN1 resulted in increased severity of diseases caused by B. cinerea and Pst DC3000. However, silencing of SlSRN1 resulted in increased tolerance against oxidative and drought stresses. Furthermore, silencing of SlSRN1 accelerated accumulation of reactive oxygen species but attenuated expression of defense genes after infection by B. cinerea. Our results demonstrate that SlSRN1 is a positive regulator of defense response against B. cinerea and Pst DC3000 but is a negative regulator for oxidative and drought stress response in tomato.

  2. Metal-responsive promoter DNA compaction by the ferric uptake regulator

    OpenAIRE

    Roncarati, Davide; Pelliciari, Simone; Doniselli, Nicola; Maggi, Stefano; Vannini, Andrea; Valzania, Luca; Mazzei, Luca; Zambelli, Barbara; Rivetti, Claudio; Danielli, Alberto

    2016-01-01

    Short-range DNA looping has been proposed to affect promoter activity in many bacterial species and operator configurations, but only few examples have been experimentally investigated in molecular detail. Here we present evidence for a metal-responsive DNA condensation mechanism controlled by the Helicobacter pylori ferric uptake regulator (Fur), an orthologue of the widespread Fur family of prokaryotic metal-dependent regulators. H. pylori Fur represses the transcription of the essential ar...

  3. Emotional Intensity and Emotion Regulation in Response to Autobiographical Memories During Dysphoria

    DEFF Research Database (Denmark)

    del Palacio Gonzalez, Adriana; Berntsen, Dorthe; Watson, Lynn Ann

    2017-01-01

    Retrieving personal memories may provoke different emotions and a need for emotion regulation. Emotional responses have been studied scarcely in relation to autobiographical memory retrieval. We examined the emotional response to everyday involuntary (spontaneously arising) and voluntary...... (strategically retrieved) memories, and how this response may be different during dysphoria. Participants (20 dysphoric and 23 non-depressed) completed a structured diary where the intensity of basic emotions and regulation strategies employed upon retrieval of memories were rated. Brooding, memory suppression......, and emotional suppression were higher for all individuals’ involuntary memories than voluntary memories. Negative emotions and regulation strategies were greater for dysphoric individuals for both involuntary and voluntary memories after controlling for the valence of the remembered events. The results provide...

  4. Regulation of IgE Responses by γδ T Cells.

    Science.gov (United States)

    Huang, Yafei; Yang, Zhifang; McGowan, Jessica; Huang, Hua; O'Brien, Rebecca L; Born, Willi K

    2015-04-01

    Immunoglobulin E (IgE) antibodies play a crucial role in host defense against parasite infections. However, inappropriate IgE responses are also involved in the pathogenesis of allergic diseases. The generation of IgE antibodies is a tightly controlled process regulated by multiple transcription factors, cytokines, and immune cells including γδ T cells. Accumulating evidence demonstrates that γδ T cells play a critical role in regulating IgE responses; however, both IgE-enhancing and IgE-suppressive effects are suggested for these cells in different experimental systems. In this review, we examine the available evidence and discuss the role of γδ T cells in IgE regulation both in the context of antigen-induced immune responses and in the state of partial immunodeficiency.

  5. Global SUMO proteome responses guide gene regulation, mRNA biogenesis, and plant stress responses.

    NARCIS (Netherlands)

    M.J. Mazur; H.A. van den Burg

    2012-01-01

    Small Ubiquitin-like MOdifier (SUMO) is a key regulator of abiotic stress, disease resistance, and development in plants. The identification of >350 plant SUMO targets has revealed many processes modulated by SUMO and potential consequences of SUMO on its targets. Importantly, highly related protein

  6. Neuronal regulation of ascaroside response during mate response behavior in the nematode Caenorhabditis elegans

    Science.gov (United States)

    Small-molecule signaling plays an important role in the biology of Caenorhabditis elegans. We have previously shown that ascarosides, glycosides of the dideoxysugar ascarylose regulate both development and behavior in C. elegans The mating signal consists of a synergistic blend of three dauer-induc...

  7. A universally conserved ATPase regulates the oxidative stress response in Escherichia coli.

    Science.gov (United States)

    Wenk, Meike; Ba, Qiaorui; Erichsen, Veronika; MacInnes, Katherine; Wiese, Heike; Warscheid, Bettina; Koch, Hans-Georg

    2012-12-21

    YchF is an evolutionarily conserved ATPase of unknown function. In humans, the YchF homologue hOla1 appears to influence cell proliferation and was found to be up-regulated in many tumors. A possible involvement in regulating the oxidative stress response was also suggested, but details on the underlying mechanism are lacking. For gaining insight into YchF function, we used Escherichia coli as a model organism and found that YchF overexpression resulted in H(2)O(2) hypersensitivity. This was not caused by transcriptional or translational down-regulation of H(2)O(2)-scavenging enzymes. Instead, we observed YchF-dependent inhibition of catalase activity and a direct interaction with the major E. coli catalase KatG. KatG inhibition was dependent on the ATPase activity of YchF and was regulated by post-translational modifications, most likely including an H(2)O(2)-dependent dephosphorylation. We furthermore showed that YchF expression is repressed by the transcription factor OxyR and further post-translationally modified in response to H(2)O(2). In summary, our data show that YchF functions as a novel negative regulator of the oxidative stress response in E. coli. Considering the available data on hOla1, YchF/Ola1 most likely execute similar functions in bacteria and humans, and their up-regulation inhibits the ability of the cells to scavenge damaging reactive oxygen species.

  8. CDPK1, a calcium-dependent protein kinase, regulates transcriptional activator RSG in response to gibberellins.

    Science.gov (United States)

    Nakata, Masaru; Yuasa, Takashi; Takahashi, Yohsuke; Ishida, Sarahmi

    2009-05-01

    The homeostasis of gibberellins (GAs) is maintained by negative-feedback regulation in plant cells. REPRESSION OF SHOOT GROWTH (RSG) is a transcriptional activator with a basic Leu zipper domain suggested to contribute GA feedback regulation by the transcriptional regulation of genes encoding GA biosynthetic enzymes. The 14-3-3 signaling proteins negatively regulate RSG by sequestering it in the cytoplasm in response to GAs. The phosphorylation on Ser-114 of RSG is essential for 14-3-3 binding of RSG; however, the kinase that catalyzes the reaction is unknown. Recently a Ca(2+)-dependent protein kinase (CDPK) was identified as an RSG kinase that promotes 14-3-3 binding of RSG by phosphorylation of the Ser-114 of RSG. Our results suggest that CDPK decodes the Ca(2+) signal produced by GAs and regulates the intracellular localization of RSG in plant cells.

  9. Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin.

    Science.gov (United States)

    Ortells, M Carmen; Morancho, Beatriz; Drews-Elger, Katherine; Viollet, Benoit; Laderoute, Keith R; López-Rodríguez, Cristina; Aramburu, Jose

    2012-05-01

    Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses.

  10. STATc is a key regulator of the transcriptional response to hyperosmotic shock

    Directory of Open Access Journals (Sweden)

    Eichinger Ludwig

    2007-05-01

    Full Text Available Abstract Background Dictyostelium discoideum is frequently subjected to environmental changes in its natural habitat, the forest soil. In order to survive, the organism had to develop effective mechanisms to sense and respond to such changes. When cells are faced with a hypertonic environment a complex response is triggered. It starts with signal sensing and transduction and leads to changes in cell shape, the cytoskeleton, transport processes, metabolism and gene expression. Certain aspects of the Dictyostelium osmotic stress response have been elucidated, however, no comprehensive picture was available up to now. Results To better understand the D. discoideum response to hyperosmotic conditions, we performed gene expression profiling using DNA microarrays. The transcriptional profile of cells treated with 200 mM sorbitol during a 2-hour time course revealed a time-dependent induction or repression of 809 genes, more than 15% of the genes on the array, which peaked 45 to 60 minutes after the hyperosmotic shock. The differentially regulated genes were applied to cluster analysis and functional annotation using gene GO terms. Two main responses appear to be the down-regulation of the metabolic machinery and the up-regulation of the stress response system, including STATc. Further analysis of STATc revealed that it is a key regulator of the transcriptional response to hyperosmotic shock. Approximately 20% of the differentially regulated genes were dependent on the presence of STATc. Conclusion At least two signalling pathways are activated in Dictyostelium cells subjected to hypertonicity. STATc is responsible for the transcriptional changes of one of them.

  11. Interval ridge regression (iRR) as a fast and robust method for quantitative prediction and variable selection applied to edible oil adulteration.

    Science.gov (United States)

    Jović, Ozren; Smrečki, Neven; Popović, Zora

    2016-04-01

    A novel quantitative prediction and variable selection method called interval ridge regression (iRR) is studied in this work. The method is performed on six data sets of FTIR, two data sets of UV-vis and one data set of DSC. The obtained results show that models built with ridge regression on optimal variables selected with iRR significantly outperfom models built with ridge regression on all variables in both calibration (6 out of 9 cases) and validation (2 out of 9 cases). In this study, iRR is also compared with interval partial least squares regression (iPLS). iRR outperfomed iPLS in validation (insignificantly in 6 out of 9 cases and significantly in one out of 9 cases for poil, a well known health beneficial nutrient, is studied in this work by mixing it with cheap and widely used oils such as soybean (So) oil, rapeseed (R) oil and sunflower (Su) oil. Binary mixture sets of hempseed oil with these three oils (HSo, HR and HSu) and a ternary mixture set of H oil, R oil and Su oil (HRSu) were considered. The obtained accuracy indicates that using iRR on FTIR and UV-vis data, each particular oil can be very successfully quantified (in all 8 cases RMSEPoil (R(2)>0.99).

  12. The Atypical Response Regulator AtvR Is a New Player in Pseudomonas aeruginosa Response to Hypoxia and Virulence.

    Science.gov (United States)

    Kaihami, Gilberto Hideo; Breda, Leandro Carvalho Dantas; de Almeida, José Roberto Fogaça; de Oliveira Pereira, Thays; Nicastro, Gianlucca Gonçalves; Boechat, Ana Laura; de Almeida, Sandro Rogério; Baldini, Regina Lúcia

    2017-08-01

    Two-component systems are widespread in bacteria, allowing adaptation to environmental changes. The classical pathway is composed of a histidine kinase that phosphorylates an aspartate residue in the cognate response regulator (RR). RRs lacking the phosphorylatable aspartate also occur, but their function and contribution during host-pathogen interactions are poorly characterized. AtvR (PA14_26570) is the only atypical response regulator with a DNA-binding domain in the opportunistic pathogen Pseudomonas aeruginosa Macrophage infection with the atvR mutant strain resulted in higher levels of tumor necrosis factor alpha secretion as well as increased bacterial clearance compared to those for macrophages infected with the wild-type strain. In an acute pneumonia model, mice infected with the atvR mutant presented increased amounts of proinflammatory cytokines, increased neutrophil recruitment to the lungs, reductions in bacterial burdens, and higher survival rates in comparison with the findings for mice infected with the wild-type strain. Further, several genes involved in hypoxia/anoxia adaptation were upregulated upon atvR overexpression, as seen by high-throughput transcriptome sequencing (RNA-Seq) analysis. In addition, atvR was more expressed in hypoxia in the presence of nitrate and required for full expression of nitrate reductase genes, promoting bacterial growth under this condition. Thus, AtvR would be crucial for successful infection, aiding P. aeruginosa survival under conditions of low oxygen tension in the host. Taken together, our data demonstrate that the atypical response regulator AtvR is part of the repertoire of transcriptional regulators involved in the lifestyle switch from aerobic to anaerobic conditions. This finding increases the complexity of regulation of one of the central metabolic pathways that contributes to Pseudomonas ubiquity and versatility. Copyright © 2017 American Society for Microbiology.

  13. Victimization and Biological Stress Responses in Urban Adolescents: Emotion Regulation as a Moderator.

    Science.gov (United States)

    Kliewer, Wendy

    2016-09-01

    Associations between urban adolescents' victimization experiences and biological stress responses were examined, as well as emotion regulation as a moderator of these associations. Data from a 4-wave longitudinal study with a low-income, community-based sample (n = 242; 91 % African American; 57 % female; M = 11.98, SD = 1.56 years at baseline) revealed that victimization, assessed over 3 study waves, was associated with an attenuated cortisol response to a stress interview at the final study wave, indicating that responses of the Hypothalamus-Pituitary-Adrenal (HPA) axis were dysregulated. Cortisol responses were moderated by caregiver-reported adolescent emotion regulation, suggesting that this modifiable protective factor that is taught in many school-based prevention programs could help reduce harm associated with HPA axis dysregulation linked to victimization.

  14. Neurotoxin-induced selective ubiquitination and regulation of MEF2A isoform in neuronal stress response

    OpenAIRE

    She, Hua; Yang, Qian; Mao, Zixu

    2012-01-01

    The myocyte enhancer factor 2A-D (MEF2) proteins are members of the MCM1-agamous-deficiens-serum (MADS) response factor family of transcription factors. Various MEF2 isoform proteins are enriched in neurons and exhibit distinct patterns of expression in different regions of the brain. In neurons, MEF2 functions as a converging factor to regulate many neuronal functions including survival. MEF2 activities are tightly controlled in neurons in response to stress. Whether stress signal may differ...

  15. Integrated Regulation of Toll-like Receptor Responses by Notch and Interferon-γ Pathways

    OpenAIRE

    2008-01-01

    Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6 and IL-12. Cooperation by these pathways to increase target gene expression was mediated the Notch pathway component and transcription factor RB...

  16. Neutrophils that infiltrate the central nervous system regulate T cell responses

    DEFF Research Database (Denmark)

    Zehntner, Simone P; Brickman, Cristina; Bourbonnière, Lyne;

    2005-01-01

    Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high......, and activated Gr-1high neutrophils within the target organ determines the outcome of inflammatory and potentially autoimmune T cell responses....

  17. PGC-1alpha down-regulation affects the antioxidant response in Friedreich's ataxia.

    Directory of Open Access Journals (Sweden)

    Daniele Marmolino

    Full Text Available BACKGROUND: Cells from individuals with Friedreich's ataxia (FRDA show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARgamma Coactivator 1-alpha (PGC-1alpha, a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models. METHODOLOGY/PRINCIPAL FINDINGS: We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse to determine basal superoxide dismutase 2 (SOD2 levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma agonist (Pioglitazone or with a cAMP-dependent protein kinase (AMPK agonist (AICAR restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord. CONCLUSIONS/SIGNIFICANCE: PGC-1alpha down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.

  18. PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia

    Science.gov (United States)

    Marmolino, Daniele; Manto, Mario; Acquaviva, Fabio; Vergara, Paola; Ravella, Ajay; Monticelli, Antonella; Pandolfo, Massimo

    2010-01-01

    Background Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARγ) Coactivator 1-alpha (PGC-1α), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models. Methodology/Principal Findings We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1α. Compared to control cells, PGC-1α and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1α direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1α activation with the PPARγ agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord. Conclusions/Significance PGC-1α down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARγ agonists, suggesting a potential therapeutic approach for FRDA. PMID:20383327

  19. Stomatal responses to vapour pressure deficit are regulated by high speed gene expression in angiosperms.

    Science.gov (United States)

    McAdam, Scott A M; Sussmilch, Frances C; Brodribb, Timothy J

    2016-03-01

    Plants dynamically regulate water use by the movement of stomata on the surface of leaves. Stomatal responses to changes in vapour pressure deficit (VPD) are the principal regulator of daytime transpiration and water use efficiency in land plants. In angiosperms, stomatal responses to VPD appear to be regulated by the phytohormone abscisic acid (ABA), yet the origin of this ABA is controversial. After a 20 min exposure of plants, from three diverse angiosperm species, to a doubling in VPD, stomata closed, foliar ABA levels increased and the expression of the gene encoding the key, rate-limiting carotenoid cleavage enzyme (9-cis-epoxycarotenoid dioxygenase, NCED) in the ABA biosynthetic pathway was significantly up-regulated. The NCED gene was the only gene in the ABA biosynthetic pathway to be up-regulated over the short time scale corresponding to the response of stomata. The closure of stomata and rapid increase in foliar ABA levels could not be explained by the release of ABA from internal stores in the leaf or the hydrolysis of the conjugate ABA-glucose ester. These results implicate an extremely rapid de novo biosynthesis of ABA, mediated by a single gene, as the means by which angiosperm stomata respond to natural changes in VPD. © 2015 John Wiley & Sons Ltd.

  20. RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response.

    Directory of Open Access Journals (Sweden)

    Tao Zhang

    2014-10-01

    Full Text Available Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43 is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD. Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases.

  1. RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response

    Science.gov (United States)

    Zhang, Tao; Baldie, Gerard; Periz, Goran; Wang, Jiou

    2014-01-01

    Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases. PMID:25329970

  2. Transcriptional profiling of Petunia seedlings reveals candidate regulators of the cold stress response

    Directory of Open Access Journals (Sweden)

    Bei eLi

    2015-03-01

    Full Text Available Petunias are important ornamentals with the capacity for cold acclimation. So far, there is limited information concerning gene regulation and signaling pathways related to the cold stress response in petunias. A custom-designed petunia microarray representing 24816 genes was used to perform transcriptome profiling in petunia seedlings subjected to cold at 2°C for 0.5 h, 2 h, 24 h and 5 d. A total of 2071 transcripts displayed differential expression patterns under cold stress, of which 1149 were up-regulated and 922 were down-regulated. Gene ontology enrichment analysis demarcated related biological processes, suggesting a possible link between flavonoid metabolism and plant adaptation to low temperatures. Many novel stress-responsive regulators were revealed, suggesting that diverse regulatory pathways may exist in petunias in addition to the well-characterized CBF pathway. The expression changes of selected genes under cold and other abiotic stress conditions were confirmed by real-time RT-PCR. Furthermore, weighted gene co-expression network analysis divided the petunia genes on the array into 65 modules that showed high co-expression and identified stress-specific hub genes with high connectivity. Our identification of these transcriptional responses and groups of differentially expressed regulators will facilitate the functional dissection of the molecular mechanism in petunias responding to environment stresses and extend our ability to improve cold tolerance in plants.

  3. A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation.

    Science.gov (United States)

    Wu, Songlin; Wang, Pei; Xiao, Chen; Li, Zheng; Yang, Bing; Fu, Jieyang; Chen, Jing; Wan, Neng; Ma, Cong; Li, Maoteng; Yang, Xiangliang; Zhan, Yi

    2016-08-10

    Physiological processes such as metabolism, cell apoptosis and immune responses, must be strictly regulated to maintain their homeostasis and achieve their normal physiological functions. The speed with which bio-molecular homeostatic regulation occurs directly determines the ability of an organism to adapt to conditional changes. To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes was constructed using DNA origami nanotechnology. This nano-fingers device functioned in linked open and closed phases using two types of DNA tweezers, which were covalently coupled with aptamers that captured specific molecules when the tweezer arms were sufficiently close. Via this specific interaction mechanism, certain physiological processes could be simultaneously regulated from two directions by capturing one biofactor and releasing the other to enhance the regulatory capacity of the device. To validate the universal application of this device, regulation of the homeostasis of the blood coagulant thrombin was attempted using the nano-fingers device. It was successfully demonstrated that this nano-fingers device achieved coagulation buffering upon the input of fuel DNA. This nano-device could also be utilized to regulate the homeostasis of other types of bio-molecules.

  4. Regulation of Secondary Metabolism by the Velvet Complex Is Temperature-Responsive in Aspergillus

    Directory of Open Access Journals (Sweden)

    Abigail L. Lind

    2016-12-01

    Full Text Available Sensing and responding to environmental cues is critical to the lifestyle of filamentous fungi. How environmental variation influences fungi to produce a wide diversity of ecologically important secondary metabolites (SMs is not well understood. To address this question, we first examined changes in global gene expression of the opportunistic human pathogen, Aspergillus fumigatus, after exposure to different temperature conditions. We found that 11 of the 37 SM gene clusters in A. fumigatus were expressed at higher levels at 30° than at 37°. We next investigated the role of the light-responsive Velvet complex in environment-dependent gene expression by examining temperature-dependent transcription profiles in the absence of two key members of the Velvet protein complex, VeA and LaeA. We found that the 11 temperature-regulated SM gene clusters required VeA at 37° and LaeA at both 30 and 37° for wild-type levels of expression. Interestingly, four SM gene clusters were regulated by VeA at 37° but not at 30°, and two additional ones were regulated by VeA at both temperatures but were substantially less so at 30°, indicating that the role of VeA and, more generally of the Velvet complex, in the regulation of certain SM gene clusters is temperature-dependent. Our findings support the hypothesis that fungal secondary metabolism is regulated by an intertwined network of transcriptional regulators responsive to multiple environmental factors.

  5. DNA consensus sequence motif for binding response regulator PhoP, a virulence regulator of Mycobacterium tuberculosis.

    Science.gov (United States)

    He, Xiaoyuan; Wang, Shuishu

    2014-12-30

    Tuberculosis has reemerged as a serious threat to human health because of the increasing prevalence of drug-resistant strains and synergetic infection with HIV, prompting an urgent need for new and more efficient treatments. The PhoP-PhoR two-component system of Mycobacterium tuberculosis plays an important role in the virulence of the pathogen and thus represents a potential drug target. To study the mechanism of gene transcription regulation by response regulator PhoP, we identified a high-affinity DNA sequence for PhoP binding using systematic evolution of ligands by exponential enrichment. The sequence contains a direct repeat of two 7 bp motifs separated by a 4 bp spacer, TCACAGC(N4)TCACAGC. The specificity of the direct-repeat sequence for PhoP binding was confirmed by isothermal titration calorimetry and electrophoretic mobility shift assays. PhoP binds to the direct repeat as a dimer in a highly cooperative manner. We found many genes previously identified to be regulated by PhoP that contain the direct-repeat motif in their promoter sequences. Synthetic DNA fragments at the putative promoter-binding sites bind PhoP with variable affinity, which is related to the number of mismatches in the 7 bp motifs, the positions of the mismatches, and the spacer and flanking sequences. Phosphorylation of PhoP increases the affinity but does not change the specificity of DNA binding. Overall, our results confirm the direct-repeat sequence as the consensus motif for PhoP binding and thus pave the way for identification of PhoP directly regulated genes in different mycobacterial genomes.

  6. The MAP kinase substrate MKS1 is a regulator of plant defense responses

    DEFF Research Database (Denmark)

    Andreasson, Erik; Jenkins, Thomas; Brodersen, Peter

    2005-01-01

    Arabidopsis MAP kinase 4 (MPK4) functions as a regulator of pathogen defense responses, because it is required for both repression of salicylic acid (SA)-dependent resistance and for activation of jasmonate (JA)-dependent defense gene expression. To understand MPK4 signaling mechanisms, we used...

  7. Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling.

    Science.gov (United States)

    Toritsuka, M; Kimoto, S; Muraki, K; Kitagawa, M; Kishimoto, T; Sawa, A; Tanigaki, K

    2017-03-07

    Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.

  8. Study on the effectiveness of Responsive Aggression Regulation Therapy (Re-ART)

    NARCIS (Netherlands)

    Hoogsteder, L.M.; Kuijpers, N.; Stams, G.J.J.M.; van Horn, J.E.; Hendriks, J.; Wissink, I.B.

    2014-01-01

    This article describes a pre-test/post-test quasi-experimental study of the effectiveness of Responsive Aggression Regulation Therapy (Re-ART), a Dutch intervention for 16- to 21-year-old juveniles. Re-ART aims to decrease severe aggressive behavior using a cognitive behavioral approach combined

  9. Coupling of protein localization and cell movements by a dynamically localized response regulator in Myxococcus xanthus

    DEFF Research Database (Denmark)

    Leonardy, Simone; Freymark, Gerald; Hebener, Sabrina

    2007-01-01

    Myxococcus xanthus cells harbor two motility machineries, type IV pili (Tfp) and the A-engine. During reversals, the two machineries switch polarity synchronously. We present a mechanism that synchronizes this polarity switching. We identify the required for motility response regulator (Rom...

  10. Neuroendocrine modulation of the inflammatory response in common carp: adrenaline regulates leukocyte profile and activity

    NARCIS (Netherlands)

    Kepka, M.; Verburg-van Kemenade, B.M.L.; Chadzinska, M.K.

    2013-01-01

    Inflammatory responses have to be carefully controlled, as high concentrations and/or prolonged action of inflammation-related molecules (e.g. reactive oxygen species, nitric oxide and pro-inflammatory cytokines) can be detrimental to host tissue and organs. One of the potential regulators of the in

  11. Conservation of the response regulator gene gacA in Pseudomonas species

    NARCIS (Netherlands)

    Souza, J.T.; Mazzola, M.; Raaijmakers, J.M.

    2003-01-01

    The response regulator gene gacA influences the production of several secondary metabolites in both pathogenic and beneficial Pseudomonas spp. In this study, we developed primers and a probe for the gacA gene of Pseudomonas species and sequenced a 425 bp fragment of gacA from ten Pseudomonas strains

  12. Study on the effectiveness of Responsive Aggression Regulation Therapy (Re-ART)

    NARCIS (Netherlands)

    Hoogsteder, L.M.; Kuijpers, N.; Stams, G.J.J.M.; van Horn, J.E.; Hendriks, J.; Wissink, I.B.

    2014-01-01

    This article describes a pre-test/post-test quasi-experimental study of the effectiveness of Responsive Aggression Regulation Therapy (Re-ART), a Dutch intervention for 16- to 21-year-old juveniles. Re-ART aims to decrease severe aggressive behavior using a cognitive behavioral approach combined wit

  13. CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses.

    Science.gov (United States)

    Lai, Alvina Grace; Doherty, Colleen J; Mueller-Roeber, Bernd; Kay, Steve A; Schippers, Jos H M; Dijkwel, Paul P

    2012-10-16

    Organisms have evolved endogenous biological clocks as internal timekeepers to coordinate metabolic processes with the external environment. Here, we seek to understand the mechanism of synchrony between the oscillator and products of metabolism known as Reactive Oxygen Species (ROS) in Arabidopsis thaliana. ROS-responsive genes exhibit a time-of-day-specific phase of expression under diurnal and circadian conditions, implying a role of the circadian clock in transcriptional regulation of these genes. Hydrogen peroxide production and scavenging also display time-of-day phases. Mutations in the core-clock regulator, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress. Mis-expression of EARLY FLOWERING 3, LUX ARRHYTHMO, and TIMING OF CAB EXPRESSION 1 affect ROS production and transcription, indicating a global effect of the clock on the ROS network. We propose CCA1 as a master regulator of ROS homeostasis through association with the Evening Element in promoters of ROS genes in vivo to coordinate time-dependent responses to oxidative stress. We also find that ROS functions as an input signal that affects the transcriptional output of the clock, revealing an important link between ROS signaling and circadian output. Temporal coordination of ROS signaling by CCA1 and the reciprocal control of circadian output by ROS reveal a mechanistic link that allows plants to master oxidative stress responses.

  14. Transcript-specific translational regulation in the unfolded protein response of Saccharomyces cerevisiae.

    Science.gov (United States)

    Payne, Tom; Hanfrey, Colin; Bishop, Amy L; Michael, Anthony J; Avery, Simon V; Archer, David B

    2008-02-20

    Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes stress and induces the unfolded protein response (UPR). Genome-wide analysis of translational regulation in response to the UPR-inducing agent dithiothreitol in Saccharomyces cerevisiae is reported. Microarray analysis, confirmed using qRT-PCR, identified transcript-specific translational regulation. Transcripts with functions in ribosomal biogenesis and assembly were translationally repressed. In contrast, mRNAs from known UPR genes, encoding the UPR transcription factor Hac1p, the ER-oxidoreductase Ero1p and the ER-associated protein degradation (ERAD) protein Der1p, were enriched in polysomal fractions, indicating translational up-regulation. Splicing of HAC1 mRNA is shown to be required for efficient ribosomal loading.

  15. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL

    Science.gov (United States)

    Choi, Soo-Ho; Gonen, Ayelet; Diehl, Cody J; Kim, Jungsu; Almazan, Felicidad; Witztum, Joseph L; Miller, Yury I

    2015-01-01

    Adaptive immunity, which plays an important role in the development of atherosclerosis, is mediated by major histocompatibility complex (MHC)-dependent antigen presentation. In atherosclerotic lesions, macrophages constitute an important class of antigen-presenting cells that activate adaptive immune responses to oxidized low-density lipoprotein (OxLDL). It has been reported that autophagy regulates adaptive immune responses by enhancing antigen presentation to MHC class II (MHC-II). In a previous study, we have demonstrated that SYK (spleen tyrosine kinase) regulates generation of reactive oxygen species (ROS) and activation of MAPK8/JNK1 in macrophages. Because ROS and MAPK8 are known to regulate autophagy, in this study we investigated the role of SYK in autophagy, MHC-II expression and adaptive immune response to OxLDL. We demonstrate that OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages. Gene knockout and pharmacological inhibitors of NOX2 and MAPK8 reduced OxLDL-induced autophagy. Using bone marrow-derived macrophages isolated from wild-type and myeloid-specific SYK knockout mice, we demonstrate that SYK regulates OxLDL-induced ROS generation, MAPK8 activation, BECN1-BCL2 dissociation, autophagosome formation and presentation of OxLDL-derived antigens to CD4+ T cells. ldlr−/− syk−/− mice fed a high-fat diet produced lower levels of IgG to malondialdehyde (MDA)-LDL, malondialdehyde-acetaldehyde (MAA)-LDL, and OxLDL compared to ldlr−/− mice. These results provide new insights into the mechanisms by which SYK regulates MHC-II expression via autophagy in macrophages and may contribute to regulation of adaptive immune responses in atherosclerosis. PMID:25946330

  16. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL.

    Science.gov (United States)

    Choi, Soo-Ho; Gonen, Ayelet; Diehl, Cody J; Kim, Jungsu; Almazan, Felicidad; Witztum, Joseph L; Miller, Yury I

    2015-01-01

    Adaptive immunity, which plays an important role in the development of atherosclerosis, is mediated by major histocompatibility complex (MHC)-dependent antigen presentation. In atherosclerotic lesions, macrophages constitute an important class of antigen-presenting cells that activate adaptive immune responses to oxidized low-density lipoprotein (OxLDL). It has been reported that autophagy regulates adaptive immune responses by enhancing antigen presentation to MHC class II (MHC-II). In a previous study, we have demonstrated that SYK (spleen tyrosine kinase) regulates generation of reactive oxygen species (ROS) and activation of MAPK8/JNK1 in macrophages. Because ROS and MAPK8 are known to regulate autophagy, in this study we investigated the role of SYK in autophagy, MHC-II expression and adaptive immune response to OxLDL. We demonstrate that OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages. Gene knockout and pharmacological inhibitors of NOX2 and MAPK8 reduced OxLDL-induced autophagy. Using bone marrow-derived macrophages isolated from wild-type and myeloid-specific SYK knockout mice, we demonstrate that SYK regulates OxLDL-induced ROS generation, MAPK8 activation, BECN1-BCL2 dissociation, autophagosome formation and presentation of OxLDL-derived antigens to CD4(+) T cells. ldlr(-/-) syk(-/-) mice fed a high-fat diet produced lower levels of IgG to malondialdehyde (MDA)-LDL, malondialdehyde-acetaldehyde (MAA)-LDL, and OxLDL compared to ldlr(-/-) mice. These results provide new insights into the mechanisms by which SYK regulates MHC-II expression via autophagy in macrophages and may contribute to regulation of adaptive immune responses in atherosclerosis.

  17. The small ethylene response factor ERF96 is involved in the regulation of the abscisic acid response in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Xiaoping eWang

    2015-11-01

    Full Text Available Ethylene regulates many aspects of plant growth and development including seed germination, leaf senescence, and fruit ripening, and of plant responses to environmental stimuli including both biotic and abiotic stresses. Ethylene Response Factors (ERFs are plant-specific transcription factors and are a subfamily of the AP2 (APETALA2/ERF transcription factor family. The function of many members in this large gene family remains largely unknown. ERF96, a member of the Group IX ERF family transcription factors, has recently been shown to be a transcriptional activator that is involved in plant defense response in Arabidopsis. Here we provide evidence that ERF96 is a positive regulator of abscisic acid (ABA responses. Bioinformatics analysis indicated that there are a total four small ERFs in Arabidopsis including ERF95, ERF96, ERF97 and ERF98, and that ERF96 forms a cluster with ERF95 and ERF97. By using quantitative RT-PCR, we found that ERF96 is expressed in all tissues and organs examined except roots, with relatively high expression in flowers and seeds. Results from the protoplast transfection assay results indicated that the EDLL motif-containing C-terminal domain is responsible for ERF96’s transcriptional activity. Although loss-of-function mutant of ERF96 was morphologically similar to wild type plants, transgenic plants overexpressing ERF96 had smaller rosette size and were delayed in flowering time. In ABA sensitivity assays, we found that ERF96 overexpression plants were hypersensitive to ABA in terms of ABA inhibition of seed germination, early seedling development and root elongation. Consistent with these observations, elevated transcript levels of some ABA-responsive genes including RD29A, ABI5, ABF3, ABF4, P5CS and COR15A were observed in the transgenic plants in the presence of ABA. However, in the absence of ABA treatment, the transcript levels of these ABA-responsive genes remained largely unchanged. Our experiments also showed

  18. Interaction of a plant pseudo-response regulator with a calmodulin-like protein

    Energy Technology Data Exchange (ETDEWEB)

    Perochon, Alexandre; Dieterle, Stefan; Pouzet, Cecile; Aldon, Didier; Galaud, Jean-Philippe [UMR 5546 CNRS/Universite Toulouse 3, Pole de Biotechnologie vegetale, BP 42617 Auzeville, 31326 Castanet-Tolosan cedex (France); Ranty, Benoit, E-mail: ranty@scsv.ups-tlse.fr [UMR 5546 CNRS/Universite Toulouse 3, Pole de Biotechnologie vegetale, BP 42617 Auzeville, 31326 Castanet-Tolosan cedex (France)

    2010-08-06

    Research highlights: {yields} The pseudo-response regulator PRR2 specifically binds CML9, a calmodulin-like protein {yields} The interaction is confirmed in plant cell nuclei {yields} The interaction requires an intact PRR2 protein. -- Abstract: Calmodulin (CaM) plays a crucial role in the regulation of diverse cellular processes by modulating the activities of numerous target proteins. Plants possess an extended CaM family including numerous CaM-like proteins (CMLs), most of which appear to be unique to plants. We previously demonstrated a role for CML9 in abiotic stress tolerance and seed germination in Arabidopsis thaliana. We report here the isolation of PRR2, a pseudo-response regulator as a CML9 interacting protein by screening an expression library prepared from Arabidopsis seedlings with CML9 as bait in a yeast two-hybrid system. PRR2 is similar to the response regulators of the two-component system, but lacks the invariant residue required for phosphorylation by which response regulators switch their output response, suggesting the existence of alternative regulatory mechanisms. PRR2 was found to bind CML9 and closely related CMLs but not a canonical CaM. Mapping analyses indicate that an almost complete form of PRR2 is required for interaction with CML9, suggesting a recognition mode different from the classical CaM-target peptide complex. PRR2 contains several features that are typical of transcription factors, including a GARP DNA recognition domain, a Pro-rich region and a Golden C-terminal box. PRR2 and CML9 as fusion proteins with fluorescent tags co-localized in the nucleus of plant cells, and their interaction in the nuclear compartment was validated in planta by using a fluorophore-tagged protein interaction assay. These findings suggest that binding of PRR2 to CML9 may be an important mechanism to modulate the physiological role of this transcription factor in plants.

  19. The Unfolded Protein Response Regulates Uterine Myocyte Antioxidant Responsiveness During Pregnancy.

    Science.gov (United States)

    Ramnarayanan, Saiprasad; Kyathanahalli, Chandrashekara; Ingles, Judith; Park-York, MieJung; Jeyasuria, Pancharatnam; Condon, Jennifer C

    2016-12-01

    There is considerable evidence that implicates oxidative stress in the pathophysiology of human pregnancy complications. However, the role and the mechanism of maintaining an antioxidant prosurvival uterine environment during normal pregnancy is largely unresolved. Herein we report that the highly active uterine unfolded protein response plays a key role in promoting antioxidant activity in the uterine myocyte across gestation. The unfolded protein response (UPR) senses the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and activates a signaling network that consists of the transmembrane protein kinase eukaryotic translation initiation factor 2 alpha kinase 3/PKR-like-ER kinase (EIF2AK3), which acts to decrease protein translation levels, allowing for a lowered need for protein folding during periods of ER stress. However, independent of its translational regulatory capacity, EIF2AK3-dependent signals elicit the activation of the transcription factor, nuclear factor erythroid 2-like 2 (NFE2L2) in response to oxidative stress. NFE2L2 binds to antioxidant response elements in the promoters of a variety of antioxidant genes that minimize the opportunities for generation of reactive oxygen intermediates. Our analysis demonstrates that in the absence of EIF2AK3, the uterine myocyte experiences increased levels of reactive oxygen species due to decreased NFE2L2 activation. Elevated levels of intracellular reactive oxygen species were observed in the EIF2AK3 null cells, and this was associated with the onset of apoptotic cell death. These findings confirm the prosurvival and antioxidant role of UPR-mediated EIF2AK3 activation in the context of the human uterine myocyte.

  20. Short Communication: In vitro response of papaya (Carica papaya to plant growth regulators

    Directory of Open Access Journals (Sweden)

    JAIME A. TEIXEIRA DA SILVA

    2016-01-01

    Full Text Available Abstract. Teixeira da Silva JA. 2016. In vitro response of papaya (Carica papaya to multiple plant growth regulators. Nusantara Bioscience 8: 77-82. The use of plant growth regulators (PGRs in papaya (Carica papaya L. tissue culture is essential for tissue and organ culture in vitro. In this study, in a bid to expand the information available on the response to PGRs, a wide range of PGRs, roughly divided into four groups (auxins, cytokinins, alternative PGRs, growth inhibitors and retardants was tested. Among them, the auxins 2,4-D, dicamba and picloram formed most callus (hard and soft. Callus inductions by chitosan and coconut water are novel results for papaya. Shoots only formed in response to BA and TDZ, but TDZ-induced shoots were fasciated and/or hyperhydric. These results provide novel perspectives for papaya researchers who may have recalcitrant genotypes or tissues that are unresponsive in vitro.

  1. The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses

    DEFF Research Database (Denmark)

    Marczynska, Joanna; Ozga, Aleksandra; Wlodarczyk, Agnieszka

    2014-01-01

    cells. Shedding is largely attributed to a family of a disintegrin and metalloprotease domain (ADAM) metalloproteases, including ADAM17. Although ADAM17 is well known to contribute to the innate immune response, mainly by releasing TNF-α, much less is known about whether/how this metalloprotease...... regulates adaptive immunity. To determine whether ADAM17 contributes to regulating adaptive immune responses, we took advantage of ADAM17 hypomorphic (ADAM17(ex/ex)) mice, in which ADAM17 expression is reduced by 90-95% compared with wild-type littermates. In this study, we show that that ADAM17 deficiency...... suggest a functional link between ADAM17 and ICOSL in controlling adaptive immune responses....

  2. ABOUT SOME FEATURES OF LEGAL REGULATION OF THE DISCIPLINARY RESPONSIBILITY UNDER NEW ECONOMIC POLICY

    Directory of Open Access Journals (Sweden)

    Indira Abdulkhakovna Shakirova

    2016-04-01

    Full Text Available Article is devoted to the features of the developing separate kinds of disciplinary liability in the period of new economic policy. Some features of legislative registration of a disciplinary responsibility in days of new economic policy as during the specified period there was a formation of separate types of this responsibility which treated are analyzed: disciplinary responsibility on internal regulations, disciplinary responsibility on subordination and disciplinary responsibility of employees according to the statutes on discipline and special provisions as a special type of disciplinary responsibility on subordination. The features of legal regulation of disciplinary responsibility considered in article were of great importance in further development of institute of a disciplinary liability and the legislation on a disciplinary liability.The purpose is on the basis of new achievements of legal science to comprehend process of disciplinary liability institute development.Method or methodology of work: the modern methods of learning and special historical, comparative and legal methods were used.Results: scientific analysis of theoretical, historical and legal sources, determining the peculiarity and the content of disciplinary liability institute.Application of results: conclusions achieved as a result of scientific research can find practical application in law-making activities of governmental institutions.

  3. Ethylene response factor 6 is a regulator of reactive oxygen species signaling in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Nasser Sewelam

    Full Text Available Reactive oxygen species (ROS are produced in plant cells in response to diverse biotic and abiotic stresses as well as during normal growth and development. Although a large number of transcription factor (TF genes are up- or down-regulated by ROS, currently very little is known about the functions of these TFs during oxidative stress. In this work, we examined the role of ERF6 (ETHYLENE RESPONSE FACTOR6, an AP2/ERF domain-containing TF, during oxidative stress responses in Arabidopsis. Mutant analyses showed that NADPH oxidase (RbohD and calcium signaling are required for ROS-responsive expression of ERF6. erf6 insertion mutant plants showed reduced growth and increased H2O2 and anthocyanin levels. Expression analyses of selected ROS-responsive genes during oxidative stress identified several differentially expressed genes in the erf6 mutant. In particular, a number of ROS responsive genes, such as ZAT12, HSFs, WRKYs, MAPKs, RBOHs, DHAR1, APX4, and CAT1 were more strongly induced by H2O2 in erf6 plants than in wild-type. In contrast, MDAR3, CAT3, VTC2 and EX1 showed reduced expression levels in the erf6 mutant. Taken together, our results indicate that ERF6 plays an important role as a positive antioxidant regulator during plant growth and in response to biotic and abiotic stresses.

  4. Regulating the ethylene response of a plant by modulation of F-box proteins

    Science.gov (United States)

    Guo, Hongwei [Beijing, CN; Ecker, Joseph R [Carlsbad, CA

    2014-01-07

    The relationship between F-box proteins and proteins invovled in the ethylene response in plants is described. In particular, F-box proteins may bind to proteins involved in the ethylene response and target them for degradation by the ubiquitin/proteasome pathway. The transcription factor EIN3 is a key transcription factor mediating ethylne-regulated gene expression and morphological responses. EIN3 is degraded through a ubiquitin/proteasome pathway mediated by F-box proteins EBF1 and EBF2. The link between F-box proteins and the ethylene response is a key step in modulating or regulating the response of a plant to ethylene. Described herein are transgenic plants having an altered sensitivity to ethylene, and methods for making transgenic plant haing an althered sensitivity to ethylene by modulating the level of activity of F-box proteins. Methods of altering the ethylene response in a plant by modulating the activity or expression of an F-box protein are described. Also described are methods of identifying compounds that modulate the ethylene response in plants by modulating the level of F-box protein expression or activity.

  5. Glutamate dehydrogenase and glutamine synthetase are regulated in response to nitrogen availability in Myocbacterium smegmatis

    Directory of Open Access Journals (Sweden)

    van Helden Paul

    2010-05-01

    Full Text Available Abstract Background The assimilation of nitrogen is an essential process in all prokaryotes, yet a relatively limited amount of information is available on nitrogen metabolism in the mycobacteria. The physiological role and pathogenic properties of glutamine synthetase (GS have been extensively investigated in Mycobacterium tuberculosis. However, little is known about this enzyme in other mycobacterial species, or the role of an additional nitrogen assimilatory pathway via glutamate dehydrogenase (GDH, in the mycobacteria as a whole. We investigated specific enzyme activity and transcription of GS and as well as both possible isoforms of GDH (NAD+- and NADP+-specific GDH under varying conditions of nitrogen availability in Mycobacterium smegmatis as a model for the mycobacteria. Results It was found that the specific activity of the aminating NADP+-GDH reaction and the deaminating NAD+-GDH reaction did not change appreciably in response to nitrogen availability. However, GS activity as well as the deaminating NADP+-GDH and aminating NAD+-GDH reactions were indeed significantly altered in response to exogenous nitrogen concentrations. Transcription of genes encoding for GS and the GDH isoforms were also found to be regulated under our experimental conditions. Conclusions The physiological role and regulation of GS in M. smegmatis was similar to that which has been described for other mycobacteria, however, in our study the regulation of both NADP+- and NAD+-GDH specific activity in M. smegmatis appeared to be different to that of other Actinomycetales. It was found that NAD+-GDH played an important role in nitrogen assimilation rather than glutamate catabolism as was previously thought, and is it's activity appeared to be regulated in response to nitrogen availability. Transcription of the genes encoding for NAD+-GDH enzymes seem to be regulated in M. smegmatis under the conditions tested and may contribute to the changes in enzyme activity

  6. Capsicum annuum WRKY transcription factor d (CaWRKYd) regulates hypersensitive response and defense response upon Tobacco mosaic virus infection.

    Science.gov (United States)

    Huh, Sung Un; Choi, La Mee; Lee, Gil-Je; Kim, Young Jin; Paek, Kyung-Hee

    2012-12-01

    WRKY transcription factors regulate biotic, abiotic, and developmental processes. In terms of plant defense, WRKY factors have important roles as positive and negative regulators via transcriptional regulation or protein-protein interaction. Here, we report the characterization of the gene encoding Capsicum annuum WRKY transcription factor d (CaWRKYd) isolated from microarray analysis in the Tobacco mosaic virus (TMV)-P(0)-inoculated hot pepper plants. CaWRKYd belongs to the WRKY IIa group, a very small clade in the WRKY subfamily, and WRKY IIa group has positive/negative regulatory roles in Arabidopsis and rice. CaWRKYd transcripts were induced by various plant defense-related hormone treatments and TMV-P(0) inoculation. Silencing of CaWRKYd affected TMV-P(0)-mediated hypersensitive response (HR) cell death and accumulation of TMV-P(0) coat protein in local and systemic leaves. Furthermore, expression of some pathogenesis-related (PR) genes and HR-related genes was reduced in the CaWRKYd-silenced plants compared with TRV2 vector control plants upon TMV-P(0) inoculation. CaWRKYd was confirmed to bind to the W-box. Thus CaWRKYd is a newly identified Capsicum annuum WRKY transcription factor that appears to be involved in TMV-P(0)-mediated HR cell death by regulating downstream gene expression.

  7. Zinc-regulated DNA binding of the yeast Zap1 zinc-responsive activator.

    Directory of Open Access Journals (Sweden)

    Avery G Frey

    Full Text Available The Zap1 transcription factor of Saccharomyces cerevisiae plays a central role in zinc homeostasis by controlling the expression of genes involved in zinc metabolism. Zap1 is active in zinc-limited cells and repressed in replete cells. At the transcriptional level, Zap1 controls its own expression via positive autoregulation. In addition, Zap1's two activation domains are regulated independently of each other by zinc binding directly to those regions and repressing activation function. In this report, we show that Zap1 DNA binding is also inhibited by zinc. DMS footprinting showed that Zap1 target gene promoter occupancy is regulated with or without transcriptional autoregulation. These results were confirmed using chromatin immunoprecipitation. Zinc regulation of DNA binding activity mapped to the DNA binding domain indicating other parts of Zap1 are unnecessary for this control. Overexpression of Zap1 overrode DNA binding regulation and resulted in constitutive promoter occupancy. Under these conditions of constitutive binding, both the zinc dose response of Zap1 activity and cellular zinc accumulation were altered suggesting the importance of DNA binding control to zinc homeostasis. Thus, our results indicated that zinc regulates Zap1 activity post-translationally via three independent mechanisms, all of which contribute to the overall zinc responsiveness of Zap1.

  8. CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2

    Science.gov (United States)

    Kigoshi, Yu; Fukuda, Tomomi; Endo, Tomoyuki; Hayasaka, Nami; Iemura, Shun-ichiro; Natsume, Toru; Tsuruta, Fuminori; Chiba, Tomoki

    2015-01-01

    Nrf2 is the pre-dominant transcription activator responsible for coordinated up-regulation of ARE-driven antioxidant and detoxification genes. The activity of Nrf2 is tightly regulated at basal levels through its ubiquitination by Cul3-Keap1 and consequential degradation. Upon exposure to stress, the Cul3-Keap1 ligase is inhibited, leading to Nrf2 stabilization and activation. Here we describe CACUL1/CAC1 as a positive regulator of the Nrf2 pathway. We found that CACUL1 is up-regulated by Nrf2-activating oxidative stresses in cells and in mice. The association of CACUL1 with the Cul3-Keap1 complex led to a decrease in Nrf2 ubiquitination levels at non-stressed as well as stressed conditions, and sensitized cells for higher Nrf2 activation. Furthermore, CACUL1 knock-down led to a decrease in Nrf2 activity and cell viability under stress. Our results show that CACUL1 is a regulator of Nrf2 ubiquitination, adding another regulatory layer to the Nrf2 antioxidant stress response. PMID:26238671

  9. Shp2 Deficiency Impairs the Inflammatory Response Against Haemophilus influenzae by Regulating Macrophage Polarization.

    Science.gov (United States)

    Zhao, Lifang; Xia, Jingyan; Li, Tiantian; Zhou, Hui; Ouyang, Wei; Hong, Zhuping; Ke, Yuehai; Qian, Jing; Xu, Feng

    2016-08-15

    Macrophages can polarize and differentiate to regulate initiation, development, and cessation of inflammation during pulmonary infection with nontypeable Haemophilus influenzae (NTHi). However, the underlying molecular mechanisms driving macrophage phenotypic differentiation are largely unclear. Our study investigated the role of Shp2, a Src homology 2 domain-containing phosphatase, in the regulation of pulmonary inflammation and bacterial clearance. Shp2 levels were increased upon NTHi stimulation. Selective inhibition of Shp2 in mice led to an attenuated inflammatory response by skewing macrophages toward alternatively activated macrophage (M2) polarization. Upon pulmonary NTHi infection, Shp2(-/-) mice, in which the gene encoding Shp2 in monocytes/macrophages was deleted, showed an impaired inflammatory response and decreased antibacterial ability, compared with wild-type controls. In vitro data demonstrated that Shp2 regulated activated macrophage (M1) gene expression via activation of p65-nuclear factor-κB signaling, independent of p38 and extracellular regulated kinase-mitogen-activated proteins kinase signaling pathways. Taken together, our study indicates that Shp2 is required to orchestrate macrophage function and regulate host innate immunity against pulmonary bacterial infection.

  10. Genotype-specific regulation of cold-responsive genes in cypress (Cupressus sempervirens L.).

    Science.gov (United States)

    Pedron, Luca; Baldi, Paolo; Hietala, Ari M; La Porta, Nicola

    2009-05-15

    Cold acclimation in plants involves a very complex molecular response, with the regulation of many different genes and metabolic pathways. In this work fifteen cypress (Cupressus sempervirens) genes putatively regulated during cold exposure were isolated and their expression was studied in five cypress genotypes, along 15 days of treatment at 3 degrees C. Treated samples of shoots were collected from four year old cypress seedlings and a subtractive hybridization approach (PCR-Select) was performed after mRNA extraction. Fifteen genes were selected according to sequence similarities after a GenBank search and their expression was studied using Real-time PCR. Among these genes, five (ELIP, aquaporin, dehydrin and two cold-induced proteins) and four (oleosin, chlorophyll a/b-binding protein, oxidoreductase and rubisco activase) resulted respectively up- and down-regulated by the treatment in all tested genotypes. Finally, three genes (metal-binding protein, nodulin-like protein and beta-amylase) showed remarkable different pattern among genotypes. A consistent relationship was found between the cold regulation of the genes studied and their putative function, suggesting the existence of different cold response pathways in cypress. The possible roles of the low temperature-regulated sequences and of the individual expression differences during cypress cold acclimation are proposed and discussed.

  11. A Capacitor-Free, Fast Transient Response Linear Voltage Regulator In a 180nm CMOS

    DEFF Research Database (Denmark)

    Deleuran, Alexander N.; Lindbjerg, Nicklas; Pedersen, Martin K.

    2015-01-01

    A 1.8 V capacitor-free linear regulator with fast transient response based on a new topology with a fast and slow regulation loop is presented. The design has been laid out and simulated in a 0.18 µm CMOS process. The design has a low component count and is tailored for system-on-chip integration....... A current step load from 0-50 mA with a rise time of 1 µs results in an undershoot in the output voltage of 140 mV for a period of 39 ns. The regulator sources up to 50 mA current load.......A 1.8 V capacitor-free linear regulator with fast transient response based on a new topology with a fast and slow regulation loop is presented. The design has been laid out and simulated in a 0.18 µm CMOS process. The design has a low component count and is tailored for system-on-chip integration...

  12. FurA contributes to the oxidative stress response regulation of Mycobacterium avium ssp. paratuberculosis.

    Science.gov (United States)

    Eckelt, Elke; Meißner, Thorsten; Meens, Jochen; Laarmann, Kristin; Nerlich, Andreas; Jarek, Michael; Weiss, Siegfried; Gerlach, Gerald-F; Goethe, Ralph

    2015-01-01

    The ferric uptake regulator A (FurA) is known to be involved in iron homeostasis and stress response in many bacteria. In mycobacteria the precise role of FurA is still unclear. In the presented study, we addressed the functional role of FurA in the ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) by construction of a furA deletion strain (MAPΔfurA). RNA deep sequencing revealed that the FurA regulon consists of repressed and activated genes associated to stress response or intracellular survival. Not a single gene related to metal homeostasis was affected by furA deletion. A decisive role of FurA during intracellular survival in macrophages was shown by significantly enhanced survival of MAPΔfurA compared to the wildtype, indicating that a principal task of mycobacterial FurA is oxidative stress response regulation in macrophages. This resistance was not associated with altered survival of mice after long term infection with MAP. Our results demonstrate for the first time, that mycobacterial FurA is not involved in the regulation of iron homeostasis. However, they provide strong evidence that FurA contributes to intracellular survival as an oxidative stress sensing regulator.

  13. Adolescent RSA responses during an anger discussion task: Relations to emotion regulation and adjustment.

    Science.gov (United States)

    Cui, Lixian; Morris, Amanda Sheffield; Harrist, Amanda W; Larzelere, Robert E; Criss, Michael M; Houltberg, Benjamin J

    2015-06-01

    The current study examined associations between adolescent respiratory sinus arrhythmia (RSA) during an angry event discussion task and adolescents' emotion regulation and adjustment. Data were collected from 206 adolescents (10-18 years of age, M age = 13.37). Electrocardiogram (ECG) and respiration data were collected from adolescents, and RSA values and respiration rates were computed. Adolescents reported on their own emotion regulation, prosocial behavior, and aggressive behavior. Multilevel latent growth modeling was employed to capture RSA responses across time (i.e., linear and quadratic changes; time course approach), and adolescent emotion regulation and adjustment variables were included in the model to test their links to RSA responses. Results indicated that high RSA baseline was associated with more adolescent prosocial behavior. A pattern of initial RSA decreases (RSA suppression) in response to angry event recall and subsequent RSA increases (RSA rebound) were related to better anger and sadness regulation and more prosocial behavior. However, RSA was not significantly linked to adolescent aggressive behavior. We also compared the time course approach with the conventional linear approach and found that the time course approach provided more meaningful and rich information. The implications of adaptive RSA change patterns are discussed.

  14. Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants.

    Science.gov (United States)

    Sirohi, Gunjan; Pandey, Bipin K; Deveshwar, Priyanka; Giri, Jitender

    2016-03-01

    Diverse environmental stimuli largely affect the ionic balance of soil, which have a direct effect on growth and crop yield. Details are fast emerging on the genetic/molecular regulators, at whole-genome levels, of plant responses to mineral deficiencies in model and crop plants. These genetic regulators determine the root architecture and physiological adaptations for better uptake and utilization of minerals from soil. Recent evidence also shows the potential roles of epigenetic mechanisms in gene regulation, driven by minerals imbalance. Mineral deficiency or sufficiency leads to developmental plasticity in plants for adaptation, which is preceded by a change in the pattern of gene expression. Notably, such changes at molecular levels are also influenced by altered chromatin structure and methylation patterns, or involvement of other epigenetic components. Interestingly, many of the changes induced by mineral deficiency are also inheritable in the form of epigenetic memory. Unravelling these mechanisms in response to mineral deficiency would further advance our understanding of this complex plant response. Further studies on such approaches may serve as an exciting interaction model of epigenetic and genetic regulations of mineral homeostasis in plants and designing strategies for crop improvement.

  15. 25 CFR Appendix A to Subpart D - Cultural Resource and Environmental Requirements for the IRR Program

    Science.gov (United States)

    2010-04-01

    .... 10. 7 U.S.C. 4201, Farmland Protection Policy Act. 11. 50 CFR part 402, Endangered Species Act regulations. 12. 7 CFR part 658, Farmland Protection Policy Act regulations. 13. 40 CFR part 93, Air Quality.... 23 CFR part 771, Environmental Impact and Related Procedures. 15. 23 CFR part 772, Procedures...

  16. With great control comes great responsibility: the relationship between perceived academic control, student responsibility, and self-regulation.

    Science.gov (United States)

    Fishman, Evan J

    2014-12-01

    Students' perceived control over academic outcomes has been linked to their use of self-regulated strategies. However, students' sense of responsibility, or internal commitment to produce such outcomes, has not often been considered in this relationship. The purpose of this study was to examine the relationships between perceived academic control (PAC), student responsibility (SR), and knowledge building (KB). Participants were 152 undergraduate students enrolled in an educational technology course. An exploratory factor analysis was conducted to demonstrate the distinction between the PAC and SR constructs. A series of regression analyses were conducted to address the research hypotheses, and a bootstrap test was used to assess the mediating role of SR in the relationship between the PAC variables and KB. Initial evidence regarding the uniqueness of the PAC and SR constructs was provided. PAC (both primary control and secondary control [SC]) were positively and significantly related to SR. KB was positively and significantly related to SR, as was SC. Additionally, SR partially mediated the relationship between the PAC variables and KB. The findings showed that those who perceived the capability to achieve academic outcomes were more likely to feel internally obligated to produce such outcomes. The same was true for students who perceived the capability to psychologically adjust to academic situations. The results also demonstrated that students' sense of responsibility for academic outcomes played a partially mediating role in the relationship between their perceptions of control and reported use of self-regulated behaviour. © 2014 The British Psychological Society.

  17. HAUSP-nucleolin interaction is regulated by p53-Mdm2 complex in response to DNA damage response.

    Science.gov (United States)

    Lim, Key-Hwan; Park, Jang-Joon; Gu, Bon-Hee; Kim, Jin-Ock; Park, Sang Gyu; Baek, Kwang-Hyun

    2015-08-04

    HAUSP (herpes virus-associated ubiquitin specific protease, known as ubiquitin specific protease 7), one of DUBs, regulates the dynamics of the p53 and Mdm2 network in response to DNA damage by deubiquitinating both p53 and its E3 ubiquitin ligase, Mdm2. Its concerted action increases the level of functional p53 by preventing proteasome-dependent degradation of p53. However, the protein substrates that are targeted by HAUSP to mediate DNA damage responses in the context of the HAUSP-p53-Mdm2 complex are not fully identified. Here, we identified nucleolin as a new substrate for HAUSP by proteomic analysis. Nucleolin has two HAUSP binding sites in its N- and C-terminal regions, and the mutation of HAUSP interacting peptides on nucleolin disrupts their interaction and it leads to the increased level of nucleolin ubiquitination. In addition, HAUSP regulates the stability of nucleolin by removing ubiquitin from nucleolin. Nucleolin exists as a component of the HAUSP-p53-Mdm2 complex, and both Mdm2 and p53 are required for the interaction between HAUSP and nucleolin. Importantly, the irradiation increases the HAUSP-nucleolin interaction, leading to nucleolin stabilization significantly. Taken together, this study reveals a new component of the HAUSP-p53-Mdm2 complex that governs dynamic cellular responses to DNA damage.

  18. Regulation of reactionary dentin formation by odontoblasts in response to polymicrobial invasion of dentin matrix

    Science.gov (United States)

    Charadram, Nattida; Farahani, Ramin M; Harty, Derek; Rathsam, Catherine; Swain, Michael V; Hunter, Neil

    2011-01-01

    Odontoblast synthesis of dentin proceeds through discrete but overlapping phases characterized by formation of a patterned organic matrix followed by remodelling and active mineralization. Microbial invasion of dentin in caries triggers an adaptive response by odontoblasts, culminating in formation of a structurally altered reactionary dentin, marked by biochemical and architectonic modifications including diminished tubularity. Scanning electron microscopy of the collagen framework in reactionary dentin revealed a radically modified yet highly organized meshwork as indicated by fractal and lacunarity analyses. Immuno-gold labelling demonstrated increased density and regular spatial distribution of dentin sialoprotein (DSP) in reactionary dentin. DSP contributes putative hydroxyapatite nucleation sites on the collagen scaffold. To further dissect the formation of this altered dentin matrix, the associated enzymatic machinery was investigated. Analysis of extracted dentin matrix indicated increased activity of matrix metalloproteinase-2 (MMP-2) in the reactionary zone referenced to physiologic dentin. Likewise, gene expression analysis of micro-dissected odontoblast layer revealed up-regulation of MMP-2. Parallel up-regulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) and membrane type 1- matrix metalloproteinase (MT1-MMP) was observed in response to caries. Next, modulation of odontoblastic dentinogenic enzyme repertoire was addressed. In the odontoblast layer expression of Toll-like receptors was markedly altered in response to bacterial invasion. In carious teeth TLR-2 and the gene encoding the corresponding adaptor protein MyD88 were down-regulated whereas genes encoding TLR-4 and adaptor proteins TRAM and Mal/TIRAP were up-regulated. TLR-4 signalling mediated by binding of bacterial products has been linked to up-regulation of MMP-2. Further, increased expression of genes encoding components of the TGF-β signalling pathway, namely SMAD-2 and SMAD-4

  19. White sturgeon (Acipenser transmontanus) acid-base regulation differs in response to different types of acidoses.

    Science.gov (United States)

    Shartau, Ryan B; Baker, Dan W; Brauner, Colin J

    2017-03-11

    White sturgeon (Acipenser transmontanus) completely protect intracellular tissue pH (pHi) despite large reductions in extracellular (blood) pH (pHe), termed preferential pHi regulation, in response to elevated environmental PCO2 (hypercarbia) and in general appear to be relatively resilient to stressors. Preferential pHi regulation is thought to be associated with hypercarbia tolerance in general, but has also recently been observed to protect pHi against metabolic acidoses induced by exhaustive exercise and anoxia in a tropical air breathing catfish. We hypothesized that preferential pHi regulation may also be a general strategy of acid-base regulation in sturgeon. To address this hypothesis, severe acidoses were imposed to reduce pHe, and the presence or absence of preferential pHi regulation was assessed in red blood cells (RBC), heart, brain, liver and white muscle. A respiratory acidosis was imposed using hyperoxia, while metabolic acidoses were induced by exhaustive exercise, anoxia or air exposure. Reductions in pHe occurred following hyperoxia (0.15 units), exhaustive exercise (0.30 units), anoxia (0.10 units) and air exposure (0.35 units); all acidoses reduced RBC pHi. Following hyperoxia, heart, brain and liver pHi were preferentially regulated against the reduction in pHe, similar to hypercarbia exposure. Following all metabolic acidoses heart pHi was protected and brain pHi remained unchanged following exhaustive exercise and air exposure, however, brain pHi was reduced following anoxia. Liver and white muscle pHi were reduced following all metabolic acidoses. These results suggest preferential pHi regulation may be a general strategy during respiratory acidoses but during metabolic acidoses, the response differs between source of acidoses and tissues.

  20. Arabidopsis microRNA expression regulation in a wide range of abiotic stress responses.

    Science.gov (United States)

    Barciszewska-Pacak, Maria; Milanowska, Kaja; Knop, Katarzyna; Bielewicz, Dawid; Nuc, Przemyslaw; Plewka, Patrycja; Pacak, Andrzej M; Vazquez, Franck; Karlowski, Wojciech; Jarmolowski, Artur; Szweykowska-Kulinska, Zofia

    2015-01-01

    Arabidopsis microRNA expression regulation was studied in a wide array of abiotic stresses such as drought, heat, salinity, copper excess/deficiency, cadmium excess, and sulfur deficiency. A home-built RT-qPCR mirEX platform for the amplification of 289 Arabidopsis microRNA transcripts was used to study their response to abiotic stresses. Small RNA sequencing, Northern hybridization, and TaqMan® microRNA assays were performed to study the abundance of mature microRNAs. A broad response on the level of primary miRNAs (pri-miRNAs) was observed. However, stress response at the level of mature microRNAs was rather confined. The data presented show that in most instances, the level of a particular mature miRNA could not be predicted based on the level of its pri-miRNA. This points to an essential role of posttranscriptional regulation of microRNA expression. New Arabidopsis microRNAs responsive to abiotic stresses were discovered. Four microRNAs: miR319a/b, miR319b.2, and miR400 have been found to be responsive to several abiotic stresses and thus can be regarded as general stress-responsive microRNA species.

  1. APUM5, encoding a Pumilio RNA binding protein, negatively regulates abiotic stress responsive gene expression

    Science.gov (United States)

    2014-01-01

    Background A mutant screening was carried out previously to look for new genes related to the Cucumber mosaic virus infection response in Arabidopsis. A Pumilio RNA binding protein-coding gene, Arabidopsis Pumilio RNA binding protein 5 (APUM5), was obtained from this screening. Results APUM5 transcriptional profiling was carried out using a bioinformatics tool. We found that APUM5 was associated with both biotic and abiotic stress responses. However, bacterial and fungal pathogen infection susceptibility was not changed in APUM5 transgenic plants compared to that in wild type plants although APUM5 expression was induced upon pathogen infection. In contrast, APUM5 was involved in the abiotic stress response. 35S-APUM5 transgenic plants showed hypersensitive phenotypes under salt and drought stresses during germination, primary root elongation at the seedling stage, and at the vegetative stage in soil. We also showed that some abiotic stress-responsive genes were negatively regulated in 35S-APUM5 transgenic plants. The APUM5-Pumilio homology domain (PHD) protein bound to the 3′ untranslated region (UTR) of the abiotic stress-responsive genes which contained putative Pumilio RNA binding motifs at the 3′ UTR. Conclusions These results suggest that APUM5 may be a new post-transcriptional regulator of the abiotic stress response by direct binding of target genes 3′ UTRs. PMID:24666827

  2. The bHLH transcription factor POPEYE regulates response to iron deficiency in Arabidopsis roots.

    Science.gov (United States)

    Long, Terri A; Tsukagoshi, Hironaka; Busch, Wolfgang; Lahner, Brett; Salt, David E; Benfey, Philip N

    2010-07-01

    Global population increases and climate change underscore the need for better comprehension of how plants acquire and process nutrients such as iron. Using cell type-specific transcriptional profiling, we identified a pericycle-specific iron deficiency response and a bHLH transcription factor, POPEYE (PYE), that may play an important role in this response. Functional analysis of PYE suggests that it positively regulates growth and development under iron-deficient conditions. Chromatin immunoprecipitation-on-chip analysis and transcriptional profiling reveal that PYE helps maintain iron homeostasis by regulating the expression of known iron homeostasis genes and other genes involved in transcription, development, and stress response. PYE interacts with PYE homologs, including IAA-Leu Resistant3 (ILR3), another bHLH transcription factor that is involved in metal ion homeostasis. Moreover, ILR3 interacts with a third protein, BRUTUS (BTS), a putative E3 ligase protein, with metal ion binding and DNA binding domains, which negatively regulates the response to iron deficiency. PYE and BTS expression is also tightly coregulated. We propose that interactions among PYE, PYE homologs, and BTS are important for maintaining iron homeostasis under low iron conditions.

  3. MicroRNA-mediated networks underlie immune response regulation in papillary thyroid carcinoma

    Science.gov (United States)

    Huang, Chen-Tsung; Oyang, Yen-Jen; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

    2014-09-01

    Papillary thyroid carcinoma (PTC) is a common endocrine malignancy with low death rate but increased incidence and recurrence in recent years. MicroRNAs (miRNAs) are small non-coding RNAs with diverse regulatory capacities in eukaryotes and have been frequently implied in human cancer. Despite current progress, however, a panoramic overview concerning miRNA regulatory networks in PTC is still lacking. Here, we analyzed the expression datasets of PTC from The Cancer Genome Atlas (TCGA) Data Portal and demonstrate for the first time that immune responses are significantly enriched and under specific regulation in the direct miRNA-target network among distinctive PTC variants to different extents. Additionally, considering the unconventional properties of miRNAs, we explore the protein-coding competing endogenous RNA (ceRNA) and the modulatory networks in PTC and unexpectedly disclose concerted regulation of immune responses from these networks. Interestingly, miRNAs from these conventional and unconventional networks share general similarities and differences but tend to be disparate as regulatory activities increase, coordinately tuning the immune responses that in part account for PTC tumor biology. Together, our systematic results uncover the intensive regulation of immune responses underlain by miRNA-mediated networks in PTC, opening up new avenues in the management of thyroid cancer.

  4. An alternative retinoic acid-responsive Stra6 promoter regulated in response to retinol deficiency.

    Science.gov (United States)

    Laursen, Kristian B; Kashyap, Vasundhra; Scandura, Joseph; Gudas, Lorraine J

    2015-02-13

    Cellular uptake of vitamin A (retinol) is essential for many biological functions. The Stra6 protein binds the serum retinol-binding protein, RBP4, and acts in conjunction with the enzyme lecithin:retinol acyltransferase to facilitate retinol uptake in some cell types. We show that in embryonic stem (ES) cells and in some tissues, the Stra6 gene encodes two distinct mRNAs transcribed from two different promoters. Whereas both are all-trans-retinoic acid (RA)-responsive in ES cells, the downstream promoter contains a half-site RA response element (RARE) and drives an ∼ 13-fold, RA-associated increase in luciferase reporter activity. We employed CRISPR-Cas9 genome editing to show that the endogenous RARE is required for RA-induced transcription of both Stra6 isoforms. We further demonstrate that in ES cells, 1) both RARγ and RXRα are present at the Stra6 RARE; 2) RA increases co-activator p300 (KAT3B) binding and histone H3 Lys-27 acetylation at both promoters; 3) RA decreases Suz12 levels and histone H3 Lys-27 trimethylation epigenetic marks at both promoters; and 4) these epigenetic changes are diminished in the absence of RARγ. In the brains of WT mice, both the longer and the shorter Stra6 transcript (Stra6L and Stra6S, respectively) are highly expressed, whereas these transcripts are found only at low levels in RARγ(-/-) mice. In the brains of vitamin A-deficient mice, both Stra6L and Stra6S levels are decreased. In contrast, in the vitamin A-deficient kidneys, the Stra6L levels are greatly increased, whereas Stra6S levels are decreased. Our data show that kidneys respond to retinol deficiency by differential Stra6 promoter usage, which may play a role in the retention of retinol when vitamin A is low.

  5. Microtubules regulate GEF-H1 in response to extracellular matrix stiffness

    Science.gov (United States)

    Heck, Jessica N.; Ponik, Suzanne M.; Garcia-Mendoza, Maria G.; Pehlke, Carolyn A.; Inman, David R.; Eliceiri, Kevin W.; Keely, Patricia J.

    2012-01-01

    Breast epithelial cells sense the stiffness of the extracellular matrix through Rho-mediated contractility. In turn, matrix stiffness regulates RhoA activity. However, the upstream signaling mechanisms are poorly defined. Here we demonstrate that the Rho exchange factor GEF-H1 mediates RhoA activation in response to extracellular matrix stiffness. We demonstrate the novel finding that microtubule stability is diminished by a stiff three-dimensional (3D) extracellular matrix, which leads to the activation of GEF-H1. Surprisingly, activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway did not contribute to stiffness-induced GEF-H1 activation. Loss of GEF-H1 decreases cell contraction of and invasion through 3D matrices. These data support a model in which matrix stiffness regulates RhoA through microtubule destabilization and the subsequent release and activation of GEF-H1. PMID:22593214

  6. Strategic down-regulation of attentional resources as a mechanism of proactive response inhibition.

    Science.gov (United States)

    Langford, Zachary D; Krebs, Ruth M; Talsma, Durk; Woldorff, Marty G; Boehler, C N

    2016-08-01

    Efficiently avoiding inappropriate actions in a changing environment is central to cognitive control. One mechanism contributing to this ability is the deliberate slowing down of responses in contexts where full response cancellation might occasionally be required, referred to as proactive response inhibition. The present electroencephalographic (EEG) study investigated the role of attentional processes in proactive response inhibition in humans. To this end, we compared data from a standard stop-signal task, in which stop signals required response cancellation ('stop-relevant'), to data where possible stop signals were task-irrelevant ('stop-irrelevant'). Behavioral data clearly indicated the presence of proactive slowing in the standard stop-signal task. A novel single-trial analysis was used to directly model the relationship between response time and the EEG data of the go-trials in both contexts within a multilevel linear models framework. We found a relationship between response time and amplitude of the attention-related N1 component in stop-relevant blocks, a characteristic that was fully absent in stop-irrelevant blocks. Specifically, N1 amplitudes were lower the slower the response time, suggesting that attentional resources were being strategically down-regulated to control response speed. Drift diffusion modeling of the behavioral data indicated that multiple parameters differed across the two contexts, likely suggesting the contribution from independent brain mechanisms to proactive slowing. Hence, the attentional mechanism of proactive response control we report here might coexist with known mechanisms that are more directly tied to motoric response inhibition. As such, our study opens up new research avenues also concerning clinical conditions that feature deficits in proactive response inhibition.

  7. Migrants dans l’ombre. Causes, dynamiques, politiques de l’immigration irrégulière

    OpenAIRE

    Ambrosini, Maurizio

    2013-01-01

    L’article tente de répondre à trois questions : 1) Qu’est-ce que l’immigration irrégulière et comment la définit-on ? 2) Pourquoi persiste-t-elle, se reproduit-elle et se révèle-t-elle si difficile à éradiquer ? 3) Pourquoi les mesures de régularisation s’avèrent-elles à leur tour récurrentes et difficilement évitables ? Dans les vingt-sept pays de l’Union européenne, dans les dix dernières années, entre 5 et 6 millions de personnes ont été régularisées. L’article essaie de montrer, sur un pl...

  8. Emergency Response Program Designing Based On Case Study ERP Regulations In Ilam Gas Refinery

    Directory of Open Access Journals (Sweden)

    Mehdi Tahmasbi

    2015-08-01

    Full Text Available The study of Emergency response plan designing is one of the most important prevention approaches in crisis management. This study aims to design emergency response plan based on case study ERP regulations in Ilam gas refinery. On the basis of risk assessment and identification techniques such as HAZOP and FMEA in Ilam gas refinery the risks have been prioritized and then according to this prioritization the design of possible scenarios which have the highest rate of occurrence and the highest level of damage has been separated. Possible scenarios were simulated with PHAST software. Then emergency response program has been designed for the special mode or similar cases. According to the internal emergency response plan for Ilam gas refinery and predictable conditions of the process special instructions should be considered at the time of the incident to suffer the least damage on people and environment in the shortest time possible.

  9. Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

    Science.gov (United States)

    Alexandrou, Aris T.

    2014-01-01

    Abstract Significance: There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIR-regulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Recent Advances: Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. Critical Issues: The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Future Directions: Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk. Antioxid. Redox Signal. 20, 1463–1480. PMID:24180340

  10. Gene up-regulation in response to predator kairomones in the water flea, Daphnia pulex

    Directory of Open Access Journals (Sweden)

    Okada Yasukazu

    2010-04-01

    Full Text Available Abstract Background Numerous cases of predator-induced polyphenisms, in which alternate phenotypes are produced in response to extrinsic stimuli, have been reported in aquatic taxa to date. The genus Daphnia (Branchiopoda, Cladocera provides a model experimental system for the study of the developmental mechanisms and evolutionary processes associated with predator-induced polyphenisms. In D. pulex, juveniles form neckteeth in response to predatory kairomones released by Chaoborus larvae (Insecta, Diptera. Results Previous studies suggest that the timing of the sensitivity to kairomones in D. pulex can generally be divided into the embryonic and postembryonic developmental periods. We therefore examined which of the genes in the embryonic and first-instar juvenile stages exhibit different expression levels in the presence or absence of predator kairomones. Employing a candidate gene approach and identifying differentially-expressed genes revealed that the morphogenetic factors, Hox3, extradenticle and escargot, were up-regulated by kairomones in the postembryonic stage and may potentially be responsible for defense morph formation. In addition, the juvenile hormone pathway genes, JHAMT and Met, and the insulin signaling pathway genes, InR and IRS-1, were up-regulated in the first-instar stage. It is well known that these hormonal pathways are involved in physiological regulation following morphogenesis in many insect species. During the embryonic stage when morphotypes were determined, one of the novel genes identified by differential display was up-regulated, suggesting that this gene may be related to morphotype determination. Biological functions of the up-regulated genes are discussed in the context of defense morph formation. Conclusions It is suggested that, following the reception of kairomone signals, the identified genes are involved in a series of defensive phenotypic alterations and the production of a defensive phenotype.

  11. Gene up-regulation in response to predator kairomones in the water flea, Daphnia pulex.

    Science.gov (United States)

    Miyakawa, Hitoshi; Imai, Maki; Sugimoto, Naoki; Ishikawa, Yuki; Ishikawa, Asano; Ishigaki, Hidehiko; Okada, Yasukazu; Miyazaki, Satoshi; Koshikawa, Shigeyuki; Cornette, Richard; Miura, Toru

    2010-04-30

    Numerous cases of predator-induced polyphenisms, in which alternate phenotypes are produced in response to extrinsic stimuli, have been reported in aquatic taxa to date. The genus Daphnia (Branchiopoda, Cladocera) provides a model experimental system for the study of the developmental mechanisms and evolutionary processes associated with predator-induced polyphenisms. In D. pulex, juveniles form neckteeth in response to predatory kairomones released by Chaoborus larvae (Insecta, Diptera). Previous studies suggest that the timing of the sensitivity to kairomones in D. pulex can generally be divided into the embryonic and postembryonic developmental periods. We therefore examined which of the genes in the embryonic and first-instar juvenile stages exhibit different expression levels in the presence or absence of predator kairomones. Employing a candidate gene approach and identifying differentially-expressed genes revealed that the morphogenetic factors, Hox3, extradenticle and escargot, were up-regulated by kairomones in the postembryonic stage and may potentially be responsible for defense morph formation. In addition, the juvenile hormone pathway genes, JHAMT and Met, and the insulin signaling pathway genes, InR and IRS-1, were up-regulated in the first-instar stage. It is well known that these hormonal pathways are involved in physiological regulation following morphogenesis in many insect species. During the embryonic stage when morphotypes were determined, one of the novel genes identified by differential display was up-regulated, suggesting that this gene may be related to morphotype determination. Biological functions of the up-regulated genes are discussed in the context of defense morph formation. It is suggested that, following the reception of kairomone signals, the identified genes are involved in a series of defensive phenotypic alterations and the production of a defensive phenotype.

  12. Cell cycle regulators guide mitochondrial activity in radiation-induced adaptive response.

    Science.gov (United States)

    Alexandrou, Aris T; Li, Jian Jian

    2014-03-20

    There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIR-regulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk.

  13. Arabidopsis CBF3 and DELLAs positively regulate each other in response to low temperature

    Science.gov (United States)

    Zhou, Mingqi; Chen, Hu; Wei, Donghui; Ma, Hong; Lin, Juan

    2017-01-01

    The C-repeat binding factor (CBF) is crucial for regulation of cold response in higher plants. In Arabidopsis, the mechanism of CBF3-caused growth retardation is still unclear. Our present work shows that CBF3 shares the similar repression of bioactive gibberellin (GA) as well as upregulation of DELLA proteins with CBF1 and -2. Genetic analysis reveals that DELLAs play an essential role in growth reduction mediated by CBF1, -2, -3 genes. The in vivo and in vitro evidences demonstrate that GA2-oxidase 7 gene is a novel CBF3 regulon. Meanwhile, DELLAs contribute to cold induction of CBF1, -2, -3 genes through interaction with jasmonate (JA) signaling. We conclude that CBF3 promotes DELLAs accumulation through repressing GA biosynthesis and DELLAs positively regulate CBF3 involving JA signaling. CBFs and DELLAs collaborate to retard plant growth in response to low temperature. PMID:28051152

  14. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.

    Science.gov (United States)

    Xu, Xingzhi; Lee, Juhie; Stern, David F

    2004-08-13

    Microcephalin (MCPH1) is the first gene identified among at least six loci that contribute to the autosomal recessive disease, primary microcephaly. MCPH1, like NFBD1/MDC1, 53BP1, and BRCA1, encodes a protein with twin carboxyl-terminal BRCT domains (PTCB). Here, we report that Mcph1 forms ionizing radiation-induced foci. Down-regulation of Mcph1, like other PTCBs, by siRNA, impairs ionizing radiation-induced intra-S-phase and G(2)/M checkpoints. Inhibition of the expression of Mcph1 decreases both protein and transcript levels of endogenous Brca1 but not exogenous Brca1. Mcph1 inhibition also decreases both endogenous and heterologous Chk1 transcripts and protein. We conclude that Mcph1 is involved in DNA damage-induced cellular responses, and we propose that regulation of Brca1 and/or Chk1 by Mcph1 may contribute to these cellular responses.

  15. Neuroticism and responsiveness to error feedback: adaptive self-regulation versus affective reactivity.

    Science.gov (United States)

    Robinson, Michael D; Moeller, Sara K; Fetterman, Adam K

    2010-10-01

    Responsiveness to negative feedback has been seen as functional by those who emphasize the value of reflecting on such feedback in self-regulating problematic behaviors. On the other hand, the very same responsiveness has been viewed as dysfunctional by its link to punishment sensitivity and reactivity. The present 4 studies, involving 203 undergraduate participants, sought to reconcile such discrepant views in the context of the trait of neuroticism. In cognitive tasks, individuals were given error feedback when they made mistakes. It was found that greater tendencies to slow down following error feedback were associated with higher levels of accuracy at low levels of neuroticism but lower levels of accuracy at high levels of neuroticism. Individual differences in neuroticism thus appear crucial in understanding whether behavioral alterations following negative feedback reflect proactive versus reactive mechanisms and processes. Implications for understanding the processing basis of neuroticism and adaptive self-regulation are discussed.

  16. The complex logic of stringent response regulation in Caulobacter crescentus: starvation signalling in an oligotrophic environment.

    Science.gov (United States)

    Boutte, Cara C; Crosson, Sean

    2011-05-01

    Bacteria rapidly adapt to nutritional changes via the stringent response, which entails starvation-induced synthesis of the small molecule, ppGpp, by RelA/SpoT homologue (Rsh) enzymes. Binding of ppGpp to RNA polymerase modulates the transcription of hundreds of genes and remodels the physiology of the cell. Studies of the stringent response have primarily focused on copiotrophic bacteria such as Escherichia coli; little is known about how stringent signalling is regulated in species that live in consistently nutrient-limited (i.e. oligotrophic) environments. Here we define the input logic and transcriptional output of the stringent response in the oligotroph, Caulobacter crescentus. The sole Rsh protein, SpoT(CC), binds to and is regulated by the ribosome, and exhibits AND-type control logic in which amino acid starvation is a necessary but insufficient signal for activation of ppGpp synthesis. While both glucose and ammonium starvation upregulate the synthesis of ppGpp, SpoT(CC) detects these starvation signals by two independent mechanisms. Although the logic of stringent response control in C. crescentus differs from E. coli, the global transcriptional effects of elevated ppGpp are similar, with the exception of 16S rRNA transcription, which is controlled independently of spoT(CC). This study highlights how the regulatory logic controlling the stringent response may be adapted to the nutritional niche of a bacterial species.

  17. Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries.

    Directory of Open Access Journals (Sweden)

    Sonya Hui

    Full Text Available We recently identified sphingosine-1-phosphate (S1P signaling and the cystic fibrosis transmembrane conductance regulator (CFTR as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i express critical S1P signaling elements, (ii constrict in response to S1P and (iii lose myogenic responsiveness following S1P receptor antagonism (JTE013. However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.

  18. Basal transcription machinery: role in regulation of stress response in eukaryotes

    Indian Academy of Sciences (India)

    Parag Sadhale; Jiyoti Verma; Aruna Naorem

    2007-04-01

    The holoenzyme of prokaryotic RNA polymerase consists of the core enzyme, made of two , , ’ and subunits, which lacks promoter selectivity and a sigma () subunit which enables the core enzyme to initiate transcription in a promoter dependent fashion. A stress sigma factor s, in prokaryotes seems to regulate several stress response genes in conjunction with other stress specific regulators. Since the basic principles of transcription are conserved from simple bacteria to multicellular complex organisms, an obvious question is: what is the identity of a counterpart of s, that is closest to the core polymerase and that dictates transcription of stress regulated genes in general? In this review, we discuss the logic behind the suggestion that like in prokaryotes, eukaryotes also have a common functional unit in the transcription machinery through which the stress specific transcription factors regulate rapid and highly controlled induction of gene expression associated with generalized stress response and point to some candidates that would fit the bill of the eukaryotic s.

  19. SOG1: a master regulator of the DNA damage response in plants.

    Science.gov (United States)

    Yoshiyama, Kaoru Okamoto

    2016-01-01

    The DNA damage response (DDR) is a critical mechanism to maintain the genome stability of an organism upon exposure to endogenous and exogenous DNA-damaging factors. The DDR system is particularly important for plants as these organisms, owing to their intrinsic immobility, are inevitably exposed to environmental stress factors, some of which induce DNA damage. Arabidopsis thaliana has orthologs of several DDR factors that are present in animals; however, some of the important animal regulators, such as the tumor suppressor p53 and the DDR kinases CHK1 and CHK2, have not been found in plants. These observations imply a unique DDR system in plants. The present review focuses on recent advances in our understanding of the DDR in A. thaliana and, in particular, on the function and role of SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a plant-specific transcription factor that regulates the DDR. The most obvious response to DNA damage in A. thaliana is a rapid and robust change in the transcriptional regulation of numerous genes, in which SOG1 is an essential regulatory factor. Mutation of SOG1 causes various defects in the activation of cell cycle arrest, programmed cell death, and endoreduplication in response to DNA damage. These observations indicate that SOG1 is a master regulator of the DDR. Phylogenetic analyses of SOG1 reveal that orthologs of this crucial transcription factor are present not only in angiosperms but also in gymnosperms, suggesting that the SOG1 system is conserved across spermatophytes. Finally, future prospects for SOG1 research are also discussed.

  20. Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element.

    OpenAIRE

    1991-01-01

    Diabetes mellitus is characterized by insulin deficiency and high plasma glucagon levels, which can be normalized by insulin replacement. It has previously been reported that glucagon gene expression is negatively regulated by insulin at the transcriptional level. By transfection studies, I have now localized a DNA control element that mediates insulin effects on glucagon gene transcription. This element also confers insulin responsiveness to a heterologous promoter. DNA-binding proteins that...

  1. Excitatory amino acid receptors in the basolateral amygdala regulate anxiety responses in the social interaction test.

    Science.gov (United States)

    Sajdyk, T J; Shekhar, A

    1997-08-01

    Blocking GABA(A) receptors in the basolateral amygdala (BLA) elicits increases in heart rate (HR), blood pressure (BP) and anxiety responses by enhancing a glutamate mediated excitation. The present study was conducted to determine the role of the ionotropic glutamate receptors within the BLA in regulating HR, BP and experimental anxiety. Blocking basal glutamate excitation had no significant effect on HR or BP, but did elicit a significant anxiolytic-like effect.

  2. Negative regulation of the innate antiviral immune response by TRIM62 from orange spotted grouper.

    Science.gov (United States)

    Yang, Ying; Huang, Youhua; Yu, Yepin; Zhou, Sheng; Wang, Shaowen; Yang, Min; Qin, Qiwei; Huang, Xiaohong

    2016-10-01

    Increased reports uncovered that mammalian tripartite motif-containing 62 (TRIM62) exerts crucial roles in cancer and innate immune response. However, the roles of fish TRIM62 in antiviral immune response remained uncertain. In this study, a TRIM62 gene was cloned from orange spotted grouper (EcTRIM62) and its roles in grouper RNA virus infection was elucidated in vitro. EcTRIM62 shared 99% and 83% identity to bicolor damselfish (Stegastes partitus) and human (Homo sapiens), respectively. Sequence alignment indicated that EcTRIM62 contained three domains, including a RING-finger domain, a B-box domain and a SPRY domain. In healthy grouper, the transcript of EcTRIM62 was predominantly detected in brain and liver, followed by heart, skin, spleen, fin, gill, intestine, and stomach. Subcellular localization analysis indicated that bright fluorescence spots were observed in the cytoplasm of EcTRIM62-transfected grouper spleen (GS) cells. During red-spotted grouper nervous necrosis (RGNNV) infection, overexpression of EcTRIM62 significantly enhanced the severity of CPE and increased viral gene transcriptions. Furthermore, the ectopic expression of EcTRIM62 significantly decreased the transcription level of interferon signaling molecules, including interferon regulatory factor 3 (IRF3), IRF7, interferon-stimulated gene 15 (ISG15), melanoma differentiation-associated protein 5 (MDA5), myxovirus resistance gene MXI, and MXII, suggesting that the negative regulation of interferon immune response by EcTRIM62 might directly contributed to its enhancing effect on RGNNV replication. Furthermore, our results also demonstrated that overexpression of EcTRIM62 was able to differently regulate the expression levels of pro-inflammation cytokines. In addition, we found the ectopic expression of EcTIRM62 negatively regulated MDA5-, but not mediator of IRF3 activation (MITA)-induced interferon immune response. Further studies showed that the deletion of RING domain and SPRY domain

  3. Child-care chaos and teachers' responsiveness: The indirect associations through teachers' emotion regulation and coping.

    Science.gov (United States)

    Jeon, Lieny; Hur, Eunhye; Buettner, Cynthia K

    2016-12-01

    Teachers in early child-care settings are key contributors to children's development. However, the role of teachers' emotional abilities (i.e., emotion regulation and coping skills) and the role of teacher-perceived environmental chaos in relation to their responsiveness to children are understudied. The current study explored the direct and indirect associations between teachers' perceptions of child-care chaos and their self-reported contingent reactions towards children's negative emotions and challenging social interactions via teachers' emotional regulation and coping strategies. The sample consisted of 1129 preschool-aged classroom teachers in day care and public pre-K programs across the US. We first found that child-care chaos was directly associated with teachers' non-supportive reactions after controlling for multiple program and teacher characteristics. In addition, teachers in more chaotic child-care settings had less reappraisal and coping skills, which in turn, was associated with lower levels of positive responsiveness to children. Teachers reporting a higher degree of chaos used more suppression strategies, which in turn, was associated with teachers' non-supportive reactions and fewer expressive encouragement reactions to children's emotions. Results of this exploratory study suggest that it is important to prepare teachers to handle chaotic environments with clear guidelines and rules. In order to encourage teachers' supportive responses to children, intervention programs are needed to address teachers' coping and emotion regulation strategies in early childhood education.

  4. Flow-rate Characteristics Measurement of Regulators Based on the Pressure Response in an Isothermal Tank

    Institute of Scientific and Technical Information of China (English)

    FAN Wei; ZHANG Hongli; WANG Tao; PENG Guangzheng; ONEYAMA Naotake

    2009-01-01

    Regulators are important components in pneumatic system, and their flow-rate characteristics are the key parameters for designers. According to the correlatively international standard and national standard of China, which describe the flow-rate characteristics measurement method of pneumatic regulators, the pressure and the flow are measured point by point, and then the flow-rate characteristics curve is plotted point to point. This method has some disadvantages, such as equipment complexity, much air consumption, and low efficiency. To settle the problems presented above, this paper puts forward a new high efficient and energy saving flow-rate characteristics measurement method of regulators, which is based on the pressure response when charging and discharging to an isothermal tank without any flow meters. The measurement principle, the system and the steps are introduced. And the tracking differentiator is used for the data processing of the pressure difference. Two typical kinds of regulators were experimentally investigated, and their flow-rate characteristics curves were obtained with the new and the conventional method, respectively. Comparatively, it's proved that this new method is feasible because it is not only able to meet the demand of the measurement precision, but also to save energy and improve efficiency. Compared to the conventional method, the new method takes only about 1/10 amount of time and consumes about only 1/30 amount of air. Hopefully it will be able to serve as an international standard of flow-rate characteristics measurement method of regulators.

  5. The oxygen-responsive transcriptional regulator FNR of Escherichia coli: the search for signals and reactions.

    Science.gov (United States)

    Unden, G; Schirawski, J

    1997-07-01

    The FNR (fumarate and nitrate reductase regulation) protein of Escherichia coli is an oxygen-responsive transcriptional regulator required for the switch from aerobic to anaerobic metabolism. In the absence of oxygen, FNR changes from the inactive to the active state. The sensory and the regulatory functions reside in separate domains of FNR. The sensory domain contains a Fe-S cluster, which is of the [4Fe-4S]2+ type under anaerobic conditions. It is suggested that oxygen is supplied to the cytoplasmic FNR by diffusion and inactivates FNR by direct interaction. Reactivation under anoxic conditions requires cellular reductants. In vitro, the Fe-S cluster is converted to a [3Fe-4S]+ or a [2Fe-2S]2+ cluster by oxygen, resulting in FNR inactivation. After prolonged incubation with oxygen, the Fe-S cluster is destroyed. Reassembly of the [4Fe-4S]2+ cluster might require cellular proteins, such as the NifS-like protein of E. coli. In this review, the rationale for regulation of alternative metabolic pathways by FNR and other oxygen-dependent regulators is discussed. Only the terminal reductases of respiration, and not the dehydrogenases, are regulated in such a way as to achieve maximal H+/e- ratios and ATP yields.

  6. Characterizing human skin blood flow regulation in response to different local skin temperature perturbations.

    Science.gov (United States)

    Wu, Y; Nieuwenhoff, M D; Huygen, F J P M; van der Helm, F C T; Niehof, S; Schouten, A C

    2017-05-01

    Small nerve fibers regulate local skin blood flow in response to local thermal perturbations. Small nerve fiber function is difficult to assess with classical neurophysiological tests. In this study, a vasomotor response model in combination with a heating protocol was developed to quantitatively characterize the control mechanism of small nerve fibers in regulating skin blood flow in response to local thermal perturbation. The skin of healthy subjects' hand dorsum (n=8) was heated to 42°C with an infrared lamp, and then naturally cooled down. The distance between the lamp and the hand was set to three different levels in order to change the irradiation intensity on the skin and implement three different skin temperature rise rates (0.03°C/s, 0.02°C/s and 0.01°C/s). A laser Doppler imager (LDI) and a thermographic video camera recorded the temporal profile of the skin blood flow and the skin temperature, respectively. The relationship between the skin blood flow and the skin temperature was characterized by a vasomotor response model. The model fitted the skin blood flow response well with a variance accounted for (VAF) between 78% and 99%. The model parameters suggested a similar mechanism for the skin blood flow regulation with the thermal perturbations at 0.03°C/s and 0.02°C/s. But there was an accelerated skin vasoconstriction after a slow heating (0.01°C/s) (p-value<0.05). An attenuation of the skin vasodilation was also observed in four out of the seven subjects during the slow heating (0.01°C/s). Our method provides a promising way to quantitatively assess the function of small nerve fibers non-invasively and non-contact.

  7. MicroRNA as type I interferon-regulated transcripts and modulators of the innate immune response

    Directory of Open Access Journals (Sweden)

    Samuel C Forster

    2015-07-01

    Full Text Available Type I interferons (IFNs are an important family of cytokines that regulate innate and adaptive immune responses to pathogens, in cancer and inflammatory diseases. While the regulation and role of protein-coding genes involved in these responses are well characterized, the role of non-coding microRNAs in the IFN responses is less developed. We review the emerging picture of microRNA regulation of the IFN response at the transcriptional and post-transcriptional level. This response forms an important regulatory loop, several microRNAs target transcripts encoding components at many steps of the type I IFN response, both production and action, at the receptor, signaling, transcription factor and regulated gene level. Not only do IFNs regulate positive signaling molecules, but also negative regulators such as SOCS1. In total, 36 microRNA are reported as IFN regulated. Given this apparent multipronged targeting of the IFN response by microRNAs and their well characterized capacity to buffer responses in other situations, the prospects of improved sequencing and microRNA targeting technologies will facilitate the elucidation of the broader regulatory networks of microRNA in this important biological context, and their therapeutic and diagnostic potential.

  8. Polycomb protein EZH2 regulates cancer cell fate decision in response to DNA damage.

    Science.gov (United States)

    Wu, Z; Lee, S T; Qiao, Y; Li, Z; Lee, P L; Lee, Y J; Jiang, X; Tan, J; Aau, M; Lim, C Z H; Yu, Q

    2011-11-01

    Polycomb protein histone methyltransferase enhancer of Zeste homologe 2 (EZH2) is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating DNA damage response. Here, we show that EZH2 is an important determinant of cell fate decision in response to genotoxic stress. EZH2 depletion results in abrogation of both cell cycle G1 and G2/M checkpoints, directing DNA damage response toward predominant apoptosis in both p53-proficient and p53-deficient cancer cells, but not in normal cells. Mechanistically, EZH2 regulates DNA damage response in p53 wild-type cells mainly through transcriptional repression of FBXO32, which binds to and directs p21 for proteasome-mediated degradation, whereas it affects p53-deficient cells through regulating Chk1 activation by a distinct mechanism. Furthermore, pharmacological depletion of EZH2 phenocopies the effects of EZH2 knockdown on cell cycle checkpoints and apoptosis. These data unravel a crucial role of EZH2 in determining the cancer cell outcome following DNA damage and suggest that therapeutic targeting oncogenic EZH2 might serve as a strategy for improving conventional chemotherapy in a given malignancy.

  9. Topical insulin application improves healing by regulating the wound inflammatory response.

    Science.gov (United States)

    Chen, Xuelian; Liu, Yan; Zhang, Xiong

    2012-01-01

    Inflammation, the initiating stage of wound healing, is characterized by increased endothelial permeability, infiltration of inflammatory cells, and secretion of numerous growth factors and chemokines. By controlling wound contamination and infection, as well as inducing the repairing process, inflammatory response plays an irreplaceable role during wound healing. We utilized a variety of approaches to observe the effect of insulin on wound inflammatory response, specifically the effect of insulin on the function of wound macrophages. We also investigated whether insulin-regulated inflammatory response contributed to insulin-induced healing. Mice excisional wounds treated with insulin showed advanced infiltration and resolution of macrophages, which correlated with the expression of monocyte chemotactic protein-1, a potent chemotactic factor for macrophages. Blockage of monocyte chemotactic protein-1 resulted in reduced macrophages infiltration and impaired wound healing despite the presence of insulin. In vitro studies showed insulin-facilitated monocytes/macrophages chemotaxis, pinocytosis/phagocytosis, and secretion of inflammatory mediators as well. Our study strongly suggests that insulin is a potent healing accelerant. Regulating wound inflammatory response, especially the quantity and function of macrophages, is one of the mechanisms explaining insulin-induced accelerated wound healing.

  10. Caffeine Induces the Stress Response and Up-Regulates Heat Shock Proteins in Caenorhabditis elegans.

    Science.gov (United States)

    Al-Amin, Mohammad; Kawasaki, Ichiro; Gong, Joomi; Shim, Yhong-Hee

    2016-02-01

    Caffeine has both positive and negative effects on physiological functions in a dose-dependent manner. C. elegans has been used as an animal model to investigate the effects of caffeine on development. Caffeine treatment at a high dose (30 mM) showed detrimental effects and caused early larval arrest. We performed a comparative proteomic analysis to investigate the mode of action of high-dose caffeine treatment in C. elegans and found that the stress response proteins, heat shock protein (HSP)-4 (endoplasmic reticulum [ER] chaperone), HSP-6 (mitochondrial chaperone), and HSP-16 (cytosolic chaperone), were induced and their expression was regulated at the transcriptional level. These findings suggest that high-dose caffeine intake causes a strong stress response and activates all three stress-response pathways in the worms, including the ER-, mitochondrial-, and cytosolic pathways. RNA interference of each hsp gene or in triple combination retarded growth. In addition, caffeine treatment stimulated a food-avoidance behavior (aversion phenotype), which was enhanced by RNAi depletion of the hsp-4 gene. Therefore, up-regulation of hsp genes after caffeine treatment appeared to be the major responses to alleviate stress and protect against developmental arrest.

  11. Differential control of Zap1-regulated genes in response to zinc deficiency in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Wu Chang-Yi

    2008-08-01

    Full Text Available Abstract Background The Zap1 transcription factor is a central player in the response of yeast to changes in zinc status. We previously used transcriptome profiling with DNA microarrays to identify 46 potential Zap1 target genes in the yeast genome. In this new study, we used complementary methods to identify additional Zap1 target genes. Results With alternative growth conditions for the microarray experiments and a more sensitive motif identification algorithm, we identified 31 new potential targets of Zap1 activation. Moreover, an analysis of the response of Zap1 target genes to a range of zinc concentrations and to zinc withdrawal over time demonstrated that these genes respond differently to zinc deficiency. Some genes are induced under mild zinc deficiency and act as a first line of defense against this stress. First-line defense genes serve to maintain zinc homeostasis by increasing zinc uptake, and by mobilizing and conserving intracellular zinc pools. Other genes respond only to severe zinc limitation and act as a second line of defense. These second-line defense genes allow cells to adapt to conditions of zinc deficiency and include genes involved in maintaining secretory pathway and cell wall function, and stress responses. Conclusion We have identified several new targets of Zap1-mediated regulation. Furthermore, our results indicate that through the differential regulation of its target genes, Zap1 prioritizes mechanisms of zinc homeostasis and adaptive responses to zinc deficiency.

  12. Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1.

    Science.gov (United States)

    Turner, Elizebeth C; Kinsella, B Therese

    2012-11-01

    Prostacyclin and its prostacyclin receptor, the I Prostanoid (IP), play essential roles in regulating hemostasis and vascular tone and have been implicated in a range cardio-protective effects but through largely unknown mechanisms. In this study, the influence of cholesterol on human IP [(h)IP] gene expression was investigated in cultured vascular endothelial and platelet-progenitor megakaryocytic cells. Cholesterol depletion increased human prostacyclin receptor (hIP) mRNA, hIP promoter-directed reporter gene expression, and hIP-induced cAMP generation in all cell types. Furthermore, the constitutively active sterol-response element binding protein (SREBP)1a, but not SREBP2, increased hIP mRNA and promoter-directed gene expression, and deletional and mutational analysis uncovered an evolutionary conserved sterol-response element (SRE), adjacent to a known functional Sp1 element, within the core hIP promoter. Moreover, chromatin immunoprecipitation assays confirmed direct cholesterol-regulated binding of SREBP1a to this hIP promoter region in vivo, and immunofluorescence microscopy corroborated that cholesterol depletion significantly increases hIP expression levels. In conclusion, the hIP gene is directly regulated by cholesterol depletion, which occurs through binding of SREBP1a to a functional SRE within its core promoter. Mechanistically, these data establish that cholesterol can regulate hIP expression, which may, at least in part, account for the combined cardio-protective actions of low serum cholesterol through its regulation of IP expression within the human vasculature.

  13. Proximity of Radiation Desiccation Response Motif to the core promoter is essential for basal repression as well as gamma radiation-induced gyrB gene expression in Deinococcus radiodurans.

    Science.gov (United States)

    Anaganti, Narasimha; Basu, Bhakti; Mukhopadhyaya, Rita; Apte, Shree Kumar

    2017-03-02

    The radioresistant D. radiodurans regulates its DNA damage regulon (DDR) through interaction between a 17bp palindromic cis-regulatory element called the Radiation Desiccation Response Motif (RDRM), the DdrO repressor and a protease IrrE. The role of RDRM in regulation of DDR was dissected by constructing RDRM sequence-, position- or deletion-variants of Deinococcal gyrB gene (DR0906) promoter and by RDRM insertion in the non-RDRM groESL gene (DR0606) promoter, and monitoring the effect of such modifications on the basal as well as gamma radiation inducible promoter activity by quantifying fluorescence of a GFP reporter. RDRM sequence-variants revealed that the conservation of sequence at the 5th and 13th position and the ends of RDRM is essential for basal repression by interaction with DdrO. RDRM position-variants showed that the sequence acts as a negative regulatory element only when located around transcription start site (TSS) and within the span of RNA polymerase (RNAP) binding region. RDRM deletion-variants indicated that the 5' sequence of RDRM possibly possesses an enhancer-like element responsible for higher expression yields upon repressor clearance post-irradiation. The results suggest that RDRM plays both a negative as well as a positive role of in the regulation of DDR in D. radiodurans.

  14. Role of proteoglycans in the regulation of the skeletal muscle fibrotic response.

    Science.gov (United States)

    Brandan, Enrique; Gutierrez, Jaime

    2013-09-01

    Myogenesis consists of a highly organized and regulated sequence of cellular processes aimed at forming or repairing muscle tissue. Several processes occur during myogenesis, including cell proliferation, migration, and differentiation. Cytokines, proteinases, cell adhesion molecules and growth factors are involved, either activating or inhibiting these events, and are modulated by a group of molecules called proteoglycans (PGs), which play critical roles in skeletal muscle physiology. Particularly interesting are some of the factors responsible for the fibrotic response associated with skeletal muscular dystrophies. Transforming growth factor-β and connective tissue growth factor have gained great attention as factors participating in the fibrotic response in skeletal muscle. This review is focused on the advances achieved in understanding the roles of proteoglycans as modulators of profibrotic growth factors in fibrosis associated with diseases such as skeletal muscle dystrophies.

  15. Fish and mammalian phagocytes differentially regulate pro-inflammatory and homeostatic responses in vivo.

    Directory of Open Access Journals (Sweden)

    Aja M Rieger

    Full Text Available Phagocytosis is a cellular mechanism that is important to the early induction of antimicrobial responses and the regulation of adaptive immunity. At an inflammatory site, phagocytes serve as central regulators for both pro-inflammatory and homeostatic anti-inflammatory processes. However, it remains unclear if this is a recent evolutionary development or whether the capacity to balance between these two seemingly contradictory processes is a feature already displayed in lower vertebrates. In this study, we used murine (C57BL/6 and teleost fish (C. auratus in vitro and in vivo models to assess the evolutionary conservation of this dichotomy at a site of inflammation. At the level of the macrophage, we found that teleost fish already displayed divergent pro-inflammatory and homeostatic responses following internalization of zymosan or apoptotic bodies, respectively, and that these were consistent with those of mice. However, fish and mice displayed significant differences in vivo with regards to the level of responsiveness to zymosan and apoptotic bodies, the identity of infiltrating leukocytes, their rate of infiltration, and the kinetics and strength of resulting antimicrobial responses. Unlike macrophages, significant differences were identified between teleost and murine neutrophilic responses. We report for the first time that activated murine, but not teleost neutrophils, possess the capacity to internalize apoptotic bodies. This internalization translates into reduction of neutrophil ROS production. This may play an important part in the recently identified anti-inflammatory activity that mammalian neutrophils display during the resolution phase of inflammation. Our observations are consistent with continued honing of inflammatory control mechanisms from fish to mammals, and provide added insights into the evolutionary path that has resulted in the integrated, multilayered responses that are characteristic of higher vertebrates.

  16. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria.

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    Hepworth, Matthew R; Monticelli, Laurel A; Fung, Thomas C; Ziegler, Carly G K; Grunberg, Stephanie; Sinha, Rohini; Mantegazza, Adriana R; Ma, Hak-Ling; Crawford, Alison; Angelosanto, Jill M; Wherry, E John; Koni, Pandelakis A; Bushman, Frederic D; Elson, Charles O; Eberl, Gérard; Artis, David; Sonnenberg, Gregory F

    2013-06-06

    Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal

  17. Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading.

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    Ignatova, Irena D; Angdisen, Jerry; Moran, Erin; Schulman, Ira G

    2013-07-01

    The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-α (NR1H3) and LXRβ (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXRα subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene-selective response to cholesterol loading occurs, even in the presence of LXRα binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXRα to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective.

  18. A Simple Auxin Transcriptional Response System Regulates Multiple Morphogenetic Processes in the Liverwort Marchantia polymorpha.

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    Flores-Sandoval, Eduardo; Eklund, D Magnus; Bowman, John L

    2015-05-01

    In land plants comparative genomics has revealed that members of basal lineages share a common set of transcription factors with the derived flowering plants, despite sharing few homologous structures. The plant hormone auxin has been implicated in many facets of development in both basal and derived lineages of land plants. We functionally characterized the auxin transcriptional response machinery in the liverwort Marchantia polymorpha, a member of the basal lineage of extant land plants. All components known from flowering plant systems are present in M. polymorpha, but they exist as single orthologs: a single MpTOPLESS (TPL) corepressor, a single MpTRANSPORT inhibitor response 1 auxin receptor, single orthologs of each class of auxin response factor (ARF; MpARF1, MpARF2, MpARF3), and a single negative regulator auxin/indole-3-acetic acid (MpIAA). Phylogenetic analyses suggest this simple system is the ancestral condition for land plants. We experimentally demonstrate that these genes act in an auxin response pathway--chimeric fusions of the MpTPL corepressor with heterodimerization domains of MpARF1, MpARF2, or their negative regulator, MpIAA, generate auxin insensitive plants that lack the capacity to pattern and transition into mature stages of development. Our results indicate auxin mediated transcriptional regulation acts as a facilitator of branching, differentiation and growth, rather than acting to determine or specify tissues during the haploid stage of the M. polymorpha life cycle. We hypothesize that the ancestral role of auxin is to modulate a balance of differentiated and pluri- or totipotent cell states, whose fates are determined by interactions with combinations of unrelated transcription factors.

  19. SIRT1 Regulates the Inflammatory Response of Vascular Adventitial Fibroblasts through Autophagy and Related Signaling Pathway.

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    Wang, Wei-Rong; Li, Ting-Ting; Jing, Ting; Li, Yan-Xiang; Yang, Xiao-Feng; He, Yan-Hao; Zhang, Wei; Lin, Rong; Zhang, Ji-Ye

    2017-01-01

    Autophagy is a lysosomal degradation pathway that is essential for cellular survival, differentiation, and homeostasis. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, plays a pivotal role in modulation of autophagy. Recent studies found that autophagy was involved in the regulation of inflammatory response. In this study, we aimed to determine the effect of SIRT1 on autophagy and inflammation, and whether autophagy can regulate the inflammatory response in vascular adventitial fibroblasts (VAFs). Cell autophagy was evaluated by fluorescence microscope and transmission electron microscopy. The expression of protein and mRNA were determined by Western blot analysis and real time-PCR. The production of cytokine was detected by ELISA. TNF-α induced autophagy and increased SIRT1 expression in VAFs. SIRT1 activator resveratrol enhanced TNF-α-induced VAF autophagy. In contrast, SIRT1 knockdown attenuated VAF autophagy. Both the Akt inhibitor MK2206 and mTOR inhibitor rapamycin further increased TNF-α-induced VAF autophagy. Furthermore, SIRT1 knockdown increased Akt phosphorylation and inhibited the autophagy in VAFs. However, MK2206 attenuated the effect of SIRT1 knockdown on VAF autophagy. In addition, ingenuity pathway analysis showed that there is a relationship between cell autophagy and inflammation. We found that SIRT1 knockdown increased the expression of NLRP3 and interleukin (IL)-6 and promoted the production of IL-1β in VAFs. Further study showed that autophagy activation decreased the expression of NLRP3 and IL-6 and inhibited the production of IL-1β, whereas autophagy inhibition increased the inflammatory response of VAFs. More importantly, our study showed that autophagy was involved in the degradation of NLRP3 through the autophagy-lysosome pathway. SIRT1 not only regulates VAF autophagy through the Akt/mTOR signaling pathway but also suppresses the inflammatory response of VAFs through autophagy. © 2017 The Author(s)Published by S. Karger AG, Basel.

  20. Systematic dissection of roles for chromatin regulators in a yeast stress response.

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    Assaf Weiner

    Full Text Available Packaging of eukaryotic genomes into chromatin has wide-ranging effects on gene transcription. Curiously, it is commonly observed that deletion of a global chromatin regulator affects expression of only a limited subset of genes bound to or modified by the regulator in question. However, in many single-gene studies it has become clear that chromatin regulators often do not affect steady-state transcription, but instead are required for normal transcriptional reprogramming by environmental cues. We therefore have systematically investigated the effects of 83 histone mutants, and 119 gene deletion mutants, on induction/repression dynamics of 170 transcripts in response to diamide stress in yeast. Importantly, we find that chromatin regulators play far more pronounced roles during gene induction/repression than they do in steady-state expression. Furthermore, by jointly analyzing the substrates (histone mutants and enzymes (chromatin modifier deletions we identify specific interactions between histone modifications and their regulators. Combining these functional results with genome-wide mapping of several histone marks in the same time course, we systematically investigated the correspondence between histone modification occurrence and function. We followed up on one pathway, finding that Set1-dependent H3K4 methylation primarily acts as a gene repressor during multiple stresses, specifically at genes involved in ribosome biosynthesis. Set1-dependent repression of ribosomal genes occurs via distinct pathways for ribosomal protein genes and ribosomal biogenesis genes, which can be separated based on genetic requirements for repression and based on chromatin changes during gene repression. Together, our dynamic studies provide a rich resource for investigating chromatin regulation, and identify a significant role for the "activating" mark H3K4me3 in gene repression.

  1. Fuz regulates craniofacial development through tissue specific responses to signaling factors.

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    Zichao Zhang

    Full Text Available The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz(-/- mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz(-/- mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz(-/- mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling.

  2. Neurotoxin-induced selective ubiquitination and regulation of MEF2A isoform in neuronal stress response.

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    She, Hua; Yang, Qian; Mao, Zixu

    2012-09-01

    The myocyte enhancer factor 2A-D (MEF2) proteins are members of the MCM1-agamous-deficiens-serum response factor family of transcription factors. Various MEF2 isoform proteins are enriched in neurons and exhibit distinct patterns of expression in different regions of the brain. In neurons, MEF2 functions as a converging factor to regulate many neuronal functions including survival. MEF2 activities are tightly controlled in neurons in response to stress. Whether stress signal may differentially regulate MEF2s remains largely unknown. In this work, we showed that MEF2A, but not MEF2C or MEF2D, was modified by ubiquitination in dopaminergic neuronal cell line SN4741 cells. MEF2A was ubiquitinated at its N'-terminus, and the ubiquitination of MEF2A was first detectable in the nuclear compartment and later in the cytoplasm. Ubiquitination of MEF2A correlated with reduced DNA-binding activity and transcriptional activity. More importantly, disturbing the degradation of ubiquitinated MEF2A through proteasome pathway by neurotoxins known to induce Parkinson's disease features in model animals caused accumulation of ubiquitinated MEF2A, reduced MEF2 activity, and impaired cellular viability. Our work thus provides the first evidence to demonstrate an isoforms-specific regulation of MEF2s by ubiquitination-proteasome pathway in dopaminergic neuronal cell by neurotoxins, suggesting that stress signal and cellular context-dependent dysregulation of MEF2s may underlie the loss of neuronal viability.

  3. Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

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    Eloi R. Verrier

    2016-10-01

    Full Text Available Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs, including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.

  4. Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes.

    Science.gov (United States)

    Verrier, Eloi R; Colpitts, Che C; Bach, Charlotte; Heydmann, Laura; Zona, Laetitia; Xiao, Fei; Thumann, Christine; Crouchet, Emilie; Gaudin, Raphaël; Sureau, Camille; Cosset, François-Loïc; McKeating, Jane A; Pessaux, Patrick; Hoshida, Yujin; Schuster, Catherine; Zeisel, Mirjam B; Baumert, Thomas F

    2016-10-25

    Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. Corporate Social Responsibility or Government Regulation? Evidence on Oil Spill Prevention

    Directory of Open Access Journals (Sweden)

    Jedrzej G. Frynas

    2012-12-01

    Full Text Available Major oil spills normally occur from oil pipelines and oil tankers that are under operational control of companies, namely, oil companies and tanker owners. There are two generic responses for changing the behavior of companies with regard to oil spill prevention: mandatory government regulation or voluntary initiatives often pursued under the banner of Corporate Social Responsibility (CSR. Here we investigate to what extent voluntary CSR initiatives can be effective in oil spill prevention. A global perspective on voluntary mechanisms is taken by looking at the progress of 20 oil and gas firms from around the world toward oil spill prevention, using the companies' 2010 sustainability reports for self-reported oil spill information. The analysis includes ten oil companies from OECD countries (including Exxon and Shell, among others and 10 oil companies from non-OECD countries (including Brazil's Petrobras and Indian Oil, among others. The study finds that oil spill prevention has generally improved over recent decades. Government regulation played a significant part in these improvements whereas it is less clear to what extent CSR played a significant part in these improvements. Some of CSR's key limitations are highlighted. It is not suggested that CSR should be abandoned; however, new hybrid forms of regulation that combine voluntary and mandatory elements are advocated.

  6. Inter-regulation of the unfolded protein response and auxin signaling.

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    Chen, Yani; Aung, Kyaw; Rolčík, Jakub; Walicki, Kathryn; Friml, Jiří; Brandizzi, Federica

    2014-01-01

    The unfolded protein response (UPR) is a signaling network triggered by overload of protein-folding demand in the endoplasmic reticulum (ER), a condition termed ER stress. The UPR is critical for growth and development; nonetheless, connections between the UPR and other cellular regulatory processes remain largely unknown. Here, we identify a link between the UPR and the phytohormone auxin, a master regulator of plant physiology. We show that ER stress triggers down-regulation of auxin receptors and transporters in Arabidopsis thaliana. We also demonstrate that an Arabidopsis mutant of a conserved ER stress sensor IRE1 exhibits defects in the auxin response and levels. These data not only support that the plant IRE1 is required for auxin homeostasis, they also reveal a species-specific feature of IRE1 in multicellular eukaryotes. Furthermore, by establishing that UPR activation is reduced in mutants of ER-localized auxin transporters, including PIN5, we define a long-neglected biological significance of ER-based auxin regulation. We further examine the functional relationship of IRE1 and PIN5 by showing that an ire1 pin5 triple mutant enhances defects of UPR activation and auxin homeostasis in ire1 or pin5. Our results imply that the plant UPR has evolved a hormone-dependent strategy for coordinating ER function with physiological processes.

  7. Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage

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    Eric J. Jaehnig

    2013-07-01

    Full Text Available DNA damage activates checkpoint kinases that induce several downstream events, including widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs are not well understood. Here, we integrate kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics to map kinases and downstream TFs to transcriptional regulatory networks. Specifically, we investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1 in the transcriptional response to DNA damage caused by methyl methanesulfonate. The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network involves at least nine TFs, many of which have Rad53-dependent phosphorylation sites, as regulators of checkpoint-kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network that regulates stress response genes independently of the checkpoint kinases.

  8. Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo.

    Science.gov (United States)

    Deignan, Lisa; Pinheiro, Marco T; Sutcliffe, Catherine; Saunders, Abbie; Wilcockson, Scott G; Zeef, Leo A H; Donaldson, Ian J; Ashe, Hilary L

    2016-07-01

    The BMP signaling pathway has a conserved role in dorsal-ventral axis patterning during embryonic development. In Drosophila, graded BMP signaling is transduced by the Mad transcription factor and opposed by the Brinker repressor. In this study, using the Drosophila embryo as a model, we combine RNA-seq with Mad and Brinker ChIP-seq to decipher the BMP-responsive transcriptional network underpinning differentiation of the dorsal ectoderm during dorsal-ventral axis patterning. We identify multiple new BMP target genes, including positive and negative regulators of EGF signaling. Manipulation of EGF signaling levels by loss- and gain-of-function studies reveals that EGF signaling negatively regulates embryonic BMP-responsive transcription. Therefore, the BMP gene network has a self-regulating property in that it establishes a balance between its activity and that of the antagonistic EGF signaling pathway to facilitate correct patterning. In terms of BMP-dependent transcription, we identify key roles for the Zelda and Zerknüllt transcription factors in establishing the resulting expression domain, and find widespread binding of insulator proteins to the Mad and Brinker-bound genomic regions. Analysis of embryos lacking the BEAF-32 insulator protein shows reduced transcription of a peak BMP target gene and a reduction in the number of amnioserosa cells, the fate specified by peak BMP signaling. We incorporate our findings into a model for Mad-dependent activation, and discuss its relevance to BMP signal interpretation in vertebrates.

  9. The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans.

    Science.gov (United States)

    Block, Dena H S; Twumasi-Boateng, Kwame; Kang, Hae Sung; Carlisle, Jolie A; Hanganu, Alexandru; Lai, Ty Yu-Jen; Shapira, Michael

    2015-05-01

    GATA transcription factors play critical roles in cellular differentiation and development. However, their roles in mature tissues are less understood. In C. elegans larvae, the transcription factor ELT-2 regulates terminal differentiation of the intestine. It is also expressed in the adult intestine, where it was suggested to maintain intestinal structure and function, and where it was additionally shown to contribute to infection resistance. To study the function of elt-2 in adults we characterized elt-2-dependent gene expression following its knock-down specifically in adults. Microarray analysis identified two ELT-2-regulated gene subsets: one, enriched for hydrolytic enzymes, pointed at regulation of constitutive digestive functions as a dominant role of adult elt-2; the second was enriched for immune genes that are induced in response to Pseudomonas aeruginosa infection. Focusing on the latter, we used genetic analyses coupled to survival assays and quantitative RT-PCR to interrogate the mechanism(s) through which elt-2 contributes to immunity. We show that elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1. This demonstrates a mechanism through which the constitutively nuclear elt-2 can impact induced responses, and play a dominant role in C. elegans immunity.

  10. Sa-Lrp from Sulfolobus acidocaldarius is a versatile, glutamine-responsive, and architectural transcriptional regulator.

    Science.gov (United States)

    Vassart, Amelia; Van Wolferen, Marleen; Orell, Alvaro; Hong, Ye; Peeters, Eveline; Albers, Sonja-Verena; Charlier, Daniel

    2013-02-01

    Sa-Lrp is a member of the leucine-responsive regulatory protein (Lrp)-like family of transcriptional regulators in Sulfolobus acidocaldarius. Previously, we demonstrated the binding of Sa-Lrp to the control region of its own gene in vitro. However, the function and cofactor of Sa-Lrp remained an enigma. In this work, we demonstrate that glutamine is the cofactor of Sa-Lrp by inducing the formation of octamers and increasing the DNA-binding affinity and sequence specificity. In vitro protein-DNA interaction assays indicate that Sa-Lrp binds to promoter regions of genes with a variety of functions including ammonia assimilation, transcriptional control, and UV-induced pili synthesis. DNA binding occurs with a specific affinity for AT-rich binding sites, and the protein induces DNA bending and wrapping upon binding, indicating an architectural role of the regulator. Furthermore, by analyzing an Sa-lrp deletion mutant, we demonstrate that the protein affects transcription of some of the genes of which the promoter region is targeted and that it is an important determinant of the cellular aggregation phenotype. Taking all these results into account, we conclude that Sa-Lrp is a glutamine-responsive global transcriptional regulator with an additional architectural role.

  11. Overexpression, purification and crystallization of the response regulator NsrR involved in nisin resistance.

    Science.gov (United States)

    Khosa, Sakshi; Hoeppner, Astrid; Kleinschrodt, Diana; Smits, Sander H J

    2015-10-01

    A number of Gram-positive bacteria produce a class of bacteriocins called `lantibiotics'. These lantibiotics are ribosomally synthesized peptides that possess high antimicrobial activity against Gram-positive bacteria, including clinically challenging pathogens, and are therefore potential alternatives to antibiotics. All lantibiotic producer strains and some Gram-positive nonproducer strains express protein systems to circumvent a suicidal effect or to become resistant, respectively. Two-component systems consisting of a response regulator and a histidine kinase upregulate the expression of these proteins. One of the best-characterized lantibiotics is nisin, which is produced by Lactococcus lactis and possesses bactericidal activity against various Gram-positive bacteria, including some human pathogenic strains. Within many human pathogenic bacterial strains inherently resistant to nisin, a response regulator, NsrR, has been identified which regulates the expression of proteins involved in nisin resistance. In the present study, an expression and purification protocol was established for the NsrR protein from Streptococcus agalactiae COH1. The protein was successfully crystallized using the vapour-diffusion method, resulting in crystals that diffracted X-rays to 1.4 Å resolution.

  12. The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans.

    Directory of Open Access Journals (Sweden)

    Dena H S Block

    2015-05-01

    Full Text Available GATA transcription factors play critical roles in cellular differentiation and development. However, their roles in mature tissues are less understood. In C. elegans larvae, the transcription factor ELT-2 regulates terminal differentiation of the intestine. It is also expressed in the adult intestine, where it was suggested to maintain intestinal structure and function, and where it was additionally shown to contribute to infection resistance. To study the function of elt-2 in adults we characterized elt-2-dependent gene expression following its knock-down specifically in adults. Microarray analysis identified two ELT-2-regulated gene subsets: one, enriched for hydrolytic enzymes, pointed at regulation of constitutive digestive functions as a dominant role of adult elt-2; the second was enriched for immune genes that are induced in response to Pseudomonas aeruginosa infection. Focusing on the latter, we used genetic analyses coupled to survival assays and quantitative RT-PCR to interrogate the mechanism(s through which elt-2 contributes to immunity. We show that elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1. This demonstrates a mechanism through which the constitutively nuclear elt-2 can impact induced responses, and play a dominant role in C. elegans immunity.

  13. Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.

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    Kishore V L Parsa

    2006-07-01

    Full Text Available Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.

  14. In vivo phosphorylation dynamics of the Bordetella pertussis virulence-controlling response regulator BvgA.

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    Boulanger, Alice; Chen, Qing; Hinton, Deborah M; Stibitz, Scott

    2013-04-01

    We have used protein electrophoresis through polyacrylamide gels derivatized with the proprietary ligand Phos-tag™ to separate the response regulator BvgA from its phosphorylated counterpart BvgA∼P. This approach has allowed us to readily ascertain the degree of phosphorylation of BvgA in in vitro reactions, or in crude lysates of Bordetella pertussis grown under varying laboratory conditions. We have used this technique to examine the kinetics of BvgA phosphorylation after shift of B. pertussis cultures from non-permissive to permissive conditions, or of its dephosphorylation following a shift from permissive to non-permissive conditions. Our results provide the first direct evidence that levels of BvgA∼P in vivo correspond temporally to the expression of early and late BvgA-regulated virulence genes. We have also examined a number of other aspects of BvgA function predicted from previous studies and by analogy with other two-component response regulators. These include the site of BvgA phosphorylation, the exclusive role of the cognate BvgS sensor kinase in its phosphorylation in Bordetella pertussis, and the effect of the T194M mutation on phosphorylation. We also detected the phosphorylation of a small but consistent fraction of BvgA purified after expression in Escherichia coli.

  15. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination.

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    Hu, Hongbo; Wang, Hui; Xiao, Yichuan; Jin, Jin; Chang, Jae-Hoon; Zou, Qiang; Xie, Xiaoping; Cheng, Xuhong; Sun, Shao-Cong

    2016-03-07

    Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.

  16. Dynamic regulation of partner abundance mediates response of reef coral symbioses to environmental change.

    Science.gov (United States)

    Cunning, R; Vaughan, N; Gillette, P; Capo, T R; Matté, J L; Baker, A C

    2015-05-01

    Regulating partner abunclance may allow symmotic organisms to mediate interaction outcomes, facilitating adaptive responses to environmental change. To explore the capacity for-adaptive regulation in an ecologically important endosymbiosis, we studied the population dynamics of symbiotic algae in reef-building corals under different abiotic contexts. We found high natural variability in symbiont abundance in corals across reefs, but this variability converged to different symbiont-specific abundances when colonies were maintained under constant conditions. When conditions changed seasonally, symbiont abundance readjusted to new equilibria. We explain these patterns using an a priori model of symbiotic costs and benefits to the coral host, which shows that the observed changes in symbiont abundance are consistent with the maximization of interaction benefit under different environmental conditions. These results indicate that, while regulating symbiont abundance helps hosts sustain maximum benefit in a dynamic environment, spatiotemporal variation in abiotic factors creates a broad range of symbiont abundances (and interaction outcomes) among corals that may account for observed natural variability in performance (e.g., growth rate) and stress tolerance (e.g., bleaching susceptibility). This cost or benefit framework provides a new perspective on the dynamic regulation of reef coral symbioses and illustrates that the dependence of interaction outcomes on biotic and abiotic contexts may be important in understanding how diverse mutualisms respond to environmental change.

  17. Hydraulic response and nitrogen retention in bioretention mesocosms with regulated outlets: part II--nitrogen retention.

    Science.gov (United States)

    Lucas, William C; Greenway, Margaret

    2011-08-01

    We observed dissolved nitrogen retention in vegetated bioretention mesocosms using different media with varying hydraulic conductivities. Elevated outlets were installed to regulate hydraulic response, with one treatment left free draining. The treatments (three replicates each) were loaded weekly with 50 cm of effluent averaging 2.47 mg/L nitrogen oxides (NOx) and 4.67 mg/L total nitrogen for 1 year. The NOx and total nitrogen retention by the outlet regulated treatments was significantly greater than the unregulated treatment. The systems then were dosed 6 times with 53 cm of synthetic stormwater averaging 0.77 mg/ L NOx and 1.46 mg/L total nitrogen, applied over 90 minutes. The outlet regulated treatment retained 68% NOx and 60% total nitrogen, while the corresponding free draining treatment retained 25% NOx and 27% total nitrogen. Over the following winter, the outlet regulated treatment retained 50% NOx and 73% total nitrogen, while the corresponding free draining treatment exported 17% more NOx, while retaining 50% total nitrogen.

  18. Fitting into the harsh reality: regulation of iron-deficiency responses in dicotyledonous plants.

    Science.gov (United States)

    Ivanov, Rumen; Brumbarova, Tzvetina; Bauer, Petra

    2012-01-01

    Iron is an essential element for life on Earth and its shortage, or excess, in the living organism may lead to severe health disorders. Plants serve as the primary source of dietary iron and improving crop iron content is an important step towards a better public health. Our review focuses on the control of iron acquisition in dicotyledonous plants and monocots that apply a reduction-based strategy in order to mobilize and import iron from the rhizosphere. Achieving a balance between shortage and excess of iron requires a tight regulation of the activity of the iron uptake system. A number of studies, ranging from single gene characterization to systems biology analyses, have led to the rapid expansion of our knowledge on iron uptake in recent years. Here, we summarize the novel insights into the regulation of iron acquisition and internal mobilization from intracellular stores. We present a detailed view of the main known regulatory networks defined by the Arabidopsis regulators FIT and POPEYE (PYE). Additionally, we analyze the root and leaf iron-responsive regulatory networks, revealing novel potential gene interactions and reliable iron-deficiency marker genes. We discuss perspectives and open questions with regard to iron sensing and post-translational regulation.

  19. The effect of methylphenidate and clonidine on response inhibition and state regulation in children with ADHD.

    Science.gov (United States)

    van der Meere, J; Gunning, B; Stemerdink, N

    1999-02-01

    The goal of this study was to evaluate the effect of methylphenidate (MPH) and clonidine in comparison with placebo on response inhibition and state regulation in children with Attention Deficit Hyperactivity Disorder (ADHD). The study utilised a double-blind cross-over design in which children were randomly assigned without replacement to placebo, MPH, and clonidine following baseline assessment. The primary dependent measures were derived from children's performance (reaction time and errors) on a GO-NO GO task under three conditions that altered the inter-stimulus interval (ISI) for presented GO-NO GO stimuli: ISI of 1 sec (fast condition), 4 sec (medium condition), and 8 sec (slow condition). Findings indicated no difference in task performance between groups treated for 7 weeks with placebo, MPH, and clonidine. We concluded that the state regulation problem in ADHD is resistant to MPH and clonidine.

  20. Enhancing Social Responsibility within Global Supply Chains: Is Legal Regulation the Optimal Solution?

    Directory of Open Access Journals (Sweden)

    Katerina Peterková

    2011-03-01

    Full Text Available This paper was presented at the first meeting of the NSU study group “Conceptions of ethical and social values in post-secular society: Towards a new ethical imagination in a cosmopolitan world society”, held on January 28-30, 2011 at Copenhagen Business School. First, this paper examines the voluntary (ethical v. mandatory (legal basis of corporate social responsibility (CSR. Second, it examines the relationship between CSR, law and business ethics. Third, it tries to answer the question if there is a need for a hard[2] legal regulation of CSR within international supply relationships or if ethical norms, e.g. expressed in the form of self-regulation, may better serve the purpose. And finally, it suggests possible ways for the future development of suitable regulatory methods for enhancing social standards within international supply chains. The questions are approached solely from the perspectives of legal theory and socio-legal analysis.

  1. Regulation of urea synthesis during the acute phase response in rats

    DEFF Research Database (Denmark)

    Thomsen, Karen Louise; Jessen, Niels; Buch Møller, Andreas

    2013-01-01

    of the tumor necrosis factor-α (TNF-α)-induced acute-phase response in rats. We used four methods to study the regulation of urea synthesis: We examined urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, the in vivo capacity of urea-N synthesis (CUNS), and known humoral...... regulators of CUNS at 1, 3, 24, and 72 h after TNF-α injection (25 μg/kg iv rrTNF-α) in rats. Serum acute-phase proteins and their liver mRNA levels were also measured. The urea cycle enzyme mRNA levels acutely decreased and then gradually normalized, whereas the urea cycle enzyme proteins remained...

  2. Could FaRP-like peptides participate in regulation of hyperosmotic stress responses in plants?

    Directory of Open Access Journals (Sweden)

    Francois eBouteau

    2014-08-01

    Full Text Available The ability to respond to hyperosmotic stress is one of numerous conserved cellular processes that most of the organisms have to face during their life. In metazoans, some peptides belonging to the FMRFamide-like peptide (FLP family were shown to participate to osmoregulation via regulation of ion channels; this is, a well-known response to hyperosmotic stress in plants. Thus, we explored whether FLPs exist and regulate osmotic stress in plants. First, we demonstrated the response of Arabidopsis thaliana cultured cells to a metazoan FLP (FLRF. We found that Arabidopis thaliana express genes that display typical FLP repeated sequences, which end in RF and are surrounded by K or R, which is typical of cleavage sites and suggests bioactivity; however, the terminal G, allowing an amidation process in metazoan, seems to be replaced by W. Using synthetic peptides, we showed that amidation appears unnecessary to bioactivity in A. thaliana, and we provide evidence that these putative FLPs could be involved in physiological processes related to hyperosmotic stress responses in plants, urging further studies on this topic.

  3. Jasmonic acid carboxyl methyltransferase regulates development and herbivory-induced defense response in rice

    Institute of Scientific and Technical Information of China (English)

    Jinfeng Qi; Yonggen Lou; Jiancai Li; Xiu Han; Ran Li; Jianqiang Wu; Haixin Yu; Lingfei Hu; Yutao Xiao; Jing Lu

    2016-01-01

    Jasmonic acid (JA) and related metabolites play a key role in plant defense and growth. JA carboxyl methyltransferase (JMT) may be involved in plant defense and development by methylating JA to methyl jasmonate (MeJA) and thus influencing the concentrations of JA and related metabolites. However, no JMT gene has been well characterized in monocotyledon defense and development at the molecular level. After we cloned a rice JMT gene, OsJMT1, whose encoding protein was localized in the cytosol, we found that the recombinant OsJMT1 protein catalyzed JA to MeJA. OsJMT1 is up-regulated in response to infestation with the brown planthopper (BPH; Nilaparvata lugens). Plants in which OsJMT1 had been overexpressed (oe-JMT plants) showed reduced height and yield. These oe-JMT plants also exhibited increased MeJA levels but reduced levels of herbivore-induced JA and jasmonoyl-isoleucine (JA-Ile). The oe-JMT plants were more attractive to BPH female adults but showed increased resistance to BPH nymphs, probably owing to the different responses of BPH female adults and nymphs to the changes in levels of H2O2 and MeJA in oe-JMT plants. These results indicate that OsJMT1, by altering levels of JA and related metabolites, plays a role in regulating plant development and herbivore-induced defense responses in rice.

  4. Insulin demand regulates β cell number via the unfolded protein response.

    Science.gov (United States)

    Sharma, Rohit B; O'Donnell, Amy C; Stamateris, Rachel E; Ha, Binh; McCloskey, Karen M; Reynolds, Paul R; Arvan, Peter; Alonso, Laura C

    2015-10-01

    Although stem cell populations mediate regeneration of rapid turnover tissues, such as skin, blood, and gut, a stem cell reservoir has not been identified for some slower turnover tissues, such as the pancreatic islet. Despite lacking identifiable stem cells, murine pancreatic β cell number expands in response to an increase in insulin demand. Lineage tracing shows that new β cells are generated from proliferation of mature, differentiated β cells; however, the mechanism by which these mature cells sense systemic insulin demand and initiate a proliferative response remains unknown. Here, we identified the β cell unfolded protein response (UPR), which senses insulin production, as a regulator of β cell proliferation. Using genetic and physiologic models, we determined that among the population of β cells, those with an active UPR are more likely to proliferate. Moreover, subthreshold endoplasmic reticulum stress (ER stress) drove insulin demand-induced β cell proliferation, through activation of ATF6. We also confirmed that the UPR regulates proliferation of human β cells, suggesting that therapeutic UPR modulation has potential to expand β cell mass in people at risk for diabetes. Together, this work defines a stem cell-independent model of tissue homeostasis, in which differentiated secretory cells use the UPR sensor to adapt organ size to meet demand.

  5. Regulation of Serum Response Factor and Adiponectin by PPARγ Agonist Docosahexaenoic Acid

    Directory of Open Access Journals (Sweden)

    Clayton Johnson

    2011-01-01

    Full Text Available Recent studies indicate that significant health benefits involving the regulation of signaling proteins result from the consumption of omega-3 polyunsaturated fatty acids (ω-3 PUFAs. Serum response factor (SRF is involved in transcriptional regulation of muscle growth and differentiation. SRF levels are increased in the aging heart muscle. It has not been examined whether SRF is made by adipocytes and whether SRF secretion by adipocytes is modulated by PPARγ agonist DHA. Adiponectin is made exclusively by adipocytes. We and others have previously reported that PUFAs such as DHA increase adiponectin levels and secretion in adipocytes. Here we show that DHA downregulates SRF with a simultaneous upregulation of adiponectin and that both these responses are reversible by PPARγ antagonist. Furthermore, there appears to be a direct relationship between DHA exposure and increased levels of membrane-associated high-density adiponectin, as well as lower levels of membrane-associated SRF. Thus, we find that the levels of SRF and adiponectin are inversely related in response to treatment with PPARγ agonist DHA. Decreased levels of SRF along with increase in membrane-associated adiponectin could in part mediate the health benefits of DHA.

  6. A novel ethylene responsive factor CitERF13 plays a role in photosynthesis regulation.

    Science.gov (United States)

    Xie, Xiu-Lan; Xia, Xiao-Jian; Kuang, Sheng; Zhang, Xi-Li; Yin, Xue-Ren; Yu, Jing-Quan; Chen, Kun-Song

    2017-03-01

    Ethylene responsive factors (ERFs) act as critical downstream components of the ethylene signalling pathway in regulating plant development and stress responses. However little is known about its role in regulation of photosynthesis. Here, we identified an ethylene-inducible ERF gene in citrus, CitERF13. Transient over-expression of CitERF13 in N. tabacum leaves, resulted in a significant decrease in net photosynthetic rate. Closer examination of photosynthetic activity of PSII and PSI indicated that CitERF13 overexpression led to declines of Fv/Fm, Y(II) and Y(I). However, change in NPQ was less pronounced. CitERF13 overexpression also significantly reduced Vc,max, Jmax and AQY, indicating inhibition of the Calvin cycle. The expression of photosynthesis-related genes was suppressed to a variable extent in leaf blades transiently over-expressing CitERF13. CitERF13 transient overexpression in tobacco or citrus both resulted in a decline of Chlorophyll content and CitERF13 overexpressing tobacco leaf disc was more susceptible to chlorosis in response to MV-mediated oxidative stress. The results suggest that CitERF13 is potentially involved in suppressing photosynthesis through multiple pathways, for instance, inhibiting photochemical activity of photosynthesis, CO2 carboxylation capacity and chlorophyll metabolism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. From top to bottom: the two faces of HIPK2 for regulation of the hypoxic response.

    Science.gov (United States)

    Calzado, Marco A; De La Vega, Laureano; Munoz, Eduardo; Schmitz, M Lienhard

    2009-06-01

    Oxygen deprivation (hypoxia) triggers a complex network of signaling pathways that result in changed gene expression patterns in order to cope with this challenge. Recent work has identified the serine/threonine kinase HIPK2 as a novel regulatory protein participating in hypoxic gene regulation. HIPK2 can affect apical as well as downstream events during the hypoxic response. Under normoxic conditions, HIPK2-mediated phosphorylation of the ubiquitin E3 ligase Siah2 weakens mutual binding and destabilizes the phosphorylated E3 ligase. Low oxygen levels result in strongly increased HIPK2/Siah2 interactions that lead to efficient polyubiquitylation and proteasomal degradation of the kinase. At the apical level, the Siah2 inhibiting phosphorylations are lost, thus allowing Siah2-dependent proteolysis of dioxygenases which in turn allows for activation of transcription factor HIF. Downstream events of the hypoxic response are affected by the proteasomal elimination of HIPK2 from gene repressing complexes, an event that allows for full induction of gene expression. Thus HIPK2 can regulate a subset of HIF-dependent and -independent genes during the hypoxic response.

  8. GH3-mediated auxin homeostasis links growth regulation with stress adaptation response in Arabidopsis.

    Science.gov (United States)

    Park, Jung-Eun; Park, Ju-Young; Kim, Youn-Sung; Staswick, Paul E; Jeon, Jin; Yun, Ju; Kim, Sun-Young; Kim, Jungmook; Lee, Yong-Hwan; Park, Chung-Mo

    2007-03-30

    Plants constantly monitor environmental fluctuations to optimize their growth and metabolism. One example is adaptive growth occurring in response to biotic and abiotic stresses. Here, we demonstrate that GH3-mediated auxin homeostasis is an essential constituent of the complex network of auxin actions that regulates stress adaptation responses in Arabidopsis. Endogenous auxin pool is regulated, at least in part, through negative feedback by a group of auxin-inducible GH3 genes encoding auxin-conjugating enzymes. An Arabidopsis mutant, wes1-D, in which a GH3 gene WES1 is activated by nearby insertion of the (35)S enhancer, exhibited auxin-deficient traits, including reduced growth and altered leaf shape. Interestingly, WES1 is also induced by various stress conditions as well as by salicylic acid and abscisic acid. Accordingly, wes1-D was resistant to both biotic and abiotic stresses, and stress-responsive genes, such as pathogenesis-related genes and CBF genes, were upregulated in this mutant. In contrast, a T-DNA insertional mutant showed reduced stress resistance. We therefore propose that GH3-mediated growth suppression directs reallocation of metabolic resources to resistance establishment and represents the fitness costs of induced resistance.

  9. Response to Xanthomonas campestris pv. vesicatoria in tomato involves regulation of ethylene receptor gene expression.

    Science.gov (United States)

    Ciardi, J A; Tieman, D M; Lund, S T; Jones, J B; Stall, R E; Klee, H J

    2000-05-01

    Although ethylene regulates a wide range of defense-related genes, its role in plant defense varies greatly among different plant-microbe interactions. We compared ethylene's role in plant response to virulent and avirulent strains of Xanthomonas campestris pv. vesicatoria in tomato (Lycopersicon esculentum Mill.). The ethylene-insensitive Never ripe (Nr) mutant displays increased tolerance to the virulent strain, while maintaining resistance to the avirulent strain. Expression of the ethylene receptor genes NR and LeETR4 was induced by infection with both virulent and avirulent strains; however, the induction of LeETR4 expression by the avirulent strain was blocked in the Nr mutant. To determine whether ethylene receptor levels affect symptom development, transgenic plants overexpressing a wild-type NR cDNA were infected with virulent X. campestris pv. vesicatoria. Like the Nr mutant, the NR overexpressors displayed greatly reduced necrosis in response to this pathogen. NR overexpression also reduced ethylene sensitivity in seedlings and mature plants, indicating that, like LeETR4, this receptor is a negative regulator of ethylene response. Therefore, pathogen-induced increases in ethylene receptors may limit the spread of necrosis by reducing ethylene sensitivity.

  10. Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?

    Directory of Open Access Journals (Sweden)

    Gerhard Fritz

    2015-09-01

    Full Text Available The Ras-related C3 botulinum toxin substrate 1 (Rac1 belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR that are related to DNA repair, survival and cell death.

  11. Arabidopsis MSI1 Is Required for Negative Regulation of the Response to Drought Stress

    Institute of Scientific and Technical Information of China (English)

    Cristina Alexandre; Yvonne M(o)ller-Steinbach; Nicole Sch(o)nrock; Wilhelm Gruissem; Lars Hennig

    2009-01-01

    Arabidopsis MSI1 has fundamental functions in plant development.MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1,and it interacts with the Retinoblastoma-related protein 1.Altered levels of MSI1 result in pleiotropic phenotypes,reflecting the complexity of MSI1 protein functions.In order to uncover additional functions of MSI1,we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels (msil-cs).Surprisingly,the known functions of MSI1 could only account for a minor part of the transcriptional changes in msi1-cs plants.One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress.We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.

  12. 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.

    Science.gov (United States)

    DelNero, Peter; Lane, Maureen; Verbridge, Scott S; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia

    2015-07-01

    Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.

  13. CD4(+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.

    Directory of Open Access Journals (Sweden)

    Jamie C Zampell

    Full Text Available INTRODUCTION: Lymphedema is a chronic disorder that occurs commonly after lymph node removal for cancer treatment and is characterized by swelling, fibrosis, inflammation, and adipose deposition. Although previous histological studies have investigated inflammatory changes that occur in lymphedema, the precise cellular make up of the inflammatory infiltrate remains unknown. It is also unclear if this inflammatory response plays a causal role in the pathology of lymphedema. The purpose of this study was therefore to characterize the inflammatory response to lymphatic stasis and determine if these responses are necessary for the pathological changes that occur in lymphedema. METHODS: We used mouse-tail lymphedema and axillary lymph node dissection (ANLD models in order to study tissue inflammatory changes. Single cell suspensions were created and analyzed using multi-color flow cytometry to identify individual cell types. We utilized antibody depletion techniques to analyze the causal role of CD4+, CD8+, and CD25+ cells in the regulation of inflammation, fibrosis, adipose deposition, and lymphangiogenesis. RESULTS: Lymphedema in the mouse-tail resulted in a mixed inflammatory cell response with significant increases in T-helper, T-regulatory, neutrophils, macrophages, and dendritic cell populations. Interestingly, we found that ALND resulted in significant increases in T-helper cells suggesting that these adaptive immune responses precede changes in macrophage and dendritic cell infiltration. In support of this we found that depletion of CD4+, but not CD8 or CD25+ cells, significantly decreased tail lymphedema, inflammation, fibrosis, and adipose deposition. In addition, depletion of CD4+ cells significantly increased lymphangiogenesis both in our tail model and also in an inflammatory lymphangiogenesis model. CONCLUSIONS: Lymphedema and lymphatic stasis result in CD4+ cell inflammation and infiltration of mature T-helper cells. Loss of CD4+ but

  14. Control of the C. albicans cell wall damage response by transcriptional regulator Cas5.

    Directory of Open Access Journals (Sweden)

    Vincent M Bruno

    2006-03-01

    Full Text Available The fungal cell wall is vital for growth, development, and interaction of cells with their environment. The response to cell wall damage is well understood from studies in the budding yeast Saccharomyces cerevisiae, where numerous cell wall integrity (CWI genes are activated by transcription factor ScRlm1. Prior evidence suggests the hypothesis that both response and regulation may be conserved in the major fungal pathogen Candida albicans. We have tested this hypothesis by using a new C. albicans genetic resource: we have screened mutants defective in putative transcription factor genes for sensitivity to the cell wall biosynthesis inhibitor caspofungin. We find that the zinc finger protein CaCas5, which lacks a unique ortholog in S. cerevisiae, governs expression of many CWI genes. CaRlm1 has a modest role in this response. The transcriptional coactivator CaAda2 is also required for expression of many CaCas5-dependent genes, as expected if CaCas5 recruits CaAda2 to activate target gene transcription. Many caspofungin-induced C. albicans genes specify endoplasmic reticulum and secretion functions. Such genes are not induced in S. cerevisiae, but promote its growth in caspofungin. We have used a new resource to identify a key C. albicans transcriptional regulator of CWI genes and antifungal sensitivity. Our gene expression findings indicate that both divergent and conserved response genes may have significant functional roles. Our strategy may be broadly useful for identification of pathogen-specific regulatory pathways and critical response genes.

  15. The Pepper CaOSR1 Protein Regulates the Osmotic Stress Response via Abscisic Acid Signaling.

    Science.gov (United States)

    Park, Chanmi; Lim, Chae Woo; Lee, Sung Chul

    2016-01-01

    Plants are sessile organisms, and their growth and development is detrimentally affected by environmental stresses such as drought and high salinity. Defense mechanisms are tightly regulated and complex processes, which respond to changing environmental conditions; however, the precise mechanisms that function under adverse conditions remain unclear. Here, we report the identification and functional characterization of the CaOSR1 gene, which functions in the adaptive response to abiotic stress. We found that CaOSR1 gene expression in pepper leaves was up-regulated after exposure to abscisic acid (ABA), drought, and high salinity. In addition, we demonstrated that the fusion protein of CaOSR1 with green fluorescent protein (GFP) is localized in the nucleus. We used CaOSR1-silenced pepper plants and CaOSR1-OX-overexpressing (OX) transgenic Arabidopsis plants to show that the CaOSR1 protein regulates the osmotic stress response. CaOSR1-silenced pepper plants showed increased drought susceptibility, and this was accompanied by a high transpiration rate. CaOSR1-OX plants displayed phenotypes that were hypersensitive to ABA and hyposensitive to osmotic stress, during the seed germination and seedling growth stages; furthermore, these plants exhibited enhanced drought tolerance at the adult stage, and this was characterized by higher leaf temperatures and smaller stomatal apertures because of ABA hypersensitivity. Taken together, our data indicate that CaOSR1 positively regulates osmotic stress tolerance via ABA-mediated cell signaling. These findings suggest an involvement of a novel protein in ABA and osmotic stress signalings in plants.

  16. Mesenchymal Stem Cells Exhibit Regulated Exocytosis in Response to Chemerin and IGF.

    Directory of Open Access Journals (Sweden)

    J Dinesh Kumar

    Full Text Available Mesenchymal stem cells (MSCs play important roles in tissue repair and cancer progression. Our recent work suggests that some mesenchymal cells, notably myofibroblasts exhibit regulated exocytosis resembling that seen in neuroendocrine cells. We now report that MSCs also exhibit regulated exocytosis. Both a G-protein coupled receptor agonist, chemerin, and a receptor tyrosine kinase stimulant, IGF-II, evoked rapid increases in secretion of a marker protein, TGFβig-h3. The calcium ionophore, ionomycin, also rapidly increased secretion of TGFβig-h3 while inhibitors of translation (cycloheximide or secretory protein transport (brefeldin A had no effect, indicating secretion from preformed secretory vesicles. Inhibitors of the chemerin and IGF receptors specifically reduced the secretory response. Confocal microscopy of MSCs loaded with Fluo-4 revealed chemerin and IGF-II triggered intracellular Ca2+ oscillations requiring extracellular calcium. Immunocytochemistry showed co-localisation of TGFβig-h3 and MMP-2 to secretory vesicles, and transmission electron-microscopy showed dense-core secretory vesicles in proximity to the Golgi apparatus. Proteomic studies on the MSC secretome identified 64 proteins including TGFβig-h3 and MMP-2 that exhibited increased secretion in response to IGF-II treatment for 30min and western blot of selected proteins confirmed these data. Gene ontology analysis of proteins exhibiting regulated secretion indicated functions primarily associated with cell adhesion and in bioassays chemerin increased adhesion of MSCs and adhesion, proliferation and migration of myofibroblasts. Thus, MSCs exhibit regulated exocytosis that is compatible with an early role in tissue remodelling.

  17. Phytochrome A and B Regulate Primary Metabolism in Arabidopsis Leaves in Response to Light

    Directory of Open Access Journals (Sweden)

    Xiaozhen Han

    2017-08-01

    Full Text Available Primary metabolism is closely linked to plant productivity and quality. Thus, a better understanding of the regulation of primary metabolism by photoreceptors has profound implications for agricultural practices and management. This study aims at identifying the role of light signaling in the regulation of primary metabolism, with an emphasis on starch. We first screened seven cryptochromes and phytochromes mutants for starch phenotype. The phyAB mutant showed impairment in starch accumulation while its biomass, chlorophyll fluorescence parameters, and leaf anatomy were unaffected, this deficiency being present over the whole vegetative growth period. Mutation of plastidial nucleoside diphosphate kinase-2 (NDPK2, acting downstream of phytochromes, also caused a deficit in starch accumulation. Besides, the glucose-1-phosphate adenylyltransferase small subunit (APS1 was down-regulated in phyAB. Those results suggest that PHYAB affect starch accumulation through NDPK2 and APS1. Then, we determined changes in starch and primary metabolites in single phyA, single phyB, double phyAB grown in light conditions differing in light intensity and/or light spectral content. PHYA is involved in starch accumulation in all the examined light conditions, whereas PHYB only exhibits a role under low light intensity (44 ± 1 μmol m-2 s-1 or low R:FR (11.8 ± 0.6. PCA analysis of the metabolic profiles in the mutants and wild type (WT suggested that PHYB acts as a major regulator of the leaf metabolic status in response to light intensity. Overall, we propose that PHYA and PHYB signaling play essential roles in the control of primary metabolism in Arabidopsis leaves in response to light.

  18. Eukaryotic elongation factor 2 kinase regulates the cold stress response by slowing translation elongation.

    Science.gov (United States)

    Knight, John R P; Bastide, Amandine; Roobol, Anne; Roobol, Jo; Jackson, Thomas J; Utami, Wahyu; Barrett, David A; Smales, C Mark; Willis, Anne E

    2015-01-15

    Cells respond to external stress conditions by controlling gene expression, a process which occurs rapidly via post-transcriptional regulation at the level of protein synthesis. Global control of translation is mediated by modification of translation factors to allow reprogramming of the translatome and synthesis of specific proteins that are required for stress protection or initiation of apoptosis. In the present study, we have investigated how global protein synthesis rates are regulated upon mild cooling. We demonstrate that although there are changes to the factors that control initiation, including phosphorylation of eukaryotic translation initiation factor 2 (eIF2) on the α-subunit, the reduction in the global translation rate is mediated by regulation of elongation via phosphorylation of eukaryotic elongation factor 2 (eEF2) by its specific kinase, eEF2K (eukaryotic elongation factor 2 kinase). The AMP/ATP ratio increases following cooling, consistent with a reduction in metabolic rates, giving rise to activation of AMPK (5'-AMP-activated protein kinase), which is upstream of eEF2K. However, our data show that the major trigger for activation of eEF2K upon mild cooling is the release of Ca2+ ions from the endoplasmic reticulum (ER) and, importantly, that it is possible to restore protein synthesis rates in cooled cells by inhibition of this pathway at multiple points. As cooling has both therapeutic and industrial applications, our data provide important new insights into how the cellular responses to this stress are regulated, opening up new possibilities to modulate these responses for medical or industrial use at physiological or cooler temperatures.

  19. Soft regulation of inflammatory immune responses%炎症免疫反应软调节

    Institute of Scientific and Technical Information of China (English)

    魏伟

    2016-01-01

    炎症反应和免疫反应在整体、组织、细胞和分子等各层次密不可分。该文提出炎症免疫反应( inflammatory immune responses, IIR)是机体炎症免疫相关细胞依据内外环境变化所表现出的适度或异常的系统反应;简述了参与IIR的炎症免疫细胞(巨噬细胞、树突细胞、T 细胞、B 细胞等及其亚型)、非炎症免疫细胞(如胶质细胞、内皮细胞、上皮细胞、成纤维细胞、滑膜细胞、肝细胞等)及细胞因子/受体信号转导的研究进展,指出了目前临床上使用的影响IIR药物存在的问题,提出炎症免疫反应软调节( soft regulation of inflammato-ry immune responses,SRIIR)是研发治疗IIR相关疾病创新药物的新方向。%Inflammation reaction and immune response are in-separable in the levels of system, tissue, cell and molecule. In-flammatory immune responses ( IIR) is proposed in this paper, which is defined a moderate or abnormal system responses of in-flammatory immune related cells in responding to the internal and external environment changes of body. It is described briefly that the research progresses of inflammatory immune cells ( e. g. , macrophages, dendritic cells, T cells and B cells, etc. ) and non-inflammatory immune cells ( e. g. , glial cells, endothe-lial cells, epithelial cells, fibroblasts, synovial cells and liver cells, etc. ) , and cytokines/receptor signal transduction in-volved in IIR. Moreover, the existing problems about regulating IIR drugs clinically are summarized. It is firstly put forward that soft regulation of inflammatory immune responses ( SRIIR) is a new direction of discovery and development of new drugs for the treatment of IIR related diseases.

  20. Posttranscriptional regulation of gene expression—adding another layer of complexity to the DNA damage response

    Science.gov (United States)

    Boucas, Jorge; Riabinska, Arina; Jokic, Mladen; Herter-Sprie, Grit S.; Chen, Shuhua; Höpker, Katja; Reinhardt, H. Christian

    2012-01-01

    In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle and allow time for DNA repair, or, if the extend of damage is beyond repair capacity, induce apoptosis. This signaling network, which is collectively referred to as the DNA damage response (DDR), is primarily thought to consist of two components—a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes and a delayed transcriptional response that promotes a prolonged cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves potent posttranscriptional regulatory mechanisms that control the cellular response to DNA damage. Although much has been written on the relevance of the DDR in cancer and on the post-transcriptional role of microRNAs (miRs) in cancer, the post-transcriptional regulation of the DDR by non-coding RNAs and RNA-binding proteins (RBPs) still remains elusive in large parts. Here, we review the recent developments in this exciting new area of research in the cellular response to genotoxic stress. We put specific emphasis on the role of RBPs and the control of their function through DNA damage-activated protein kinases. PMID:22936947

  1. Posttranscriptional regulation of gene expression – adding another layer of complexity to the DNA damage response

    Directory of Open Access Journals (Sweden)

    Jorge eBoucas

    2012-08-01

    Full Text Available In response to DNA damage, cells activate a complex, kinase-based signaling network to arrest the cell cycle and allow time for DNA repair, or, if the extend of damage is beyond repair capacity, induce apoptosis. This signaling network, which is collectively referred to as the DNA damage response (DDR, is primarily thought to consist of two components – a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes and a delayed transcriptional response that promotes a prolonged cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves potent posttranscriptional regulatory mechanisms that control the cellular response to DNA damage. Although much has been written on the relevance of the DDR in cancer and on the post-transcriptional role of microRNAs (miRs in cancer, the post-transcriptional regulation of the DDR by non-coding RNAs and RNA-binding proteins (RBPs still remains elusive in large parts. Here, we review the recent developments in this exciting new area of research in the cellular response to genotoxic stress. We put specific emphasis on the role of RNA-binding proteins and the control of their function through DNA damage-activated protein kinases.

  2. Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

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    S. Viganò

    2012-01-01

    Full Text Available The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

  3. EEG-arousal regulation as predictor of treatment response in patients suffering from obsessive compulsive disorder.

    Science.gov (United States)

    Dohrmann, Anna-Lena; Stengler, Katarina; Jahn, Ina; Olbrich, Sebastian

    2017-10-01

    Aim of this study was to analyze whether electroencephalogram (EEG)-based CNS-arousal markers differ for patients suffering from obsessive compulsive disorder (OCD) that either respond or do not respond to cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs) or their combination. Further the study aimed to identify specific response-predictors for the different therapy approaches. CNS-arousal from 51 unmedicated patients during fifteen-minute resting state was assessed using VIGALL (Vigilance Algorithm Leipzig). Clinical Global Impression (CGI) scores were used to assess response or non-response after three to six months following therapy (CBT, n=18; SSRI, n=11 or combination, n=22). Differences between Responders (R) and Non-Responders (NR) were identified using multivariate analysis of covariance (MANCOVA) models. MANCOVA revealed that Responders spent significant less time at the highest CNS-arousal stage 0. Further, low amounts of the highest CNS-arousal stages were specifically predictive for a response to a combined treatment approach. The fact that CNS-arousal markers allowed discrimination between Responders and Non-Responders and also between Responders of different treatment arms underlines a possible clinical value of EEG-based markers. These results encourage further research on EEG-arousal regulation for determining pathophysiological subgroups for treatment response. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  4. In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons.

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    Joana Fernandes

    Full Text Available Transient global cerebral ischemia induces profound changes in the transcriptome of brain cells, which is partially associated with the induction or repression of genes that influence the ischemic response. However, the mechanisms responsible for the selective vulnerability of hippocampal neurons to global ischemia remain to be clarified. To identify molecular changes elicited by ischemic insults, we subjected hippocampal primary cultures to oxygen-glucose deprivation (OGD, an in vitro model for global ischemia that resulted in delayed neuronal death with an excitotoxic component. To investigate changes in the transcriptome of hippocampal neurons submitted to OGD, total RNA was extracted at early (7 h and delayed (24 h time points after OGD and used in a whole-genome RNA microarray. We observed that at 7 h after OGD there was a general repression of genes, whereas at 24 h there was a general induction of gene expression. Genes related with functions such as transcription and RNA biosynthesis were highly regulated at both periods of incubation after OGD, confirming that the response to ischemia is a dynamic and coordinated process. Our analysis showed that genes for synaptic proteins, such as those encoding for PICK1, GRIP1, TARPγ3, calsyntenin-2/3, SAPAP2 and SNAP-25, were down-regulated after OGD. Additionally, OGD decreased the mRNA and protein expression levels of the GluA1 AMPA receptor subunit as well as the GluN2A and GluN2B subunits of NMDA receptors, but increased the mRNA expression of the GluN3A subunit, thus altering the composition of ionotropic glutamate receptors in hippocampal neurons. Together, our results present the expression profile elicited by in vitro ischemia in hippocampal neurons, and indicate that OGD activates a transcriptional program leading to down-regulation in the expression of genes coding for synaptic proteins, suggesting that the synaptic proteome may change after ischemia.

  5. Regulation of the STARS signaling pathway in response to endurance and resistance exercise and training.

    Science.gov (United States)

    Lamon, Séverine; Wallace, Marita A; Stefanetti, Renae J; Rahbek, Stine K; Vendelbo, Mikkel H; Russell, Aaron P; Vissing, Kristian

    2013-09-01

    The striated muscle activator of Rho signaling (STARS) protein and members of its downstream signaling pathway, including myocardin-related transcription factor-A (MRTF-A) and SRF, are increased in response to prolonged resistance exercise training but also following a single bout of endurance cycling. The aim of the present study was to measure and compare the regulation of STARS, MRTF-A and SRF mRNA and protein following 10 weeks of endurance training (ET) versus resistance training (RT), as well as before and following a single bout of endurance (EE) versus resistance exercise (RE). Following prolonged training, STARS, MRTF-A and SRF mRNA levels were all increased by similar magnitude, irrespective of training type. In the training-habituated state, STARS mRNA increased following a single-bout RE when measured 2.5 and 5 h post-exercise and had returned to resting level by 22 h following exercise. MRTF-A and SRF mRNA levels were decreased by 2.5, 5, and 22 h following a single bout of RE and EE exercise when compared to their respective basal levels, with no significant difference seen between the groups at any of the time points. No changes in protein levels were observed following the two modes of exercise training or a single bout of exercise. This study demonstrates that the stress signals elicited by ET and RT result in a comparable regulation of members of the STARS pathway. In contrast, a single bout of EE and RE, performed in the trained state, elicit different responses. These observations suggest that in the trained state, the acute regulation of the STARS pathway following EE or RE may be responsible for exercise-specific muscle adaptations.

  6. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice.

    Science.gov (United States)

    Maiers, Jessica L; Kostallari, Enis; Mushref, Malek; deAssuncao, Thiago M; Li, Haiyang; Jalan-Sakrikar, Nidhi; Huebert, Robert C; Cao, Sheng; Malhi, Harmeet; Shah, Vijay H

    2017-03-01

    Fibrogenesis encompasses the deposition of matrix proteins, such as collagen I, by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a small interfering RNA screen, we identified Transport and Golgi organization 1 (TANGO1) as a potential participant in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild-type (WT) HSCs, both TANGO1 and the UPR were induced by transforming growth factor β (TGFβ). As the UPR up-regulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for up-regulating TANGO1 in response to TGFβ, and this mechanism is mediated by the transcription factor X-box binding protein 1 (XBP1). In vivo, murine and human cirrhotic tissue displayed increased TANGO1 messenger RNA levels. Finally, TANGO1(+/-) mice displayed less hepatic fibrosis compared to WT mice in two separate murine models: CCl4 and bile duct ligation. Loss of TANGO1 leads to procollagen I retention in the ER, which promotes UPR-mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR-dependent mechanism that requires the transcription factor, XBP1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. The work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis. (Hepatology 2017;65:983-998). © 2016 by

  7. Adaptation of the Agrobacterium tumefaciens VirG response regulator to activate transcription in plants.

    Science.gov (United States)

    Czarnecka-Verner, Eva; Salem, Tarek A; Gurley, William B

    2016-02-01

    The Agrobacterium tumefaciens VirG response regulator of the VirA/VirG two-component system was adapted to function in tobacco protoplasts. The subcellular localization of VirG and VirA proteins transiently expressed in onion cells was determined using GFP fusions. Preliminary studies using Gal4DBD-VP16 fusions with VirG and Escherichia coli UhpA, and NarL response regulators indicated compatibility of these bacterial proteins with the eukaryotic transcriptional apparatus. A strong transcriptional activator based on tandem activation domains from the Drosophila fushi tarazu and Herpes simplex VP16 was created. Selected configurations of the two-site Gal4-vir box GUS reporters were activated by chimeric effectors dependent on either the yeast Gal4 DNA-binding domain or that of VirG. Transcriptional induction of the GUS reporter was highest for the VirE19-element promoter with both constitutive and wild-type VirG-tandem activation domain effectors. Multiple VirE19 elements increased the reporter activity proportionately, indicating that the VirG DNA binding domain was functional in plants. The VirG constitutive-Q-VP16 effector was more active than the VirG wild-type. In both the constitutive and wild-type forms of VirG, Q-VP16 activated transcription of the GUS reporter best when located at the C-terminus, i.e. juxtaposed to the VirG DNA binding domain. These results demonstrate the possibility of using DNA binding domains from bacterial response regulators and their cognate binding elements in the engineering of plant gene expression.

  8. Cyclic AMP Receptor Protein Acts as a Transcription Regulator in Response to Stresses in Deinococcus radiodurans.

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    Su Yang

    Full Text Available The cyclic AMP receptor protein family of transcription factors regulates various metabolic pathways in bacteria, and also play roles in response to environmental changes. Here, we identify four homologs of the CRP family in Deinococcus radiodurans, one of which tolerates extremely high levels of oxidative stress and DNA-damaging reagents. Transcriptional levels of CRP were increased under hydrogen peroxide (H2O2 treatment during the stationary growth phase, indicating that CRPs function in response to oxidative stress. By constructing all CRP single knockout mutants, we found that the dr0997 mutant showed the lowest tolerance toward H2O2, ultraviolet radiation, ionizing radiation, and mitomycin C, while the phenotypes of the dr2362, dr0834, and dr1646 mutants showed slight or no significant differences from those of the wild-type strain. Taking advantage of the conservation of the CRP-binding site in many bacteria, we found that transcription of 18 genes, including genes encoding chromosome-partitioning protein (dr0998, Lon proteases (dr0349 and dr1974, NADH-quinone oxidoreductase (dr1506, thiosulfate sulfurtransferase (dr2531, the DNA repair protein UvsE (dr1819, PprA (dra0346, and RecN (dr1447, are directly regulated by DR0997. Quantitative real-time polymerase chain reaction (qRT-PCR analyses showed that certain genes involved in anti-oxidative responses, DNA repair, and various cellular pathways are transcriptionally attenuated in the dr0997 mutant. Interestingly, DR0997 also regulate the transcriptional levels of all CRP genes in this bacterium. These data suggest that DR0997 contributes to the extreme stress resistance of D. radiodurans via its regulatory role in multiple cellular pathways, such as anti-oxidation and DNA repair pathways.

  9. ALTERATIONS TO PLBS AND PLANTLETS OF HYBRID CYMBIDIUM (ORCHIDACEAE IN RESPONSE TO PLANT GROWTH REGULATORS

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    Jaime A. TEIXEIRA DA SILVA

    2015-12-01

    Full Text Available A previous study examined, in detail, the morphological response of hybrid Cymbidium Twilight Moon ‘Day Light’ protocorm-like bodies (PLBs to 26 plant growth regulators (PGRs. In this study, flow cytometric analyses of the PLBs derived from several of these PGR treatments revealed changes in the ploidy of PLBs while the ploidy of plant leaves remained constant. The SPAD value of leaves of plants derived from PGR treatments changed significantly. The choice of PGR must be accompanied by careful scrutiny of the possible resulting changes to morphology and physiological parameters.

  10. Response of pine hypocotyl sections to growth regulators and related substances

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    J. Zakrzewski

    2015-01-01

    Full Text Available Growth response of Pinus silvestris hypocotyl sections to some synthetic growth regulators and related substances was studied. Elongation of hypocotyl sections was stimulated by naphtaleneacetic acid, indole-3-acetic acid, in-dole-3-propionic acid, indole-3-butyric acid, 2,4-dichlorophenoxyacetic acid, indoleaoetic amide, indoleacetic nitrile and coumarin. Indole-3-acetic acid and naphtaleneacetic acid extended period of growth up to 16 and 24 hours, respectively. Growth was inhibited by kinetin, trans-cinnamic acid and 2,3,5-tri-iodobenzoic acid. No effect of gibberellic acid, tryptophan and biotin was observed.

  11. Ethylene Response Factor Sl-ERF.B.3 Is Responsive to Abiotic Stresses and Mediates Salt and Cold Stress Response Regulation in Tomato

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    Imen Klay

    2014-01-01

    Full Text Available Sl-ERF.B.3 (Solanum lycopersicum ethylene response factor B.3 gene encodes for a tomato transcription factor of the ERF (ethylene responsive factor family. Our results of real-time RT-PCR showed that Sl-ERF.B.3 is an abiotic stress responsive gene, which is induced by cold, heat, and flooding, but downregulated by salinity and drought. To get more insight into the role of Sl-ERF.B.3 in plant response to separate salinity and cold, a comparative study between wild type and two Sl-ERF.B.3 antisense transgenic tomato lines was achieved. Compared with wild type, Sl-ERF.B.3 antisense transgenic plants exhibited a salt stress dependent growth inhibition. This inhibition was significantly enhanced in shoots but reduced in roots, leading to an increased root to shoot ratio. Furthermore, the cold stress essay clearly revealed that introducing antisense Sl-ERF.B.3 in transgenic tomato plants reduces their cell injury and enhances their tolerance against 14 d of cold stress. All these results suggest that Sl-ERF.B.3 gene is involved in plant response to abiotic stresses and may play a role in the layout of stress symptoms under cold stress and in growth regulation under salinity.

  12. Metabolic Regulation and Coordination of the Metabolism in Bacteria in Response to a Variety of Growth Conditions.

    Science.gov (United States)

    Shimizu, Kazuyuki

    2016-01-01

    Living organisms have sophisticated but well-organized regulation system. It is important to understand the metabolic regulation mechanisms in relation to growth environment for the efficient design of cell factories for biofuels and biochemicals production. Here, an overview is given for carbon catabolite regulation, nitrogen regulation, ion, sulfur, and phosphate regulations, stringent response under nutrient starvation as well as oxidative stress regulation, redox state regulation, acid-shock, heat- and cold-shock regulations, solvent stress regulation, osmoregulation, and biofilm formation, and quorum sensing focusing on Escherichia coli metabolism and others. The coordinated regulation mechanisms are of particular interest in getting insight into the principle which governs the cell metabolism. The metabolism is controlled by both enzyme-level regulation and transcriptional regulation via transcription factors such as cAMP-Crp, Cra, Csr, Fis, P(II)(GlnB), NtrBC, CysB, PhoR/B, SoxR/S, Fur, MarR, ArcA/B, Fnr, NarX/L, RpoS, and (p)ppGpp for stringent response, where the timescales for enzyme-level and gene-level regulations are different. Moreover, multiple regulations are coordinated by the intracellular metabolites, where fructose 1,6-bisphosphate (FBP), phosphoenolpyruvate (PEP), and acetyl-CoA (AcCoA) play important roles for enzyme-level regulation as well as transcriptional control, while α-ketoacids such as α-ketoglutaric acid (αKG), pyruvate (PYR), and oxaloacetate (OAA) play important roles for the coordinated regulation between carbon source uptake rate and other nutrient uptake rate such as nitrogen or sulfur uptake rate by modulation of cAMP via Cya.

  13. Structure of the Response Regulator NsrR from Streptococcus agalactiae, Which Is Involved in Lantibiotic Resistance.

    Science.gov (United States)

    Khosa, Sakshi; Hoeppner, Astrid; Gohlke, Holger; Schmitt, Lutz; Smits, Sander H J

    2016-01-01

    Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria. Interestingly, several clinically relevant and human pathogenic strains are inherently resistant towards lantibiotics. The expression of the genes responsible for lantibiotic resistance is regulated by a specific two-component system consisting of a histidine kinase and a response regulator. Here, we focused on a response regulator involved in lantibiotic resistance, NsrR from Streptococcus agalactiae, and determined the crystal structures of its N-terminal receiver domain and C-terminal DNA-binding effector domain. The C-terminal domain exhibits a fold that classifies NsrR as a member of the OmpR/PhoB subfamily of regulators. Amino acids involved in phosphorylation, dimerization, and DNA-binding were identified and demonstrated to be conserved in lantibiotic resistance regulators. Finally, a model of the full-length NsrR in the active and inactive state provides insights into protein dimerization and DNA-binding.

  14. A novel mode of regulation of the Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR mediated by Stk1 protein phosphorylation.

    Science.gov (United States)

    Canova, Marc J; Baronian, Grégory; Brelle, Solène; Cohen-Gonsaud, Martin; Bischoff, Markus; Molle, Virginie

    2014-04-25

    The Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR is known as an important response regulator, member of the VraTSR three-component signal transduction system that modulates the expression of the cell wall stress stimulon in response to a number of different cell wall active antibiotics. Given its crucial role in regulating gene expression in response to antibiotic challenges, VraR must be tightly regulated. We report here for the first time in S. aureus convergence of two major signal transduction systems, serine/threonine protein kinase and two (three)-component systems. We demonstrate that VraR can be phosphorylated by the staphylococcal Ser/Thr protein kinase Stk1 and that phosphorylation negatively affects its DNA-binding properties. Mass spectrometric analyses and site-directed mutagenesis identified Thr106, Thr119, Thr175 and Thr178 as phosphoacceptors. A S. aureus ΔvraR mutant expressing a VraR derivative that mimics constitutive phosphorylation, VraR_Asp, still exhibited markedly decreased antibiotic resistance against different cell wall active antibiotics, when compared to the wild-type, suggesting that VraR phosphorylation may represent a novel and presumably more general mechanism of regulation of the two (three)-component systems in staphylococci.

  15. Translational regulation of protein synthesis, in response to light, at a critical stage of Volvox development

    Energy Technology Data Exchange (ETDEWEB)

    Kirk, M.M.; Kirk, D.L.

    1985-06-01

    In Volvox cultures synchronized by a light-dark cycle, juveniles containing presumptive somatic and reproductive cells are produced during the dark, but their cells do not differentiate until after the lights come on. The pattern of protein synthesis changes rapidly after the lights come on. Action spectra and effects of photosynthesis inhibitors indicate that this protein synthetic change is not simply a consequence of renewed flow of energy from illuminated chloroplasts. Actinomycin, at a level adequate to block the response to heat shock, has virtually no effect on the response of the same cells to light; furthermore, RNAs isolated from unilluminated and illuminated juveniles yield indistinguishable in vitro translation products. The authors conclude, therefore, that this effect of light is exerted almost exclusively at the translational level, generating one of the most striking examples of translational regulation yet described.

  16. Membrane regulation of the stress response from prokaryotic models to mammalian cells.

    Science.gov (United States)

    Vigh, Laszlo; Nakamoto, Hitoshi; Landry, Jacques; Gomez-Munoz, Antonio; Harwood, John L; Horvath, Ibolya

    2007-10-01

    "Membrane regulation" of stress responses in various systems is widely studied. In poikilotherms, membrane rigidification could be the first reaction to cold perception: reducing membrane fluidity of membranes at physiological temperatures is coupled with enhanced cold inducibility of a number of genes, including desaturases (see J.L. Harwood's article in this Proceedings volume). A similar role of changes in membrane physical state in heat (oxidative stress, etc.) sensing- and signaling gained support recently from prokaryotes to mammalian cells. Stress-induced remodeling of membrane lipids could influence generation, transduction, and deactivation of stress signals, either through global effects on the fluidity of the membrane matrix, or by specific interactions of boundary (or raft) lipids with receptor proteins, lipases, ion channels, etc. Our data point to membranes not only as targets of stress, but also as sensors in activating a stress response.

  17. Expression of Thyroid Hormone Responsive SPOT 14 Gene Is Regulated by Estrogen in Chicken (Gallus gallus).

    Science.gov (United States)

    Ren, Junxiao; Xu, Naiyi; Zheng, Hang; Tian, Weihua; Li, Hong; Li, Zhuanjian; Wang, Yanbin; Tian, Yadong; Kang, Xiangtao; Liu, Xiaojun

    2017-08-31

    Thyroid hormone responsive spot 14 (THRSP) is a small nuclear protein that responds rapidly to thyroid hormone. It has been shown that THRSP is abundant in lipogenic tissues such as liver, fat and the mammary gland in mammals. The THRSP gene acts as a key lipogenic activator and can be activated by thyroid hormone triiodothyronine (T3), glucose, carbohydrate and insulin. Here we report that chicken THRSP is also abundant in lipogenic tissues including the liver and the abdominal fat, and its expression levels increased with sex maturation and reached the highest level at the peak of egg production. Structure analysis of the THRSP gene indicates that there is a conscious estrogen response element (ERE) located in the -2390 - -2402 range of the gene promoter region. Further studies by ChIP-qPCR proved that the ERα interacts with the putative ERE site. In addition, THRSP was significantly upregulated (P estrogen and is involved in the estrogen regulation network in chicken.

  18. Cauliflower mosaic virus protein P6 inhibits signaling responses to salicylic acid and regulates innate immunity.

    Directory of Open Access Journals (Sweden)

    Andrew J Love

    Full Text Available Cauliflower mosaic virus (CaMV encodes a multifunctional protein P6 that is required for translation of the 35S RNA and also acts as a suppressor of RNA silencing. Here we demonstrate that P6 additionally acts as a pathogenicity effector of an unique and novel type, modifying NPR1 (a key regulator of salicylic acid (SA- and jasmonic acid (JA-dependent signaling and inhibiting SA-dependent defence responses We find that that transgene-mediated expression of P6 in Arabidopsis and transient expression in Nicotiana benthamiana has profound effects on defence signaling, suppressing expression of representative SA-responsive genes and increasing expression of representative JA-responsive genes. Relative to wild-type Arabidopsis P6-expressing transgenics had greatly reduced expression of PR-1 following SA-treatment, infection by CaMV or inoculation with an avirulent bacterial pathogen Pseudomonas syringae pv tomato (Pst. Similarly transient expression in Nicotiana benthamiana of P6 (including a mutant form defective in translational transactivation activity suppressed PR-1a transcript accumulation in response to Agrobacterium infiltration and following SA-treatment. As well as suppressing the expression of representative SA-regulated genes, P6-transgenic Arabidopsis showed greatly enhanced susceptibility to both virulent and avirulent Pst (titres elevated 10 to 30-fold compared to non-transgenic controls but reduced susceptibility to the necrotrophic fungus Botrytis cinerea. Necrosis following SA-treatment or inoculation with avirulent Pst was reduced and delayed in P6-transgenics. NPR1 an important regulator of SA/JA crosstalk, was more highly expressed in the presence of P6 and introduction of the P6 transgene into a transgenic line expressing an NPR1:GFP fusion resulted in greatly increased fluorescence in nuclei even in the absence of SA. Thus in the presence of P6 an inactive form of NPR1 is mislocalized in the nucleus even in uninduced plants

  19. Novel Role of TRPML2 in the Regulation of the Innate Immune Response.

    Science.gov (United States)

    Sun, Lu; Hua, Yinan; Vergarajauregui, Silvia; Diab, Heba I; Puertollano, Rosa

    2015-11-15

    TRPMLs (or mucolipins) constitute a family of endosomal cation channels with homology to the transient receptor potential superfamily. In mammals, the TRPML family includes three members: TRPML1-3. Although TRPML1 and TRPML3 have been well characterized, the cellular function of TRPML2 has remained elusive. To address TRPML2 function in a physiologically relevant cell type, we first analyzed TRPML2 expression in different mouse tissues and organs and found that it was predominantly expressed in lymphoid organs and kidney. Quantitative RT-PCR revealed tight regulation of TRPML2 at the transcriptional level. Although TRPML2 expression was negligible in resting macrophages, TRPML2 mRNA and protein levels dramatically increased in response to TLR activation both in vitro and in vivo. Conversely, TRPML1 and TRPML3 levels did not change upon TLR activation. Immunofluorescence analysis demonstrated that endogenous TRPML2 primarily localized to recycling endosomes both in culture and primary cells, in contrast with TRPML1 and TRPML3, which distribute to the late and early endosomal pathway, respectively. To better understand the in vivo function of TRPML2, we generated a TRPML2-knockout mouse. We found that the production of several chemokines, in particular CCL2, was severely reduced in TRPML2-knockout mice. Furthermore, TRPML2-knockout mice displayed impaired recruitment of peripheral macrophages in response to i.p. injections of LPS or live bacteria, suggesting a potential defect in the immune response. Overall, our study reveals interesting differences in the regulation and distribution of the members of the TRPML family and identifies a novel role for TRPML2 in the innate immune response.

  20. Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis.

    Directory of Open Access Journals (Sweden)

    Marta L DeDiego

    2011-10-01

    Full Text Available Severe acute respiratory syndrome virus (SARS-CoV that lacks the envelope (E gene (rSARS-CoV-ΔE is attenuated in vivo. To identify factors that contribute to rSARS-CoV-ΔE attenuation, gene expression in cells infected by SARS-CoV with or without E gene was compared. Twenty-five stress response genes were preferentially upregulated during infection in the absence of the E gene. In addition, genes involved in signal transduction, transcription, cell metabolism, immunoregulation, inflammation, apoptosis and cell cycle and differentiation were differentially regulated in cells infected with rSARS-CoV with or without the E gene. Administration of E protein in trans reduced the stress response in cells infected with rSARS-CoV-ΔE or with respiratory syncytial virus, or treated with drugs, such as tunicamycin and thapsigargin that elicit cell stress by different mechanisms. In addition, SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1 of the unfolded protein response, but not the PKR-like ER kinase (PERK or activating transcription factor 6 (ATF-6 pathways, and reduced cell apoptosis. Overall, the activation of the IRE-1 pathway was not able to restore cell homeostasis, and apoptosis was induced probably as a measure to protect the host by limiting virus production and dissemination. The expression of proinflammatory cytokines was reduced in rSARS-CoV-ΔE-infected cells compared to rSARS-CoV-infected cells, suggesting that the increase in stress responses and the reduction of inflammation in the absence of the E gene contributed to the attenuation of rSARS-CoV-ΔE.

  1. ISO New England: Results of Ancillary Service Pilot Programs, Alternative Technology Regulation Pilot Program and Demand Response Reserves Pilot Program

    Energy Technology Data Exchange (ETDEWEB)

    Lowell, Jon [ISO New England, Holyoke, MA (United States); Yoshimura, Henry [ISO New England, Holyoke, MA (United States)

    2011-10-26

    This PowerPoint presentation compares performance of pilot program assets and generation resources in alternative technology regulation and demand response reserves for flywheels and residential electric thermal storage.

  2. Crosstalk between the unfolded protein response and pathways that regulate pathogenic development in Ustilago maydis.

    Science.gov (United States)

    Heimel, Kai; Freitag, Johannes; Hampel, Martin; Ast, Julia; Bölker, Michael; Kämper, Jörg

    2013-10-01

    The unfolded protein response (UPR) is a conserved eukaryotic signaling pathway regulating endoplasmic reticulum (ER) homeostasis during ER stress, which results, for example, from an increased demand for protein secretion. Here, we characterize the homologs of the central UPR regulatory proteins Hac1 (for Homologous to ATF/CREB1) and Inositol Requiring Enzyme1 in the plant pathogenic fungus Ustilago maydis and demonstrate that the UPR is tightly interlinked with the b mating-type-dependent signaling pathway that regulates pathogenic development. Exact timing of UPR is required for virulence, since premature activation interferes with the b-dependent switch from budding to filamentous growth. In addition, we found crosstalk between UPR and the b target Clampless1 (Clp1), which is essential for cell cycle release and proliferation in planta. The unusual C-terminal extension of the U. maydis Hac1 homolog, Cib1 (for Clp1 interacting bZIP1), mediates direct interaction with Clp1. The interaction between Clp1 and Cib1 promotes stabilization of Clp1, resulting in enhanced ER stress tolerance that prevents deleterious UPR hyperactivation. Thus, the interaction between Cib1 and Clp1 constitutes a checkpoint to time developmental progression and increased secretion of effector proteins at the onset of biotrophic development. Crosstalk between UPR and the b mating-type regulated developmental program adapts ER homeostasis to the changing demands during biotrophy.

  3. TCR Down-Regulation Controls Virus-Specific CD8+ T Cell Responses

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte Menné; Haks, Mariëlle; Nielsen, Bodil

    2008-01-01

    The CD3gamma di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3gamma di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8(+) T cells is impaired...... in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic...... molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8(+) T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3gamma-mediated TCR down-regulation in virus...

  4. Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

    Institute of Scientific and Technical Information of China (English)

    Annette; Graham; Anne-Marie; Allen

    2015-01-01

    The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.

  5. Serum response factor play a regulative role in the gene expression in heart failure

    Institute of Scientific and Technical Information of China (English)

    Xiaoxia WU; Guang ZHI; Tao WAN; Jiajin WU

    2005-01-01

    To investigate the relationship between transcription factor and the change of protein expression levels in heart failure. Methods Bioinformatic method was used to analyze the data of binding-sites on the 5 ' flaking regions of four genes whose mRNA level changed in failing heart from three databases about nucleic acid-EMBL, transcriptional regulation factor-TRANSFAC and protein-SWISS-PORT.The expression level of selected transcription factor was determined by immunohischemical method.Results Nine transcription factors were inferred to influence the proteins' levels in occurrence and development of heart failure.Serum response factor (SRF) was selected from the nine factors and assayed. The results showed that there was a higher level of SRF in healthy group than in chronic heart failure (CHF), and the level was associated with the degree of CHF. It was also found that there was a relative higher level of SRF in the acute myocardial infarction (AMI) than that in CHF, but which was lower than the healthy. Conclusion It showed that SRF had a quantitative change in the development of heart failure, and suggested SRF might play an important regulative role in heart failure. The expression changes of proteins related to myocardial function might be regulated by the quantitative change of transcription factor(s).

  6. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response.

    Science.gov (United States)

    van der Lee, Robin; Feng, Qian; Langereis, Martijn A; Ter Horst, Rob; Szklarczyk, Radek; Netea, Mihai G; Andeweg, Arno C; van Kuppeveld, Frank J M; Huynen, Martijn A

    2015-10-01

    The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50%) that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1), and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1). Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/), obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research.

  7. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response.

    Directory of Open Access Journals (Sweden)

    Robin van der Lee

    2015-10-01

    Full Text Available The RIG-I-like receptor (RLR pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50% that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1, and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1. Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/, obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research.

  8. Primed T cell responses to chemokines are regulated by the immunoglobulin-like molecule CD31.

    Directory of Open Access Journals (Sweden)

    Madhav Kishore

    Full Text Available CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naïve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity.

  9. Ascending mechanisms of stress integration: Implications for brainstem regulation of neuroendocrine and behavioral stress responses.

    Science.gov (United States)

    Myers, Brent; Scheimann, Jessie R; Franco-Villanueva, Ana; Herman, James P

    2017-03-01

    In response to stress, defined as a real or perceived threat to homeostasis or well-being, brain systems initiate divergent physiological and behavioral processes that mobilize energy and promote adaptation. The brainstem contains multiple nuclei that engage in autonomic control and reflexive responses to systemic stressors. However, brainstem nuclei also play an important role in neuroendocrine responses to psychogenic stressors mediated by the hypothalamic-pituitary-adrenocortical axis. Further, these nuclei integrate neuroendocrine responses with stress-related behaviors, significantly impacting mood and anxiety. The current review focuses on the prominent brainstem monosynaptic inputs to the endocrine paraventricular hypothalamic nucleus (PVN), including the periaqueductal gray, raphe nuclei, parabrachial nuclei, locus coeruleus, and nucleus of the solitary tract (NTS). The NTS is a particularly intriguing area, as the region contains multiple cell groups that provide neurochemically-distinct inputs to the PVN. Furthermore, the NTS, under regulatory control by glucocorticoid-mediated feedback, integrates affective processes with physiological status to regulate stress responding. Collectively, these brainstem circuits represent an important avenue for delineating interactions between stress and health.

  10. The Ruggie Framework: Polycentric regulation and the implications for corporate social responsibility

    Directory of Open Access Journals (Sweden)

    Mark B. Taylor

    2011-05-01

    Full Text Available The United Nations ‘Protect, Respect and Remedy’ Framework,developed by the U.N. Special Representative JohnRuggie, brings together social expectations and law into anemerging policy framework of direct relevance to corporatesocial responsibility, CSR. The principle source of theFramework’s significance for the policy and practice of CSRis its definition of the theory of business responsibility forhuman rights as arising from business activities and relationships,and its deployment of due diligence for humanrights risk as the core operational concept of this theory ofresponsibility. The article considers the responsibility torespect human rights in light of theories about polycentricregulatory regimes and draws the conclusion that the RuggieFramework creates a regulator dynamic in which bothvoluntarism and law have relevant and reinforcing roles toplay in governing business behavior. In the wake of theadaptation of the Framework by the UN, the challenge forthe field of CSR will be to adapt to an emerging reality inwhich business responsibility for ‘the social’ is increasinglya question of compliance and beyond.

  11. The levels of RAC3 expression are up regulated by TNF in the inflammatory response.

    Science.gov (United States)

    Alvarado, Cecilia Viviana; Rubio, María Fernanda; Fernández Larrosa, Pablo Nicolas; Panelo, Laura Carolina; Azurmendi, Pablo Javier; Ruiz Grecco, Marina; Martínez-Nöel, Giselle Astrid; Costas, Mónica Alejandra

    2014-01-01

    RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB) that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF), one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

  12. The levels of RAC3 expression are up regulated by TNF in the inflammatory response

    Directory of Open Access Journals (Sweden)

    Cecilia Viviana Alvarado

    2014-01-01

    Full Text Available RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF, one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

  13. GATA transcription factors as tissue-specific master regulators for induced responses.

    Science.gov (United States)

    Block, Dena Hs; Shapira, Michael

    2015-01-01

    GATA transcription factors play important roles in directing developmental genetic programs and cell differentiation, and are conserved in animals, plants and fungi. C. elegans has 11 GATA-type transcription factors that orchestrate development of the gut, epidermis and vulva. However, the expression of certain GATA proteins persists into adulthood, where their function is less understood. Accumulating evidence demonstrates contributions of 2 terminal differentiation GATA transcription factors, ELT-2 and ELT-3, to epithelial immune responses in the adult intestine and epidermis (hypodermis), respectively. Involvement in other stress responses has also been documented. We recently showed that ELT-2 acted as a tissue-specific master regulator, cooperating with 2 transcription factors activated by the p38 pathway, ATF-7 and SKN-1, to control immune responses in the adult C. elegans intestine. Here, we discuss the broader implications of these findings for understanding the involvement of GATA transcription factors in adult stress responses, and draw parallels between ELT-2 and ELT-3 to speculate that the latter may fulfill similar tissue-specific functions in the epidermis.

  14. Autophagy contributes to regulation of the hypoxia response during submergence in Arabidopsis thaliana.

    Science.gov (United States)

    Chen, Liang; Liao, Bin; Qi, Hua; Xie, Li-Juan; Huang, Li; Tan, Wei-Juan; Zhai, Ning; Yuan, Li-Bing; Zhou, Ying; Yu, Lu-Jun; Chen, Qin-Fang; Shu, Wensheng; Xiao, Shi

    2015-01-01

    Autophagy involves massive degradation of intracellular components and functions as a conserved system that helps cells to adapt to adverse conditions. In mammals, hypoxia rapidly stimulates autophagy as a cell survival response. Here, we examine the function of autophagy in the regulation of the plant response to submergence, an abiotic stress that leads to hypoxia and anaerobic respiration in plant cells. In Arabidopsis thaliana, submergence induces the transcription of autophagy-related (ATG) genes and the formation of autophagosomes. Consistent with this, the autophagy-defective (atg) mutants are hypersensitive to submergence stress and treatment with ethanol, the end product of anaerobic respiration. Upon submergence, the atg mutants have increased levels of transcripts of anaerobic respiration genes (alcohol dehydrogenase 1, ADH1 and pyruvate decarboxylase 1, PDC1), but reduced levels of transcripts of other hypoxia- and ethylene-responsive genes. Both submergence and ethanol treatments induce the accumulation of reactive oxygen species (ROS) in the rosettes of atg mutants more than in the wild type. Moreover, the production of ROS by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases is necessary for plant tolerance to submergence and ethanol, submergence-induced expression of ADH1 and PDC1, and activation of autophagy. The submergence- and ethanol-sensitive phenotypes in the atg mutants depend on a complete salicylic acid (SA) signaling pathway. Together, our findings demonstrate that submergence-induced autophagy functions in the hypoxia response in Arabidopsis by modulating SA-mediated cellular homeostasis.

  15. 5-Lipoxygenase negatively regulates Th1 response during Brucella abortus infection in mice.

    Science.gov (United States)

    Fahel, Júlia Silveira; de Souza, Mariana Bueno; Gomes, Marco Túlio Ribeiro; Corsetti, Patricia P; Carvalho, Natalia B; Marinho, Fabio A V; de Almeida, Leonardo A; Caliari, Marcelo V; Machado, Fabiana Simão; Oliveira, Sergio Costa

    2015-03-01

    Brucella abortus is a Gram-negative bacterium that infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. A Th1-mediated immune response plays a critical role in host control of this pathogen. Recent findings indicate contrasting roles for lipid mediators in host responses against infections. 5-Lipoxygenase (5-LO) is an enzyme required for the production of the lipid mediators leukotrienes and lipoxins. To determine the involvement of 5-LO in host responses to B. abortus infection, we intraperitoneally infected wild-type and 5-LO-deficient mice and evaluated the progression of infection and concomitant expression of immune mediators. Here, we demonstrate that B. abortus induced the upregulation of 5-LO mRNA in wild-type mice. Moreover, this pathogen upregulated the production of the lipid mediators leukotriene B4 and lipoxin A4 in a 5-LO-dependent manner. 5-LO-deficient mice displayed lower bacterial burdens in the spleen and liver and less severe liver pathology, demonstrating an enhanced resistance to infection. Host resistance paralleled an increased expression of the proinflammatory mediators interleukin-12 (IL-12), gamma interferon (IFN-γ), and inducible nitric oxide synthase (iNOS) during the course of infection. Moreover, we demonstrated that 5-LO downregulated the expression of IL-12 in macrophages during B. abortus infection. Our results suggest that 5-LO has a major involvement in B. abortus infection, by functioning as a negative regulator of the protective Th1 immune responses against this pathogen.

  16. Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Nordgren, Kendra K.S., E-mail: knordgre@d.umn.edu; Wallace, Kendall B., E-mail: kwallace@d.umn.edu

    2014-01-01

    Doxorubicin (DOX) is a widely prescribed treatment for a broad scope of cancers, but clinical utility is limited by the cumulative, dose-dependent cardiomyopathy that occurs with repeated administration. DOX-induced cardiotoxicity is associated with the production of reactive oxygen species (ROS) and oxidation of lipids, DNA and proteins. A major cellular defense mechanism against such oxidative stress is activation of the Keap1/Nrf2-antioxidant response element (ARE) signaling pathway, which transcriptionally regulates expression of antioxidant genes such as Nqo1 and Gstp1. In the present study, we address the hypothesis that an initial event associated with DOX-induced oxidative stress is activation of the Keap1/Nrf2-dependent expression of antioxidant genes and that this is regulated through drug-induced changes in redox status of the Keap1 protein. Incubation of H9c2 rat cardiac myoblasts with DOX resulted in a time- and dose-dependent decrease in non-protein sulfhydryl groups. Associated with this was a near 2-fold increase in Nrf2 protein content and enhanced transcription of several of the Nrf2-regulated down-stream genes, including Gstp1, Ugt1a1, and Nqo1; the expression of Nfe2l2 (Nrf2) itself was unaltered. Furthermore, both the redox status and the total amount of Keap1 protein were significantly decreased by DOX, with the loss of Keap1 being due to both inhibited gene expression and increased autophagic, but not proteasomal, degradation. These findings identify the Keap1/Nrf2 pathway as a potentially important initial response to acute DOX-induced oxidative injury, with the primary regulatory events being the oxidation and autophagic degradation of the redox sensor Keap1 protein. - Highlights: • DOX caused a ∼2-fold increase in Nrf2 protein content. • DOX enhanced transcription of several Nrf2-regulated down-stream genes. • Redox status and total amount of Keap1 protein were significantly decreased by DOX. • Loss of Keap1 protein was due to

  17. Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

    LENUS (Irish Health Repository)

    Burke, J P

    2012-02-01

    BACKGROUND: Fibroblasts isolated from strictures in Crohn\\'s disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn\\'s stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.

  18. Transcriptional and proteomic analyses of two-component response regulators in multidrug-resistant Mycobacterium tuberculosis.

    Science.gov (United States)

    Zhou, Lei; Yang, Liu; Zeng, Xianfei; Danzheng, Jiacuo; Zheng, Qing; Liu, Jiayun; Liu, Feng; Xin, Yijuan; Cheng, Xiaodong; Su, Mingquan; Ma, Yueyun; Hao, Xiaoke

    2015-07-01

    Two-component systems (TCSs) have been reported to exhibit a sensing and responding role under drug stress that induces drug resistance in several bacterial species. However, the relationship between TCSs and multidrug resistance in Mycobacterium tuberculosis has not been comprehensively analysed to date. In this study, 90 M. tuberculosis clinical isolates were analysed using 15-loci mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeat (VNTR) typing and repetitive extragenic palindromic (rep)-PCR-based DNA fingerprinting. The results showed that all of the isolates were of the Beijing lineage, and strains with a drug-susceptible phenotype had not diverged into similar genotype clusters. Expression analysis of 13 response regulators of TCSs using real-time PCR and tandem mass spectrometry (MS/MS) proteomic analysis demonstrated that four response regulator genes (devR, mtrA, regX3 and Rv3143) were significantly upregulated in multidrug-resistant (MDR) strains compared with the laboratory strain H37Rv as well as drug-susceptible and isoniazid-monoresistant strains (PMycobacterium bovis BCG did not alter its sensitivity to the four antitubercular drugs. This suggests that upregulation of devR, which is common in MDR-TB strains, might be induced by drug stress and hypoxic adaptation following the acquisition of multidrug resistance.

  19. Conservation of thiol-oxidative stress responses regulated by SigR orthologues in actinomycetes

    Science.gov (United States)

    Kim, Min-Sik; Dufour, Yann S.; Yoo, Ji Sun; Cho, Yoo-Bok; Park, Joo-Hong; Nam, Gi-Baeg; Kim, Hae Min; Lee, Kang-Lok; Donohue, Timothy J.; Roe, Jung-Hye

    2015-01-01

    Summary Numerous thiol-reactive compounds cause oxidative stress where cells counteract by activation of survival strategies regulated by thiol-based sensors. In Streptomyces coelicolor, a model actinomycete, a sigma/antisigma pair SigR/RsrA controls the response to thiol-oxidative stress. To unravel its full physiological functions, chromatin immuno-precipitation combined with sequence and transcript analyses were employed to identify 108 SigR target genes in S. coelicolor and to predict orthologous regulons across actinomycetes. In addition to reported genes for thiol homeostasis, protein degradation and ribosome modulation, 64 additional operons were identified suggesting new functions of this global regulator. We demonstrate that SigR maintains the level and activity of the housekeeping sigma factor HrdB during thiol-oxidative stress, a novel strategy for stress responses. We also found that SigR defends cells against UV and thiol-reactive damages, in which repair UvrA takes a part. Using a refined SigR-binding sequence model, SigR orthologues and their targets were predicted in 42 actinomycetes. This revealed a conserved core set of SigR targets to function for thiol homeostasis, protein quality control, possible modulation of transcription and translation, flavin-mediated redox reactions, and Fe-S delivery. The composition of the SigR regulon reveals a robust conserved physiological mechanism to deal with thiol-oxidative stress from bacteria to human. PMID:22651816

  20. MicroRNA-146a: A dominant, negative regulator of the innate immune response

    Directory of Open Access Journals (Sweden)

    Stephanie eBooth

    2014-11-01

    Full Text Available MicroRNAs (miRNAs are a class of small non-coding RNA molecules that can play critical roles as regulators of numerous pathways and biological processes including the immune response. Emerging as one of the most important miRNAs to orchestrate immune and inflammatory signaling, often through its recognized target genes, IRAK1 and TRAF6, is microRNA-146a (miR-146a. MiR-146a is one, of a small number of miRNAs, whose expression is strongly induced following challenge of cells with bacterial endotoxin, and prolonged expression has been linked to immune tolerance, implying that it acts as a fine tuning mechanism to prevent an overstimulation of the inflammatory response. In other cells, miR-146a has been shown to play a role in the control of the differentiation of megakaryocytic and monocytic lineages, adaptive immunity and cancer. In this review, we discuss the central role prescribed to miR-146a in innate immunity. We particularly focus on the role played by miR-146a in the regulation and signaling mediated by one of the main pattern recognition receptors, Toll/IL-1 receptors (TLRs. Additionally, we also discuss the role of miR-146a in several classes of autoimmune pathologies where this miRNA has been shown to be dysregulated, as well as its potential role in the pathobiology of neurodegenerative diseases.

  1. Serum response factor controls transcriptional network regulating epidermal function and hair follicle morphogenesis.

    Science.gov (United States)

    Lin, Congxing; Hindes, Anna; Burns, Carole J; Koppel, Aaron C; Kiss, Alexi; Yin, Yan; Ma, Liang; Blumenberg, Miroslav; Khnykin, Denis; Jahnsen, Frode L; Crosby, Seth D; Ramanan, Narendrakumar; Efimova, Tatiana

    2013-03-01

    Serum response factor (SRF) is a transcription factor that regulates the expression of growth-related immediate-early, cytoskeletal, and muscle-specific genes to control growth, differentiation, and cytoskeletal integrity in different cell types. To investigate the role for SRF in epidermal development and homeostasis, we conditionally knocked out SRF in epidermal keratinocytes. We report that SRF deletion disrupted epidermal barrier function leading to early postnatal lethality. Mice lacking SRF in epidermis displayed morphogenetic defects, including an eye-open-at-birth phenotype and lack of whiskers. SRF-null skin exhibited abnormal morphology, hyperplasia, aberrant expression of differentiation markers and transcriptional regulators, anomalous actin organization, enhanced inflammation, and retarded hair follicle (HF) development. Transcriptional profiling experiments uncovered profound molecular changes in SRF-null E17.5 epidermis and revealed that many previously identified SRF target CArG box-containing genes were markedly upregulated in SRF-null epidermis, indicating that SRF may function to repress transcription of a subset of its target genes in epidermis. Remarkably, when transplanted onto nude mice, engrafted SRF-null skin lacked hair but displayed normal epidermal architecture with proper expression of differentiation markers, suggesting that although keratinocyte SRF is essential for HF development, a cross-talk between SRF-null keratinocytes and the surrounding microenvironment is likely responsible for the barrier-deficient mutant epidermal phenotype.

  2. Dopamine D2 receptors preferentially regulate the development of light responses of the inner retina

    Science.gov (United States)

    Tian, Ning; Xu, Hong-ping; Wang, Ping

    2014-01-01

    Retinal light responsiveness measured via electroretinography undergoes developmental modulation and is thought to be critically regulated by both visual experience and dopamine. The primary goal of this study is to determine whether the dopamine D2 receptor regulates the visual experience-dependent functional development of the retina. Accordingly, we recorded electroretinograms from wild type mice and mice with a genetic deletion of the gene that encodes the dopamine D2 receptor raised under normal cyclic light conditions and constant darkness. Our results demonstrate that mutation of the dopamine D2 receptors preferentially increases the amplitude of the inner retinal light responses evoked by high intensity light measured as oscillatory potentials in adult mice. During postnatal development, all three major components of electroretinograms, the a-wave, b-wave and oscillatory potentials, increase with age. Comparatively, mutation of the dopamine D2 receptors preferentially reduces the age-dependent increase of b-waves evoked by low intensity light. Light deprivation from birth reduces the amplitude of b-waves and completely diminishes the increased amplitude of oscillatory potentials. Taken together, these results demonstrate that the dopamine D2 receptor plays an important role in the activity-dependent functional development of the mouse retina. PMID:25393815

  3. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening.

    Science.gov (United States)

    Breitel, Dario A; Chappell-Maor, Louise; Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-03-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process.

  4. Paradoxical sleep deprivation activates hypothalamic nuclei that regulate food intake and stress response.

    Science.gov (United States)

    Galvão, Milene de Oliveira Lara; Sinigaglia-Coimbra, Rita; Kawakami, Suzi Emiko; Tufik, Sergio; Suchecki, Deborah

    2009-09-01

    A large body of evidence has shown that prolonged paradoxical sleep deprivation (PSD) results in hypothalamic-pituitary-adrenal (HPA) axis activation, and in loss of body weight despite an apparent increase of food intake, reflecting increased energy expenditure. The flowerpot technique for PSD is an efficient paradigm for investigating the relationships among metabolic regulation and stress response. The purpose of the present study was to examine the mechanisms involved in the effects of 96 h of PSD on metabolism regulation, feeding behaviour and stress response by studying corticotrophin-releasing hormone (CRH) and orexin (ORX) immunoreactivity in specific hypothalamic nuclei. Once-daily assessments of body weight, twice-daily measurements of (spillage-corrected) food intake, and once-daily determinations of plasma adrenocorticotropic hormone (ACTH) and corticosterone were made throughout PSD or at corresponding times in control rats (CTL). Immunoreactivity for CRH in the paraventricular nucleus of the hypothalamus and for ORX in the hypothalamic lateral area was evaluated at the end of the experimental period. PSD resulted in increased diurnal, but not nocturnal, food intake, producing no significant changes in global food intake. PSD augmented the immunoreactivity for CRH and plasma ACTH and corticosterone levels, characterizing activation of the HPA axis. PSD also markedly increased the ORX immunoreactivity. The average plasma level of corticosterone correlated negatively with body weight gain throughout PSD. These results indicate that augmented ORX and CRH immunoreactivity in specific hypothalamic nuclei may underlie some of the metabolic changes consistently described in PSD.

  5. Putrescine regulating by stress-responsive MAPK cascade contributes to bacterial pathogen defense in Arabidopsis.

    Science.gov (United States)

    Kim, Su-Hyun; Kim, Sun-Hwa; Yoo, Seung-Jin; Min, Kwang-Hyun; Nam, Seung-Hee; Cho, Baik Ho; Yang, Kwang-Yeol

    2013-08-09

    Polyamines in plants are involved in various physiological and developmental processes including abiotic and biotic stress responses. We investigated the expression of ADCs, which are key enzymes in putrescine (Put) biosynthesis, and roles of Put involving defense response in Arabidopsis. The increased expression of ADC1 and ADC2, and the induction of Put were detected in GVG-NtMEK2(DD) transgenic Arabidopsis, whereas, their performance was partially compromised in GVG-NtMEK2(DD)/mpk3 and GVG-NtMEK2(DD)/mpk6 mutant following DEX treatment. The expression of ADC2 was highly induced by Pst DC3000 inoculation, while the transcript levels of ADC1 were slightly up-regulated. Compared to the WT plant, Put content in the adc2 knock-out mutant was reduced after Pst DC3000 inoculation, and showed enhanced susceptibility to pathogen infection. The adc2 mutant exhibited reduced expression of PR-1 after bacterial infection and the growth of the pathogen was about 4-fold more than that in the WT plant. Furthermore, the disease susceptibility of the adc2 mutant was recovered by the addition of exogenous Put. Taken together, these results suggest that Arabidopsis MPK3 and MPK6 play a positive role in the regulation of Put biosynthesis, and that Put contributes to bacterial pathogen defense in Arabidopsis.

  6. Fibulin-6 regulates pro-fibrotic TGF-β responses in neonatal mouse ventricular cardiac fibroblasts.

    Science.gov (United States)

    Chowdhury, Arpita; Hasselbach, Lisa; Echtermeyer, Frank; Jyotsana, Nidhi; Theilmeier, Gregor; Herzog, Christine

    2017-02-17

    Fibulin-6, an essential component of extracellular matrix determines the architecture of cellular junctions in tissues undergoing strain. Increased expression and deposition of fibulin-6 facilitates fibroblast migration in response to TGF-β, following myocardial infarction in mouse heart. The underlying mechanism still remains elusive. In conjunction with our previous study, we have now demonstrated that in fibulin-6 knockdown (KD) fibroblasts, not only TGF-β dependent migration, but also stress fiber formation, cellular networking and subsequently fibroblast wound contraction is almost abrogated. SMAD dependent TGF-β pathway shows ~75% decreased translocation of R-SMAD and co-SMAD into the nucleus upon fibulin-6 KD. Consequently, SMAD dependent pro-fibrotic gene expression is considerably down regulated to basal levels both in mRNA and protein. Also, investigating the non-SMAD pathways we observed a constitutive increase in pERK-levels in fibulin-6 KD fibroblast compared to control, but no change was seen in pAKT. Immunoprecipitation studies revealed 60% reduced interaction of TGF-β receptor II and I (TGFRII and I) accompanied by diminished phosphorylation of TGFRI at serin165 in fibulin-6 KD cells. In conclusion, fibulin-6 plays an important role in regulating TGF-β mediated responses, by modulating TGF-β receptor dimerization and activation to further trigger downstream pathways.

  7. Coordinated response of renal medullary enzymes regulating net sorbitol production in diuresis and antidiuresis.

    Science.gov (United States)

    Sands, J M; Schrader, D C

    1990-07-01

    The renal response to changes in hydration includes variation in intracellular sorbitol, a major inner medullary osmolyte. To examine the mechanism for changes in net sorbitol production, we measured activities of enzymes regulating sorbitol production (aldose reductase) and degradation (sorbitol dehydrogenase) in untreated, water diuretic, and antidiuretic (water restriction and/or vasopressin administration) rats. Collecting duct segments dissected from collagenase-treated kidneys of Sprague-Dawley rats were divided into outer medullary and three distinct inner medullary regions. Aldose reductase activity increased during antidiuresis and decreased during diuresis. In contrast, sorbitol dehydrogenase activity was very low during antidiuresis and increased during diuresis. These changes in enzyme activity were found after 3 days, but not after 1 day, of water diuresis/antidiuresis. Enzyme activity changed only in the deepest 50% of the inner medullary collecting duct. Thus, there is coordinated regulation of aldose reductase and sorbitol dehydrogenase activities so that (a) during water diuresis, aldose reductase activity decreases while sorbitol dehydrogenase activity increases; and (b) during antidiuresis (water restriction and/or vasopressin administration), aldose reductase activity increases while sorbitol dehydrogenase activity remains low. We conclude that long-term osmoregulation in response to physiologic stimuli involves both aldose reductase and sorbitol dehydrogenase activities in rat terminal inner medullary collecting duct segments.

  8. lncRNAs regulate the innate immune response to viral infection.

    Science.gov (United States)

    Ouyang, Jing; Hu, Jiayue; Chen, Ji-Long

    2016-01-01

    Long noncoding RNAs (lncRNAs) are extensively expressed in mammalian cells and play a crucial role as RNA regulators in various cellular processes. Increasing data reveal that they function in innate antiviral immunity through complex mechanisms. Thousands of lncRNAs are regulated by RNA virus or DNA virus infection. The significant differential expression of lncRNAs is induced by virus or host antiviral signaling mediated by interferons (IFNs) and tumor necrosis factor-α. In turn, these lncRNAs modulate the host immune response including the pathogen recognition receptor (PRR)-related signaling, the translocation and activation of transcription factors, the production of IFNs and cytokines, the IFN-activated JAK-STAT signaling and the transcription of antiviral IFN-stimulated genes (ISGs). Using gain- or loss-of-function analysis, the effect of lncRNAs on viral replication has been investigated to elucidate the essential role of lncRNA in the host-virus interaction. lncRNAs have shown specifically elevated or decreased levels in patients with viral diseases, suggesting the possibility of clinical application as biomarkers. Here we review the current advances of viral infection-associated host lncRNAs, their functional significance in different aspects of antiviral immune response, the specific mechanisms and unsolved issues. We also summarize the regulation of lncRNAs by viruses, PRR agonists and cytokines. In addition, virus-encoded lncRNAs and their functional involvement in host-virus interaction are addressed. WIREs RNA 2016, 7:129-143. doi: 10.1002/wrna.1321 For further resources related to this article, please visit the WIREs website.

  9. Infant intestinal Enterococcus faecalis down-regulates inflammatory responses in human intestinal cell lines

    Institute of Scientific and Technical Information of China (English)

    Shugui Wang; Lydia Hui Mei Ng; Wai Ling Chow; Yuan Kun Lee

    2008-01-01

    AIM:To investigate the ability of Lactic acid bacteria (LAB)to modulate inflammatory reaction in human intestinal celllines(Caco-2,HT-29 and HCT 116).Different strains of LAB isolatedfrom new born infants and fermented milk,together withthestrains obtained from culture collectionsweretested.METHODS:LABs were treated with human intestinal cell lines.ELISA was used to detect IL-8 and TGF-β protein secretion.Cytokines and Toll like receptors (TLRs) gene expression were assessed using RT-PCR.Conditional medium,sonicated bacteria and UV killed bacteria were used to find the effecter molecules on the bacteria.Carbohydrate oxidation and protein digestion were applied to figure out the molecules'residues.Adhesion assays were further carried out.RESULTS:It was found that Enterococcus faecalis is the main immune modulator among the LABs by downregulation of IL-8 secretion and upregulation of TGF-β.Strikingly,the effect was only observed in four strains of E.faecalis out of the 27 isolated and tested.This implies strain dependent immunomodulation in the host.In addition,E.faecalis may regulate inflammatory responses through TLR3,TLR4,TLR9 and TRAF6.Carbohydrates on the bacterial cell surface are involved in both its adhesion to intestinal cells and regulation of inflammatory responses in the host.CONCLUSION:These data provide a case for the modulation of intestinal mucosal immunity in which specific strains of E.faecalis have uniquely evolved to maintain colonic homeostasis and regulate inflammatoryresponses.

  10. Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses.

    Science.gov (United States)

    Nagai, Jun; Owada, Kazuki; Kitamura, Yoshiteru; Goshima, Yoshio; Ohshima, Toshio

    2016-03-01

    Central nervous system (CNS) regeneration is restricted by both the lack of neurotrophic responses and the presence of inhibitory factors. As of yet, a common mediator of these two pathways has not been identified. Microtubule dynamics is responsible for several key processes after CNS injuries: intracellular trafficking of receptors for neurotrophic factors, axonal retraction by inhibitory factors, and secondary tissue damages by inflammation and scarring. Kinases regulating microtubule organization, such as Cdk5 or GSK3β, may play pivotal roles during CNS recovery, but the molecular mechanisms remain to be elucidated. Collapsin response mediator protein 2 (CRMP2) stabilizes cytoskeletal polymerization, while CRMP2 phosphorylation by Cdk5 and GSK3β loses its affinity for cytoskeleton proteins, leading to the inhibition of axonal growth. Here, we characterized CRMP2 phosphorylation as the first crucial factor regulating neurotrophic and inhibitory responses after spinal cord injury (SCI). We found that pharmacological inhibition of GSK3β enhanced brain-derived neurotrophic factor (BDNF)-induced axonal growth response in cultured dorsal root ganglion (DRG) neurons. DRG neurons from CRMP2 knock-in (Crmp2KI/KI) mice, where CRMP2 phosphorylation was eliminated, showed elevated sensitivity to BDNF as well. Additionally, cultured Crmp2KI/KI neurons exhibited suppressed axonal growth inhibition by chondroitin sulfate proteoglycan (CSPG). These data suggest a couple of new molecular insights: the BDNF/GSK3β/CRMP2 and CSPG/GSK3β/CRMP2 pathways. Next, we tested the significance of CRMP2 phosphorylation after CNS injury in vivo. The phosphorylation level of CRMP2 was enhanced in the injured spinal cord. Crmp2KI/KI mice exhibited prominent recovery of locomotive and nociceptive functions after SCI, which correlated with the enhanced axonal growth of the motor and sensory neurons. Neuroprotective effects against SCI, such as microtubule stabilization, reduced inflammation

  11. Nutrient-responsive regulation determines biodiversity in a colicin-mediated bacterial community.

    Science.gov (United States)

    Hol, Felix J H; Voges, Mathias J; Dekker, Cees; Keymer, Juan E

    2014-08-27

    Antagonistic interactions mediated by antibiotics are strong drivers of bacterial community dynamics which shape biodiversity. Colicin production by Escherichia coli is such an interaction that governs intraspecific competition and is involved in promoting biodiversity. It is unknown how environmental cues affect regulation of the colicin operon and thus influence antibiotic-mediated community dynamics. Here, we investigate the community dynamics of colicin-producing, -sensitive, and -resistant/non-producer E. coli strains that colonize a microfabricated spatially-structured habitat. Nutrients are found to strongly influence community dynamics: when growing on amino acids and peptides, colicin-mediated competition is intense and the three strains do not coexist unless spatially separated at large scales (millimeters). Surprisingly, when growing on sugars, colicin-mediated competition is minimal and the three strains coexist at the micrometer scale. Carbon storage regulator A (CsrA) is found to play a key role in translating the type of nutrients into the observed community dynamics by controlling colicin release. We demonstrate that by mitigating lysis, CsrA shapes the community dynamics and determines whether the three strains coexist. Indeed, a mutant producer that is unable to suppress colicin release, causes the collapse of biodiversity in media that would otherwise support co-localized growth of the three strains. Our results show how the environmental regulation of an antagonistic trait shapes community dynamics. We demonstrate that nutrient-responsive regulation of colicin release by CsrA, determines whether colicin producer, resistant non-producer, and sensitive strains coexist at small spatial scales, or whether the sensitive strain is eradicated. This study highlights how molecular-level regulatory mechanisms that govern interference competition give rise to community-level biodiversity patterns.

  12. 计算内部收益率(IRR)的改进方法%A improvable method of calculation of inner revenue rate

    Institute of Scientific and Technical Information of China (English)

    王羽; 刘伟; 杨转运

    2005-01-01

    通常内部收益率(IRR)的算法是通过线性插值法计算,虽简单易懂,但误差较大.这里作者提出了一种非线性方程的迭代解法,此法在不大量增加计算量的同时,可极大的提高IRR值的计算精度.

  13. Regulation of Arabidopsis defense responses against Spodoptera littoralis by CPK-mediated calcium signaling

    Directory of Open Access Journals (Sweden)

    Ishihama Nobuaki

    2010-05-01

    Full Text Available Abstract Background Plant Ca2+ signals are involved in a wide array of intracellular signaling pathways after pest invasion. Ca2+-binding sensory proteins such as Ca2+-dependent protein kinases (CPKs have been predicted to mediate the signaling following Ca2+ influx after insect herbivory. However, until now this prediction was not testable. Results To investigate the roles CPKs play in a herbivore response-signaling pathway, we screened the characteristics of Arabidopsis CPK mutants damaged by a feeding generalist herbivore, Spodoptera littoralis. Following insect attack, the cpk3 and cpk13 mutants showed lower transcript levels of plant defensin gene PDF1.2 compared to wild-type plants. The CPK cascade was not directly linked to the herbivory-induced signaling pathways that were mediated by defense-related phytohormones such as jasmonic acid and ethylene. CPK3 was also suggested to be involved in a negative feedback regulation of the cytosolic Ca2+ levels after herbivory and wounding damage. In vitro kinase assays of CPK3 protein with a suite of substrates demonstrated that the protein phosphorylates transcription factors (including ERF1, HsfB2a and CZF1/ZFAR1 in the presence of Ca2+. CPK13 strongly phosphorylated only HsfB2a, irrespective of the presence of Ca2+. Furthermore, in vivo agroinfiltration assays showed that CPK3-or CPK13-derived phosphorylation of a heat shock factor (HsfB2a promotes PDF1.2 transcriptional activation in the defense response. Conclusions These results reveal the involvement of two Arabidopsis CPKs (CPK3 and CPK13 in the herbivory-induced signaling network via HsfB2a-mediated regulation of the defense-related transcriptional machinery. This cascade is not involved in the phytohormone-related signaling pathways, but rather directly impacts transcription factors for defense responses.

  14. The yeast Sks1p kinase signaling network regulates pseudohyphal growth and glucose response.

    Directory of Open Access Journals (Sweden)

    Cole Johnson

    2014-03-01

    Full Text Available The yeast Saccharomyces cerevisiae undergoes a dramatic growth transition from its unicellular form to a filamentous state, marked by the formation of pseudohyphal filaments of elongated and connected cells. Yeast pseudohyphal growth is regulated by signaling pathways responsive to reductions in the availability of nitrogen and glucose, but the molecular link between pseudohyphal filamentation and glucose signaling is not fully understood. Here, we identify the glucose-responsive Sks1p kinase as a signaling protein required for pseudohyphal growth induced by nitrogen limitation and coupled nitrogen/glucose limitation. To identify the Sks1p signaling network, we applied mass spectrometry-based quantitative phosphoproteomics, profiling over 900 phosphosites for phosphorylation changes dependent upon Sks1p kinase activity. From this analysis, we report a set of novel phosphorylation sites and highlight Sks1p-dependent phosphorylation in Bud6p, Itr1p, Lrg1p, Npr3p, and Pda1p. In particular, we analyzed the Y309 and S313 phosphosites in the pyruvate dehydrogenase subunit Pda1p; these residues are required for pseudohyphal growth, and Y309A mutants exhibit phenotypes indicative of impaired aerobic respiration and decreased mitochondrial number. Epistasis studies place SKS1 downstream of the G-protein coupled receptor GPR1 and the G-protein RAS2 but upstream of or at the level of cAMP-dependent PKA. The pseudohyphal growth and glucose signaling transcription factors Flo8p, Mss11p, and Rgt1p are required to achieve wild-type SKS1 transcript levels. SKS1 is conserved, and deletion of the SKS1 ortholog SHA3 in the pathogenic fungus Candida albicans results in abnormal colony morphology. Collectively, these results identify Sks1p as an important regulator of filamentation and glucose signaling, with additional relevance towards understanding stress-responsive signaling in C. albicans.

  15. Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses.

    Science.gov (United States)

    Shin, Hee Soon; Shon, Dong-Hwa

    2015-01-01

    An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders.

  16. Transcription factor veracity: is GBF3 responsible for ABA-regulated expression of Arabidopsis Adh?

    Science.gov (United States)

    Lu, G; Paul, A L; McCarty, D R; Ferl, R J

    1996-01-01

    Assignment of particular transcription factors to specific roles in promoter elements can be problematic, especially in systems such as the G-box, where multiple factors of overlapping specificity exist. In the Arabidopsis alcohol dehydrogenase (Adh) promoter, the G-box regulates expression in response to cold and dehydration, presumably through the action of abscisic acid (ABA), and is bound by a nuclear protein complex in vivo during expression in cell cultures. In this report, we test the conventional wisdom of biochemical approaches used to identify DNA binding proteins and assess their specific interactions by using the G-box and a nearby half G-box element of the Arabidopsis Adh promoter as a model system. Typical in vitro assays demonstrated specific interaction of G-box factor 3 (GBF3) with both the G-box and the half G-box element. Dimethyl sulfate footprint analysis confirmed that the in vitro binding signature of GBF3 essentially matches the footprint signature detected in vivo at the G-box. Because RNA gel blot data indicated that GBF3 is itself induced by ABA, we might have concluded that GBF3 is indeed the GBF responsible in cell cultures for binding to the Adh G-box and is therefore responsible for ABA-regulated expression of Adh. Potential limitations of this conclusion are exposed by the fact that other GBFs bind the G-box with the same signature as GBF3, and subtle differences between in vivo and in vitro footprint signatures indicate that factors other than or in addition to GBF3 interact with the half G-box element. PMID:8672884

  17. Nickel-responsive regulation of two novel Helicobacter pylori NikR-targeted genes.

    Science.gov (United States)

    Jones, M D; Ademi, I; Yin, X; Gong, Y; Zamble, D B

    2015-04-01

    Nickel is an essential transition metal for the survival of Helicobacter pylori in the acidic human stomach. The nickel-responsive transcriptional regulator HpNikR is important for maintaining healthy cytosolic nickel concentrations through the regulation of multiple genes, but its complete regulon and role in nickel homeostasis are not well understood. To investigate potential gene targets of HpNikR, ChIP sequencing was performed using H. pylori grown at neutral pH in nickel-supplemented media and this experiment identified HPG27_866 (frpB2) and HPG27_1499 (ceuE). These two genes are annotated to encode a putative iron transporter and a nickel-binding, periplasmic component of an ABC transporter, respectively. In vitro DNA-binding assays revealed that HpNikR binds both gene promoter sequences in a nickel-responsive manner with affinities on the order of ∼10(-7) M. The recognition sites of HpNikR were identified and loosely correlate with the HpNikR pseudo-consensus sequence (TATTATT-N11-AATAATA). Quantitative PCR experiments revealed that HPG27_866 and HPG27_1499 are transcriptionally repressed following growth of H. pylori G27 in nickel-supplemented media, and that this response is dependent on HpNikR. In contrast, iron supplementation results in activation of HPG27_1499, but no impact on the expression of HPG27_866 was observed. Metal analysis of the Δ866 strain revealed that HPG27_866 has an impact on nickel accumulation. These studies demonstrate that HPG27_866 and HPG27_1499 are both direct targets of HpNikR and that HPG27_866 influences nickel uptake in H. pylori.

  18. NR4A2 is regulated by gastrin and influences cellular responses of gastric adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    Kristine Misund

    Full Text Available The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2 expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1, suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2. Collectively, our results uncover a role of NR4A2 in gastric adenocarcinoma cells, and suggest that both the level and the localization of NR4A2 protein are of importance regarding the cellular responses of these cells.

  19. Cyclic di-GMP regulation of the bvg-repressed genes and the orphan response regulator RisA in Bordetella pertussis

    Science.gov (United States)

    Expression of Bordetella pertussis virulence factors is activated by the BvgAS two-component system. Under modulating growth conditions BvgAS indirectly represses another set of genes through the action of BvgR, a bvg-activated protein. BvgR blocks activation of the response regulator RisA which is ...

  20. The tetraspanin protein CD37 regulates IgA responses and anti-fungal immunity.

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    Annemiek B van Spriel

    2009-03-01

    Full Text Available Immunoglobulin A (IgA secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA(+ plasma cells remain poorly understood. Here, we report that the B cell-expressed tetraspanin CD37 inhibits IgA immune responses in vivo. CD37-deficient (CD37-/- mice exhibit a 15-fold increased level of IgA in serum and significantly elevated numbers of IgA(+ plasma cells in spleen, mucosal-associated lymphoid tissue, as well as bone marrow. Analyses of bone marrow chimeric mice revealed that CD37-deficiency on B cells was directly responsible for the increased IgA production. We identified high local interleukin-6 (IL-6 production in germinal centers of CD37-/- mice after immunization. Notably, neutralizing IL-6 in vivo reversed the increased IgA response in CD37-/- mice. To demonstrate the importance of CD37-which can associate with the pattern-recognition receptor dectin-1-in immunity to infection, CD37-/- mice were exposed to Candida albicans. We report that CD37-/- mice are evidently better protected from infection than wild-type (WT mice, which was accompanied by increased IL-6 levels and C. albicans-specific IgA antibodies. Importantly, adoptive transfer of CD37-/- serum mediated protection in WT mice and the underlying mechanism involved direct neutralization of fungal cells by IgA. Taken together, tetraspanin protein CD37 inhibits IgA responses and regulates the anti-fungal immune response.

  1. Conserved transcriptional responses to cyanobacterial stressors are mediated by alternate regulation of paralogous genes in Daphnia.

    Science.gov (United States)

    Asselman, Jana; Pfrender, Michael E; Lopez, Jacqueline A; De Coninck, Dieter I M; Janssen, Colin R; Shaw, Joseph R; De Schamphelaere, Karel A C

    2015-04-01

    Despite a significant increase in genomic data, our knowledge of gene functions and their transcriptional responses to environmental stimuli remains limited. Here, we use the model keystone species Daphnia pulex to study environmental responses of genes in the context of their gene family history to better understand the relationship between genome structure and gene function in response to environmental stimuli. Daphnia were exposed to five different treatments, each consisting of a diet supplemented with one of five cyanobacterial species, and a control treatment consisting of a diet of only green algae. Differential gene expression profiles of Daphnia exposed to each of these five cyanobacterial species showed that genes with known functions are more likely to be shared by different expression profiles, whereas genes specific to the lineage of Daphnia are more likely to be unique to a given expression profile. Furthermore, while only a small number of nonlineage-specific genes were conserved across treatment type, there was a high degree of overlap in expression profiles at the functional level. The conservation of functional responses across the different cyanobacterial treatments can be attributed to the treatment-specific expression of different paralogous genes within the same gene family. Comparison with available gene expression data in the literature suggests differences in nutritional composition in diets with cyanobacterial species compared to diets of green algae as a primary driver for cyanobacterial effects on Daphnia. We conclude that conserved functional responses in Daphnia across different cyanobacterial treatments are mediated through alternate regulation of paralogous gene families. © 2015 John Wiley & Sons Ltd.

  2. Regulation of Mucosal Immune Responses – The Missing Link in IBD?

    Directory of Open Access Journals (Sweden)

    Charles O Elson

    1996-01-01

    Full Text Available Although the etiology of inflammatory bowel disease (IBD remains unknown, a major working hypothesis is that it represents a dysregulated immune response to common enteric bacterial antigens. Until recently there has been a relative dearth of experimental models to study this hypothesis. However, exciting developments in experimental models of colitis, including spontaneous, transgenic and knockout mice, now allow this and other hypotheses to be tested. The regulation of mucosal immune responses is not well understood in the normal animal, much less in those with chronic intestinal inflammation. Clearly the CD4 Th1 and Th2 pathways are important in the host response to microbial pathogens, and recent data indicate that the intestinal mucosa seems to be a site of preferential Th2 responses toward exogenous antigens. Deletion of certain cytokine genes involved in maintaining this Th1/Th2 balance (interleukin [IL]-2, IL-10 resulted in colitis, although deletion of others (IL-4, interferon-gamma that are also involved did not. Whether these cytokine gene deletions cause a dysregulation of the mucosal immune response has yet to be shown. However, the importance of regulation can be demonstrated in a model in which a normal CD4+ T cell subset (CD45Rbhigh is transferred into syngeneic severe combined immunodeficiency syndrome recipients. This results in a striking colitis over the ensuing weeks with chronic diarrhea and wasting of the animals. If the reciprocal CD4+ subset (CD45Rblow is co-transferred or if whole CD4+ T cells are transferred no colitis ensues. Therefore, T cells capable of causing colitis are present in normal animals but are prevented from doing so by immunoregulatory mechanisms. The antigens that drive the colitis in several of these models (IL-2 knockout mouse, human leukocyte antigen B27/β2M transgenic rat appear to be those of the normal enteric bacterial flora because germ-free animals do not get the disease. Spontaneously

  3. Structural basis of response regulator inhibition by a bacterial anti-activator protein.

    Directory of Open Access Journals (Sweden)

    Melinda D Baker

    2011-12-01

    Full Text Available The complex interplay between the response regulator ComA, the anti-activator RapF, and the signaling peptide PhrF controls competence development in Bacillus subtilis. More specifically, ComA drives the expression of genetic competence genes, while RapF inhibits the interaction of ComA with its target promoters. The signaling peptide PhrF accumulates at high cell density and upregulates genetic competence by antagonizing the interaction of RapF and ComA. How RapF functions mechanistically to inhibit ComA activity and how PhrF in turn antagonizes the RapF-ComA interaction were unknown. Here we present the X-ray crystal structure of RapF in complex with the ComA DNA binding domain. Along with biochemical and genetic studies, the X-ray crystal structure reveals how RapF mechanistically regulates ComA function. Interestingly, we found that a RapF surface mimics DNA to block ComA binding to its target promoters. Furthermore, RapF is a monomer either alone or in complex with PhrF, and it undergoes a conformational change upon binding to PhrF, which likely causes the dissociation of ComA from the RapF-ComA complex. Finally, we compare the structure of RapF complexed with the ComA DNA binding domain and the structure of RapH complexed with Spo0F. This comparison reveals that RapF and RapH have strikingly similar overall structures, and that they have evolved different, non-overlapping surfaces to interact with diverse cellular targets. To our knowledge, the data presented here reveal the first atomic level insight into the inhibition of response regulator DNA binding by an anti-activator. Compounds that affect the interaction of Rap and Rap-like proteins with their target domains could serve to regulate medically and commercially important phenotypes in numerous Bacillus species, such as sporulation in B. anthracis and sporulation and the production of Cry protein endotoxin in B. thuringiensis.

  4. Global regulation of gene expression in response to cysteine availability in Clostridium perfringens

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    André Gaelle

    2010-09-01

    Full Text Available Abstract Background Cysteine has a crucial role in cellular physiology and its synthesis is tightly controlled due to its reactivity. However, little is known about the sulfur metabolism and its regulation in clostridia compared with other firmicutes. In Clostridium perfringens, the two-component system, VirR/VirS, controls the expression of the ubiG operon involved in methionine to cysteine conversion in addition to the expression of several toxin genes. The existence of links between the C. perfringens virulence regulon and sulfur metabolism prompted us to analyze this metabolism in more detail. Results We first performed a tentative reconstruction of sulfur metabolism in C. perfringens and correlated these data with the growth of strain 13 in the presence of various sulfur sources. Surprisingly, C. perfringens can convert cysteine to methionine by an atypical still uncharacterized pathway. We further compared the expression profiles of strain 13 after growth in the presence of cystine or homocysteine that corresponds to conditions of cysteine depletion. Among the 177 genes differentially expressed, we found genes involved in sulfur metabolism and controlled by premature termination of transcription via a cysteine specific T-box system (cysK-cysE, cysP1 and cysP2 or an S-box riboswitch (metK and metT. We also showed that the ubiG operon was submitted to a triple regulation by cysteine availability via a T-box system, by the VirR/VirS system via the VR-RNA and by the VirX regulatory RNA. In addition, we found that expression of pfoA (theta-toxin, nagL (one of the five genes encoding hyaluronidases and genes involved in the maintenance of cell redox status was differentially expressed in response to cysteine availability. Finally, we showed that the expression of genes involved in [Fe-S] clusters biogenesis and of the ldh gene encoding the lactate dehydrogenase was induced during cysteine limitation. Conclusion Several key functions for the

  5. Association of attachment disorganization, attachment-related emotion regulation, and cortisol response after standardized psychosocial stress procedure: A pilot study

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    Petrowski Katja

    2017-01-01

    Full Text Available Attachment representations are related to maintaining biological homeostasis, including physiological stress and emotional regulation. Therefore, recent research has focused on attachment stress regulation and hypothalamus pituitary adrenal (HPA axis reactivity. However, the attachment disorganization underlying emotion regulation associated with the HPA axis response has not yet been investigated. In our study, the attachment representation and the HPA-axis reactivity by cortisol level before and after the Trier Social Stress Test were assessed in a sample of 98 healthy non-clinical subjects. As expected, approximately 30% of this sample showed a disorganized attachment representation. The subjects’ unresolved attachment (breakdown of emotional regulation showed a prolonged cortisol recovery. No differences were found between the attachment patterns in the increase and the delta of the cortisol response. However, the cortisol reactivity differed significantly for the occurrence of emotional regulation. The subjects with a high occurrence of attachment-related emotion regulation showed a higher cortisol response than the subjects with an unresolved attachment and the ones with a low occurrence of attachment-related emotion regulation. Regulating the negative emotions of stressful situations may require more attention as it might lead to an increased activation of the physiological system.

  6. Apple F-box Protein MdMAX2 Regulates Plant Photomorphogenesis and Stress Response

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    Jian-Ping An

    2016-11-01

    Full Text Available MAX2 (MORE AXILLARY GROWTH2 is involved in diverse physiological processes, including photomorphogenesis, the abiotic stress response, as well as karrikin and strigolactone signaling-mediated shoot branching. In this study, MdMAX2, an F-box protein that is a homolog of Arabidopsis MAX2, was identified and characterized. Overexpression of MdMAX2 in apple calli enhanced the accumulation of anthocyanin. Ectopic expression of MdMAX2 in Arabidopsis exhibited photomorphogenesis phenotypes, including increased anthocyanin content and decreased hypocotyl length. Further study indicated that MdMAX2 might promote plant photomorphogenesis by affecting the auxin signaling as well as other plant hormones. Transcripts of MdMAX2 were noticeably up-regulated in response to NaCl and Mannitol treatments. Moreover, compared with the wild type, the MdMAX2-overexpressing apple calli and Arabidopsis exhibited increased tolerance to salt and drought stresses. Taken together, these results suggest that MdMAX2 plays a positive regulatory role in plant photomorphogenesis and stress response.

  7. Regulating Inflammation Using Acid-Responsive Electrospun Fibrous Scaffolds for Skin Scarless Healing

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    Ziming Yuan

    2014-01-01

    Full Text Available Skin injury in adult mammals brings about a series of events and inflammation in the wounded area is initiated first and provides lots of inflammatory factors, which is critical for the final scar formation. While the postinjured skin of fetus and nude mice heals scarlessly owing to the absence of inflammation or immunodeficient, we designed a feasible acid-responsive ibuprofen-loaded poly(L-lactide (PLLA fibrous scaffolds via doping sodium bicarbonate to prevent excessive inflammation and achieve scarless healing finally. The morphological results of in vivo experiments revealed that animals treated with acid-responsive ibuprofen-loaded PLLA fibrous scaffolds exhibited alleviative inflammation, accelerated healing process, and regulated collagen deposition via interference in the collagen distribution, the α-smooth muscle actin (α-SMA, and the basic fibroblast growth factor (bFGF expression. The lower ratios of collagen I/collagen III and TGF-β1/TGF-β3 and higher ratio of matrix metalloproteinase-1 (MMP-1/tissue inhibitor of metalloproteinase-1 (TIMP-1 in acid-responsive ibuprofen-loaded PLLA fibrous scaffolds group were confirmed by real-time qPCR as well. These results suggest that inhibiting the excessive inflammation will result in regular collagen distribution and appropriate ratio between the factors, which promote or suppress the scar formation, then decrease the scar area, and finally achieve the scarless healing.

  8. Regulating inflammation using acid-responsive electrospun fibrous scaffolds for skin scarless healing.

    Science.gov (United States)

    Yuan, Ziming; Zhao, Jingwen; Chen, Yigang; Yang, Zhili; Cui, Wenguo; Zheng, Qi

    2014-01-01

    Skin injury in adult mammals brings about a series of events and inflammation in the wounded area is initiated first and provides lots of inflammatory factors, which is critical for the final scar formation. While the postinjured skin of fetus and nude mice heals scarlessly owing to the absence of inflammation or immunodeficient, we designed a feasible acid-responsive ibuprofen-loaded poly(L-lactide) (PLLA) fibrous scaffolds via doping sodium bicarbonate to prevent excessive inflammation and achieve scarless healing finally. The morphological results of in vivo experiments revealed that animals treated with acid-responsive ibuprofen-loaded PLLA fibrous scaffolds exhibited alleviative inflammation, accelerated healing process, and regulated collagen deposition via interference in the collagen distribution, the α-smooth muscle actin (α-SMA), and the basic fibroblast growth factor (bFGF) expression. The lower ratios of collagen I/collagen III and TGF-β1/TGF-β3 and higher ratio of matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in acid-responsive ibuprofen-loaded PLLA fibrous scaffolds group were confirmed by real-time qPCR as well. These results suggest that inhibiting the excessive inflammation will result in regular collagen distribution and appropriate ratio between the factors, which promote or suppress the scar formation, then decrease the scar area, and finally achieve the scarless healing.

  9. Transparency and Accountability of Government Regulations as an Integral Part of Social Responsibility Effectiveness

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    Elena A. Frolova

    2016-09-01

    Full Text Available In the paper the author's view on the role of government in promoting social responsibility of business and the individual is described. The main features of the socio-economic situation in Russia today are presented (horizontal and vertical mobility of the population, a small number of organizations and the extra-centralized public authorities, the predominance of personal relations between economic agents. The necessity of increasing the role of individuals and businesses in the social system is substantiated and the basic directions of activity are suggested (prosocial preferences, interpersonal trust, redistribution of social responsibility. Transparency and accountability of public authorities are very powerful tool to improve the quality of governance and it is one of the important conditions for the social responsibility, as well as to economic performance in modern Russia. The legitimacy of government is a multidimensional issue. And if we take into account the Russian features it is necessary to point out public control and enforcement, quality of formal institutions, and effectiveness of enforcement mechanisms. Also governance is important to enhance quality of regulation.

  10. The hypothalamic-pituitary response in SLE. Regulation of prolactin, growth hormone and cortisol release.

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    Rovenský, J; Blazícková, S; Rauová, L; Jezová, D; Koska, J; Lukác, J; Vigas, M

    1998-01-01

    It has been suggested that neuroendocrine regulation plays an important role in the pathogenesis and activation of autoimmune diseases. The aim of this investigation was to clarify the hypothalamic-pituitary response to a well-defined stimulus under standardised conditions in patients with SLE. Plasma concentrations of prolactin (PRL), growth hormone (GH) and cortisol were determined in venous blood drawn through an indwelling cannula during insulin-induced hypoglycaemia (0.1 U/kg b.w., i.v.) in ten patients and in 12 age-, gender- and weight-matched healthy subjects. Basal PRL concentrations were higher in patients vs healthy controls (12 vs 6 ng/ml, P < 0.01), though still within the physiological range. Insulin-induced plasma PRL and GH were significantly increased both in patients and healthy subjects; however, the increments or areas under the curves were not different in the two groups. Plasma cortisol response showed moderate attenuation in patients. Sensitivity of pituitary lactotrothrops to thyrotropin-releasing hormone (TRH) administration (200 microg, i.v.) was the same in patients and control subjects. In SLE patients with low activity of the disease the sensitivity of pituitary PRL release to TRH administration remained unchanged. The hypothalamic response to stress stimulus (hypoglycaemia) was comparable in patients and healthy subjects.

  11. Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior

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    Divya Mehta

    2016-01-01

    Full Text Available We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G×E interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G×E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life.

  12. Coupling of transcriptional response to oxidative stress and secondary metabolism regulation in filamentous fungi.

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    Montibus, Mathilde; Pinson-Gadais, Laëtitia; Richard-Forget, Florence; Barreau, Christian; Ponts, Nadia

    2015-01-01

    To survive sudden and potentially lethal changes in their environment, filamentous fungi must sense and respond to a vast array of stresses, including oxidative stresses. The generation of reactive oxygen species, or ROS, is an inevitable aspect of existence under aerobic conditions. In addition, in the case of fungi with pathogenic lifestyles, ROS are produced by the infected hosts and serve as defense weapons via direct toxicity, as well as effectors in fungal cell death mechanisms. Filamentous fungi have thus developed complex and sophisticated responses to evade oxidative killing. Several steps are determinant in these responses, including the activation of transcriptional regulators involved in the control of the antioxidant machinery. Gathering and integrating the most recent advances in knowledge of oxidative stress responses in fungi are the main objectives of this review. Most of the knowledge coming from two models, the yeast Saccharomyces cerevisiae and fungi of the genus Aspergillus, is summarized. Nonetheless, recent information on various other fungi is delivered when available. Finally, special attention is given on the potential link between the functional interaction between oxidative stress and secondary metabolism that has been suggested in recent reports, including the production of mycotoxins.

  13. The regulation of immune responses by DC derived Type I IFN

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    Jennifer eGommerman

    2013-04-01

    Full Text Available Our immune system bears the tremendous task of mounting effective anti-microbial responses whilst maintaining immunoregulatory functions to avoid autoimmunity. In order to quickly respond to pathogens, Dendritic cells (DC are armed with pattern recognition receptors (PRRs, allowing them to recognize highly conserved pathogen-associated molecular patterns (PAMPs that are uniquely expressed by invading microbes. PRR activation can trigger DCs to release the pleiotropic cytokine, Type I IFN, which facilitates various biological functions in different immune cell types. In this review, we will discuss the classical PRR-induced Type I IFN response in DCs as well as describe a novel mechanism for Type I IFN induction by the Tumor-Necrosis Factor receptor superfamily (TNFRSF members, TNFR-1 and Lymphotoxin-β receptor (LTβR. While PRR activation during viral infection, produces large amounts of Type I IFN in a relative short period of time, TNFRSF-induced Type I IFN expression is modest with gradual kinetics. Type I IFN can exert pro-inflammatory effects, but in some cases it also facilitates immune-regulatory functions. Therefore, DCs are important regulators of immune responses by carefully modulating Type I IFN expression.

  14. Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior

    Science.gov (United States)

    Eapen, Valsamma; Kohlhoff, Jane; Mendoza Diaz, Antonio; Barnett, Bryanne; Silove, Derrick; Dadds, Mark R.

    2016-01-01

    We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR) gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm) and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G × E) interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G × E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life. PMID:27872764

  15. Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

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    Chuan Hua He

    2013-08-01

    Full Text Available Members of the 18 glycosyl hydrolase (GH 18 gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1, which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2 and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

  16. Regulation of intestinal immune responses through TLR activation: implications for pro- and prebiotics

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    Sander eDe Kivit

    2014-02-01

    Full Text Available The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g. inflammatory bowel disease, irritable bowel syndrome (IBS, allergic gastroenteritis (e.g. eosinophilic gastroenteritis and allergic IBS and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLR play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.

  17. Neurotoxicity induced by arsenic in Gallus Gallus: Regulation of oxidative stress and heat shock protein response.

    Science.gov (United States)

    Zhao, Panpan; Guo, Ying; Zhang, Wen; Chai, Hongliang; Xing, Houjuan; Xing, Mingwei

    2017-01-01

    Arsenic, a naturally occurring heavy metal pollutant, is one of the functioning risk factors for neurological toxicity in humans. However, little is known about the effects of arsenic on the nervous system of Gallus Gallus. To investigate whether arsenic induce neurotoxicity and influence the oxidative stress and heat shock proteins (Hsps) response in chickens, seventy-two 1-day-old male Hy-line chickens were treated with different doses of arsenic trioxide (As2O3). The histological changes, antioxidant enzyme activity, and the expressions of Hsps were detected. Results showed slightly histology changes were obvious in the brain tissues exposure to arsenic. The activities of Glutathione peroxidase (GSH-Px) and catalase (CAT) were decreased compared to the control, whereas the malondialdehyde (MDA) content was increased gradually along with increase in diet-arsenic. The mRNA levels of Hsps and protein expressions of Hsp60 and Hsp70 were up-regulated. These results suggested that sub-chronic exposure to arsenic induced neurotoxicity in chickens. Arsenic exposure disturbed the balance of oxidants and antioxidants. Increased heat shock response tried to protect chicken brain tissues from tissues damage caused by oxidative stress. The mechanisms of neurotoxicity induced by arsenic include oxidative stress and heat shock protein response in chicken brain tissues.

  18. Compensatory evolution of gene regulation in response to stress by Escherichia coli lacking RpoS.

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    Daniel M Stoebel

    2009-10-01

    Full Text Available The RpoS sigma factor protein of Escherichia coli RNA polymerase is the master transcriptional regulator of physiological responses to a variety of stresses. This stress response comes at the expense of scavenging for scarce resources, causing a trade-off between stress tolerance and nutrient acquisition. This trade-off favors non-functional rpoS alleles in nutrient-poor environments. We used experimental evolution to explore how natural selection modifies the regulatory network of strains lacking RpoS when they evolve in an osmotically stressful environment. We found that strains lacking RpoS adapt less variably, in terms of both fitness increase and changes in patterns of transcription, than strains with functional RpoS. This phenotypic uniformity was caused by the same adaptive mutation in every independent population: the insertion of IS10 into the promoter of the otsBA operon. OtsA and OtsB are required to synthesize the osmoprotectant trehalose, and transcription of otsBA requires RpoS in the wild-type genetic background. The evolved IS10 insertion rewires expression of otsBA from RpoS-dependent to RpoS-independent, allowing for partial restoration of wild-type response to osmotic stress. Our results show that the regulatory networks of bacteria can evolve new structures in ways that are both rapid and repeatable.

  19. Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome.

    Science.gov (United States)

    Iyama, Teruaki; Wilson, David M

    2016-01-16

    Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage and is most rapid and robust as follows: ICLs>DSBs>monoadducts>oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but it did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB and, in particular, its ubiquitin-binding domain were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts but not at oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS.

  20. RirA is the iron response regulator of the rhizobactin 1021 biosynthesis and transport genes in Sinorhizobium meliloti 2011.

    Science.gov (United States)

    Viguier, Caroline; O Cuív, Páraic; Clarke, Paul; O'Connell, Michael

    2005-05-15

    The genes encoding the biosynthesis and transport of rhizobactin 1021, a siderophore produced by Sinorhizobium meliloti, are negatively regulated by iron. Mutagenesis of rirA, the rhizobial iron regulator, resulted in abolition of the iron responsive regulation of the biosynthesis and transport genes. Bioassay analysis revealed that the siderophore is produced in the presence of iron in a rirA mutant. RNA analysis and GFP fusions supported the conclusion that RirA is the mediator of iron-responsive transcriptional repression of the two transcripts encoding the biosynthesis and transport genes. RirA in S. meliloti appears to fulfil the role often observed for Fur in other bacterial species. The regulator was found to mediate the iron-responsive expression of two additional genes, smc02726 and dppA1, repressing the former while activating the latter. The rirA mutant nodulated the host plant Medicago sativa (alfalfa) and fixed nitrogen as effectively as the wild type.

  1. Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease.

    Science.gov (United States)

    Panicker, Nikhil; Saminathan, Hariharan; Jin, Huajun; Neal, Matthew; Harischandra, Dilshan S; Gordon, Richard; Kanthasamy, Kavin; Lawana, Vivek; Sarkar, Souvarish; Luo, Jie; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2015-07-08

    Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFα rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPS- and TNFα-induced MAP kinase phosphorylation and activation of the NFκB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn(+/+)) and Fyn knock-out (Fyn(-/-)) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn(-/-) and PKCδ (-/-) mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD. Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major

  2. Grouper TRIM13 exerts negative regulation of antiviral immune response against nodavirus.

    Science.gov (United States)

    Huang, Youhua; Yang, Min; Yu, Yepin; Yang, Ying; Zhou, Linli; Huang, Xiaohong; Qin, Qiwei

    2016-08-01

    -inflammatory factors. Together, our results firstly demonstrated that fish TRIM13 exerted negative regulation of antiviral response against nodavirus infection.

  3. Theoretical insight into the heat shock response (HSR) regulation in Lactobacillus casei and L. rhamnosus.

    Science.gov (United States)

    Rossi, Franca; Zotta, Teresa; Iacumin, Lucilla; Reale, Anna

    2016-08-07

    The understanding of the heat shock response (HSR) in lactobacilli from a regulatory point of view is still limited, though an increased knowledge on the regulation of this central stress response can lead to improvements in the exploitation of these health promoting microorganisms. Therefore the aim of this in silico study, that is the first to be carried out for members of the Lactobacillus genus, was predicting how HSR influences cell functions in the food associated and probiotic species Lactobacillus casei and Lactobacillus rhamnosus. To this purpose, thirteen whole genomes of these bacteria were analyzed to identify which genes involved in HSR are present. It was found that all the genomes share 25 HSR related genes, including those encoding protein repair systems, HSR repressors, HrcA and CtsR, and the positive regulators of HSR, alternative σ factors σ(32) and σ(24). Two genes encoding a σ(70)/σ(24) factor and a Lon protease, respectively, were found only in some genomes. The localization of the HSR regulators binding sites in genomes was analyzed in order to identify regulatory relationships driving HSR in these lactobacilli. It was observed that the binding site for the HrcA repressor is found upstream of the hrcA-grpE-dnaK-dnaJ and groES-groEL gene clusters, of two hsp genes, clpE, clpL and clpP, while the CtsR repressor binding site precedes the ctsR-clpC operon, clpB, clpE and clpP. Therefore the ClpE-ClpP protease complex is dually regulated by HrcA and CtsR. Consensus sequences for the promoters recognized by the HSR alternative σ factors were defined for L. casei and L. rhamnosus and were used in whole genome searches to identify the genes that are possibly regulated by these transcription factors and whose expression level is expected to increases in HSR. The results were validated by applying the same procedure of promoter consensus generation and whole genome search to an additional 11 species representative of the main Lactobacillus

  4. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.

    Science.gov (United States)

    Gądek-Michalska, Anna; Tadeusz, Joanna; Rachwalska, Paulina; Bugajski, Jan

    2013-01-01

    pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to acute and chronic stress involve cytokines, NO and PG systems that regulate and turn off responses that would be potentially harmful for cellular homeostasis and overall health.

  5. HYPOXIHYPOBAROTHERAPY IN REGULATION OF NEUROHUMORAL AND CYTOKINE RESPONSE IN REHABILITATION OF CHILDREN WITH BRONCHIAL ASTHMA

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    G.D. Alemanova

    2009-01-01

    Full Text Available The effect of hypoxihypobarotherapy in children with bronchial asthma at the rehabilitation stage on the clinicals and dynamics of immunity response to the disease has been studied. Clinical efficacy of hypoxihypobarotherapy was 63,3% in moderate asthma. Positive dynamics of immunological indicators and neuropeptides have manifested in reduced of IL 4, IL 5, IL 18 and substance P serum levels. Use of hypoxihypobarotherapy in children with bronchial asthma has resulted in favourable clinical and immune dynamics and positive alteration of neurohumoral regulation mechanisms and reduced intensity of neurogenic inflammation. Determining immunological indicators, including neuropeptides, may serve as an additional criterion for assessing the efficacy of this treatment in children with bronchial asthma at the rehabilitation stage.Key words: children, bronchial asthma, pneumotherapy, hypoxihypobarotherapy, neuropeptides, cytokines.

  6. Nitric oxide: orchestrating hypoxia regulation through mitochondrial respiration and the endoplasmic reticulum stress response

    Institute of Scientific and Technical Information of China (English)

    Weiming XU; Ian G. CHARLES; Salvador MONCADA

    2005-01-01

    Mitochondria have long been considered to be the powerhouse of the living cell, generating energy in the form of the molecule ATP via the process of oxidative phosphorylation. In the past 20 years, it has been recognised that they also play an important role in the implementation of apoptosis, or programmed cell death. More recently it has become evident that mitochondria also participate in the orchestration of cellular defence responses. At physiological concentrations,the gaseous molecule nitric oxide (NO) inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competition with oxygen. This interaction underlies the mitochondrial actions of NO, which range from the physiological regulation of cell respiration, through mitochondrial signalling, to the development of "metabolic hypoxia" - a situation in which, although oxygen is available, the cell is unable to utilise it.

  7. Jasmonic acid interacts with abscisic acid to regulate plant responses to water stress conditions

    Science.gov (United States)

    de Ollas, Carlos; Arbona, Vicent; Gómez-Cadenas, Aurelio

    2015-01-01

    Phytohormones are key players in signaling environmental stress conditions. Hormone profiling together with proline accumulation were studied in leaves and roots of different mutant lines of Arabidopsis. Regulation of proline accumulation in this system seems complex and JA-deficient (jar1-1) and JA-insensitive (jai1) lines accumulating high levels of proline despite their very low ABA levels seems to discard an ABA-dependent response. However, the pattern of proline accumulation in jai1 seedlings parallels that of ABA. Under stress conditions, there is an opposite pattern of ABA accumulation in roots of jar1-1/coi1-16 (in which ABA only slightly increase) and jai1 (in which ABA increase is even higher than in WT plants). This also makes JA-ABA crosstalk complex and discards any lineal pathway that could explain this hormonal interaction. PMID:26340066

  8. The Solanum lycopersicum auxin response factor SlARF2 participates in regulating lateral root formation and flower organ senescence.

    Science.gov (United States)

    Ren, Zhenxin; Liu, Ruiyuan; Gu, Wenting; Dong, Xicun

    2017-03-01

    ARF2 as apleiotropic developmental regulator has been reported in Arabidopsis thaliana and tomato (Solanum lycopersicum). The present study showed SlARF2 transcripts in all tomato plant tissues but with higher accumulation in flowers. During bud-anthesis stages, SlARF2 transcripts showed a dynamic expression pattern in sepal, stamen, ovary and petal. Hormone treatment analysis suggested that SlARF2 transcript accumulation was positively regulated by auxin and gibberellic acid, and negatively regulated by ethylene in tomato seedlings. Phenotypes and molecular analyses of SlARF2-upregulated transgenic tomato indicated that SlARF2 regulated tomato lateral root formation and flower organ senescence may be partially mediated by regulating the gene expression of auxin and ethylene response factors. The data enlarges the functional characterization of SlARF2 in tomato, and broadens our understanding of auxin signaling in regulating plant growth and development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Regulation of Rac1 and Reactive Oxygen Species Production in Response to Infection of Gastrointestinal Epithelia.

    Directory of Open Access Journals (Sweden)

    Gerco den Hartog

    2016-01-01

    Full Text Available Generation of reactive oxygen species (ROS during infection is an immediate host defense leading to microbial killing. APE1 is a multifunctional protein induced by ROS and after induction, protects against ROS-mediated DNA damage. Rac1 and NAPDH oxidase (Nox1 are important contributors of ROS generation following infection and associated with gastrointestinal epithelial injury. The purpose of this study was to determine if APE1 regulates the function of Rac1 and Nox1 during oxidative stress. Gastric or colonic epithelial cells (wild-type or with suppressed APE1 were infected with Helicobacter pylori or Salmonella enterica and assessed for Rac1 and NADPH oxidase-dependent superoxide production. Rac1 and APE1 interactions were measured by co-immunoprecipitation, confocal microscopy and proximity ligation assay (PLA in cell lines or in biopsy specimens. Significantly greater levels of ROS were produced by APE1-deficient human gastric and colonic cell lines and primary gastric epithelial cells compared to control cells after infection with either gastric or enteric pathogens. H. pylori activated Rac1 and Nox1 in all cell types, but activation was higher in APE1 suppressed cells. APE1 overexpression decreased H. pylori-induced ROS generation, Rac1 activation, and Nox1 expression. We determined that the effects of APE1 were mediated through its N-terminal lysine residues interacting with Rac1, leading to inhibition of Nox1 expression and ROS generation. APE1 is a negative regulator of oxidative stress in the gastrointestinal epithelium during bacterial infection by modulating Rac1 and Nox1. Our results implicate APE1 in novel molecular interactions that regulate early stress responses elicited by microbial infections.

  10. Role and regulation of autophagy in heat stress responses of tomato plants.

    Science.gov (United States)

    Zhou, Jie; Wang, Jian; Yu, Jing-Quan; Chen, Zhixiang

    2014-01-01

    As sessile organisms, plants are constantly exposed to a wide spectrum of stress conditions such as high temperature, which causes protein misfolding. Misfolded proteins are highly toxic and must be efficiently removed to reduce cellular proteotoxic stress if restoration of native conformations is unsuccessful. Although selective autophagy is known to function in protein quality control by targeting degradation of misfolded and potentially toxic proteins, its role and regulation in heat stress responses have not been analyzed in crop plants. In the present study, we found that heat stress induced expression of autophagy-related (ATG) genes and accumulation of autophagosomes in tomato plants. Virus-induced gene silencing (VIGS) of tomato ATG5 and ATG7 genes resulted in increased sensitivity of tomato plants to heat stress based on both increased development of heat stress symptoms and compromised photosynthetic parameters of heat-stressed leaf tissues. Silencing of tomato homologs for the selective autophagy receptor NBR1, which targets ubiquitinated protein aggregates, also compromised tomato heat tolerance. To better understand the regulation of heat-induced autophagy, we found that silencing of tomato ATG5, ATG7, or NBR1 compromised heat-induced expression of not only the targeted genes but also other autophagy-related genes. Furthermore, we identified two tomato genes encoding proteins highly homologous to Arabidopsis WRKY33 transcription factor, which has been previously shown to interact physically with an autophagy protein. Silencing of tomato WRKY33 genes compromised tomato heat tolerance and reduced heat-induced ATG gene expression and autophagosome accumulation. Based on these results, we propose that heat-induced autophagy in tomato is subject to cooperative regulation by both WRKY33 and ATG proteins and plays a critical role in tomato heat tolerance, mostly likely through selective removal of heat-induced protein aggregates.

  11. Role and Regulation of Autophagy in Heat Stress Responses of Tomato Plants

    Directory of Open Access Journals (Sweden)

    Jie eZhou

    2014-04-01

    Full Text Available As sessile organisms, plants are constantly exposed to a wide spectrum of stress conditions such as high temperature, which causes protein misfolding. Misfolded proteins are highly toxic and must be efficiently removed to reduce cellular proteotoxic stress if restoration of native conformations is unsuccessful. Although selective autophagy is known to function in protein quality control by targeting degradation of misfolded and potentially toxic proteins, its role and regulation in heat stress responses have not been analyzed in crop plants. In the present study, we found that heat stress induced expression of autophagy-related (ATG genes and accumulation of autophagosomes in tomato plants. Virus-induced gene silencing of tomato ATG5 and ATG7 genes resulted in increased sensitivity of tomato plants to heat stress based on both increased development of heat stress symptoms and compromised photosynthetic parameters of heat-stressed leaf tissues. Silencing of tomato homologs for the selective autophagy receptor NBR1, which targets ubiquitinated protein aggregates, also compromised tomato heat tolerance. To better understand the regulation of heat-induced autophagy, we found that silencing of tomato ATG5, ATG7 or NBR1 compromised heat-induced expression of not only the targeted genes but also other autophagy-related genes. Furthermore, we identified two tomato genes encoding proteins highly homologous to Arabidopsis WRKY33 transcription factor, which has been previously shown to interact physically with an autophagy protein. Silencing of tomato WRKY33 genes compromised tomato heat tolerance and reduced heat-induced ATG gene expression and autophagosome accumulation. Based on these results, we propose that heat-induced autophagy in tomato is subject to cooperative regulation by both WRKY33 and ATG proteins and plays a critical role in tomato heat tolerance, mostly likely through selective removal of heat-induced protein aggregates.

  12. Plant community structure regulates responses of prairie soil respiration to decadal experimental warming.

    Science.gov (United States)

    Xu, Xia; Shi, Zheng; Li, Dejun; Zhou, Xuhui; Sherry, Rebecca A; Luo, Yiqi

    2015-10-01

    Soil respiration is recognized to be influenced by temperature, moisture, and ecosystem production. However, little is known about how plant community structure regulates responses of soil respiration to climate change. Here, we used a 13-year field warming experiment to explore the mechanisms underlying plant community regulation on feedbacks of soil respiration to climate change in a tallgrass prairie in Oklahoma, USA. Infrared heaters were used to elevate temperature about 2 °C since November 1999. Annual clipping was used to mimic hay harvest. Our results showed that experimental warming significantly increased soil respiration approximately from 10% in the first 7 years (2000-2006) to 30% in the next 6 years (2007-2012). The two-stage warming stimulation of soil respiration was closely related to warming-induced increases in ecosystem production over the years. Moreover, we found that across the 13 years, warming-induced increases in soil respiration were positively affected by the proportion of aboveground net primary production (ANPP) contributed by C3 forbs. Functional composition of the plant community regulated warming-induced increases in soil respiration through the quantity and quality of organic matter inputs to soil and the amount of photosynthetic carbon (C) allocated belowground. Clipping, the interaction of clipping with warming, and warming-induced changes in soil temperature and moisture all had little effect on soil respiration over the years (all P > 0.05). Our results suggest that climate warming may drive an increase in soil respiration through altering composition of plant communities in grassland ecosystems.

  13. Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons.

    Directory of Open Access Journals (Sweden)

    Aaron Uschakov

    Full Text Available We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA of hypocretin/orexin (hcrt/orx neurons was changed to an inhibition following sleep deprivation (SD. Here we describe that in control condition (CC, i.e. following 2 hours of natural sleep in the morning, the α(2-adrenergic receptor (α(2-AR agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC, it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK channels. Since concentrations of clonidine up to a thousand times (100 µM higher than those effective in SDC (100 nM, were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABA(B agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α(2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α(2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α(2-ARs associated with GIRK channels is normally down-regulated (or desensitized in hcrt/orx neurons to only become available for their inhibition following sleep deprivation.

  14. Transcriptional regulation of the Hansenula polymorpha GSH2 gene in the response to cadmium ion treatment

    Directory of Open Access Journals (Sweden)

    O. V. Blazhenko

    2014-02-01

    Full Text Available In a previous study we cloned GSH2 gene, encoding γ-glutamylcysteine synthetase (γGCS in the yeast Hansenula рolymorpha. In this study an analysis of molecular organisation of the H. рolymorpha GSH2 gene promoter was conducted and the potential binding sites of Yap1, Skn7, Creb/Atf1, and Cbf1 transcription factors were detected. It was established that full regulation of GSH2 gene expression in the response to cadmium and oxidative stress requires the length of GSH2 promoter to be longer than 450 bp from the start of translation initiation. To study the transcriptional regulation of H. polymorpha GSH2 gene recombinant strain, harbouring­ a reporter system, in which 1.832 kb regulatory region of GSH2 gene was fused to structural and terminatory regions of alcohol oxidase gene, was constructed. It was shown that maximum increase in H. polymorpha GSH2 gene transcription by 33% occurs in the rich medium under four-hour incubation with 1 μM concentration of cadmium ions. In the minimal medium the GSH2 gene expression does not correlate with the increased total cellular glutathione levels under cadmium ion treatment. We assume that the increased content of total cellular glutathione under cadmium stress in the yeast H. polymorpha probably is not controlled on the level of GSH2 gene transcription.

  15. Rice Homeobox Transcription Factor HOX1a Positively Regulates Gibberellin Responses by Directly Suppressing EL1

    Institute of Scientific and Technical Information of China (English)

    Bi-Qing Wen; Mei-Qing Xing; Hua Zhang Cheng Dai; Hong-Wei Xue

    2011-01-01

    Homeobox transcription factors are involved in various aspects of plant development,including maintenance of the biosynthesis and signaling pathways of different hormones.However,few direct targets of homeobox proteins have been identified.We here show that overexpression of rice homeobox gene HOX1a resulted in enhanced gibberellin (GA) response,indicating a positive effect of HOX1a in GA signaling.HOX1a is induced by GA and encodes a homeobox transcription factor with transcription repression activity.In addition,HOX1a suppresses the transcription of early flowering1 (EL1),a negative regulator of GA signaling,and further electrophoretic mobility shift assay and chromatin immunoprecipitation analysis revealed that HOX1a directly bound to the promoter region of EL1 to suppress its expression and stimulate GA signaling.These results demonstrate that HOX1a functions as a positive regulator of GA signaling by suppressing EL1,providing informative hints on the study of GA signaling.

  16. Defence responses of arabidopsis thaliana to infection by pseudomonas syringae are regulated by the circadian clock

    KAUST Repository

    Bhardwaj, Vaibhav

    2011-10-31

    The circadian clock allows plants to anticipate predictable daily changes in abiotic stimuli, such as light; however, whether the clock similarly allows plants to anticipate interactions with other organisms is unknown. Here we show that Arabidopsis thaliana (Arabidopsis) has circadian clock-mediated variation in resistance to the virulent bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), with plants being least susceptible to infection in the subjective morning. We suggest that the increased resistance to Pst DC3000 observed in the morning in Col-0 plants results from clock-mediated modulation of pathogen associated molecular pattern (PAMP)-triggered immunity. Analysis of publicly available microarray data revealed that a large number of Arabidopsis defence-related genes showed both diurnal- and circadian-regulation, including genes involved in the perception of the PAMP flagellin which exhibit a peak in expression in the morning. Accordingly, we observed that PAMP-triggered callose deposition was significantly higher in wild-type plants inoculated with Pst DC3000 hrpA in the subjective morning than in the evening, while no such temporal difference was evident in arrhythmic plants. Our results suggest that PAMP-triggered immune responses are modulated by the circadian clock and that temporal regulation allows plants to anticipate and respond more effectively to pathogen challenges in the daytime. © 2011 Bhardwaj et al.

  17. The CKH2/PKL chromatin remodeling factor negatively regulates cytokinin responses in Arabidopsis calli.

    Science.gov (United States)

    Furuta, Kaori; Kubo, Minoru; Sano, Kiyomi; Demura, Taku; Fukuda, Hiroo; Liu, Yao-Guang; Shibata, Daisuke; Kakimoto, Tatsuo

    2011-04-01

    Cytokinins promote cell division and chloroplast development in tissue culture. We previously isolated two mutants of Arabidopsis thaliana, ckh1 (cytokinin-hypersensitive 1) and ckh2, which produce rapidly growing green calli in response to lower levels of cytokinins than those found in the wild type. Here we report that the product of the CKH2 gene is PICKLE, a protein resembling the CHD3 class of SWI/SNF chromatin remodeling factors. We also show that inhibition of histone deacetylase by trichostatin A (TSA) partially substituted for cytokinins, but not for auxin, in the promotion of callus growth, indicating that chromatin remodeling and histone deacetylation are intimately related to cytokinin-induced callus growth. A microarray experiment revealed that either the ckh1 mutation or the ckh2 mutation caused hypersensitivity to cytokinins in terms of gene expression, especially of photosynthesis-related genes. The ckh1 and ckh2 mutations up-regulated nuclear-encoded genes, but not plastid-encoded genes, whereas TSA deregulated both nuclear- and plastid-encoded genes. The ckh1 ckh2 double mutant showed synergistic phenotypes: the callus grew with a green color independently of exogenous cytokinins. A yeast two-hybrid experiment showed protein interaction between CKH1/EER4/AtTAF12b and CKH2/PKL. These results suggest that CKH1/EER4/AtTAF12b and CKH2/PKL may act together on cytokinin-regulated genes.

  18. Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing

    Science.gov (United States)

    Kavanaugh, Gina; Zhao, Runxiang; Guo, Yan; Mohni, Kareem N.; Glick, Gloria; Lacy, Monica E.; Hutson, M. Shane; Ascano, Manuel

    2015-01-01

    Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair. PMID:26100022

  19. cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

    Energy Technology Data Exchange (ETDEWEB)

    Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui; Ha, Hyunil, E-mail: hyunil74@hotmail.com; Lee, Zang Hee, E-mail: zang1959@snu.ac.kr

    2010-07-23

    Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

  20. Genotype-dependent regulation of drought-responsive genes in tolerant and sensitive sugarcane cultivars.

    Science.gov (United States)

    da Silva, Manassés Daniel; de Oliveira Silva, Roberta Lane; Ferreira Neto, José Ribamar Costa; Benko-Iseppon, Ana Maria; Kido, Ederson Akio

    2017-10-30

    Drought is the most damaging among the major abiotic stresses. Transcriptomic studies allow a global overview of expressed genes, providing the basis for molecular markers development. Here, the HT-SuperSAGE technique allowed the evaluation of four drought-tolerant cultivars and four-sensitive cultivars, after 24h of irrigation suppression. We identified 9831 induced unitags from roots of the tolerant cultivars with different regulations by the -sensitive cultivars after the applied stress. These unitags allowed a proposal of 15 genes, whose expressed profiles were validated by RT-qPCR, evaluating each cultivar independently. These genes covered broad metabolic processes: ethylene stress attenuation (ACCD); root growth (β-EXP8); protein degradation [ubiquitination pathway (E2, 20SPβ4); plant proteases (AP, C13)]; oxidative detoxification (TRX); fatty acid synthesis (ACC); amino acid transport (AAT), and carbohydrate metabolism [glycolysis (PFK, TPI, FBA); TCA cycle (LDP, MDH); pentose phosphate pathway (TKT)]. The expressed profiles showed a genotype-dependent regulation of the target genes. Two drought-tolerant cultivars (SP83-2847; CTC6) presented each one, nine of the induced genes. Among the -sensitive cultivars, CTC13 induced only one, while SP90-1636 induced two genes. These genes should help breeders to identify accessions managing drought stress tolerance responses, showing better ethylene stress attenuation, energy allocation, amino acid transport, and protein homeostasis. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan.

    Science.gov (United States)

    Schumpert, Charles A; Anderson, Craig; Dudycha, Jeffry L; Patel, Rekha C

    2016-02-01

    The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR inDaphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2.

  2. Radiation protection and the safe use of X-ray equipment: Laws, regulations and responsibilities

    Directory of Open Access Journals (Sweden)

    Charles Petrus Herbst

    2012-06-01

    Full Text Available Lately, South Africa’s regulatory framework for electromagnetic medical devices has come under considerable pressure. In this article the legislative framework and regulatory infrastructure are scrutinized, by looking at how the legislature has given form to protective measures against ionizing radiation. Although the Hazardous Substances Act provides for effective protection against radiation, poor administration led to insufficient staffing levels, uncertainty about Regulations and licensing conditions and therefore undermines a sound radiation protection infrastructure. The legal basis of enforcing licensing conditions through a website without proper consultation with interested and affected parties is questionable and ineffective in controlling radiation levels. Effective and legal radiation control is possible by activating the National Advisory Committee on Electronic Products provided for in Regulation R326 published in 1979, but never implemented. The possible impact of annual quality assurance tests currently enforced through licensing conditions on the radiation dose of the population is not cost effective as new training and accreditation structures had to be created. The fact that generally more than 80% of overexposures are caused by human error is a clear indication that training of the daily users of X-ray equipment should be emphasized and not the training and accreditation of the technicians responsible for a single quality assurance test per year. Constructive engagement with the professional bodies involved in the medical use of X-rays through a National Advisory Committee on Electronic Products may be a cost effective solution for lowering radiation dose to the population.

  3. Regulation of the DNA Damage Response by DNA-PKcs Inhibitory Phosphorylation of ATM.

    Science.gov (United States)

    Zhou, Yi; Lee, Ji-Hoon; Jiang, Wenxia; Crowe, Jennie L; Zha, Shan; Paull, Tanya T

    2017-01-05

    Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage. In contrast, phospho-blocking mutations at one cluster of sites increase the frequency of apoptosis during normal cell growth. DNA-PKcs, which is integral to the non-homologous end joining pathway, thus negatively regulates ATM activity through phosphorylation of ATM. These observations illuminate an important regulatory mechanism for ATM that also controls DNA repair pathway choice.

  4. Plasmacytoid DCs regulate recall responses by rapid induction of IL-10 in memory T cells.

    Science.gov (United States)

    Kvale, Espen O; Fløisand, Yngvar; Lund-Johansen, Fridtjof; Rollag, Halvor; Farkas, Lorant; Ghanekar, Smita; Brandtzaeg, Per; Jahnsen, Frode L; Olweus, Johanna

    2007-04-15

    Dendritic cells (DCs) are believed to regulate T cell-mediated immunity primarily by directing differentiation of naive T cells. Here, we show that a large fraction of CD4(+) memory cells produce IL-10 within the first hours after interaction with plasmacytoid DCs (PDCs). In contrast, CD11c(+) DCs induce IFN-gamma and little IL-10. IL-10-secreting T cells isolated after 36 hours of culture with PDCs suppressed antigen-induced T-cell proliferation by an IL-10-dependent mechanism, but were distinct from natural and type 1 regulatory T cells. They proliferated strongly and continued to secrete IL-10 during expansion with PDCs, and after restimulation with immature monocyte-derived DCs or CD11c(+) DCs. The IL-10-producing T cells acquired the ability to secrete high levels of IFN-gamma after isolation and subsequent coculture with PDCs or CD11c(+) DCs. Compared to CD11c(+) DCs, PDCs were superior in their ability to selectively expand T cells that produced cytokines on repeated antigenic challenge. The DC-dependent differences in cytokine profiles were observed with viral recall antigen or staphylococcal enterotoxin B and were independent of extracellular type I interferon or IL-10. Our results show that DCs can regulate memory responses and that PDCs rapidly induce regulatory cytokines in effector T cells that can suppress bystander activity.

  5. The MAP kinase substrate MKS1 is a regulator of plant defense responses.

    Science.gov (United States)

    Andreasson, Erik; Jenkins, Thomas; Brodersen, Peter; Thorgrimsen, Stephan; Petersen, Nikolaj H T; Zhu, Shijiang; Qiu, Jin-Long; Micheelsen, Pernille; Rocher, Anne; Petersen, Morten; Newman, Mari-Anne; Bjørn Nielsen, Henrik; Hirt, Heribert; Somssich, Imre; Mattsson, Ole; Mundy, John

    2005-07-20

    Arabidopsis MAP kinase 4 (MPK4) functions as a regulator of pathogen defense responses, because it is required for both repression of salicylic acid (SA)-dependent resistance and for activation of jasmonate (JA)-dependent defense gene expression. To understand MPK4 signaling mechanisms, we used yeast two-hybrid screening to identify the MPK4 substrate MKS1. Analyses of transgenic plants and genome-wide transcript profiling indicated that MKS1 is required for full SA-dependent resistance in mpk4 mutants, and that overexpression of MKS1 in wild-type plants is sufficient to activate SA-dependent resistance, but does not interfere with induction of a defense gene by JA. Further yeast two-hybrid screening revealed that MKS1 interacts with the WRKY transcription factors WRKY25 and WRKY33. WRKY25 and WRKY33 were shown to be in vitro substrates of MPK4, and a wrky33 knockout mutant was found to exhibit increased expression of the SA-related defense gene PR1. MKS1 may therefore contribute to MPK4-regulated defense activation by coupling the kinase to specific WRKY transcription factors.

  6. Downstream ecosystem responses to middle reach regulation of river discharge in the Heihe River Basin, China

    Science.gov (United States)

    Zhao, Yan; Wei, Yongping; Li, Shoubo; Wu, Bingfang

    2016-11-01

    Understanding the oasis ecosystem responses to upstream regulation is a challenge for catchment management in the context of ecological restoration. This empirical study aimed to understand how oasis ecosystems, including water, natural vegetation and cultivated land, responded to the implementation of the Ecological Water Diversion Project (EWDP) in the Heihe River in China. The annual Landsat images from 1987 to 2015 were firstly used to characterize the spatial extent, frequency index and fractional coverage (for vegetation only) of these three oasis ecosystems and their relationships with hydrological (river discharge) and climatic variables (regional temperature and precipitation) were explored with linear regression models. The results show that river regulation of the middle reaches identified by the discharge allocation to the downstream basin experiences three stages, namely decreasing inflow (1987-1999), increasing inflow (2000-2007) and relative stable inflow (2008-2015). Both the current and previous years' combined inflow determines the surface area of the terminal lake (R2 = 0.841). Temperature has the most significant role in determining broad vegetation distribution, whereas hydrological variables had a significant effect only in near-river-channel regions. Agricultural development since the execution of the EWDP might have curtailed further vegetation recovery. These findings are important for the catchment managers' decisions about future water allocation plans.

  7. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Robert N Schuck

    Full Text Available Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs, which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH, our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.

  8. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening.

    Directory of Open Access Journals (Sweden)

    Dario A Breitel

    2016-03-01

    Full Text Available The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A, a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA. Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1 protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process.

  9. Unfolded protein response and activated degradative pathways regulation in GNE myopathy.

    Directory of Open Access Journals (Sweden)

    Honghao Li

    Full Text Available Although intracellular beta amyloid (Aβ accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP deposition including unfolded protein response (UPR, ubiquitin proteasome system (UPS activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94, glucose-regulated protein 78 (GRP78, calreticulin and calnexin and valosin containing protein (VCP were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.

  10. The DC-HIL/syndecan-4 pathway regulates autoimmune responses through myeloid-derived suppressor cells.

    Science.gov (United States)

    Chung, Jin-Sung; Tamura, Kyoichi; Akiyoshi, Hideo; Cruz, Ponciano D; Ariizumi, Kiyoshi

    2014-03-15

    Having discovered that the dendritic cell (DC)-associated heparan sulfate proteoglycan-dependent integrin ligand (DC-HIL) receptor on APCs inhibits T cell activation by binding to syndecan-4 (SD-4) on T cells, we hypothesized that the DC-HIL/SD-4 pathway may regulate autoimmune responses. Using experimental autoimmune encephalomyelitis (EAE) as a disease model, we noted an increase in SD-4(+) T cells in lymphoid organs of wild-type (WT) mice immunized for EAE. The autoimmune disease was also more severely induced (clinically, histologically, and immunophenotypically) in mice knocked out for SD-4 compared with WT cohorts. Moreover, infusion of SD-4(-/-) naive T cells during EAE induction into Rag2(-/-) mice also led to increased severity of EAE in these animals. Similar to SD-4 on T cells, DC-HIL expression was upregulated on myeloid cells during EAE induction, with CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) as the most expanded population and most potent T cell suppressor among the myeloid cells examined. The critical role of DC-HIL was supported by DC-HIL gene deletion or anti-DC-HIL treatment, which abrogated T cell suppressor activity of MDSCs, and also by DC-HIL activation inducing MDSC expression of IFN-γ, NO, and reactive oxygen species. Akin to SD-4(-/-) mice, DC-HIL(-/-) mice manifested exacerbated EAE. Adoptive transfer of MDSCs from EAE-affected WT mice into DC-HIL(-/-) mice reduced EAE severity to the level of EAE-immunized WT mice, an outcome that was precluded by depleting DC-HIL(+) cells from the infused MDSC preparation. Our findings indicate that the DC-HIL/SD-4 pathway regulates autoimmune responses by mediating the T cell suppressor function of MDSCs.

  11. Regulation of the p53 response and its relationship to cancer.

    Science.gov (United States)

    Meek, David W

    2015-08-01

    p53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence (a permanent non-proliferative state) or apoptosis. Consistent with this role, p53 activity is compromised in a high proportion of all cancer types, either through mutation of the TP53 gene (encoding p53) or changes in the status of p53 modulators. p53 has additional roles, which may overlap with its tumour-suppressive capacity, in processes including the DNA damage response, metabolism, aging, stem cell differentiation and fertility. Moreover, many mutant p53 proteins, termed 'gain-of-function' (GOF), acquire new activities that help drive cancer aggression. p53 is regulated mainly through protein turnover and operates within a negative-feedback loop with its transcriptional target, MDM2 (murine double minute 2), an E3 ubiquitin ligase which mediates the ubiquitylation and proteasomal degradation of p53. Induction of p53 is achieved largely through uncoupling the p53-MDM2 interaction, leading to elevated p53 levels. Various stress stimuli acting on p53 (such as hyperproliferation and DNA damage) use different, but overlapping, mechanisms to achieve this. Additionally, p53 activity is regulated through critical context-specific or fine-tuning events, mediated primarily through post-translational mechanisms, particularly multi-site phosphorylation and acetylation. In the present review, I broadly examine these events, highlighting their regulatory contributions, their ability to integrate signals from cellular events towards providing most appropriate response to stress conditions and their importance for tumour suppression. These are fascinating aspects of molecular oncology that hold the key to understanding the molecular pathology of cancer and the routes by which it may be tackled therapeutically.

  12. Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis.

    Directory of Open Access Journals (Sweden)

    Niraj K Nirala

    2013-06-01

    Full Text Available The sphingolipid ceramide elicits several stress responses, however, organisms survive despite increased ceramide but how they do so is poorly understood. We demonstrate here that the AKT/FOXO pathway regulates survival in increased ceramide environment by metabolic adaptation involving changes in glycolysis and lipolysis through novel downstream targets. We show that ceramide kinase mutants accumulate ceramide and this leads to reduction in energy levels due to compromised oxidative phosphorylation. Mutants show increased activation of Akt and a consequent decrease in FOXO levels. These changes lead to enhanced glycolysis by upregulating the activity of phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase to provide energy. A second major consequence of AKT/FOXO reprogramming in the mutants is the increased mobilization of lipid from the gut through novel lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous reduction of these targets by knockdown experiments results in semi or total lethality of the mutants, demonstrating the importance of activating them. The efficiency of these adaptive mechanisms decreases with age and leads to reduction in adult life span of the mutants. In particular, mutants develop cardiac dysfunction with age, likely reflecting the high energy requirement of a well-functioning heart. The lipases also regulate physiological triacylglycerol homeostasis and are important for energy metabolism since midgut specific reduction of them in wild type flies results in increased sensitivity to starvation and accumulation of triglycerides leading to cardiac defects. The central findings of increased AKT activation, decreased FOXO level and activation of phosphoglyceromutase and pyruvate kinase are also observed in mice heterozygous for ceramide transfer protein suggesting a conserved role of this pathway in mammals. These data reveal novel glycolytic and non-autonomous lipolytic pathways in

  13. Turtles (Chelodina longicollis) regulate muscle metabolic enzyme activity in response to seasonal variation in body temperature.

    Science.gov (United States)

    Seebacher, F; Sparrow, J; Thompson, M B

    2004-04-01

    Fluctuations in the thermal environment may elicit different responses in animals: migration to climatically different areas, regulation of body temperature, modification of biochemical reaction rates, or assuming a state of dormancy. Many ectothermic reptiles are active over a range of body temperatures that vary seasonally. Here we test the hypothesis that metabolic enzyme activity acclimatises seasonally in freshwater turtles (Chelodina longicollis) in addition to, or instead of, behavioural regulation of body temperatures. We measured body temperatures in free-ranging turtles (n = 3) by radiotelemetry, and we assayed phosphofructokinase (PFK), lactate dehydrogenase (LDH), citrate synthase (CS) and cytochrome c oxidase (CCO) activities in early autumn (March, n = 10 turtles), late autumn (May, n = 7) and mid-winter (July, n = 7) over a range of assay temperatures (10 degrees C, 15 degrees C, 20 degrees C, 25 degrees C). Body temperatures were either not different from, or higher than expected from a theoretical null-distribution of a randomly moving animal. Field body temperatures at any season were lower, however, than expected from animals that maximised their sun exposure. Turtles maintained constant PFK, LDH and CCO activities in different months, despite body temperature differences of nearly 13.0 degrees C between March (average daily body temperature = 24.4 degrees C) and July (average = 11.4 degrees C). CS activity did not vary between March and May (average daily body temperature = 20.2 degrees C), but it decreased in July. Thus C. longicollis use a combination of behavioural thermoregulation and biochemical acclimatisation in response to seasonally changing thermal conditions. Ectothermic reptiles were often thought not to acclimatise biochemically, and our results show that behavioural attainment of a preferred body temperature is not mandatory for activity or physiological performance in turtles.

  14. An auxin responsive CLE gene regulates shoot apical meristem development in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Hongyan eGuo

    2015-05-01

    Full Text Available Plant hormone auxin regulates most, if not all aspects of plant growth and development, including lateral root formation, organ pattering, apical dominance and tropisms. Peptide hormones are peptides with hormone activities. Some of the functions of peptide hormones in regulating plant growth and development are similar to that of auxin, however, the relationship between auxin and peptide hormones remains largely unknown. Here we report the identification of OsCLE48, a rice (Oryza sativa CLE (CLAVATA3/ENDOSPERM SURROUNDING REGION gene, as an auxin response gene, and the functional characterization of OsCLE48 in Arabidopsis and rice. OsCLE48 encodes a CLE peptide hormone that is similar to Arabidopsis CLEs. RT-PCR analysis showed that OsCLE48 was induced by exogenously application of IAA (indole-3-acetic acid, a naturally occurred auxin. Expression of integrated OsCLE48p:GUS reporter gene in transgenic Arabidopsis plants was also induced by exogenously IAA treatment. These results indicate that OsCLE48 is an auxin responsive gene. Histochemical staining showed that GUS activity was detected in all the tissue and organs of the OsCLE48p:GUS transgenic Arabidopsis plants. Expression of OsCLE48 under the control of the 35S promoter in Arabidopsis inhibited shoot apical meristem development. Expression of OsCLE48 under the control of the CLV3 native regulatory elements almost completely complemented clv3-2 mutant phenotypes, suggesting that OsCLE48 is functionally similar to CLV3. On the other hand, expression of OsCLE48 under the control of the 35S promoter in Arabidopsis has little, if any effects on root apical meristem development, and transgenic rice plants overexpressing OsCLE48 are morphologically indistinguishable from wild type plants, suggesting that the functions of some CLE peptides may not be fully conserved in Arabidopsis and rice.

  15. Conformational transition of response regulator RR468 in a two-component system signal transduction process.

    Science.gov (United States)

    Banerjee, Rahul; Yan, Honggao; Cukier, Robert I

    2014-05-08

    Signal transduction can be accomplished via a two-component system (TCS) consisting of a histidine kinase (HK) and a response regulator (RR). In this work, we simulate the response regulator RR468 from Thermotoga maritima, in which phosphorylation and dephosphorylation of a conserved aspartate residue acts as a switch via a large conformational change concentrated in three proximal loops. A detailed view of the conformational transition is obscured by the lack of stability of the intermediate states, which are difficult to detect using common structural biology techniques. Molecular dynamics (MD) trajectories of the inactive and active conformations were run, and show that the inactive (or active) trajectories do not exhibit sampling of the active (or inactive) conformations on this time scale. Targeted MD (TMD) was used to generate trajectories that span the inactive and active conformations and provide a view of how a localized event like phosphorylation can lead to conformational changes elsewhere in the protein, especially in the three proximal loops. The TMD trajectories are clustered to identify stages along the transition path. Residue interaction networks are identified that point to key residues having to rearrange in the process of transition. These are identified using both hydrogen bond analysis and residue interaction strength measurements. Potentials of mean force are generated for key residue rearrangements to ascertain their free energy barriers. We introduce methods that attempt to extrapolate from one conformation to the other and find that the most fluctuating proximal loop can transit part way from one to the other, suggesting that this conformational information is embedded in the sequence.

  16. Brain arousal regulation as response predictor for antidepressant therapy in major depression

    Science.gov (United States)

    Schmidt, Frank M.; Sander, Christian; Dietz, Marie-Elisa; Nowak, Claudia; Schröder, Thomas; Mergl, Roland; Schönknecht, Peter; Himmerich, Hubertus; Hegerl, Ulrich

    2017-01-01

    A tonically high level of brain arousal and its hyperstable regulation is supposed to be a pathogenic factor in major depression. Preclinical studies indicate that most antidepressants may counteract this dysregulation. Therefore, it was hypothesized that responders to antidepressants show a) a high level of EEG-vigilance (an indicator of brain arousal) and b) a more stable EEG-vigilance regulation than non-responders. In 65 unmedicated depressed patients 15-min resting-state EEGs were recorded off medication (baseline). In 57 patients an additional EEG was recorded 14 ± 1 days following onset of antidepressant treatment (T1). Response was defined as a ≥50% HAMD-17-improvement after 28 ± 1 days of treatment (T2), resulting in 29 responders and 36 non-responders. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). At baseline responders and non-responders differed in distribution of overall EEG-vigilance stages (F2,133 = 4.780, p = 0.009), with responders showing significantly more high vigilance stage A and less low vigilance stage B. The 15-minutes Time-course of EEG-vigilance did not differ significantly between groups. Exploratory analyses revealed that responders showed a stronger decline in EEG-vigilance levels from baseline to T1 than non-responders (F2,130 = 4.978, p = 0.005). Higher brain arousal level in responders to antidepressants supports the concept that dysregulation of brain arousal is a possible predictor of treatment response in affective disorders. PMID:28345662

  17. Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

    Energy Technology Data Exchange (ETDEWEB)

    Herrou, Julien; Willett, Jonathan W.; Czyz, Daniel M.; Babnigg, Gyorgy; Kim, Youngchang; Crosson, Sean

    2017-03-01

    Brucella abortus sigma(E1) is an EcfG family sigma factor that regulates the transcription of dozens of genes in response to diverse stress conditions and is required for maintenance of chronic infection in a mouse model. A putative ATP-binding cassette transporter operon, bab1_0223-bab1_0226, is among the most highly activated gene sets in the sigma(E1) regulon. The proteins encoded by the operon resemble quaternary ammonium-compatible solute importers but are most similar in sequence to the broadly conserved YehZYXW system, which remains largely uncharacterized. Transcription of yehZYXW is activated by the general stress sigma factor sigma(S) in Enterobacteriaceae, which suggests a functional role for this transport system in bacterial stress response across the classes Alphaproteobacteria and Gammaproteobacteria. We present evidence that B. abortus YehZYXW does not function as an importer of known compatible solutes under physiological conditions and does not contribute to the virulence defect of a sigma(E1)- null strain. The sole in vitro phenotype associated with genetic disruption of this putative transport system is reduced growth in the presence of high Li+ ion concentrations. A crystal structure of B. abortus YehZ revealed a class II periplasmic binding protein fold with significant structural homology to Archaeoglobus fulgidus ProX, which binds glycine betaine. However, the structure of the YehZ ligand-binding pocket is incompatible with high-affinity binding to glycine betaine. This is consistent with weak measured binding of YehZ to glycine betaine and related compatible solutes. We conclude that YehZYXW is a conserved, stress-regulated transport system that is phylogenetically and functionally distinct from quaternary ammonium-compatible solute importers

  18. Sex differences in the response to environmental cues regulating seasonal reproduction in birds.

    Science.gov (United States)

    Ball, Gregory F; Ketterson, Ellen D

    2008-01-27

    Although it is axiomatic that males and females differ in relation to many aspects of reproduction related to physiology, morphology and behaviour, relatively little is known about possible sex differences in the response to cues from the environment that control the timing of seasonal breeding. This review concerns the environmental regulation of seasonal reproduction in birds and how this process might differ between males and females. From an evolutionary perspective, the sexes can be expected to differ in the cues they use to time reproduction. Female reproductive fitness typically varies more as a function of fecundity selection, while male reproductive fitness varies more as a function sexual selection. Consequently, variation in the precision of the timing of egg laying is likely to have more serious fitness consequences for females than for males, while variation in the timing of recrudescence of the male testes and accompanying territory establishment and courtship are likely to have more serious fitness consequences for males. From the proximate perspective, sex differences in the control of reproduction could be regulated via the response to photoperiod or in the relative importance and action of supplementary factors (such as temperature, food supply, nesting sites and behavioural interactions) that adjust the timing of reproduction so that it is in step with local conditions. For example, there is clear evidence in several temperate zone avian species that females require both supplementary factors and long photoperiods in order for follicles to develop, while males can attain full gonadal size based on photoperiodic stimulation alone. The neuroendocrine basis of these sex differences is not well understood, though there are many candidate mechanisms in the brain as well as throughout the entire hypothalamo-pituitary-gonadal axis that might be important.

  19. Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes.

    Science.gov (United States)

    Thangjam, G S; Kondaiah, P

    2009-10-01

    Arecoline, an arecanut alkaloid present in the saliva of betel quid chewers, has been implicated in the pathogenesis of a variety of inflammatory oral diseases, including oral submucous fibrosis and periodontitis. To understand the molecular basis of arecoline action in epithelial changes associated with these diseases, we investigated the effects of arecoline on human keratinocytes with respect to cell growth regulation and the expression of stress-responsive genes. Human keratinocyte cells (of the HaCaT cell line) were treated with arecoline, following which cell viability was assessed using the Trypan Blue dye-exclusion assay, cell growth and proliferation were analyzed using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) and 5-bromo-2-deoxyuridine incorporation assays, cell cycle arrest and generation of reactive oxygen species were examined using flow cytometry, and gene expression changes were investigated using the reverse transcription-polymerase chain reaction technique. The role of oxidative stress, muscarinic acetylcholine receptor and mitogen-activated protein kinase (MAPK) pathways were studied using specific inhibitors. Western blot analysis was performed to study p38 MAPK activation. Arecoline induced the generation of reactive oxygen species and cell cycle arrest at the G1/G0 phase in HaCaT cells without affecting the expression of p21/Cip1. Arecoline-induced epithelial cell death at higher concentrations was caused by oxidative trauma without eliciting apoptosis. Sublethal concentrations of arecoline upregulated the expression of the following stress-responsive genes: heme oxygenase-1; ferritin light chain; glucose-6-phosphate dehydrogenase; glutamate-cysteine ligase catalytic subunit; and glutathione reductase. Additionally, there was a dose-dependent induction of interleukin-1alfa mRNA by arecoline via oxidative stress and p38 MAPK activation. Our data highlight the role of oxidative stress in arecoline-mediated cell death

  20. Shrimp miRNAs regulate innate immune response against white spot syndrome virus infection.

    Science.gov (United States)

    Kaewkascholkul, Napol; Somboonviwat, Kulwadee; Asakawa, Shuichi; Hirono, Ikuo; Tassanakajon, Anchalee; Somboonwiwat, Kunlaya

    2016-07-01

    MicroRNAs are short noncoding RNAs of RNA interference pathways that regulate gene expression through partial complementary base-pairing to target mRNAs. In this study, miRNAs that are expressed in white spot syndrome virus (WSSV)-infected Penaeus monodon, were identified using next generation sequencing. Forty-six miRNA homologs were identified from WSSV-infected shrimp hemocyte. Stem-loop real-time RT-PCR analysis showed that 11 out of 16 selected miRNAs were differentially expressed upon WSSV infection. Of those, pmo-miR-315 and pmo-miR-750 were highly responsive miRNAs. miRNA target prediction revealed that the miRNAs were targeted at 5'UTR, ORF, and 3'UTR of several immune-related genes such as genes encoding antimicrobial peptides, signaling transduction proteins, heat shock proteins, oxidative stress proteins, proteinases or proteinase inhibitors, proteins in blood clotting system, apoptosis-related proteins, proteins in prophenoloxidase system, pattern recognition proteins and other immune molecules. The highly conserved miRNA homolog, pmo-bantam, was characterized for its function in shrimp. The pmo-bantam was predicted to target the 3'UTR of Kunitz-type serine protease inhibitor (KuSPI). Binding of pmo-bantam to the target sequence of KuSPI gene was analyzed by luciferase reporter assay. Correlation of pmo-bantam and KuSPI expression was observed in lymphoid organ of WSSV-infected shrimp. These results implied that miRNAs might play roles as immune gene regulators in shrimp antiviral response.

  1. Fibronectin Matrix Remodeling in the Regulation of the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression

    Science.gov (United States)

    2011-09-01

    the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression PRINCIPAL INVESTIGATOR: Paula J. McKeown-Longo, Ph.D...2011 4. TITLE AND SUBTITLE Fibronectin Matrix Remodeling in the Regulation of the 5a. CONTRACT NUMBER W81XWH-10-1-0755 Inflammatory Response within...hypothesis that force dependent unfolding of fibronectin in the tumor stroma drives an inflammatory response within the lung tumor microenvironment

  2. A G-protein β subunit, AGB1, negatively regulates the ABA response and drought tolerance by down-regulating AtMPK6-related pathway in Arabidopsis.

    Science.gov (United States)

    Xu, Dong-bei; Chen, Ming; Ma, Ya-nan; Xu, Zhao-shi; Li, Lian-cheng; Chen, Yao-feng; Ma, You-zhi

    2015-01-01

    Heterotrimeric G-proteins are versatile regulators involved in diverse cellular processes in eukaryotes. In plants, the function of G-proteins is primarily associated with ABA signaling. However, the downstream effectors and the molecular mechanisms in the ABA pathway remain largely unknown. In this study, an AGB1 mutant (agb1-2) was found to show enhanced drought tolerance, indicating that AGB1 might negatively regulate drought tolerance in Arabidopsis. Data showed that AGB1 interacted with protein kinase AtMPK6 that was previously shown to phosphorylate AtVIP1, a transcription factor responding to ABA signaling. Our study found that transcript levels of three ABA responsive genes, AtMPK6, AtVIP1 and AtMYB44 (downstream gene of AtVIP1), were significantly up-regulated in agb1-2 lines after ABA or drought treatments. Other ABA-responsive and drought-inducible genes, such as RD29A (downstream gene of AtMYB44), were also up-regulated in agb1-2 lines. Furthermore, overexpression of AtVIP1 resulted in hypersensitivity to ABA at seed germination and seedling stages, and significantly enhanced drought tolerance in transgenic plants. These results suggest that AGB1 was involved in the ABA signaling pathway and drought tolerance in Arabidopsis through down-regulating the AtMPK6, AtVIP1 and AtMYB44 cascade.

  3. A G-protein β subunit, AGB1, negatively regulates the ABA response and drought tolerance by down-regulating AtMPK6-related pathway in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Dong-bei Xu

    Full Text Available Heterotrimeric G-proteins are versatile regulators involved in diverse cellular processes in eukaryotes. In plants, the function of G-proteins is primarily associated with ABA signaling. However, the downstream effectors and the molecular mechanisms in the ABA pathway remain largely unknown. In this study, an AGB1 mutant (agb1-2 was found to show enhanced drought tolerance, indicating that AGB1 might negatively regulate drought tolerance in Arabidopsis. Data showed that AGB1 interacted with protein kinase AtMPK6 that was previously shown to phosphorylate AtVIP1, a transcription factor responding to ABA signaling. Our study found that transcript levels of three ABA responsive genes, AtMPK6, AtVIP1 and AtMYB44 (downstream gene of AtVIP1, were significantly up-regulated in agb1-2 lines after ABA or drought treatments. Other ABA-responsive and drought-inducible genes, such as RD29A (downstream gene of AtMYB44, were also up-regulated in agb1-2 lines. Furthermore, overexpression of AtVIP1 resulted in hypersensitivity to ABA at seed germination and seedling stages, and significantly enhanced drought tolerance in transgenic plants. These results suggest that AGB1 was involved in the ABA signaling pathway and drought tolerance in Arabidopsis through down-regulating the AtMPK6, AtVIP1 and AtMYB44 cascade.

  4. Auxin and ethylene regulate elongation responses to neighbor proximity signals independent of gibberellin and della proteins in Arabidopsis.

    Science.gov (United States)

    Pierik, Ronald; Djakovic-Petrovic, Tanja; Keuskamp, Diederik H; de Wit, Mieke; Voesenek, Laurentius A C J

    2009-04-01

    Plants modify growth in response to the proximity of neighbors. Among these growth adjustments are shade avoidance responses, such as enhanced elongation of stems and petioles, that help plants to reach the light and outgrow their competitors. Neighbor detection occurs through photoreceptor-mediated detection of light spectral changes (i.e. reduced red:far-red ratio [R:FR] and reduced blue light intensity). We recently showed that physiological regulation of these responses occurs through light-mediated degradation of nuclear, growth-inhibiting DELLA proteins, but this appeared to be only part of the full mechanism. Here, we present how two hormones, auxin and ethylene, coregulate DELLAs but regulate shade avoidance responses through DELLA-independent mechanisms in Arabidopsis (Arabidopsis thaliana). Auxin appears to be required for both seedling and mature plant shoot elongation responses to low blue light and low R:FR, respectively. Auxin action is increased upon exposure to low R:FR and low blue light, and auxin inhibition abolishes the elongation responses to these light cues. Ethylene action is increased during the mature plant response to low R:FR, and this growth response is abolished by ethylene insensitivity. However, ethylene is also a direct volatile neighbor detection signal that induces strong elongation in seedlings, possibly in an auxin-dependent manner. We propose that this novel ethylene and auxin control of shade avoidance interacts with DELLA abundance but also controls independent targets to regulate adaptive growth responses to surrounding vegetation.

  5. MicroRNA-761 regulates mitochondrial biogenesis in mouse skeletal muscle in response to exercise

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yanli [Affiliated Hospital of Hebei Engineering University, Handan, 056002, Hebei (China); Zhao, Chaoxian; Sun, Xuewen [Medical College of Hebei Engineering University, Handan, 056002, Hebei (China); Liu, Zhijun, E-mail: liuzhij1207@163.com [Affiliated Hospital of Hebei Engineering University, Handan, 056002, Hebei (China); Zhang, Jianzhong, E-mail: zhangjianzhong@icdc.cn [National Institute for Communicable Disease Control and Prevention (ICDC), Chinese Center for Disease Control and Prevention (China CDC), Beijing, 102206 (China)

    2015-11-06

    MicroRNAs (miRNAs) have been suggested to play critical roles in skeletal muscle in response to exercise. Previous study has shown that miR-761 was involved in a novel model regulating the mitochondrial network. However, its role in mitochondrial biogenesis remains poorly understood. Therefore, the current study was aimed to examine the effect of miR-761 on mitochondrial biogenesis in skeletal muscle. Real-time quantitative PCR analysis demonstrated that aberrantly expressed miR-761 is involved in exercise activity and miR-761 is decreased by exercise training compared with the sedentary control mice. miR-761 suppresses mitochondrial biogenesis of C{sub 2}C{sub 12} myocytes by targeting the 3′-UTR of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 (PGC-1α). Overexpression of miR-761 was capable of inhibiting the protein expression levels of PGC-1α. Moreover, miR-761 overexpression suppressed the p38 MAPK signaling pathway and down-regulated the expression of phosphorylated MAPK-activated protein kinase-2 (P-MK2), a downstream kinase of p38 MAPK. The phosphorylation of activating transcription factors 2 (ATF2) that plays a functional role in linking the activation of the p38 MAPK pathway to enhanced transcription of the PGC-1α was also inhibited by the overexpression of miR-761. These findings revealed a novel regulation mechanism for miR-761 in skeletal myocytes, and contributed to a better understanding of the modulation of skeletal muscle in response to exercise. - Highlights: • Endurance exercise decreases miR-761 expression in skeletal muscle. • MiR-761 suppresses mitochondrial biogenesis in C{sub 2}C{sub 12} myocytes. • MiR-761 directly targeted PGC-1α expression. • MiR-761 suppresses p38 MAPK signaling pathways in C{sub 2}C{sub 12} myocytes. • A novel mechanism for miR-761 in skeletal myocytes is demonstrated.

  6. The known two types of transglutaminases regulate immune and stress responses in white shrimp, Litopenaeus vannamei.

    Science.gov (United States)

    Chang, Chin-Chyuan; Chang, Hao-Che; Liu, Kuan-Fu; Cheng, Winton

    2016-06-01

    Transglutaminases (TGs) play critical roles in blood coagulation, immune responses, and other biochemical functions, which undergo post-translational remodeling such as acetylation, phosphorylation and fatty acylation. Two types of TG have been identified in white shrimp, Litopenaeus vannamei, and further investigation on their potential function was conducted by gene silencing in the present study. Total haemocyte count (THC), differential haemocyte count (DHC), phenoloxidase activity, respiratory bursts (release of superoxide anion), superoxide dismutase activity, transglutaminase (TG) activity, haemolymph clotting time, and phagocytic activity and clearance efficiency to the pathogen Vibrio alginolyticus were measured when shrimps were individually injected with diethyl pyrocarbonate-water (DEPC-H2O) or TG dsRNAs. In addition, haemolymph glucose and lactate, and haemocytes crustin, lysozyme, crustacean hyperglycemic hormone (CHH), transglutaminaseI (TGI), transglutaminaseII (TGII) and clotting protein (CP) mRNA expression were determined in the dsRNA injected shrimp under hypothermal stress. Results showed that TG activity, phagocytic activity and clearance efficiency were significantly decreased, but THC, hyaline cells (HCs) and haemolymph clotting time were significantly increased in the shrimp which received LvTGI dsRNA and LvTGI + LvTGII dsRNA after 3 days. However, respiratory burst per haemocyte was significantly decreased in only LvTGI + LvTGII silenced shrimp. In hypothermal stress studies, elevation of haemolymph glucose and lactate was observed in all treated groups, and were advanced in LvTGI and LvTGI + LvTGII silenced shrimp following exposure to 22 °C. LvCHH mRNA expression was significantly up-regulated, but crustin and lysozyme mRNA expressions were significantly down-regulated in LvTGI and LvTGI + LvTGII silenced shrimp; moreover, LvTGII was significantly increased, but LvTGI was significantly decreased in LvTGI silenced shrimp

  7. Skeletal muscle gene expression in response to resistance exercise: sex specific regulation

    Directory of Open Access Journals (Sweden)

    Burant Charles F

    2010-11-01

    Full Text Available Abstract Background The molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting state and following anabolic stimuli, such as resistance exercise (RE, might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise or late recovery (24 h post-exercise time point. Muscle transcription profiles were compared in the resting state between men (n = 6 and women (n = 8, and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females. A logistic regression-based method (LRpath, following Bayesian moderated t-statistic (IMBT, was used to test gene functional groups and biological pathways enriched with differentially expressed genes. Results This investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females

  8. mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines

    Institute of Scientific and Technical Information of China (English)

    Li; He; Aiping; Zang; Min; Du; Dapeng; Ma; Chuanping; Yuan; Chun; Zhou; Jing; Mu; Huanjing; Shi; Dapeng; Li; Xulin; Huang; Qiang; Deng; Jianhua; Xiao; Huimin; Yan; Lijian; Hui; Ke; Lan; Sidong; Xiong; Xiaoxia; Li; Zhong; Huang; Hui; Xiao

    2015-01-01

    Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.

  9. Conserved ABC Transport System Regulated by the General Stress Response Pathways of Alpha- and Gammaproteobacteria

    Energy Technology Data Exchange (ETDEWEB)

    Herrou, Julien; Willett, Jonathan W.; Czyż, Daniel M.; Babnigg, Gyorgy; Kim, Youngchang; Crosson, Sean; Stock, Ann M.

    2016-12-19

    ABSTRACT

    Brucella abortusσE1is an EcfG family sigma factor that regulates the transcription of dozens of genes in response to diverse stress conditions and is required for maintenance of chronic infection in a mouse model. A putative ATP-binding cassette transporter operon,bab1_0223-bab1_0226, is among the most highly activated gene sets in the σE1regulon. The proteins encoded by the operon resemble quaternary ammonium-compatible solute importers but are most similar in sequence to the broadly conserved YehZYXW system, which remains largely uncharacterized. Transcription ofyehZYXWis activated by the general stress sigma factor σSinEnterobacteriaceae, which suggests a functional role for this transport system in bacterial stress response across the classesAlphaproteobacteriaandGammaproteobacteria. We present evidence thatB. abortusYehZYXW does not function as an importer of known compatible solutes under physiological conditions and does not contribute to the virulence defect of a σE1-null strain. The solein vitrophenotype associated with genetic disruption of this putative transport system is reduced growth in the presence of high Li+ion concentrations. A crystal structure ofB. abortusYehZ revealed a class II periplasmic binding protein fold with significant structural homology toArchaeoglobus fulgidusProX, which binds glycine betaine. However, the structure

  10. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.

    Science.gov (United States)

    Zhong, Bo; Zhang, Lu; Lei, Caoqi; Li, Ying; Mao, Ai-Ping; Yang, Yan; Wang, Yan-Yi; Zhang, Xiao-Lian; Shu, Hong-Bing

    2009-03-20

    Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. MITA (also known as STING) has recently been identified as an adaptor that links virus-sensing receptors to IRF3 activation. Here, we showed that the E3 ubiquitin ligase RNF5 interacted with MITA in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFNB1 expression, and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. These findings suggest that RNF5 negatively regulates virus-triggered signaling by targeting MITA for ubiquitination and degradation at the mitochondria.

  11. Multiple Signaling Pathways Regulate Yeast Cell Death during the Response to Mating Pheromones

    Science.gov (United States)

    Zhang, Nan-Nan; Dudgeon, Drew D.; Paliwal, Saurabh; Levchenko, Andre; Grote, Eric

    2006-01-01

    Mating pheromones promote cellular differentiation and fusion of yeast cells with those of the opposite mating type. In the absence of a suitable partner, high concentrations of mating pheromones induced rapid cell death in ∼25% of the population of clonal cultures independent of cell age. Rapid cell death required Fig1, a transmembrane protein homologous to PMP-22/EMP/MP20/Claudin proteins, but did not require its Ca2+ influx activity. Rapid cell death also required cell wall degradation, which was inhibited in some surviving cells by the activation of a negative feedback loop involving the MAP kinase Slt2/Mpk1. Mutants lacking Slt2/Mpk1 or its upstream regulators also underwent a second slower wave of cell death that was independent of Fig1 and dependent on much lower concentrations of pheromones. A third wave of cell death that was independent of Fig1 and Slt2/Mpk1 was observed in mutants and conditions that eliminate calcineurin signaling. All three waves of cell death appeared independent of the caspase-like protein Mca1 and lacked certain “hallmarks” of apoptosis. Though all three waves of cell death were preceded by accumulation of reactive oxygen species, mitochondrial respiration was only required for the slowest wave in calcineurin-deficient cells. These findings suggest that yeast cells can die by necrosis-like mechanisms during the response to mating pheromones if essential response pathways are lacking or if mating is attempted in the absence of a partner. PMID:16738305

  12. Schistosomiasis differentially affects vasoconstrictor responses: up-regulation of 5-HT receptor-mediated aorta contraction

    Directory of Open Access Journals (Sweden)

    Suellen D'Arc dos Santos Oliveira

    2011-06-01

    Full Text Available Schistosomiasis, classified by the World Health Organization as a neglected tropical disease, is an intravascular parasitic disease associated to a chronic inflammatory state. Evidence implicating inflammation in vascular dysfunction continues to mount, which, broadly defined, reflects a failure in the control of intracellular Ca2+ and consequently, vascular contraction. Therefore, we measured aorta contraction induced by 5-hydroxytryptamine (5-HT and endothelin-1 (ET-1, two important regulators of vascular contraction. Isometric aortic contractions were determined in control and Schistosoma mansoni-infected mice. In the infected animals, 5-HT induced a 50% higher contraction in relation to controls and we also observed an increased contraction in response to Ca2+ mobilisation from sarcoplasmic reticulum. Nevertheless, Rho kinase inhibition reduced the contraction in response to 5-HT equally in both groups, discarding an increase of the contractile machinery sensitivity to Ca2+. Furthermore, no alteration was observed for contractions induced by ET-1 in both groups. Our data suggest that an immune-vascular interaction occurs in schistosomiasis, altering vascular contraction outside the mesenteric portal system. More importantly, it affects distinct intracellular signalling involved in aorta contraction, in this case increasing 5-HT receptor signalling.

  13. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

    Science.gov (United States)

    Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh; Weisschuh, Nicole; Staller, Jennifer; Menendez, Irene Gonzalez; Chang, Stanley; Beck, Susanne C; Garrido, Marina Garcia; Sothilingam, Vithiyanjali; Seeliger, Mathias W; Stanzial, Franco; Benedicenti, Francesco; Inzana, Francesca; Héon, Elise; Vincent, Ajoy; Beis, Jill; Strom, Tim M; Rudolph, Günther; Roosing, Susanne; den Hollander, Anneke I; Cremers, Frans P M; Lopez, Irma; Ren, Huanan; Moore, Anthony T; Webster, Andrew R; Michaelides, Michel; Koenekoop, Robert K; Zrenner, Eberhart; Kaufman, Randal J; Tsang, Stephen H; Wissinger, Bernd; Lin, Jonathan H

    2015-01-01

    Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6−/− mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype. PMID:26029869

  14. Integrated stress response of vertebrates is regulated by four eIF2α kinases

    Science.gov (United States)

    Taniuchi, Shusuke; Miyake, Masato; Tsugawa, Kazue; Oyadomari, Miho; Oyadomari, Seiichi

    2016-01-01

    The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively. Because eIF2α is phosphorylated under various stress conditions, the existence of an additional eIF2α kinase has been suggested. To validate the existence of the unidentified eIF2α kinase, we constructed an eIF2α kinase quadruple knockout cells (4KO cells) in which the four known eIF2α kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2α was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2α kinases are sufficient for ISR and that there are no additional eIF2α kinases in vertebrates. PMID:27633668

  15. Bmi1 regulates mitochondrial function and the DNA damage response pathway.

    Science.gov (United States)

    Liu, Jie; Cao, Liu; Chen, Jichun; Song, Shiwei; Lee, In Hye; Quijano, Celia; Liu, Hongjun; Keyvanfar, Keyvan; Chen, Haoqian; Cao, Long-Yue; Ahn, Bong-Hyun; Kumar, Neil G; Rovira, Ilsa I; Xu, Xiao-Ling; van Lohuizen, Maarten; Motoyama, Noboru; Deng, Chu-Xia; Finkel, Toren

    2009-05-21

    Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.

  16. Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses.

    Science.gov (United States)

    Owczarczyk, Anna B; Schaller, Matthew A; Reed, Michelle; Rasky, Andrew J; Lombard, David B; Lukacs, Nicholas W

    2015-08-15

    Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, has been associated with the induction of autophagy and the regulation of inflammatory mediators. We found that Sirt1 was upregulated in mouse lung after RSV infection. Infected animals that received EX-527, a selective SIRT1 inhibitor, displayed exacerbated lung pathology, with increased mucus production, elevated viral load, and enhanced Th2 cytokine production. Gene expression analysis of isolated cell populations revealed that Sirt1 was most highly upregulated in RSV-treated dendritic cells (DCs). Upon RSV infection, EX-527-treated DCs, Sirt1 small interfering RNA-treated DCs, or DCs from conditional knockout (Sirt1(f/f)-CD11c-Cre(+)) mice showed downregulated inflammatory cytokine gene expression and attenuated autophagy. Finally, RSV infection of Sirt1(f/f)-CD11c-Cre(+) mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. These data indicate that SIRT1 promotes DC activation associated with autophagy-mediated processes during RSV infection, thereby directing efficient antiviral immune responses.

  17. Functional specialization of skin dendritic cell subsets in regulating T cell responses

    Directory of Open Access Journals (Sweden)

    Björn E. Clausen

    2015-10-01

    Full Text Available Dendritic cells (DC are a heterogeneous family of professional antigen presenting cells (APC classically recognized as most potent inducers of adaptive immune responses. In this respect, Langerhans cells (LC have long been considered to be prototypic immunogenic DC in the skin. More recently this view has considerably changed. The generation of in vivo cell ablation and lineage tracing models revealed the complexity of the skin DC network and, in particular, established the existence of a number of phenotypically distinct Langerin+ and negative DC populations in the dermis. Moreover, by now we appreciate that DC also exert important regulatory functions and are required for the maintenance of tolerance towards harmless foreign and self-antigens. This review summarizes our current understanding of the skin-resident DC system in the mouse and discusses emerging concepts on the functional specialization of the different skin DC subsets in regulating T cell responses. Special consideration is given to antigen cross-presentation as well as immune reactions towards contact sensitizers, cutaneous pathogens and tumors. These studies form the basis for the manipulation of the human counterparts of the murine DC subsets to promote immunity or tolerance for the treatment of human disease.

  18. A BRISC-SHMT Complex Deubiquitinates IFNAR1 and Regulates Interferon Responses

    Directory of Open Access Journals (Sweden)

    Hui Zheng

    2013-10-01

    Full Text Available Lysine63-linked ubiquitin (K63-Ub chains represent a particular ubiquitin topology that mediates proteasome-independent signaling events. The deubiquitinating enzyme (DUB BRCC36 segregates into distinct nuclear and cytoplasmic complexes that are specific for K63-Ub hydrolysis. RAP80 targets the five-member nuclear BRCC36 complex to K63-Ub chains at DNA double-strand breaks. The alternative four-member BRCC36 containing complex (BRISC lacks a known targeting moiety. Here, we identify serine hydroxymethyltransferase (SHMT as a previously unappreciated component that fulfills this function. SHMT directs BRISC activity at K63-Ub chains conjugated to the type 1 interferon (IFN receptor chain 1 (IFNAR1. BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, thus limiting its K63-Ub-mediated internalization and lysosomal degradation. BRISC-deficient cells and mice exhibit attenuated responses to IFN and are protected from IFN-associated immunopathology. These studies reveal a mechanism of DUB regulation and suggest a therapeutic use of BRISC inhibitors for treating pathophysiological processes driven by elevated IFN responses.

  19. Tomato Polyphenol Oxidase B Is Spatially and Temporally Regulated during Development and in Response to Ethylene

    Directory of Open Access Journals (Sweden)

    John C. Steffens

    2011-01-01

    Full Text Available Plant polyphenol oxidases (PPOs are ubiquitous plastid-localized enzymes. A precise analysis of PPO function in plants has been complicated by the presence of several family members with immunological cross reactivity. Previously we reported the isolation of genomic clones coding for the seven members of the tomato (Solanum lycopersicum PPO family (A, A’, B, C, D, E, and F. Here we report the complex spatial and temporal expression of one of the members, PPO B. The PPO B promoter was sequenced and subjected to homology analysis. Sequence similarities were found to nucleotide sequences of genes encoding enzymes/proteins active in the following systems: phenylpropanoid biosynthesis, signal transduction and responsiveness to hormones and stresses, fruit and seed proteins/enzymes, and photosynthesis. Chimeric gene fusions were constructed linking PPO B 5' flanking regions to the reporter gene, b-glucuronidase (GUS. The resultant transgenic plants were histochemically analyzed for GUS activity in various vegetative and reproductive tissues, and evaluated for PPO B responsiveness to ethylene induction. It was shown that PPO B expression was tissue specific, developmentally regulated, ethylene induced, and localized predominantly to mitotic or apoptotic tissues.

  20. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Yan; Hirane, Miku; Araki, Mutsumi [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Tsujiuchi, Toshifumi, E-mail: ttujiuch@life.kindai.ac.jp [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)

    2014-04-04

    Highlights: • LPA{sub 5} inhibits the cell growth and motile activities of 3T3 cells. • LPA{sub 5} suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA{sub 5} on the cell motile activities inhibited by LPA{sub 1} in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA{sub 5} in 3T3 cells. • LPA signaling via LPA{sub 5} acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA{sub 1}–LPA{sub 6}) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA{sub 1} inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA{sub 5} in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA{sub 1} and LPA{sub 5} on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA{sub 5} may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA{sub 1}.

  1. Biaryl amide compounds reduce the inflammatory response in macrophages by regulating Dectin-1.

    Science.gov (United States)

    Hyung, Kyeong Eun; Lee, Mi Ji; Lee, Yun-Jung; Lee, Do Ik; Min, Hye Young; Park, So-Young; Min, Kyung Hoon; Hwang, Kwang Woo

    2016-03-01

    Macrophages are archetypal innate immune cells that play crucial roles in the recognition and phagocytosis of invading pathogens, which they identify using pattern recognition receptors (PRRs). Dectin-1 is essential for antifungal immune responses, recognizing the fungal cellular component β-glucan, and its role as a PRR has been of increasing interest. Previously, we discovered and characterized a novel biaryl amide compound, MPS 03, capable of inhibiting macrophage phagocytosis of zymosan. Therefore, in this study we aimed to identify other biaryl amide compounds with greater effectiveness than MPS 03, and elucidate their cellular mechanisms. Several MPS 03 derivatives were screened, four of which reduced zymosan phagocytosis in a similar manner to MPS 03. To establish whether such phagocytosis inhibition influenced the production of inflammatory mediators, pro-inflammatory cytokine and nitric oxide (NO) levels were measured. The production of TNF-α, IL-6, IL-12, and NO was significantly reduced in a dose-dependent manner. Moreover, the inflammation-associated MAPK signaling pathway was also affected by biaryl amide compounds. To investigate the underlying cellular mechanism, PRR expression was measured. MPS 03 and its derivatives were found to inhibit zymosan phagocytosis by decreasing Dectin-1 expression. Furthermore, when macrophages were stimulated by zymosan after pretreatment with biaryl amide compounds, downstream transcription factors such as NFAT, AP-1, and NF-κB were downregulated. In conclusion, biaryl amide compounds reduce zymosan-induced inflammatory responses by downregulating Dectin-1 expression. Therefore, such compounds could be used to inhibit Dectin-1 in immunological experiments and possibly regulate excessive inflammatory responses.

  2. LIK1, a CERK1-interacting kinase, regulates plant immune responses in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Mi Ha Le

    Full Text Available Chitin, an integral component of the fungal cell wall, is one of the best-studied microbe-associated molecular patterns. Previous work identified a LysM receptor-like kinase (LysM-RLK1/CERK1 as the primary chitin receptor in Arabidopsis. In order to identify proteins that interact with CERK1, we conducted a yeast two-hybrid screen using the intracellular kinase domain of CERK1 as the bait. This screen identified 54 putative CERK1-interactors. Screening mutants defective in 43 of these interacting proteins identified only two, a calmodulin like protein (At3g10190 and a leucine-rich repeat receptor like kinase (At3g14840, which differed in their response to pathogen challenge. In the present work, we focused on characterizing the LRR-RLK gene where mutations altered responses to chitin elicitation. This LRR-RLK was named LysM RLK1-interacting kinase 1 (LIK1. The interaction between CERK1 and LIK1 was confirmed by co-immunoprecipitation using protoplasts and transgenic plants. In vitro experiments showed that LIK1 was directly phosphorylated by CERK1. In vivo phosphorylation assays showed that Col-0 wild-type plants have more phosphorylated LIK1 than cerk1 mutant plants, suggesting that LIK1 may be directly phosphorylated by CERK1. Lik1 mutant plants showed an enhanced response to both chitin and flagellin elicitors. In comparison to the wild-type plants, lik1 mutant plants were more resistant to the hemibiotrophic pathogen Pseudomonas syringae, but more susceptible to the necrotrophic pathogen Sclerotinia sclerotiorum. Consistent with the enhanced susceptibility to necrotrophs, lik1 mutants showed reduced expression of genes involved in jasmonic acid and ethylene signaling pathways. These data suggest that LIK1 directly interacts with CERK1 and regulates MAMP-triggered innate immunity.

  3. Sae regulator factor impairs the response to photodynamic inactivation mediated by Toluidine blue in Staphylococcus aureus.

    Science.gov (United States)

    Gándara, Lautaro; Mamone, Leandro; Dotto, Cristian; Buzzola, Fernanda; Casas, Adriana

    2016-12-01

    Photodynamic inactivation (PDI) involves the combined use of light and a photosensitizer, which, in the presence of oxygen, originates cytotoxic species capable of inactivating bacteria. Since the emergence of multi-resistant bacterial strains is becoming an increasing public health concern, PDI becomes an attractive choice. The aim of this work was to study the differential susceptibility to Toluidine blue (TB) mediated PDI (TB-PDI) of S. aureus mutants (RN6390 and Newman backgrounds) for different key regulators of virulence factors related to some extent to oxidative stress. Complete bacteria eradication of planktonic cultures of RN6390 S. aureus photosensitized with 13μM TB was obtained upon illumination with a low light dose of 4.2J/cm(2) from a non-coherent light source. Similarly, complete cell death was achieved applying 1.3μM TB and 19J/cm(2) light dose, showing that higher light doses can lead to equal cell death employing low photosensitizer concentrations. Interestingly, RN6390 in planktonic culture responded significantly better to TB-PDI than the Newman strain. We showed that deficiencies in rsbU, mgrA (transcription factors related to stress response) or agr (quorum sensing system involved in copper resistance to oxidative stress) did not modify the response of planktonic S. aureus to PDI. On the other hand, the two component system sae impaired the response to TB-PDI through a mechanism not related to the Eap adhesin. More severe conditions were needed to inactivate S. aureus biofilms (0.5mM TB, 157J/cm(2) laser light). In mutant sae biofilms, strain dependant differential susceptibilities are not noticed.

  4. Dynamic Regulation of Auxin Response during Rice Development Revealed by Newly Established Hormone Biosensor Markers

    Science.gov (United States)

    Yang, Jing; Yuan, Zheng; Meng, Qingcai; Huang, Guoqiang; Périn, Christophe; Bureau, Charlotte; Meunier, Anne-Cécile; Ingouff, Mathieu; Bennett, Malcolm J.; Liang, Wanqi; Zhang, Dabing

    2017-01-01

    The hormone auxin is critical for many plant developmental processes. Unlike the model eudicot plant Arabidopsis (Arabidopsis thaliana), auxin distribution and signaling in rice tissues has not been systematically investigated due to the absence of suitable auxin response reporters. In this study we observed the conservation of auxin signaling components between Arabidopsis and model monocot crop rice (Oryza sativa), and generated complementary types of auxin biosensor constructs, one derived from the Aux/IAA-based biosensor DII-VENUS but constitutively driven by maize ubiquitin-1 promoter, and the other termed DR5-VENUS in which a synthetic auxin-responsive promoter (DR5rev) was used to drive expression of the yellow fluorescent protein (YFP). Using the obtained transgenic lines, we observed that during the vegetative development, accumulation of DR5-VENUS signal was at young and mature leaves, tiller buds and stem base. Notably, abundant DR5-VENUS signals were observed in the cytoplasm of cortex cells surrounding lateral root primordia (LRP) in rice. In addition, auxin maxima and dynamic re-localization were seen at the initiation sites of inflorescence and spikelet primordia including branch meristems (BMs), female and male organs. The comparison of these observations among Arabidopsis, rice and maize suggests the unique role of auxin in regulating rice lateral root emergence and reproduction. Moreover, protein localization of auxin transporters PIN1 homologs and GFP tagged OsAUX1 overlapped with DR5-VENUS during spikelet development, helping validate these auxin response reporters are reliable markers in rice. This work firstly reveals the direct correspondence between auxin distribution and rice reproductive and root development at tissue and cellular level, and provides high-resolution auxin tools to probe fundamental developmental processes in rice and to establish links between auxin, development and agronomical traits like yield or root architecture. PMID

  5. SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells.

    Science.gov (United States)

    Li, Yanxiang; Wang, Ping; Yang, Xiaofeng; Wang, Weirong; Zhang, Jiye; He, Yanhao; Zhang, Wei; Jing, Ting; Wang, Bo; Lin, Rong

    2016-09-01

    Emerging evidence has indicated that vascular endothelial cells (ECs) not only form the barrier between blood and the vessel wall but also serve as conditional innate immune cells. Our previous study found that SIRT1, a class III histone deacetylase, inhibits the inflammatory response in ECs. Recent studies revealed that SIRT1 also participates in the modulation of immune responses. Although the NLRP3 inflammasome is known to be a crucial component of the innate immune system, there is no direct evidence demonstrating the anti-inflammatory effect of SIRT1 on ECs through the NLRP3 inflammasome. In this study, we observed that lipopolysaccharide (LPS) and adenosine triphosphate (ATP) triggered the activation of NLRP3 inflammasome in human umbilical vein ECs (HUVECs). Moreover, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in significant increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. Importantly, the lack of SIRT1 enhanced NLRP3 inflammasome activation and subsequent caspase-1 cleavage. On the other hand, NLRP3 siRNA blocked the activation of the NLRP3 inflammasome in HUVECs stimulated with LPS plus ATP. Further study revealed that NLRP3 inflammasome blockade significantly reduced MCP-1 and CRP production in HUVECs. In vivo studies indicated that implantation of the periarterial carotid collar inhibited arterial SIRT1 expression in rabbits. Meanwhile, treatment with a SIRT1 activator decreased the expression levels of MCP-1 and CRP in collared arteries and the interleukin (IL)-1β level in serum. Taken together, these findings indicate that NLRP3 inflammasome activation promoted endothelial inflammation and that SIRT1 inhibits the inflammatory response partly through regulation of the NLRP3 inflammasome in ECs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Chemokine regulation in response to beryllium exposure in human peripheral blood mononuclear and dendritic cells.

    Science.gov (United States)

    Hong-Geller, Elizabeth; Pardington, Paige E; Cary, Robert B; Sauer, Nancy N; Gupta, Goutam

    2006-02-01

    Exposure to beryllium (Be) induces a delayed-type hypersensitivity immune reaction in the lungs of susceptible individuals, which leads to the onset of Be sensitivity and Chronic Beryllium Disease (CBD). Although some mechanistic aspects of CBD have begun to be characterized, very little is known about the molecular mechanisms by which Be activates the host immune response. To gain insight into the cellular response to Be exposure, we have performed global microarray analysis using a mixture of peripheral blood mononuclear and dendritic cells (PBMC/DCs) from a non-CBD source to identify genes that are specifically upregulated in response to BeSO(4) stimulation, compared to a control metal salt, Al(2)(SO(4))(3). We identified a number of upregulated immunomodulatory genes, including several chemokines in the MIP-1 and GRO families. Using PBMC/DCs from three different donors, we demonstrate that BeSO(4) stimulation generally exhibits an increased rate of both chemokine mRNA transcription and release compared to Al(2)(SO(4))(3) exposure, although variations among the individual donors do exist. We show that MIP-1 alpha and MIP-1 beta neutralizing antibodies can partially inhibit the ability of BeSO(4) to stimulate cell migration of PBMC/DCs in vitro. Finally, incubation of PBMC/DCs with BeSO(4) altered the binding of the transcription factor RUNX to the MIP-1 alpha promoter consensus sequence, indicating that Be can regulate chemokine gene activation. Taken together, these results suggest a model in which Be stimulation of PBMC/DCs can modulate the expression and release of different chemokines, leading to the migration of lymphocytes to the lung and the formation of a localized environment for development of Be disease in susceptible individuals.

  7. Riboswitches. A riboswitch-containing sRNA controls gene expression by sequestration of a response regulator.

    Science.gov (United States)

    DebRoy, Sruti; Gebbie, Margo; Ramesh, Arati; Goodson, Jonathan R; Cruz, Melissa R; van Hoof, Ambro; Winkler, Wade C; Garsin, Danielle A

    2014-08-22

    The ethanolamine utilization (eut) locus of Enterococcus faecalis, containing at least 19 genes distributed over four polycistronic messenger RNAs, appears to be regulated by a single adenosyl cobalamine (AdoCbl)-responsive riboswitch. We report that the AdoCbl-binding riboswitch is part of a small, trans-acting RNA, EutX, which additionally contains a dual-hairpin substrate for the RNA binding-response regulator, EutV. In the absence of AdoCbl, EutX uses this structure to sequester EutV. EutV is known to regulate the eut messenger RNAs by binding dual-hairpin structures that overlap terminators and thus prevent transcription termination. In the presence of AdoCbl, EutV cannot bind to EutX and, instead, causes transcriptional read through of multiple eut genes. This work introduces riboswitch-mediated control of protein sequestration as a posttranscriptional mechanism to coordinately regulate gene expression.

  8. Pathway-level acceleration of glycogen catabolism by a response regulator in the cyanobacterium Synechocystis species PCC 6803.

    Science.gov (United States)

    Osanai, Takashi; Oikawa, Akira; Numata, Keiji; Kuwahara, Ayuko; Iijima, Hiroko; Doi, Yoshiharu; Saito, Kazuki; Hirai, Masami Yokota

    2014-04-01

    Response regulators of two-component systems play pivotal roles in the transcriptional regulation of responses to environmental signals in bacteria. Rre37, an OmpR-type response regulator, is induced by nitrogen depletion in the unicellular cyanobacterium Synechocystis species PCC 6803. Microarray and quantitative real-time polymerase chain reaction analyses revealed that genes related to sugar catabolism and nitrogen metabolism were up-regulated by rre37 overexpression. Protein levels of GlgP(slr1367), one of the two glycogen phosphorylases, in the rre37-overexpressing strain were higher than those of the parental wild-type strain under both nitrogen-replete and nitrogen-depleted conditions. Glycogen amounts decreased to less than one-tenth by rre37 overexpression under nitrogen-replete conditions. Metabolome analysis revealed that metabolites of the sugar catabolic pathway and amino acids were altered in the rre37-overexpressing strain after nitrogen depletion. These results demonstrate that Rre37 is a pathway-level regulator that activates the metabolic flow from glycogen to polyhydroxybutyrate and the hybrid tricarboxylic acid and ornithine cycle, unraveling the mechanism of the transcriptional regulation of primary metabolism in this unicellular cyanobacterium.

  9. The nitrogen-regulated response regulator NrrA controls cyanophycin synthesis and glycogen catabolism in the cyanobacterium Synechocystis sp. PCC 6803.

    Science.gov (United States)

    Liu, Deng; Yang, Chen

    2014-01-24

    The cellular metabolism in cyanobacteria is extensively regulated in response to changes of environmental nitrogen availability. Multiple regulators are involved in this process, including a nitrogen-regulated response regulator NrrA. However, the regulatory role of NrrA in most cyanobacteria remains to be elucidated. In this study, we combined a comparative genomic reconstruction of NrrA regulons in 15 diverse cyanobacterial species with detailed experimental characterization of NrrA-mediated regulation in Synechocystis sp. PCC 6803. The reconstructed NrrA regulons in most species included the genes involved in glycogen catabolism, central carbon metabolism, amino acid biosynthesis, and protein degradation. A predicted NrrA-binding motif consisting of two direct repeats of TG(T/A)CA separated by an 8-bp A/T-rich spacer was verified by in vitro binding assays with purified NrrA protein. The predicted target genes of NrrA in Synechocystis sp. PCC 6803 were experimentally validated by comparing the transcript levels and enzyme activities between the wild-type and nrrA-inactivated mutant strains. The effect of NrrA deficiency on intracellular contents of arginine, cyanophycin, and glycogen was studied. Severe impairments in arginine synthesis and cyanophycin accumulation were observed in the nrrA-inactivated mutant. The nrrA inactivation also resulted in a significantly decreased rate of glycogen degradation. Our results indicate that by directly up-regulating expression of the genes involved in arginine synthesis, glycogen degradation, and glycolysis, NrrA controls cyanophycin accumulation and glycogen catabolism in Synechocystis sp. PCC 6803. It is suggested that NrrA plays a role in coordinating the synthesis and degradation of nitrogen and carbon reserves in cyanobacteria.

  10. The Nitrogen-regulated Response Regulator NrrA Controls Cyanophycin Synthesis and Glycogen Catabolism in the Cyanobacterium Synechocystis sp. PCC 6803*

    Science.gov (United States)

    Liu, Deng; Yang, Chen

    2014-01-01

    The cellular metabolism in cyanobacteria is extensively regulated in response to changes of environmental nitrogen availability. Multiple regulators are involved in this process, including a nitrogen-regulated response regulator NrrA. However, the regulatory role of NrrA in most cyanobacteria remains to be elucidated. In this study, we combined a comparative genomic reconstruction of NrrA regulons in 15 diverse cyanobacterial species with detailed experimental characterization of NrrA-mediated regulation in Synechocystis sp. PCC 6803. The reconstructed NrrA regulons in most species included the genes involved in glycogen catabolism, central carbon metabolism, amino acid biosynthesis, and protein degradation. A predicted NrrA-binding motif consisting of two direct repeats of TG(T/A)CA separated by an 8-bp A/T-rich spacer was verified by in vitro binding assays with purified NrrA protein. The predicted target genes of NrrA in Synechocystis sp. PCC 6803 were experimentally validated by comparing the transcript levels and enzyme activities between the wild-type and nrrA-inactivated mutant strains. The effect of NrrA deficiency on intracellular contents of arginine, cyanophycin, and glycogen was studied. Severe impairments in arginine synthesis and cyanophycin accumulation were observed in the nrrA-inactivated mutant. The nrrA inactivation also resulted in a significantly decreased rate of glycogen degradation. Our results indicate that by directly up-regulating expression of the genes involved in arginine synthesis, glycogen degradation, and glycolysis, NrrA controls cyanophycin accumulation and glycogen catabolism in Synechocystis sp. PCC 6803. It is suggested that NrrA plays a role in coordinating the synthesis and degradation of nitrogen and carbon reserves in cyanobacteria. PMID:24337581

  11. Sphingoid base 1-phosphate phosphatase: A key regulator of sphingolipid metabolism and stress response

    Science.gov (United States)

    Mandala, Suzanne M.; Thornton, Rosemary; Tu, Zhenxing; Kurtz, Myra B.; Nickels, Joseph; Broach, James; Menzeleev, Ramil; Spiegel, Sarah

    1998-01-01

    The sphingolipid metabolites ceramide and sphingosine-1-phosphate are second messengers with opposing roles in mammalian cell growth arrest and survival; their relative cellular level has been proposed to be a rheostat that determines the fate of cells. This report demonstrates that this rheostat is an evolutionarily conserved stress-regulatory mechanism that influences growth and survival of yeast. Although the role of sphingosine-1-phosphate in yeast was not previously examined, accumulation of ceramide has been shown to induce G1 arrest and cell death. We now have identified a gene in Saccharomyces cerevisiae, LBP1, that regulates the levels of phosphorylated sphingoid bases and ceramide. LBP1 was cloned from a yeast mutant that accumulated phosphorylated long-chain sphingoid bases and diverted sphingoid base intermediates from sphingolipid pathways to glycerophospholipid biosynthesis. LBP1 and its homolog, LBP2, encode very hydrophobic proteins that contain a novel-conserved sequence motif for lipid phosphatases, and both have long-chain sphingoid base phosphate phosphatase activity. In vitro characterization of Lbp1p shows that this phosphatase is Mg2+-independent with high specificity for phosphorylated long-chain bases, phytosphingosine and sphingosine. The deletion of LBP1 results in the accumulation of phosphorylated long-chain sphingoid bases and reduced ceramide levels. Moreover, deletion of LBP1 and LBP2 results in dramatically enhanced survival upon severe heat shock. Thus, these phosphatases play a previously unappreciated role in regulating ceramide and phosphorylated sphingoid base levels in yeast, and they modulate stress responses through sphingolipid metabolites in a manner that is reminiscent of their effects on mammalian cells. PMID:9419344

  12. Winning isn't everything: mood and testosterone regulate the cortisol response in competition.

    Directory of Open Access Journals (Sweden)

    Samuele Zilioli

    Full Text Available Dominance contests are recurrent and widespread causes of stress among mammals. Studies of activation of the stress axis in social defeat - as reflected in levels of adrenal glucocorticoid, cortisol - have generated scattered and sometimes contradictory results, suggesting that biopsychological individual differences might play an important mediating role, at least in humans. In the context of a larger study of the regulation of endocrine responses to competition, we evaluated the notion that mood states, such as self-assurance and hostility, may influence cortisol reactivity to dominance cues via an interplay with baseline testosterone, considered as a potential marker of individual differences in dominance. Seventy healthy male university students (mean age 20.02, range 18-26 provided saliva samples before and after competing for fifteen minutes on a rigged computer task. After a winner was determined, all participants were assessed on their mood states through a standardized psychometric instrument (PANAS-X. Among winners of a rigged videogame competition, we found a significant interaction between testosterone and self-assurance in relation to post-competition cortisol. Specifically, self-assurance was associated with lower post-competition cortisol in subjects with high baseline testosterone levels, but no such relationship was observed in subjects with lower baseline testosterone levels. In losers of the competition no interaction effect between basal testosterone and hostility was observed. However, in this subgroup a significant negative relationship between basal testosterone and post-competition cortisol was evident. Overall, these findings provide initial support for the novel hypothesis that biological motivational predispositions (i.e. basal testosterone and state (i.e. mood changes may interact in regulating the hypothalamic-pituitary-adrenal axis activation after a social contest.

  13. Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

    Science.gov (United States)

    Ye, Fan; McCoy, Sean C; Ross, Heather H; Bernardo, Joseph A; Beharry, Adam W; Senf, Sarah M; Judge, Andrew R; Beck, Darren T; Conover, Christine F; Cannady, Darryl F; Smith, Barbara K; Yarrow, Joshua F; Borst, Stephen E

    2014-09-01

    Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth.

  14. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

    Directory of Open Access Journals (Sweden)

    Cathy Slack

    2010-03-01

    Full Text Available Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF-1 signaling (IIS pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the

  15. Social responsibility on risk assessment and cost/benefit analysis for new regulations

    Energy Technology Data Exchange (ETDEWEB)

    Boyer, T. [Univ. of Washington, Seattle, WA (United States). Dept. of Environmental Health

    1995-12-31

    Risk assessment and cost benefit analysis is an important factor to be considered for new regulations. There are hazards which cause an adverse effect on human health, particularly in the occupational setting, Maintaining the right degree of concern and caution about health and safety is critical to the well-being of the workplace. Industry must guard against excessive reaction about unknown hazards. At the same time, it is to the benefit of industry that management and employees both learn everything they can about occupational health risks thereby performing a risk assessment. Furthermore, managers and employees must take necessary and reasonable precautions against risks associated with the workplace thereby conducting cost benefit analysis. Additionally, the US Senate Committee on Labor and Human Resources must limit exposure of ``Working America`` to many toxicants (such as benzene, lead or asbestos) without panic or unnecessary constrictions in living. To take effective action requires sound risk assessment and cost benefit analysis of industry, society and law. A balance between the needs of the workforce versus the needs of management to protect the people from occupational hazards when preference is given to mandate specific workplace technology when faced with distorted market signals causing defective functioning of private job market. Public policy concerning workplace health and safety will make society better thus providing great social improvement. The key underlying issue is the analytic techniques, (risk assessment and cost benefit analysis), appropriate for evaluating social states before and after the enactment of alternative government policies. Social responsibility on risk assessment and cost benefit analysis for new regulations applies to everyone; particularly employees. Employees must be reminded there are ways to mobilize action.

  16. Transcriptional response of stress-regulated genes to industrial effluent exposure in the cockle Cerastoderma glaucum.

    Science.gov (United States)

    Karray, Sahar; Tastard, Emmanuelle; Moreau, Brigitte; Delahaut, Laurence; Geffard, Alain; Guillon, Emmanuel; Denis, Françoise; Hamza-Chaffai, Amel; Chénais, Benoît; Marchand, Justine

    2015-11-01

    This study assessed the responses of molecular biomarkers and heavy metal levels in Cerastoderma glaucum exposed for 1 week to two industrial effluents (1%) discharged into the Tunisian coastal area, F1 and F2, produced by different units of production of a phosphate treatment plant. A significant uptake of metals (Cd, Cu, Zn, and Ni) was observed in exposed cockles compared to controls, with an uptake higher for F1 than for F2. A decrease in LT50 (stress on stress test) was also observed after an exposure to the effluent F1. Treatments resulted in different patterns of messenger RNA (mRNA) expression of the different genes tested in this report. Gene transcription monitoring performed on seven genes potentially involved in the tolerance to metal exposure showed that for both exposures, mechanisms are rapidly and synchronically settled down to prevent damage to cellular components, by (1) handling and exporting out metal ions through the up-regulation of ATP-binding cassette xenobiotic transporter (ABCB1) and metallothionein (MT), (2) increasing the mRNA expression of antioxidant enzymes (catalase (CAT), superoxide dismutases, CuZnSOD and MnSOD), (3) protecting and/or repairing proteins through the expression of heat shock protein 70 (HSP70) mRNAs, and (4) increasing ATP production (through the up-regulation of cytochrome c oxidase 1 (CO1)) to provide energy for cells to tolerate stress exposure. The tools developed may be useful both for future control strategies and for the use of the cockle C. glaucum as a sentinel species.

  17. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.

    Science.gov (United States)

    Cho, Sung Hoon; Raybuck, Ariel L; Stengel, Kristy; Wei, Mei; Beck, Thomas C; Volanakis, Emmanuel; Thomas, James W; Hiebert, Scott; Haase, Volker H; Boothby, Mark R

    2016-09-08

    Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

  18. A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response

    Directory of Open Access Journals (Sweden)

    Xiaozeng Lin

    2015-12-01

    Full Text Available BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT. Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1, and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub, BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR. In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis.

  19. Loss of the Response Regulator CtrA Causes Pleiotropic Effects on Gene Expression but Does Not Affect Growth Phase Regulation in Rhodobacter capsulatus

    Energy Technology Data Exchange (ETDEWEB)

    Mercer, Ryan; Callister, Stephen J.; Lipton, Mary S.; Pasa-Tolic, Ljiljana; Strnad, Hynek; Paces, Vaclav; Beatty, J. T.; Lang, Andrew S.

    2010-06-01

    The purple non-sulfur bacterium Rhodobacter capsulatus has been extensively studied for its diverse metabolic capabilities, as well as for its production of a Gene Transfer Agent (RcGTA). Production of RcGTA requires the response regulator protein CtrA. We have used whole genome transcript and whole cell proteome analyses of wild type and ctrA mutant cultures to completely characterize the regulatory role of CtrA in R. capsulatus.