T cell-derived Lymphotoxin is Essential for anti-HSV-1 Humoral Immune Response.

Science.gov (United States)

Yang, Kaiting; Liang, Yong; Sun, Zhichen; Xue, Diyuan; Xu, Hairong; Zhu, Mingzhao; Fu, Yang-Xin; Peng, Hua

2018-05-09

B cell-derived lymphotoxin (LT) is required for the development of follicular dendritic cell clusters for the formation of primary and secondary lymphoid follicles, but the role of T cell-derived LT in antibody response has not been well demonstrated. We observed that lymphotoxin-β-receptor (LTβR) signaling is essential for optimal humoral immune response and protection against an acute HSV-1 infection. Blocking the LTβR pathway caused poor maintenance of germinal center B (GC-B) cells and follicular helper T (Tfh) cells. Using bone marrow chimeric mice and adoptive transplantation, we determined that T cell-derived LT played an indispensable role in the humoral immune response to HSV-1. Up-regulation of IFNγ by the LTβR-Ig blockade impairs the sustainability of Tfh-like cells, thus leading to an impaired humoral immune response. Our findings have identified a novel role of T cell-derived LT in the humoral immune response against HSV-1 infection. IMPORTANCE Immunocompromised people are susceptible for HSV-1 infection and lethal recurrence, which could be inhibited by anti-HSV-1 humoral immune response in the host. This study sought to explore the role of T cell-derived LT in the anti-HSV-1 humoral immune response using LT-LTβR signaling deficient mice and the LTβR-Ig blockade. The data indicate that the T cell-derived LT may play an essential role in sustaining Tfh-like cells and ensure Tfh-like cells' migration into primary or secondary follicles for further maturation. This study provides insights for vaccine development against infectious diseases. Copyright © 2018 American Society for Microbiology.

The ribonuclease Dis3 is an essential regulator of the developmental transcriptome

Directory of Open Access Journals (Sweden)

Hou Dezhi

2012-08-01

Full Text Available Abstract Background Dis3 is ribonuclease that acts directly in the processing, turnover, and surveillance of a large number of distinct RNA species. Evolutionarily conserved from eubacteria to eukaryotes and a crucial component of the RNA processing exosome, Dis3 has been shown to be essential in yeast and fly S2 cells. However, it is not known whether Dis3 has essential functions in a metazoan. This study inquires whether Dis3 is required for Drosophila development and viability and how Dis3 regulates the transcriptome in the developing fly. Results Using transgenic flies, we show that Dis3 knock down (Dis3KD retards growth, induces melanotic tumor formation, and ultimately results in 2nd instar larval lethality. In order to determine whether Dis3KD fly phenotypes were a consequence of disrupting developmentally regulated RNA turnover, we performed RNA deep sequencing analysis on total RNA isolated from developmentally staged animals. Bioinformatic analysis of transcripts from Dis3KD flies reveals substantial transcriptomic changes, most notably down-regulation in early expressed RNAs. Finally, gene ontology analysis of this early stage shows that Dis3 regulates transcripts related to extracellular structure and remodelling, neurogenesis, and nucleotide metabolism. Conclusions We conclude that Dis3 is essential for early Drosophila melanogaster development and has specific and important stage-specific roles in regulating RNA metabolism. In showing for the first time that Dis3 is required for the development of a multicellular organism, our work provides mechanistic insight into how Dis3—either independent of or associated with the RNA processing exosome—participates in cell type-specific RNA turnover in metazoan development.

Structure, inhibition, and regulation of essential lipid A enzymes.

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Zhou, Pei; Zhao, Jinshi

2017-11-01

The Raetz pathway of lipid A biosynthesis plays a vital role in the survival and fitness of Gram-negative bacteria. Research efforts in the past three decades have identified individual enzymes of the pathway and have provided a mechanistic understanding of the action and regulation of these enzymes at the molecular level. This article reviews the discovery, biochemical and structural characterization, and regulation of the essential lipid A enzymes, as well as continued efforts to develop novel antibiotics against Gram-negative pathogens by targeting lipid A biosynthesis. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. Copyright © 2016 Elsevier B.V. All rights reserved.

Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

Science.gov (United States)

Patterson, Jessica N; Cousteils, Katelyn; Lou, Jennifer W; Manning Fox, Jocelyn E; MacDonald, Patrick E; Joseph, Jamie W

2014-05-09

It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that β-cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 β-cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (KATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor α-cyano-β-(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.

Insecticidal Activity of Melaleuca alternifolia Essential Oil and RNA-Seq Analysis of Sitophilus zeamais Transcriptome in Response to Oil Fumigation.

Directory of Open Access Journals (Sweden)

Min Liao

Full Text Available The cereal weevil, Sitophilus zeamais is one of the most destructive pests of stored cereals worldwide. Frequent use of fumigants for managing stored-product insects has led to the development of resistance in insects. Essential oils from aromatic plants including the tea oil plant, Melaleuca alternifolia may provide environmentally friendly alternatives to currently used pest control agents. However, little is known about molecular events involved in stored-product insects in response to plant essential oil fumigation.M. alternifolia essential oil was shown to possess the fumigant toxicity against S. zeamais. The constituent, terpinen-4-ol was the most effective compound for fumigant toxicity. M. alternifolia essential oil significantly inhibited the activity of three enzymes in S. zeamais, including two detoxifying enzymes, glutathione S-transferase (GST, and carboxylesterase (CarE, as well as a nerve conduction enzyme, acetylcholinesterase (AChE. Comparative transcriptome analysis of S. zeamais through RNA-Seq identified a total of 3,562 differentially expressed genes (DEGs, of which 2,836 and 726 were up-regulated and down-regulated in response to M. alternifolia essential oil fumigation, respectively. Based on gene ontology (GO analysis, the majority of DEGs were involved in insecticide detoxification and mitochondrial function. Furthermore, an abundance of DEGs mapped into the metabolism pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG pathway database were associated with respiration and metabolism of xenobiotics, including cytochrome P450s, CarEs, GSTs, and ATP-binding cassette transporters (ABC transporters. Some DEGs mapped into the proteasome and phagosome pathway were found to be significantly enriched. These results led us to propose a model of insecticide action that M. alternifolia essential oil likely directly affects the hydrogen carrier to block the electron flow and interfere energy synthesis in mitochondrial

CBL-interacting protein kinase 6 negatively regulates immune response to Pseudomonas syringae in Arabidopsis.

Science.gov (United States)

Sardar, Atish; Nandi, Ashis Kumar; Chattopadhyay, Debasis

2017-06-15

Cytosolic calcium ion (Ca2+) is an essential mediator of the plant innate immune response. Here, we report that a calcium-regulated protein kinase Calcineurin B-like protein (CBL)-interacting protein kinase 6 (CIPK6) functions as a negative regulator of immunity against the bacterial pathogen Pseudomonas syringae in Arabidopsis thaliana. Arabidopsis lines with compromised expression of CIPK6 exhibited enhanced disease resistance to the bacterial pathogen and to P. syringae harboring certain but not all avirulent effectors, while restoration of CIPK6 expression resulted in abolition of resistance. Plants overexpressing CIPK6 were more susceptible to P. syringae. Enhanced resistance in the absence of CIPK6 was accompanied by increased accumulation of salicylic acid and elevated expression of defense marker genes. Salicylic acid accumulation was essential for improved immunity in the absence of CIPK6. CIPK6 negatively regulated the oxidative burst associated with perception of pathogen-associated microbial patterns (PAMPs) and bacterial effectors. Accelerated and enhanced activation of the mitogen-activated protein kinase cascade in response to bacterial and fungal elicitors was observed in the absence of CIPK6. The results of this study suggested that CIPK6 negatively regulates effector-triggered and PAMP-triggered immunity in Arabidopsis. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Assessment of the impact of market regulation in Mali on the price of essential medicines provided through the private sector.

Science.gov (United States)

Maïga, Diadié; Williams-Jones, Bryn

2010-10-01

In 1998, the government of Mali adopted a national pharmaceutical policy aimed at promoting a supply system for generic essential medicines that would guarantee equal access for all citizens. Distribution and delivery is a shared responsibility of both public and private sectors (wholesalers and pharmacies). To influence private sector behaviour, the national policy uses a combination of government regulation and market forces. In 2006, the government issued a decree fixing maximum prices in the private sector for 107 prescription drugs from the national list of 426 essential medicines. The current study assessed the impact of this intervention on the evolution of market prices (wholesale and retail), and the subsequent availability and public access to essential medicines in Mali. A cross-sectional descriptive survey was conducted in February and May 2006, and January 2009, with 16 wholesalers and 30 private drugstores in Bamako, Mali. The overall availability of essential medicines at private wholesalers (p=1) and pharmacies (p=0.53) was identical before and after the enforcement of the 2006 decree fixing maximum drug prices. Contrary to concerns expressed by wholesalers and pharmacies, and the other stakeholders, the decree did not impact negatively on availability of essential medicines. In fact, median wholesale prices in 2009 were 25.6% less than those fixed by the decree. In private pharmacies, retail prices were only 3% more expensive than the recommended prices, compared with being 25.5% more expensive prior to enforcement of the decree. The study shows that prices of essential medicines in Mali have evolved favourably towards the prices recommended by the government decree. Further, the study contributes to mounting evidence that market regulation by governments does not necessarily negatively affect drug availability; in fact, given the reduction in prices, the study shows that Malians arguably have better access to more affordable essential medicines

MAPK-mediated regulation of growth and essential oil composition in a salt-tolerant peppermint (Mentha piperita L.) under NaCl stress.

Science.gov (United States)

Li, Zhe; Wang, Wenwen; Li, Guilong; Guo, Kai; Harvey, Paul; Chen, Quan; Zhao, Zhongjuan; Wei, Yanli; Li, Jishun; Yang, Hetong

2016-11-01

Peppermint (Mentha × piperita L.) is an important and commonly used flavoring agent worldwide, and salinity is a major stress that limits plant growth and reduces crop productivity. This work demonstrated the metabolic responses of essential oil production including the yield and component composition, gene expression, enzyme activity, and protein activation in a salt-tolerant peppermint Keyuan-1 with respect to NaCl stress. Our results showed that Keyuan-1 maintained normal growth and kept higher yield and content of essential oils under NaCl stress than wild-type (WT) peppermint.Gas chromatography-mass spectrometry (GC-MS) and qPCR results showed that compared to WT seedlings, a 150-mM NaCl stress exerted no obvious changes in essential oil composition, transcriptional level of enzymes related to essential oil metabolism, and activity of pulegone reductase (Pr) in Keyuan-1 peppermint which preserved the higher amount of menthol and menthone as well as the lower content of menthofuran upon the 150-mM NaCl stress. Furthermore, it was noticed that a mitogen-activated protein kinase (MAPK) protein exhibited a time-dependent activation in the Keyuan-1 peppermint and primarily involved in the modulation of the essential oil metabolism in the transcript and enzyme levels during the 12-day treatment of 150 mM NaCl. In all, our data elucidated the effect of NaCl on metabolic responses of essential oil production, and demonstrated the MAPK-dependent regulation mechanism of essential oil biosynthesis in the salt-tolerant peppermint, providing scientific basis for the economic and ecological utilization of peppermint in saline land.

Southern states radiological emergency response laws and regulations

International Nuclear Information System (INIS)

1990-06-01

The purpose of this report is to provide a summary of the emergency response laws and regulations in place in the various states within the southern region for use by legislators, emergency response planners, the general public and all persons concerned about the existing legal framework for emergency response. SSEB expects to periodically update the report as necessary. Radiation protection regulations without emergency response provisions are not included in the summary. The radiological emergency response laws and regulations of the Southern States Energy Compact member states are in some cases disparate. Several states have very specific laws on radiological emergency response while in others, the statutory law mentions only emergency response to ''natural disasters.'' Some states have adopted extensive regulations on the topic, others have none. For this reason, any general overview must necessarily discuss laws and regulations in general terms. State-by-state breakdowns are given for specific states

Stat1-independent regulation of gene expression in response to IFN-γ

Science.gov (United States)

Ramana, Chilakamarti V.; Gil, M. Pilar; Han, Yulong; Ransohoff, Richard M.; Schreiber, Robert D.; Stark, George R.

2001-01-01

Although Stat1 is essential for cells to respond fully to IFN-γ, there is substantial evidence that, in the absence of Stat1, IFN-γ can still regulate the expression of some genes, induce an antiviral state and affect cell growth. We have now identified many genes that are regulated by IFN-γ in serum-starved Stat1-null mouse fibroblasts. The proteins induced by IFN-γ in Stat1-null cells can account for the substantial biological responses that remain. Some genes are induced in both wild-type and Stat1-null cells and thus are truly Stat1-independent. Others are subject to more complex regulation in response to IFN-γ, repressed by Stat1 in wild-type cells and activated in Stat1-null cells. Many genes induced by IFN-γ in Stat1-null fibroblasts also are induced by platelet-derived growth factor in wild-type cells and thus are likely to be involved in cell proliferation. In mouse cells expressing the docking site mutant Y440F of human IFN-γ receptor subunit 1, the mouse Stat1 is not phosphorylated in response to human IFN-γ, but c-myc and c-jun are still induced, showing that the Stat1 docking site is not required for Stat1-independent signaling. PMID:11390994

Mina: a Th2 response regulator meets TGFβ.

Science.gov (United States)

Pillai, Meenu R; Lian, Shangli; Bix, Mark

2014-12-01

The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFβ may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context. Copyright © 2014 Elsevier Ltd. All rights reserved.

Essential Features of Responsible Governance of Agricultural Biotechnology.

Science.gov (United States)

Hartley, Sarah; Gillund, Frøydis; van Hove, Lilian; Wickson, Fern

2016-05-01

Agricultural biotechnology continues to generate considerable controversy. We argue that to address this controversy, serious changes to governance are needed. The new wave of genomic tools and products (e.g., CRISPR, gene drives, RNAi, synthetic biology, and genetically modified [GM] insects and fish), provide a particularly useful opportunity to reflect on and revise agricultural biotechnology governance. In response, we present five essential features to advance more socially responsible forms of governance. In presenting these, we hope to stimulate further debate and action towards improved forms of governance, particularly as these new genomic tools and products continue to emerge.

Blimp-1 controls plasma cell function through regulation of immunoglobulin secretion and the unfolded protein response

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Tellier, Julie; Shi, Wei; Minnich, Martina; Liao, Yang; Crawford, Simon; Smyth, Gordon K; Kallies, Axel; Busslinger, Meinrad; Nutt, Stephen L

2015-01-01

Plasma cell differentiation requires silencing of B cell transcription, while establishing antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for plasma cell generation, however their function in mature plasma cells has remained elusive. We have found that while IRF4 was essential for plasma cell survival, Blimp-1 was dispensable. Blimp-1-deficient plasma cells retained their transcriptional identity, but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap of Blimp-1 and XBP-1 function was restricted to the UPR, with Blimp-1 uniquely regulating mTOR activity and plasma cell size. Thus, Blimp-1 is required for the unique physiological capacity of plasma cells that enables the secretion of protective antibody. PMID:26779600

Targeting Plant Ethylene Responses by Controlling Essential Protein-Protein Interactions in the Ethylene Pathway.

Science.gov (United States)

Bisson, Melanie M A; Groth, Georg

2015-08-01

The gaseous plant hormone ethylene regulates many processes of high agronomic relevance throughout the life span of plants. A central element in ethylene signaling is the endoplasmic reticulum (ER)-localized membrane protein ethylene insensitive2 (EIN2). Recent studies indicate that in response to ethylene, the extra-membranous C-terminal end of EIN2 is proteolytically processed and translocated from the ER to the nucleus. Here, we report that the conserved nuclear localization signal (NLS) mediating nuclear import of the EIN2 C-terminus provides an important domain for complex formation with ethylene receptor ethylene response1 (ETR1). EIN2 lacking the NLS domain shows strongly reduced affinity for the receptor. Interaction of EIN2 and ETR1 is also blocked by a synthetic peptide of the NLS motif. The corresponding peptide substantially reduces ethylene responses in planta. Our results uncover a novel mechanism and type of inhibitor interfering with ethylene signal transduction and ethylene responses in plants. Disruption of essential protein-protein interactions in the ethylene signaling pathway as shown in our study for the EIN2-ETR1 complex has the potential to guide the development of innovative ethylene antagonists for modern agriculture and horticulture. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

Regulation of the Immune Response to α-Gal and Vector-borne Diseases.

Science.gov (United States)

Cabezas-Cruz, Alejandro; Mateos-Hernández, Lourdes; Pérez-Cruz, Magdiel; Valdés, James J; Mera, Isabel G Fernández de; Villar, Margarita; de la Fuente, José

2015-10-01

Vector-borne diseases (VBD) challenge our understanding of emerging diseases. Recently, arthropod vectors have been involved in emerging anaphylactic diseases. In particular, the immunoglobulin E (IgE) antibody response to the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-gal) following a tick bite was associated with allergies to red meat, cetuximab, and gelatin. By contrast, an anti-α-gal IgM antibody response was shown to protect against mosquito-borne malaria. Herein, we highlight the interplay between the gut microbiota, vectors, transmitted pathogens, and the regulation of the immune response as a model to understand the protective or allergic effect of α-gal. Establishing the source of α-gal in arthropod vectors and the immune response to vector bites and transmitted pathogens will be essential for diagnosing, treating, and ultimately preventing these emerging anaphylactic and other vector-borne diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Southern states radiological emergency response laws and regulations

International Nuclear Information System (INIS)

1989-02-01

The radiological emergency response laws and regulations of the Southern States Energy Compact member states are in some cases disparate. Several states have very specific laws on radiological emergency response while in others, the statutory law mentions only emergency response to ''natural disasters.'' Some states have adopted extensive regulations on the topic; others have none. For this reason, any general overview must necessarily discuss laws and regulations in general terms

The systematic functional analysis of plasmodium protein kinases identifies essential regulators of mosquito transmission

KAUST Repository

Tewari, Rita; Straschil, Ursula; Bateman, Alex; Bö hme, Ulrike; Cherevach, Inna; Gong, Peng; Pain, Arnab; Billker, Oliver

2010-01-01

Although eukaryotic protein kinases (ePKs) contribute to many cellular processes, only three Plasmodium falciparum ePKs have thus far been identified as essential for parasite asexual blood stage development. To identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of ePKs in the genetically tractable rodent parasite Plasmodium berghei. Modeling domain signatures of conventional ePKs identified 66 putative Plasmodium ePKs. Kinomes are highly conserved between Plasmodium species. Using reverse genetics, we show that 23 ePKs are redundant for asexual erythrocytic parasite development in mice. Phenotyping mutants at four life cycle stages in Anopheles stephensi mosquitoes revealed functional clusters of kinases required for sexual development and sporogony. Roles for a putative SR protein kinase (SRPK) in microgamete formation, a conserved regulator of clathrin uncoating (GAK) in ookinete formation, and a likely regulator of energy metabolism (SNF1/KIN) in sporozoite development were identified. 2010 Elsevier Inc.

The systematic functional analysis of plasmodium protein kinases identifies essential regulators of mosquito transmission

KAUST Repository

Tewari, Rita

2010-10-21

Although eukaryotic protein kinases (ePKs) contribute to many cellular processes, only three Plasmodium falciparum ePKs have thus far been identified as essential for parasite asexual blood stage development. To identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of ePKs in the genetically tractable rodent parasite Plasmodium berghei. Modeling domain signatures of conventional ePKs identified 66 putative Plasmodium ePKs. Kinomes are highly conserved between Plasmodium species. Using reverse genetics, we show that 23 ePKs are redundant for asexual erythrocytic parasite development in mice. Phenotyping mutants at four life cycle stages in Anopheles stephensi mosquitoes revealed functional clusters of kinases required for sexual development and sporogony. Roles for a putative SR protein kinase (SRPK) in microgamete formation, a conserved regulator of clathrin uncoating (GAK) in ookinete formation, and a likely regulator of energy metabolism (SNF1/KIN) in sporozoite development were identified. 2010 Elsevier Inc.

Cyclic di-AMP regulation of osmotic homeostasis is essential in Group B Streptococcus.

Directory of Open Access Journals (Sweden)

Laura Devaux

2018-04-01

Full Text Available Cyclic nucleotides are universally used as secondary messengers to control cellular physiology. Among these signalling molecules, cyclic di-adenosine monophosphate (c-di-AMP is a specific bacterial second messenger recognized by host cells during infections and its synthesis is assumed to be necessary for bacterial growth by controlling a conserved and essential cellular function. In this study, we sought to identify the main c-di-AMP dependent pathway in Streptococcus agalactiae, the etiological agent of neonatal septicaemia and meningitis. By conditionally inactivating dacA, the only diadenyate cyclase gene, we confirm that c-di-AMP synthesis is essential in standard growth conditions. However, c-di-AMP synthesis becomes rapidly dispensable due to the accumulation of compensatory mutations. We identified several mutations restoring the viability of a ΔdacA mutant, in particular a loss-of-function mutation in the osmoprotectant transporter BusAB. Identification of c-di-AMP binding proteins revealed a conserved set of potassium and osmolyte transporters, as well as the BusR transcriptional factor. We showed that BusR negatively regulates busAB transcription by direct binding to the busAB promoter. Loss of BusR repression leads to a toxic busAB expression in absence of c-di-AMP if osmoprotectants, such as glycine betaine, are present in the medium. In contrast, deletion of the gdpP c-di-AMP phosphodiesterase leads to hyperosmotic susceptibility, a phenotype dependent on a functional BusR. Taken together, we demonstrate that c-di-AMP is essential for osmotic homeostasis and that the predominant mechanism is dependent on the c-di-AMP binding transcriptional factor BusR. The regulation of osmotic homeostasis is likely the conserved and essential function of c-di-AMP, but each species has evolved specific c-di-AMP mechanisms of osmoregulation to adapt to its environment.

Metabolic regulation of manganese superoxide dismutase expression via essential amino acid deprivation.

Science.gov (United States)

Aiken, Kimberly J; Bickford, Justin S; Kilberg, Michael S; Nick, Harry S

2008-04-18

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.

The response regulator YycF inhibits expression of the fatty acid biosynthesis repressor FabT in Streptococcus pneumoniae

NARCIS (Netherlands)

Mohedano, Maria L.; Amblar, Mónica; La Fuente, De Alicia; Wells, Jerry M.; López, Paloma

2016-01-01

The YycFG (also known as WalRK, VicRK, MicAB, or TCS02) two-component system (TCS) is highly conserved among Gram-positive bacteria with a low G+C content. In Streptococcus pneumoniae the YycF response regulator has been reported to be essential due to its control of pcsB gene expression.

Histone Deacetylase HDA-2 Regulates Trichoderma atroviride Growth, Conidiation, Blue Light Perception, and Oxidative Stress Responses.

Science.gov (United States)

Osorio-Concepción, Macario; Cristóbal-Mondragón, Gema Rosa; Gutiérrez-Medina, Braulio; Casas-Flores, Sergio

2017-02-01

Fungal blue-light photoreceptors have been proposed as integrators of light and oxidative stress. However, additional elements participating in the integrative pathway remain to be identified. In Trichoderma atroviride, the blue-light regulator (BLR) proteins BLR-1 and -2 are known to regulate gene transcription, mycelial growth, and asexual development upon illumination, and recent global transcriptional analysis revealed that the histone deacetylase-encoding gene hda-2 is induced by light. Here, by assessing responses to stimuli in wild-type and Δhda-2 backgrounds, we evaluate the role of HDA-2 in the regulation of genes responsive to light and oxidative stress. Δhda-2 strains present reduced growth, misregulation of the con-1 gene, and absence of conidia in response to light and mechanical injury. We found that the expression of hda-2 is BLR-1 dependent and HDA-2 in turn is essential for the transcription of early and late light-responsive genes that include blr-1, indicating a regulatory feedback loop. When subjected to reactive oxygen species (ROS), Δhda-2 mutants display high sensitivity whereas Δblr strains exhibit the opposite phenotype. Consistently, in the presence of ROS, ROS-related genes show high transcription levels in wild-type and Δblr strains but misregulation in Δhda-2 mutants. Finally, chromatin immunoprecipitations of histone H3 acetylated at Lys9/Lys14 on cat-3 and gst-1 promoters display low accumulation of H3K9K14ac in Δblr and Δhda-2 strains, suggesting indirect regulation of ROS-related genes by HDA-2. Our results point to a mutual dependence between HDA-2 and BLR proteins and reveal the role of these proteins in an intricate gene regulation landscape in response to blue light and ROS. Trichoderma atroviride is a free-living fungus commonly found in soil or colonizing plant roots and is widely used as an agent in biocontrol as it parasitizes other fungi, stimulates plant growth, and induces the plant defense system. To survive in

SuhB Is a Regulator of Multiple Virulence Genes and Essential for Pathogenesis of Pseudomonas aeruginosa

Science.gov (United States)

Li, Kewei; Xu, Chang; Jin, Yongxin; Sun, Ziyu; Liu, Chang; Shi, Jing; Chen, Gukui; Chen, Ronghao; Jin, Shouguang; Wu, Weihui

2013-01-01

ABSTRACT During initial colonization and chronic infection, pathogenic bacteria encounter distinct host environments. Adjusting gene expression accordingly is essential for the pathogenesis. Pseudomonas aeruginosa has evolved complicated regulatory networks to regulate different sets of virulence factors to facilitate colonization and persistence. The type III secretion system (T3SS) and motility are associated with acute infections, while biofilm formation and the type VI secretion system (T6SS) are associated with chronic persistence. To identify novel regulatory genes required for pathogenesis, we screened a P. aeruginosa transposon (Tn) insertion library and found suhB to be an essential gene for the T3SS gene expression. The expression of suhB was upregulated in a mouse acute lung infection model, and loss of suhB resulted in avirulence. Suppression of T3SS gene expression in the suhB mutant is linked to a defective translation of the T3SS master regulator, ExsA. Further studies demonstrated that suhB mutation led to the upregulation of GacA and its downstream small RNAs, RsmY and RsmZ, triggering T6SS expression and biofilm formation while inhibiting the T3SS. Our results demonstrate that an in vivo-inducible gene, suhB, reciprocally regulates genes associated with acute and chronic infections and plays an essential role in the pathogenesis of P. aeruginosa. PMID:24169572

Behavioral Response of Aedes aegypti Mosquito towards Essential Oils Using Olfactometer

Science.gov (United States)

Uniyal, Ashish; Tikar, Sachin N; Mendki, Murlidhar J; Singh, Ram; Shukla, Shakti V; Agrawal, Om P; Veer, Vijay; Sukumaran, Devanathan

2016-01-01

Background: Aedes aegypti mosquito is responsible for transmitting human diseases like dengue and chikungunya. Personal or space protection with insect repellents is a practical approach to reducing human mosquito contact, thereby minimizing disease transmission. Essential oils are natural volatile substances from plants used as protective measure against blood-sucking mosquitoes. Methods: Twenty-three essential oils were evaluated for their repellent effect against Ae. aegypti female mosquito in laboratory conditions using Y-tube olfactometer. Results: The essential oils exhibited varying degree of repellency. Litsea oil showed 50.31%, 60.2 %, and 77.26% effective mean repellency at 1 ppm, 10 ppm and 100 ppm respectively, while DEET exhibited 59.63%, 68.63%, 85.48% and DEPA showed 57.97%, 65.43%, and 80.62% repellency at respective above concentrations. Statistical analysis revealed that among the tested essential oils, litsea oil had effective repellency in comparison with DEET and DEPA against Ae. aegypti mosquito at all concentration. Essential oils, DEET and DEPA showed significant repellence against Ae. aegypti (Poil exhibited effective percentage repellency similar to DEET and DEPA. The essential oils are natural plant products that may be useful for developing safer and newer herbal based effective mosquito repellents. PMID:27308295

Southern states radiological emergency response laws and regulations

International Nuclear Information System (INIS)

1989-07-01

The purpose of this report is to provide a summary of the emergency response laws and regulations in place in the various states within the southern region for use by legislators, emergency response planners, the general public and all persons concerned about the existing legal framework for emergency response. SSEB expects to periodically update the report as necessary. Radiation protection regulations without emergency response provisions are not included in the summary

Growth regulators and essential oil production

OpenAIRE

Prins, Cláudia L; Vieira, Ivo J. C; Freitas, Silvério P

2010-01-01

The aroma and fragrance industry is a billion-dollar world market which grows annually. Essential oils comprise the majority of compounds used by these industries. These sets of metabolites are formed mainly by monoterpenes, which are products of the plants' secondary metabolism. Biosynthesized from mevalonate and methylerythitol phosphate, the essential oil production depends not only on genetic factors and the developmental stage of plants, but also on environmental factors which could resu...

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

Science.gov (United States)

Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Both AtrbohD and AtrbohF are essential for mediating responses to oxygen deficiency in Arabidopsis.

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Liu, Bo; Sun, Lirong; Ma, Liya; Hao, Fu-Shun

2017-06-01

Both AtrbohD and AtrbohF promote the increases in activities of ADH, PDC, LDH, and Ca 2+ levels, and induce the expression of multiple hypoxia response genes, thus improving Arabidopsis adaptation to oxygen deficiency. NADPH oxidase AtrbohD and AtrbohF cooperatively play key roles in regulation of growth and stress signaling in Arabidopsis. However, reports on AtrbohD and AtrbohF functioning together in hypoxia signaling are scarce, and the underlying mechanisms remain elusive. Here, we show that the double null mutant atrbohD/F is more sensitive to oxygen deprivation compared with wild type (WT) and the single mutant atrbohD and atrbohF. Under oxygen deficiency, enhancements of the transcripts of alcohol dehydrogenase 1 (ADH1) and pyruvate decarboxylase 1 (PDC1) and the activities of ADH, PDC and lactate dehydrogenase in WT are clearly reduced in the single mutants, and more strongly reduced in the double mutant. Moreover, increases in the production of ATP, H 2 O 2 and Ca 2+ in WT are significantly arrested in atrbohD, atrbohF, and especially in atrbohD/F. Hypoxia-promoted rise in the expression of some hypoxic responsive genes is also inhibited in atrbohD/F relative to WT, atrbohD and atrbohF. These genes include ethylene response factor 73, lactate dehydrogenase, MYB transcription factor 2, sucrose synthase 1 (SUS1), SUS4, heat stress transcription factor A2 and heat-shock protein 18.2. These results suggest that both AtrbohD and AtrbohF are essential for mediating hypoxia signaling. H 2 O 2 derived from AtrbohD and AtrbohF triggers the Ca 2+ increase and induces the expression of multiple hypoxia response genes, thus improving Arabidopsis tolerance to low-oxygen stress. These findings provide new insights into the mechanisms of AtrbohF in regulating the responses to oxygen deprivation in Arabidopsis.

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

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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.

Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation*

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Aiken, Kimberly J.; Bickford, Justin S.; Kilberg, Michael S.; Nick, Harry S.

2008-01-01

Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging. PMID:18187411

BRI1 and BAK1 interact with G proteins and regulate sugar-responsive growth and development in Arabidopsis.

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Peng, Yuancheng; Chen, Liangliang; Li, Shengjun; Zhang, Yueying; Xu, Ran; Liu, Zupei; Liu, Wuxia; Kong, Jingjing; Huang, Xiahe; Wang, Yingchun; Cheng, Beijiu; Zheng, Leiying; Li, Yunhai

2018-04-18

Sugars function as signal molecules to regulate growth, development, and gene expression in plants, yeasts, and animals. A coordination of sugar availability with phytohormone signals is crucial for plant growth and development. The molecular link between sugar availability and hormone-dependent plant growth are largely unknown. Here we report that BRI1 and BAK1 are involved in sugar-responsive growth and development. Glucose influences the physical interactions and phosphorylations of BRI1 and BAK1 in a concentration-dependent manner. BRI1 and BAK1 physically interact with G proteins that are essential for mediating sugar signaling. Biochemical data show that BRI1 can phosphorylate G protein β subunit and γ subunits, and BAK1 can phosphorylate G protein γ subunits. Genetic analyses suggest that BRI1 and BAK1 function in a common pathway with G-protein subunits to regulate sugar responses. Thus, our findings reveal an important genetic and molecular mechanism by which BR receptors associate with G proteins to regulate sugar-responsive growth and development.

Macroinvertebrate community responses to gravel augmentation in a high-gradient, Southeastern regulated river

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McManamay, Ryan A [ORNL; Orth, Dr. Donald J [Virginia Polytechnic Institute and State University; Dolloff, Dr. Charles A [United States Department of Agriculture (USDA), United States Forest Service (USFS) and Virginia Pol

2013-01-01

Sediment transport, one of the key processes of river systems, is altered or stopped by dams, leaving lower river reaches barren of sand and gravel, both of which are essential habitat for fish and macroinvertebrates. One way to compensate for losses in sediment is to supplement gravel to river reaches below impoundments. Because gravel addition has become a widespread practice, it is essential to evaluate the biotic response to restoration projects in order to improve the efficacy of future applications. The purpose of our study was to evaluate the response of the macroinvertebrate community to gravel addition in a high-gradient, regulated river in western North Carolina. We collected benthic macroinvertebrate samples from gravel-enhanced areas and unenhanced areas for 1 season before gravel addition, and for 4 seasons afterwards. Repeated measures multivariate analysis of variance indicated that the responses of macroinvertebrates to gravel addition were generally specific to individual taxa or particular functional feeding groups and did not lead to consistent patterns in overall family richness, diversity, density, or evenness. Non-metric multi-dimensional scaling showed that shifts in macroinvertebrate community composition were temporary and dependent upon site conditions and season. Correlations between macroinvertebrate response variables and substrate microhabitat variables existed with or without the inclusion of data from enhanced areas, which suggests that substrate-biotic relationships were present before gravel addition. A review of the current literature suggests that the responses of benthic macroinvertebrates to substrate restoration are inconsistent and dependent upon site conditions and the degree habitat improvement of pre-restoration site conditions.

Fumigant toxicity of essential oils to Reticulitermes flavipes

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Carol A. Clausen; Vina W. Yang

2008-01-01

Subterranean termite infestations occur in every state in the contiguous United States and are responsible for damage to wooden structures in excess of two billion dollars (U.S.) annually. Essential oils have historically been used to repel insects. They have relatively low toxicity and some of them are exempt from regulation by the Federal Insecticide Fungicide and...

Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis.

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Tanaka, Toru; Hosoi, Fumihito; Yamaguchi-Iwai, Yuko; Nakamura, Hajime; Masutani, Hiroshi; Ueda, Shugo; Nishiyama, Akira; Takeda, Shunichi; Wada, Hiromi; Spyrou, Giannis; Yodoi, Junji

2002-04-02

Thioredoxin-2 (Trx-2) is a mitochondria-specific member of the thioredoxin superfamily. Mitochondria have a crucial role in the signal transduction for apoptosis. To investigate the biological significance of Trx-2, we cloned chicken TRX-2 cDNA and generated clones of the conditional Trx-2-deficient cells using chicken B-cell line, DT40. Here we show that TRX-2 is an essential gene and that Trx-2-deficient cells undergo apoptosis upon repression of the TRX-2 transgene, showing an accumulation of intracellular reactive oxygen species (ROS). Cytochrome c is released from mitochondria, while caspase-9 and caspase-3, but not caspase-8, are activated upon inhibition of the TRX-2 transgene. In addition, Trx-2 and cytochrome c are co-immunoprecipitated in an in vitro assay. These results suggest that mitochondrial Trx-2 is essential for cell viability, playing a crucial role in the scavenging ROS in mitochondria and regulating the mitochondrial apoptosis signaling pathway.

Conformational Regulation of the Essential Epigenetic Regulator UHRF1

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Pantoja Angles, Aaron

2018-05-01

UHRF1 is an essential epigenetic regulator implicated in the maintenance of DNA methylation. While its functional state has been suggested to be allosterically regulated by phosphatidylinositol 5-phosphate and dependent on purification conditions and tags coupled to the protein, the expression system might have a broader impact on UHRF1s interaction properties. We hypothesized that the translation kinetics defined by the expression host has an impact on the folding process of the protein, which ultimately affects its structure and function. To test this idea, the cDNA of UHRF1 was recoded in order to generate optimized and harmonized sequences that were expected to alter the overall translation speed. Both proteins were expressed in Escherichia coli BL21-DE3 and their interaction profiles with H3K9me3 and unmodified H3 peptides were determined by microscale thermophoresis assays. The dissociation constants were compared by ttests in order to evaluate a possible change in the interaction properties of the optimized and harmonized proteins, compared to non-optimized UHRF1 expressed in E. coli BL21-DE3. While no difference was found for the interaction of optimized UHRF1 with the H3K9me3 peptide, a significant difference was found for its interaction with the unmodified H3 peptide. Moreover, both the interactions of harmonized UHRF1 with H3K9me3 and unmodified H3 peptides were determined to change. For this reason, we concluded that translation kinetics dependent on the expression system impacts the functional state of UHRF1. To further study this phenomenon, we expressed the consensus sequence of UHRF1 in Escherichia coli BL21-Codon Plus-(DE3)-RIL, a bacterial strain that is enriched with arginine, isoleucine, and leucine tRNA isoacceptors. Differences in its interaction profile with histone peptides were found when compared with UHRF1 expressed in Escherichia coli BL21-DE3. Since the major difference between these strains is the abundance of tRNAs, we obtained

The metabolic responses to aerial diffusion of essential oils.

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Yani Wu

Full Text Available Anxiety disorders are the most prevalent psychiatric disorders and affect a great number of people worldwide. Essential oils, take effects through inhalation or topical application, are believed to enhance physical, emotional, and spiritual well-being. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of essential oils in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive gas chromatography time-of-flight mass spectrometry (GC-TOFMS based metabonomics study that reveals the aromas-induced metabolic changes and the anxiolytic effect of aromas in elevated plus maze (EPM induced anxiety model rats. The significant alteration of metabolites in the EPM group was attenuated by aromas treatment, concurrent with the behavioral improvement with significantly increased open arms time and open arms entries. Brain tissue and urinary metabonomic analysis identified a number of altered metabolites in response to aromas intervention. These metabolic changes included the increased carbohydrates and lowered levels of neurotransmitters (tryptophan, serine, glycine, aspartate, tyrosine, cysteine, phenylalanine, hypotaurine, histidine, and asparagine, amino acids, and fatty acids in the brain. Elevated aspartate, carbohydrates (sucrose, maltose, fructose, and glucose, nucleosides and organic acids such as lactate and pyruvate were also observed in the urine. The EPM induced metabolic differences observed in urine or brain tissue was significantly reduced after 10 days of aroma inhalation, as noted with the loss of statistical significance on many of the metabolites in the aroma-EPM group. This study demonstrates, for the first time, that the metabonomics approach can capture the subtle metabolic changes resulting from exposure to essential oils

De-novo NAD+ synthesis regulates SIRT1-FOXO1 apoptotic pathway in response to NQO1 substrates in lung cancer cells.

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Liu, Huiying; Xing, Rong; Cheng, Xuefang; Li, Qingran; Liu, Fang; Ye, Hui; Zhao, Min; Wang, Hong; Wang, Guangji; Hao, Haiping

2016-09-20

Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling. Decreased uptake of tryptophan due to the downregulation of LAT1 coordinates with PARP-1 hyperactivation to induce rapid depletion of NAD+ pool. Particularly, the LAT1-NAD+-SIRT1 signaling is activated in tumor tissues of patients with non-small cell lung cancer. Because NQO1 activation is characterized with oxidative challenge induced DNA damage, these results suggest that LAT1 and de-novo NAD+ synthesis in NSCLC cells may play essential roles in sensing excessive oxidative stress.

N-wasp is essential for the negative regulation of B cell receptor signaling.

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Chaohong Liu

2013-11-01

Full Text Available Negative regulation of receptor signaling is essential for controlling cell activation and differentiation. In B-lymphocytes, the down-regulation of B-cell antigen receptor (BCR signaling is critical for suppressing the activation of self-reactive B cells; however, the mechanism underlying the negative regulation of signaling remains elusive. Using genetically manipulated mouse models and total internal reflection fluorescence microscopy, we demonstrate that neuronal Wiskott-Aldrich syndrome protein (N-WASP, which is coexpressed with WASP in all immune cells, is a critical negative regulator of B-cell signaling. B-cell-specific N-WASP gene deletion causes enhanced and prolonged BCR signaling and elevated levels of autoantibodies in the mouse serum. The increased signaling in N-WASP knockout B cells is concurrent with increased accumulation of F-actin at the B-cell surface, enhanced B-cell spreading on the antigen-presenting membrane, delayed B-cell contraction, inhibition in the merger of signaling active BCR microclusters into signaling inactive central clusters, and a blockage of BCR internalization. Upon BCR activation, WASP is activated first, followed by N-WASP in mouse and human primary B cells. The activation of N-WASP is suppressed by Bruton's tyrosine kinase-induced WASP activation, and is restored by the activation of SH2 domain-containing inositol 5-phosphatase that inhibits WASP activation. Our results reveal a new mechanism for the negative regulation of BCR signaling and broadly suggest an actin-mediated mechanism for signaling down-regulation.

Abiotic stress responses in plants: roles of calmodulin-regulated proteins

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Virdi, Amardeep S.; Singh, Supreet; Singh, Prabhjeet

2015-01-01

Intracellular changes in calcium ions (Ca2+) in response to different biotic and abiotic stimuli are detected by various sensor proteins in the plant cell. Calmodulin (CaM) is one of the most extensively studied Ca2+-sensing proteins and has been shown to be involved in transduction of Ca2+ signals. After interacting with Ca2+, CaM undergoes conformational change and influences the activities of a diverse range of CaM-binding proteins. A number of CaM-binding proteins have also been implicated in stress responses in plants, highlighting the central role played by CaM in adaptation to adverse environmental conditions. Stress adaptation in plants is a highly complex and multigenic response. Identification and characterization of CaM-modulated proteins in relation to different abiotic stresses could, therefore, prove to be essential for a deeper understanding of the molecular mechanisms involved in abiotic stress tolerance in plants. Various studies have revealed involvement of CaM in regulation of metal ions uptake, generation of reactive oxygen species and modulation of transcription factors such as CAMTA3, GTL1, and WRKY39. Activities of several kinases and phosphatases have also been shown to be modulated by CaM, thus providing further versatility to stress-associated signal transduction pathways. The results obtained from contemporary studies are consistent with the proposed role of CaM as an integrator of different stress signaling pathways, which allows plants to maintain homeostasis between different cellular processes. In this review, we have attempted to present the current state of understanding of the role of CaM in modulating different stress-regulated proteins and its implications in augmenting abiotic stress tolerance in plants. PMID:26528296

KATNAL1 regulation of sertoli cell microtubule dynamics is essential for spermiogenesis and male fertility.

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Lee B Smith

Full Text Available Spermatogenesis is a complex process reliant upon interactions between germ cells (GC and supporting somatic cells. Testicular Sertoli cells (SC support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation. It is well established that chemical perturbation of SC microtubule remodelling leads to premature GC exfoliation demonstrating that microtubule remodelling is an essential component of male fertility, yet the genes responsible for this process remain unknown. Using a random ENU mutagenesis approach, we have identified a novel mouse line displaying male-specific infertility, due to a point mutation in the highly conserved ATPase domain of the novel KATANIN p60-related microtubule severing protein Katanin p60 subunit A-like1 (KATNAL1. We demonstrate that Katnal1 is expressed in testicular Sertoli cells (SC from 15.5 days post-coitum (dpc and that, consistent with chemical disruption models, loss of function of KATNAL1 leads to male-specific infertility through disruption of SC microtubule dynamics and premature exfoliation of spermatids from the seminiferous epithelium. The identification of KATNAL1 as an essential regulator of male fertility provides a significant novel entry point into advancing our understanding of how SC microtubule dynamics promotes male fertility. Such information will have resonance both for future treatment of male fertility and the development of non-hormonal male contraceptives.

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

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Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.; Issitt, Theo; Ulyatt, Clare; Walker, John H.; Homer-Vanniasinkam, Shervanthi; Ponnambalam, Sreenivasan

2012-01-01

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: ► Endothelial cells mount a stress response under conditions of low serum. ► Endothelial VEGFR levels are

SCF(KMD) controls cytokinin signaling by regulating the degradation of type-B response regulators.

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Kim, Hyo Jung; Chiang, Yi-Hsuan; Kieber, Joseph J; Schaller, G Eric

2013-06-11

Cytokinins are plant hormones that play critical roles in growth and development. In Arabidopsis, the transcriptional response to cytokinin is regulated by action of type-B Arabidopsis response regulators (ARRs). Although central elements in the cytokinin signal transduction pathway have been identified, mechanisms controlling output remain to be elucidated. Here we demonstrate that a family of F-box proteins, called the kiss me deadly (KMD) family, targets type-B ARR proteins for degradation. KMD proteins form an S-phase kinase-associated PROTEIN1 (SKP1)/Cullin/F-box protein (SCF) E3 ubiquitin ligase complex and directly interact with type-B ARR proteins. Loss-of-function KMD mutants stabilize type-B ARRs and exhibit an enhanced cytokinin response. In contrast, plants with elevated KMD expression destabilize type-B ARR proteins leading to cytokinin insensitivity. Our results support a model in which an SCF(KMD) complex negatively regulates cytokinin responses by controlling levels of a key family of transcription factors.

Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem cells through alternative splicing of c-Mpl.

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Xiao, Nan; Laha, Suparna; Das, Shankar P; Morlock, Kayla; Jesneck, Jonathan L; Raffel, Glen D

2015-02-05

Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo. © 2015 by The American Society of Hematology.

Responsiveness to acidity via metal ion regulators mediates virulence in the gastric pathogen Helicobacter pylori.

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Bury-Moné, Stéphanie; Thiberge, Jean-Michel; Contreras, Monica; Maitournam, Aboubakar; Labigne, Agnès; De Reuse, Hilde

2004-07-01

The virulence of pathogenic bacteria is dependent on their adaptation to and survival in the stressful conditions encountered in their hosts. Helicobacter pylori exclusively colonizes the acid stomach of primates, making it an ideal study model. Little is known about how H. pylori responds to the moderately acidic conditions encountered at its colonization site, the gastric mucus layer. Thus, we compared gene expression profiles of H. pylori 26695 grown at neutral and acidic pH, and validated the data for a selection of genes by real-time polymerase chain reaction, dot-blots or enzymatic assays. During growth in acidic conditions, 56 genes were upregulated and 45 genes downregulated. We found that acidity is a signal modulating the expression of several virulence factors. Regulation of genes related to metal ion homeostasis suggests protective mechanisms involving diminished transport and enhanced storage. Genes encoding subunits of the F0F1 ATPase and of a newly identified Na+/H+ antiporter (NhaC-HP0946) were downregulated, revealing that this bacterium uses original mechanisms to control proton entry. Five of the upregulated genes encoded proteins controlling intracellular ammonia synthesis, including urease, amidase and formamidase, underlining the major role of this buffering compound in the protection against acidity in H. pylori. Regulatory networks and transcriptome analysis as well as enzymatic assays implicated two metal-responsive transcriptional regulators (NikR and Fur) and an essential two-component response regulator (HP0166, OmpR-like) as effectors of the H. pylori acid response. Finally, a nikR-fur mutant is attenuated in the mouse model, emphasizing the link between response to acidity, metal metabolism and virulence in this gastric pathogen.

The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance.

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Dib, Leila; Hayek, Peter; Sadek, Helen; Beyrouthy, Berna; Khalaf, Roy A

2008-06-01

Candida albicans is a dimorphic pathogenic fungus that causes mucosal and systemic infections. C. albicans pathogenicity is attributed to its ability to exist in different morphologic states and to respond to stress by up regulating several key genes. DDR48 is a stress-associated gene involved in DNA repair and in response to antifungal drug exposure. One allele of DDR48 was knocked out by homologous recombination that inserted a marker cassette in its position. Furthermore, reintroducing DDR48 on a plasmid created a revertant strain. Strains were grown on filamentation inducing and noninducing media, subjected to an oxidative stress challenge, injected into mice to assess virulence, and assayed for antifungal susceptibility by the E-test method. DDR48 was found to be haploid insufficient and possibly essential, since only a heterozygote, but not a homozygous, null mutant was generated. The mutant was filamentation defective on all hyphal media tested including serum and corn meal agar. Discrepancies in drug resistance profiles also were present: compared with the parental strain, DDR48/ddr48 heterozygote strain was susceptible in a dose-dependent manner to itraconazole and fluconazole and susceptible to ketoconazole. The mutant also appeared to be hypersensitive to a potentially lethal hydrogen peroxide challenge. However, no reduction in virulence of the mutant was observed. The present findings provide evidence that DDR48 is essential for filamentation, stress response, and possibly viability of C. albicans, making it a prime target for antifungal drug design.

The CWI Pathway: Regulation of the Transcriptional Adaptive Response to Cell Wall Stress in Yeast

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Ana Belén Sanz

2017-12-01

Full Text Available Fungi are surrounded by an essential structure, the cell wall, which not only confers cell shape but also protects cells from environmental stress. As a consequence, yeast cells growing under cell wall damage conditions elicit rescue mechanisms to provide maintenance of cellular integrity and fungal survival. Through transcriptional reprogramming, yeast modulate the expression of genes important for cell wall biogenesis and remodeling, metabolism and energy generation, morphogenesis, signal transduction and stress. The yeast cell wall integrity (CWI pathway, which is very well conserved in other fungi, is the key pathway for the regulation of this adaptive response. In this review, we summarize the current knowledge of the yeast transcriptional program elicited to counterbalance cell wall stress situations, the role of the CWI pathway in the regulation of this program and the importance of the transcriptional input received by other pathways. Modulation of this adaptive response through the CWI pathway by positive and negative transcriptional feedbacks is also discussed. Since all these regulatory mechanisms are well conserved in pathogenic fungi, improving our knowledge about them will have an impact in the developing of new antifungal therapies.

The adventitia: essential regulator of vascular wall structure and function.

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Stenmark, Kurt R; Yeager, Michael E; El Kasmi, Karim C; Nozik-Grayck, Eva; Gerasimovskaya, Evgenia V; Li, Min; Riddle, Suzette R; Frid, Maria G

2013-01-01

The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is composed of a variety of cells, including fibroblasts, immunomodulatory cells (dendritic cells and macrophages), progenitor cells, vasa vasorum endothelial cells and pericytes, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to influence the tone and structure of the vessel wall; to initiate and perpetuate chronic vascular inflammation; and to stimulate expansion of the vasa vasorum, which can act as a conduit for continued inflammatory and progenitor cell delivery to the vessel wall. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in.

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

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Baker, Anna W.; Satyshur, Kenneth A.; Morales, Neydis Moreno; Forest, Katrina T. (UW)

2016-02-01

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 bacteriumRamlibacter 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, theR. tataouinensisbacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR fromAgrobacterium 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 (RtBRR_mon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems.

p53- and ERK7-dependent ribosome surveillance response regulates Drosophila insulin-like peptide secretion.

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Kiran Hasygar

2014-11-01

Full Text Available Insulin-like signalling is a conserved mechanism that coordinates animal growth and metabolism with nutrient status. In Drosophila, insulin-producing median neurosecretory cells (IPCs regulate larval growth by secreting insulin-like peptides (dILPs in a diet-dependent manner. Previous studies have shown that nutrition affects dILP secretion through humoral signals derived from the fat body. Here we uncover a novel mechanism that operates cell autonomously in the IPCs to regulate dILP secretion. We observed that impairment of ribosome biogenesis specifically in the IPCs strongly inhibits dILP secretion, which consequently leads to reduced body size and a delay in larval development. This response is dependent on p53, a known surveillance factor for ribosome biogenesis. A downstream effector of this growth inhibitory response is an atypical MAP kinase ERK7 (ERK8/MAPK15, which is upregulated in the IPCs following impaired ribosome biogenesis as well as starvation. We show that ERK7 is sufficient and essential to inhibit dILP secretion upon impaired ribosome biogenesis, and it acts epistatically to p53. Moreover, we provide evidence that p53 and ERK7 contribute to the inhibition of dILP secretion upon starvation. Thus, we conclude that a cell autonomous ribosome surveillance response, which leads to upregulation of ERK7, inhibits dILP secretion to impede tissue growth under limiting dietary conditions.

Essential role of TGF-beta/Smad pathway on statin dependent vascular smooth muscle cell regulation.

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Juan Rodríguez-Vita

Full Text Available BACKGROUND: The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells. METHODOLOGY: In cultured vascular smooth muscle cells (VSMCs statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII, and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-beta/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected. CONCLUSIONS: Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs.

Providing frequency regulation reserve services using demand response scheduling

International Nuclear Information System (INIS)

Motalleb, Mahdi; Thornton, Matsu; Reihani, Ehsan; Ghorbani, Reza

2016-01-01

Highlights: • Proposing a market model for contingency reserve services using demand response. • Considering transient limitations of grid frequency for inverter-based generations. • Price-sensitive scheduling of residential batteries and water heaters using dynamic programming. • Calculating the profits of both generation companies and demand response aggregators. - Abstract: During power grid contingencies, frequency regulation is a primary concern. Historically, frequency regulation during contingency events has been the sole responsibility of the power utility. We present a practical method of using distributed demand response scheduling to provide frequency regulation during contingency events. This paper discusses the implementation of a control system model for the use of distributed energy storage systems such as battery banks and electric water heaters as a source of ancillary services. We present an algorithm which handles the optimization of demand response scheduling for normal operation and during contingency events. We use dynamic programming as an optimization tool. A price signal is developed using optimal power flow calculations to determine the locational marginal price of electricity, while sensor data for water usage is also collected. Using these inputs to dynamic programming, the optimal control signals are given as output. We assume a market model in which distributed demand response resources are sold as a commodity on the open market and profits from demand response aggregators as brokers of distributed demand response resources can be calculated. In considering control decisions for regulation of transient changes in frequency, we focus on IEEE standard 1547 in order to prevent the safety shut-off of inverter-based generation and further exacerbation of frequency droop. This method is applied to IEEE case 118 as a demonstration of the method in practice.

The Cish SH2 domain is essential for PLC-γ1 regulation in TCR stimulated CD8+ T cells.

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Guittard, Geoffrey; Dios-Esponera, Ana; Palmer, Douglas C; Akpan, Itoro; Barr, Valarie A; Manna, Asit; Restifo, Nicholas P; Samelson, Lawrence E

2018-03-28

Cish, participates within a multi-molecular E3 ubiquitin ligase complex, which ubiquitinates target proteins. It has an inhibitory effect on T cell activation mediated by PLC-γ1 regulation, and it functions as a potent checkpoint in CD8 + T cell tumor immunotherapy. To study the structural and functional relationships between Cish and PLC-γ1 during CD8 + T cell activation, we tested mutants of the Cish-SH2 (R107K) and D/BC (L222Q, C226Q) domains. We confirmed that Cish-SH2-specific binding was essential for PLC-γ1 ubiquitination and degradation. This domain was essential for the Cish-mediated inhibition of Ca 2+ release upon TCR stimulation. No effect on inhibition of cytokine release was observed with SH2 or D/BC mutants, although the absence of Cish led to an increased release of IFN-γ and TNF-α. Using imaging we showed that Cish was expressed mostly in the cytoplasm and we did not see any Cish clustering at the plasma membrane upon stimulation. We conclude that the Cish-SH2 domain is essential for PLC-γ1 regulation in TCR-stimulated CD8 + T cells.

Association genetics and transcriptome analysis reveal a gibberellin-responsive pathway involved in regulating photosynthesis.

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Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang

2016-05-01

Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights

NPY/AgRP neurons are not essential for feeding responses to glucoprivation.

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Luquet, Serge; Phillips, Colin T; Palmiter, Richard D

2007-02-01

Animals respond to hypoglycemia by eating and by stimulating gluconeogenesis. These responses to glucose deprivation are initiated by glucose-sensing neurons in the brain, but the neural circuits that control feeding behavior are not well established. Neurons in the arcuate region of the hypothalamus that express neuropeptide Y (NPY) and agouti-related protein (AgRP) have been implicated in mediating the feeding response to glucoprivation. We devised a method to selectively ablate these neurons in neonatal mice and then tested adult mice for their feeding responses to fasting, mild hypoglycemia, 2-deoxy-d-glucose and a ghrelin receptor agonist. Whereas the feeding response to the ghrelin receptor agonist was completely abrogated, the feeding response to glucoprivation was normal. The feeding response after a fast was attenuated when standard chow was available but normal with more palatable solid or liquid diet. We conclude that NPY/AgRP neurons are not necessary for generating or mediating the orexigenic response to glucose deficiency, but they are essential for the feeding response to ghrelin and refeeding on standard chow after a fast.

Phosphorylation of Nanog is Essential to Regulate Bmi1 and Promote Tumorigenesis

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Xie, Xiujie; Piao, Longzhu; Cavey, Greg S.; Old, Matthew; Teknos, Theodoros N.; Mapp, Anna K; Pan, Quintin

2014-01-01

Emerging evidence indicates that Nanog is intimately involved in tumorigenesis in part through regulation of the cancer initiating cell population. However, the regulation and role of Nanog in tumorigenesis are still poorly understood. In this study, human Nanog was identified to be phosphorylated by human PKCε at multiple residues including T200 and T280. Our work indicated that phosphorylation at T200 and T280 modulates Nanog function through several regulatory mechanisms. Results with phosphorylation-insensitive and phosphorylation-mimetic mutant Nanog revealed that phosphorylation at T200 and T280 enhance Nanog protein stability. Moreover, phosphorylation-insensitive T200A and T280A mutant Nanog had a dominant-negative function to inhibit endogenous Nanog transcriptional activity. Inactivation of Nanog was due to impaired homodimerization, DNA binding, promoter occupancy, and p300, a transcriptional co-activator, recruitment resulting in a defect in target gene promoter activation. Ectopic expression of phosphorylation-insensitive T200A or T280A mutant Nanog reduced cell proliferation, colony formation, invasion, migration, and the cancer initiating cell population in head and neck squamous cell carcinoma (HNSCC) cells. The in vivo cancer initiating ability was severely compromised in HNSCC cells expressing phosphorylation-insensitive T200A or T280A mutant Nanog; 87.5% (14/16), 12.5% (1/8), and 0% (0/8) for control, T200A, and T280A, respectively. Nanog occupied the Bmi1 promoter to directly transactivate and regulate Bmi1. Genetic ablation and rescue experiments demonstrated that Bmi1 is a critical downstream signaling node for the pleiotropic, pro-oncogenic effects of Nanog. Taken together, our study revealed, for the first time, that post-translational phosphorylation of Nanog is essential to regulate Bmi1 and promote tumorigenesis. PMID:23708658

Emotion regulation reduces loss aversion and decreases amygdala responses to losses.

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Sokol-Hessner, Peter; Camerer, Colin F; Phelps, Elizabeth A

2013-03-01

Emotion regulation strategies can alter behavioral and physiological responses to emotional stimuli and the neural correlates of those responses in regions such as the amygdala or striatum. The current study investigates the brain systems engaged when using an emotion regulation technique during financial decisions. In decision making, regulating emotion with reappraisal-focused strategies that encourage taking a different perspective has been shown to reduce loss aversion as observed both in choices and in the relative arousal responses to actual loss and gain outcomes. In the current study, we find using fMRI that behavioral loss aversion correlates with amygdala activity in response to losses relative to gains. Success in regulating loss aversion also correlates with the reduction in amygdala responses to losses but not to gains. Furthermore, across both decisions and outcomes, we find the reappraisal strategy increases baseline activity in dorsolateral and ventromedial prefrontal cortex and the striatum. The similarity of the neural circuitry observed to that seen in emotion regulation, despite divergent tasks, serves as further evidence for a role of emotion in decision making, and for the power of reappraisal to change assessments of value and thereby choices.

EIN2 mediates direct regulation of histone acetylation in the ethylene response.

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Zhang, Fan; Wang, Likai; Qi, Bin; Zhao, Bo; Ko, Eun Esther; Riggan, Nathaniel D; Chin, Kevin; Qiao, Hong

2017-09-19

Ethylene gas is essential for developmental processes and stress responses in plants. Although the membrane-bound protein EIN2 is critical for ethylene signaling, the mechanism by which the ethylene signal is transduced remains largely unknown. Here we show the levels of H3K14Ac and H3K23Ac are correlated with the levels of EIN2 protein and demonstrate EIN2 C terminus (EIN2-C) is sufficient to rescue the levels of H3K14/23Ac of ein2 -5 at the target loci, using CRISPR/dCas9-EIN2-C. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) and ChIP-reChIP-seq analyses revealed that EIN2-C associates with histone partially through an interaction with EIN2 nuclear-associated protein1 (ENAP1), which preferentially binds to the genome regions that are associated with actively expressed genes both with and without ethylene treatments. Specifically, in the presence of ethylene, ENAP1-binding regions are more accessible upon the interaction with EIN2, and more EIN3 proteins bind to the loci where ENAP1 is enriched for a quick response. Together, these results reveal EIN2-C is the key factor regulating H3K14Ac and H3K23Ac in response to ethylene and uncover a unique mechanism by which ENAP1 interacts with chromatin, potentially preserving the open chromatin regions in the absence of ethylene; in the presence of ethylene, EIN2 interacts with ENAP1, elevating the levels of H3K14Ac and H3K23Ac, promoting more EIN3 binding to the targets shared with ENAP1 and resulting in a rapid transcriptional regulation.

Ethylene response factor AtERF72 negatively regulates Arabidopsis thaliana response to iron deficiency.

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Liu, Wei; Li, Qiwei; Wang, Yi; Wu, Ting; Yang, Yafei; Zhang, Xinzhong; Han, Zhenhai; Xu, Xuefeng

2017-09-23

Ethylene regulates the plant's response to stress caused by iron (Fe) deficiency. However, specific roles of ERF proteins in response to Fe deficiency remain poorly understood. Here, we investigated the role of ERF72 in response to iron deficiency in Arabidopsis thaliana. In this study, the levels of the ethylene response factor AtERF72 increased in leaves and roots induced under the iron deficient conditions. erf72 mutant plants showed increased growth compared to wild type (WT) when grown in iron deficient medium for 5 d. erf72 mutants had increased root H + velocity and the ferric reductase activity, and increase in the expression of the iron deficiency response genes iron-regulated transporter 1 (IRT1) and H + -ATPase (HA2) levels in iron deficient conditions. Compared to WT plants, erf72 mutants retained healthy chloroplast structure with significantly higher Fe and Mg content, and decreased chlorophyll degradation gene pheophorbide a oxygenase (PAO) and chlorophyllase (CLH1) expression when grown in iron deficient media. Yeast one-hybrid analysis showed that ERF72 could directly bind to the promoter regions of iron deficiency responses genes IRT1, HA2 and CLH1. Based on our results, we suggest that ethylene released from plants under iron deficiency stress can activate the expression of ERF72, which responds to iron deficiency in the negative regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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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.

Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis.

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Felsted, Jennifer A; Chien, Cheng-Hao; Wang, Dongqing; Panessiti, Micaella; Ameroso, Dominique; Greenberg, Andrew; Feng, Guoping; Kong, Dong; Rios, Maribel

2017-12-05

The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1 + neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The essential aspect in sewerage regulation in Indonesia

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Siami, L.

2018-01-01

Several cities in Indonesia have the sewerage local regulation such as Banjarmasin, Bantul, Surakarta and Denpasar. Meanwhile, The National Government have guideline in composing domestic sewerage regulation. Each city have their own characteristic and issues that need to be carried out by the local regulation. By using SWOT analysis, this study tries to figure out several aspect that need to be included in the local regulation. International references from developed and developing countries like Japan, Phillipines, Malaysia and Thailand were also used as benchmark without neglecting the local conditions of cities in Indonesia. Several crucial aspect of local regulation are institutional authority, composition on-site and off-site system, tariff, evaluation and monitoring, as well as punishment and rewards. Both tariff and evaluation aspects need to be narrowed down into specific regulations.

Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

Directory of Open Access Journals (Sweden)

Jennifer A. Felsted

2017-12-01

Full Text Available Summary: The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1 neurons of the ventromedial hypothalamus (VMH. These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease. : Felsted et al. show a required role of the calcium channel subunit and thrombospondin receptor α2δ-1 in regulating glucose and lipid homeostasis in the ventromedial hypothalamus (VMH. These effects are caused by regulation of SF1+ neuronal activity in the VMH through non-canonical mechanisms and concomitant influences on sympathetic output. Keywords: diabetes, VMH, hypothalamus, glucose, norepinephrine, serotonin, excitability, lipid, SF1

CCR6-dependent positioning of memory B cells is essential for their ability to mount a recall response to antigen

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Elgueta, Raul; Marks, Ellen; Nowak, Elizabeth; Menezes, Shinelle; Benson, Micah; Raman, Vanitha S.; Ortiz, Carla; O’Connell, Samuel; Hess, Henry; Lord, Graham M.; Noelle, Randolph

2014-01-01

Chemokine-dependent localization of specific B cell subsets within the immune microarchitecture is essential to insure successful cognate interactions. While cognate interactions between T cells and memory B cells (Bmem)5 are essential for the secondary humoral immune responses, the chemokine response patterns of Bmem cells are largely unknown. In contrast to naïve B cells, this study shows that antigen-specific Bmem cells have heightened expression of CCR6 and a selective chemotactic response to the CCR6 ligand, CCL20. While CCR6 appears be non-essential for the initial clonal expansion and maintenance of Bmem, CCR6 is essential for the ability of Bmem to respond to a recall response to their cognate antigen. This dependency was deemed intrinsic by studies in CCR6-deficient mice and in bone-marrow chimeric mice where CCR6 deficiency was limited to the B cell lineage. Finally, the mis-positioning of CCR6-deficient Bmem was revealed by immunohistological analysis with an altered distribution of CCR6-deficient Bmem from the marginal and perifollicular to the follicular/germinal center area. PMID:25505290

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.

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

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Khairnar, Vishal; Duhan, Vikas; Maney, Sathish Kumar; Honke, Nadine; Shaabani, Namir; Pandyra, Aleksandra A.; Seifert, Marc; Pozdeev, Vitaly; Xu, Haifeng C.; Sharma, Piyush; Baldin, Fabian; Marquardsen, Florian; Merches, Katja; Lang, Elisabeth; Kirschning, Carsten; Westendorf, Astrid M.; Häussinger, Dieter; Lang, Florian; Dittmer, Ulf; Küppers, Ralf; Recher, Mike; Hardt, Cornelia; Scheffrahn, Inka; Beauchemin, Nicole; Göthert, Joachim R.; Singer, Bernhard B.; Lang, Philipp A.; Lang, Karl S.

2015-01-01

B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1−/− mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1−/− mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses. PMID:25692415

The Nutrient-Responsive Hormone CCHamide-2 Controls Growth by Regulating Insulin-like Peptides in the Brain of Drosophila melanogaster.

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Sano, Hiroko; Nakamura, Akira; Texada, Michael J; Truman, James W; Ishimoto, Hiroshi; Kamikouchi, Azusa; Nibu, Yutaka; Kume, Kazuhiko; Ida, Takanori; Kojima, Masayasu

2015-05-01

The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. Here, we show that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet β-cells; however, the role of Brs3 in insulin regulation remains elusive. Our genetic approach in Drosophila melanogaster provides the first evidence, to our knowledge, that bombesin receptor signaling with its endogenous ligand promotes insulin production.

The Sexual Dimorphism of Dietary Restriction Responsiveness in Caenorhabditis elegans

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Sakiko Honjoh

2017-12-01

Full Text Available Organismal lifespan is highly plastic in response to environmental cues, and dietary restriction (DR is the most robust way to extend lifespan in various species. Recent studies have shown that sex also is an important factor for lifespan regulation; however, it remains largely unclear how these two factors, food and sex, interact in lifespan regulation. The nematode Caenorhabditis elegans has two sexes, hermaphrodite and male, and only the hermaphrodites are essential for the short-term succession of the species. Here, we report an extreme sexual dimorphism in the responsiveness to DR in C. elegans; the essential hermaphrodites show marked longevity responses to various forms of DR, but the males show few longevity responses and sustain reproductive ability. Our analysis reveals that the sex determination pathway and the steroid hormone receptor DAF-12 regulate the sex-specific DR responsiveness, integrating sex and environmental cues to determine organismal lifespan.

mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival

International Nuclear Information System (INIS)

Feng, Yonghuai; Wu, Liusong

2017-01-01

Although mTOR (mammalian target of rapamycin) activation is frequently observed in acute myeloid leukemia (AML) patients, the precise function and the downstream targets of mTOR are poorly understood. Here we revealed that PFKFB3, but not PFKFB1, PFKFB2 nor PFKFB4 was a novel downstream substrate of mTOR signaling pathway as PFKFB3 level was augmented after knocking down TSC2 in THP1 and OCI-AML3 cells. Importantly, PFKFB3 silencing suppressed glycolysis and cell proliferation of TSC2 silencing OCI-AML3 cells and activated apoptosis pathway. These results suggested that mTOR up-regulation of PFKFB3 was essential for AML cells survival. Mechanistically, Rapamycin treatment or Raptor knockdown reduced the expression of PFKFB3 in TSC2 knockdown cells, while Rictor silencing did not have such effect. Furthermore, we also revealed that mTORC1 up-regulated PFKFB3 was dependent on hypoxia-inducible factor 1α (HIF1α), a positive regulator of glycolysis. Moreover, PFKFB3 inhibitor PFK15 and rapamycin synergistically blunted the AML cell proliferation. Taken together, PFKFB3 was a promising drug target in AML patients harboring mTOR hyper-activation.

Linking Maternal Warmth and Responsiveness to Children's Self-Regulation

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

2011-01-01

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…

The MurC ligase essential for peptidoglycan biosynthesis is regulated by the serine/threonine protein kinase PknA in Corynebacterium glutamicum.

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Fiuza, Maria; Canova, Marc J; Patin, Delphine; Letek, Michal; Zanella-Cléon, Isabelle; Becchi, Michel; Mateos, Luís M; Mengin-Lecreulx, Dominique; Molle, Virginie; Gil, José A

2008-12-26

The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (L-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recently emerged as a major physiological mechanism of regulation in prokaryotes. Herein, the hypothesis of a phosphorylation-dependent mechanism of regulation of the MurC activity was investigated in Corynebacterium glutamicum. We showed that MurC was phosphorylated in vitro by the PknA protein kinase. An analysis of the phosphoamino acid content indicated that phosphorylation exclusively occurred on threonine residues. Six phosphoacceptor residues were identified by mass spectrometry analysis, and we confirmed that mutagenesis to alanine residues totally abolished PknA-dependent phosphorylation of MurC. In vitro and in vivo ligase activity assays showed that the catalytic activity of MurC was impaired following mutation of these threonine residues. Further in vitro assays revealed that the activity of the MurC-phosphorylated isoform was severely decreased compared with the non-phosphorylated protein. To our knowledge, this is the first demonstration of a MurC ligase phosphorylation in vitro. The finding that phosphorylation is correlated with a decrease in MurC enzymatic activity could have significant consequences in the regulation of peptidoglycan biosynthesis.

The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

KAUST Repository

Yunta, Cristina; Martí nez-Ripoll, Martí n; Zhu, Jian-Kang; Albert, Armando

2011-01-01

SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

The structure of arabidopsis thaliana OST1 provides insights into the kinase regulation mechanism in response to osmotic stress

KAUST Repository

Yunta, Cristina

2011-11-01

SnRK [SNF1 (sucrose non-fermenting-1)-related protein kinase] 2.6 [open stomata 1 (OST1)] is well characterized at molecular and physiological levels to control stomata closure in response to water-deficit stress. OST1 is a member of a family of 10 protein kinases from Arabidopsis thaliana (SnRK2) that integrates abscisic acid (ABA)-dependent and ABA-independent signals to coordinate the cell response to osmotic stress. A subgroup of protein phosphatases type 2C binds OST1 and keeps the kinase dephosphorylated and inactive. Activation of OST1 relies on the ABA-dependent inhibition of the protein phosphatases type 2C and the subsequent self-phosphorylation of the kinase. The OST1 ABA-independent activation depends on a short sequence motif that is conserved among all the members of the SnRK2 family. However, little is known about the molecular mechanism underlying this regulation. The crystallographic structure of OST1 shows that ABA-independent regulation motif stabilizes the conformation of the kinase catalytically essential α C helix, and it provides the basis of the ABA-independent regulation mechanism for the SnRK2 family of protein kinases. © 2011 Elsevier Ltd. All rights reserved.

ICK is essential for cell type-specific ciliogenesis and the regulation of ciliary transport.

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Chaya, Taro; Omori, Yoshihiro; Kuwahara, Ryusuke; Furukawa, Takahisa

2014-06-02

Cilia and flagella are formed and maintained by intraflagellar transport (IFT) and play important roles in sensing and moving across species. At the distal tip of the cilia/flagella, IFT complexes turn around to switch from anterograde to retrograde transport; however, the underlying regulatory mechanism is unclear. Here, we identified ICK localization at the tip of cilia as a regulator of ciliary transport. In ICK-deficient mice, we found ciliary defects in neuronal progenitor cells with Hedgehog signal defects. ICK-deficient cells formed cilia with mislocalized Hedgehog signaling components. Loss of ICK caused the accumulation of IFT-A, IFT-B, and BBSome components at the ciliary tips. In contrast, overexpression of ICK induced the strong accumulation of IFT-B, but not IFT-A or BBSome components at ciliary tips. In addition, ICK directly phosphorylated Kif3a, while inhibition of this Kif3a phosphorylation affected ciliary formation. Our results suggest that ICK is a Kif3a kinase and essential for proper ciliogenesis in development by regulating ciliary transport at the tip of cilia. © 2014 The Authors.

Ser/Thr Phosphorylation Regulates the Fatty Acyl-AMP Ligase Activity of FadD32, an Essential Enzyme in Mycolic Acid Biosynthesis*

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Le, Nguyen-Hung; Molle, Virginie; Eynard, Nathalie; Miras, Mathieu; Stella, Alexandre; Bardou, Fabienne; Galandrin, Ségolène; Guillet, Valérie; André-Leroux, Gwenaëlle; Bellinzoni, Marco; Alzari, Pedro; Mourey, Lionel; Burlet-Schiltz, Odile; Daffé, Mamadou; Marrakchi, Hedia

2016-01-01

Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is a well known source of antituberculous drug targets. Among the promising new targets in the pathway, FadD32 is an essential enzyme required for the activation of the long meromycolic chain of mycolic acids and is essential for mycobacterial growth. Following the in-depth biochemical, biophysical, and structural characterization of FadD32, we investigated its putative regulation via post-translational modifications. Comparison of the fatty acyl-AMP ligase activity between phosphorylated and dephosphorylated FadD32 isoforms showed that the native protein is phosphorylated by serine/threonine protein kinases and that this phosphorylation induced a significant loss of activity. Mass spectrometry analysis of the native protein confirmed the post-translational modifications and identified Thr-552 as the phosphosite. Phosphoablative and phosphomimetic FadD32 mutant proteins confirmed both the position and the importance of the modification and its correlation with the negative regulation of FadD32 activity. Investigation of the mycolic acid condensation reaction catalyzed by Pks13, involving FadD32 as a partner, showed that FadD32 phosphorylation also impacts the condensation activity. Altogether, our results bring to light FadD32 phosphorylation by serine/threonine protein kinases and its correlation with the enzyme-negative regulation, thus shedding a new horizon on the mycolic acid biosynthesis modulation and possible inhibition strategies for this promising drug target. PMID:27590338

Insight in the multilevel regulation of NER

DEFF Research Database (Denmark)

Dijk, Madelon; Typas, Dimitris; Mullenders, Leon

2014-01-01

Nucleotide excision repair (NER) is a key component of the DNA damage response (DDR) and it is essential to safeguard genome integrity against genotoxic insults. The regulation of NER is primarily mediated by protein post-translational modifications (PTMs). The NER machinery removes a wide spectr...

Local and global responses in complex gene regulation networks

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Tsuchiya, Masa; Selvarajoo, Kumar; Piras, Vincent; Tomita, Masaru; Giuliani, Alessandro

2009-04-01

An exacerbated sensitivity to apparently minor stimuli and a general resilience of the entire system stay together side-by-side in biological systems. This apparent paradox can be explained by the consideration of biological systems as very strongly interconnected network systems. Some nodes of these networks, thanks to their peculiar location in the network architecture, are responsible for the sensitivity aspects, while the large degree of interconnection is at the basis of the resilience properties of the system. One relevant feature of the high degree of connectivity of gene regulation networks is the emergence of collective ordered phenomena influencing the entire genome and not only a specific portion of transcripts. The great majority of existing gene regulation models give the impression of purely local ‘hard-wired’ mechanisms disregarding the emergence of global ordered behavior encompassing thousands of genes while the general, genome wide, aspects are less known. Here we address, on a data analysis perspective, the discrimination between local and global scale regulations, this goal was achieved by means of the examination of two biological systems: innate immune response in macrophages and oscillating growth dynamics in yeast. Our aim was to reconcile the ‘hard-wired’ local view of gene regulation with a global continuous and scalable one borrowed from statistical physics. This reconciliation is based on the network paradigm in which the local ‘hard-wired’ activities correspond to the activation of specific crucial nodes in the regulation network, while the scalable continuous responses can be equated to the collective oscillations of the network after a perturbation.

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

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Zhou, Jibin; Lal, Hind; Chen, Xiongwen; Shang, Xiying; Song, Jianliang; Li, Yingxin; Kerkela, Risto; Doble, Bradley W.; MacAulay, Katrina; DeCaul, Morgan; Koch, Walter J.; Farber, John; Woodgett, James; Gao, Erhe; Force, Thomas

2010-01-01

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, α and β. Although GSK-3β has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3α in the mouse heart using gene targeting. Gsk3a–/– mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired β-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3α appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of β-adrenergic responsiveness. In the absence of GSK-3α, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of β-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3. PMID:20516643

Regulation of protein translation initiation in response to ionizing radiation

International Nuclear Information System (INIS)

Trivigno, Donatella; Bornes, Laura; Huber, Stephan M; Rudner, Justine

2013-01-01

Proliferating tumor cells require continuous protein synthesis. De novo synthesis of most proteins is regulated through cap-dependent translation. Cellular stress such as ionizing radiation (IR) blocks cap-dependent translation resulting in shut-down of global protein translation which saves resources and energy needed for the stress response. At the same time, levels of proteins required for stress response are maintained or even increased. The study aimed to analyze the regulation of signaling pathways controlling protein translation in response to IR and the impact on Mcl-1, an anti-apoptotic and radioprotective protein, which levels rapidly decline upon IR. Protein levels and processing were analyzed by Western blot. The assembly of the translational pre-initiation complex was examined by Immunoprecipitation and pull-down experiments with 7-methyl GTP agarose. To analyze IR-induced cell death, dissipation of the mitochondrial membrane potential and DNA fragmentation were determined by flow cytometry. Protein levels of the different initiation factors were down-regulated using RNA interference approach. IR induced caspase-dependent cleavage of the translational initiation factors eIF4G1, eIF3A, and eIF4B resulting in disassembly of the cap-dependent initiation complex. In addition, DAP5-dependent initiation complex that regulates IRES-dependent translation was disassembled in response to IR. Moreover, IR resulted in dephosphorylation of 4EBP1, an inhibitor of cap-dependent translation upstream of caspase activation. However, knock-down of eIF4G1, eIF4B, DAP5, or 4EBP1 did not affect IR-induced decline of the anti-apoptotic protein Mcl-1. Our data shows that cap-dependent translation is regulated at several levels in response to IR. However, the experiments indicate that IR-induced Mcl-1 decline is not a consequence of translational inhibition in Jurkat cells

Regulation of protein translation initiation in response to ionizing radiation

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Trivigno Donatella

2013-02-01

Full Text Available Abstract Background Proliferating tumor cells require continuous protein synthesis. De novo synthesis of most proteins is regulated through cap-dependent translation. Cellular stress such as ionizing radiation (IR blocks cap-dependent translation resulting in shut-down of global protein translation which saves resources and energy needed for the stress response. At the same time, levels of proteins required for stress response are maintained or even increased. The study aimed to analyze the regulation of signaling pathways controlling protein translation in response to IR and the impact on Mcl-1, an anti-apoptotic and radioprotective protein, which levels rapidly decline upon IR. Methods Protein levels and processing were analyzed by Western blot. The assembly of the translational pre-initiation complex was examined by Immunoprecipitation and pull-down experiments with 7-methyl GTP agarose. To analyze IR-induced cell death, dissipation of the mitochondrial membrane potential and DNA fragmentation were determined by flow cytometry. Protein levels of the different initiation factors were down-regulated using RNA interference approach. Results IR induced caspase-dependent cleavage of the translational initiation factors eIF4G1, eIF3A, and eIF4B resulting in disassembly of the cap-dependent initiation complex. In addition, DAP5-dependent initiation complex that regulates IRES-dependent translation was disassembled in response to IR. Moreover, IR resulted in dephosphorylation of 4EBP1, an inhibitor of cap-dependent translation upstream of caspase activation. However, knock-down of eIF4G1, eIF4B, DAP5, or 4EBP1 did not affect IR-induced decline of the anti-apoptotic protein Mcl-1. Conclusion Our data shows that cap-dependent translation is regulated at several levels in response to IR. However, the experiments indicate that IR-induced Mcl-1 decline is not a consequence of translational inhibition in Jurkat cells.

Comments on Interior’s Surface Mining Regulations.

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1981-08-05

regulations and responses to pro- posed regulati n, (2) identified studies on cost/benefit analy- sis of environme ital regulations and selected ...agricultural production at the national level, in some rural counties essentially the entire area is underlain with strippable coal. obviously, surface mining...1980).) Illinois, which has the most strippable coal reserves underlying prime farmland, has two heavily worked coal seams which are continuous. One

Cognitive emotion regulation enhances aversive prediction error activity while reducing emotional responses.

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Mulej Bratec, Satja; Xie, Xiyao; Schmid, Gabriele; Doll, Anselm; Schilbach, Leonhard; Zimmer, Claus; Wohlschläger, Afra; Riedl, Valentin; Sorg, Christian

2015-12-01

Cognitive emotion regulation is a powerful way of modulating emotional responses. However, despite the vital role of emotions in learning, it is unknown whether the effect of cognitive emotion regulation also extends to the modulation of learning. Computational models indicate prediction error activity, typically observed in the striatum and ventral tegmental area, as a critical neural mechanism involved in associative learning. We used model-based fMRI during aversive conditioning with and without cognitive emotion regulation to test the hypothesis that emotion regulation would affect prediction error-related neural activity in the striatum and ventral tegmental area, reflecting an emotion regulation-related modulation of learning. Our results show that cognitive emotion regulation reduced emotion-related brain activity, but increased prediction error-related activity in a network involving ventral tegmental area, hippocampus, insula and ventral striatum. While the reduction of response activity was related to behavioral measures of emotion regulation success, the enhancement of prediction error-related neural activity was related to learning performance. Furthermore, functional connectivity between the ventral tegmental area and ventrolateral prefrontal cortex, an area involved in regulation, was specifically increased during emotion regulation and likewise related to learning performance. Our data, therefore, provide first-time evidence that beyond reducing emotional responses, cognitive emotion regulation affects learning by enhancing prediction error-related activity, potentially via tegmental dopaminergic pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

Dynamic Nature of Noncoding RNA Regulation of Adaptive Immune Response

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Franca Citarella

2013-08-01

Full Text Available Immune response plays a fundamental role in protecting the organism from infections; however, dysregulation often occurs and can be detrimental for the organism, leading to a variety of immune-mediated diseases. Recently our understanding of the molecular and cellular networks regulating the immune response, and, in particular, adaptive immunity, has improved dramatically. For many years, much of the focus has been on the study of protein regulators; nevertheless, recent evidence points to a fundamental role for specific classes of noncoding RNAs (ncRNAs in regulating development, activation and homeostasis of the immune system. Although microRNAs (miRNAs are the most comprehensive and well-studied, a number of reports suggest the exciting possibility that long ncRNAs (lncRNAs could mediate host response and immune function. Finally, evidence is also accumulating that suggests a role for miRNAs and other small ncRNAs in autocrine, paracrine and exocrine signaling events, thus highlighting an elaborate network of regulatory interactions mediated by different classes of ncRNAs during immune response. This review will explore the multifaceted roles of ncRNAs in the adaptive immune response. In particular, we will focus on the well-established role of miRNAs and on the emerging role of lncRNAs and circulating ncRNAs, which all make indispensable contributions to the understanding of the multilayered modulation of the adaptive immune response.

S6K1 in the central nervous system regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid.

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Xia, Tingting; Cheng, Ying; Zhang, Qian; Xiao, Fei; Liu, Bin; Chen, Shanghai; Guo, Feifan

2012-10-01

It is well established that the central nervous system (CNS), especially the hypothalamus, plays an important role in regulating energy homeostasis and lipid metabolism. We have previously shown that hypothalamic corticotropin-releasing hormone (CRH) is critical for stimulating fat loss in response to dietary leucine deprivation. The molecular mechanisms underlying the CNS regulation of leucine deprivation-stimulated fat loss are, however, still largely unknown. Here, we used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6 kinase 1 (S6K1), a major downstream effector of the kinase mammalian target of rapamycin, in leucine deprivation stimulation of energy expenditure. Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor-dependent manner. Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals.

Enhancing forest tenure reforms through more responsive regulations

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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.

Jasmonate-responsive transcription factors regulating plant secondary metabolism.

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Zhou, Meiliang; Memelink, Johan

2016-01-01

Plants produce a large variety of secondary metabolites including alkaloids, glucosinolates, terpenoids and phenylpropanoids. These compounds play key roles in plant-environment interactions and many of them have pharmacological activity in humans. Jasmonates (JAs) are plant hormones which induce biosynthesis of many secondary metabolites. JAs-responsive transcription factors (TFs) that regulate the JAs-induced accumulation of secondary metabolites belong to different families including AP2/ERF, bHLH, MYB and WRKY. Here, we give an overview of the types and functions of TFs that have been identified in JAs-induced secondary metabolite biosynthesis, and highlight their similarities and differences in regulating various biosynthetic pathways. We review major recent developments regarding JAs-responsive TFs mediating secondary metabolite biosynthesis, and provide suggestions for further studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Metagenomic screening for aromatic compound-responsive transcriptional regulators.

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Taku Uchiyama

Full Text Available We applied a metagenomics approach to screen for transcriptional regulators that sense aromatic compounds. The library was constructed by cloning environmental DNA fragments into a promoter-less vector containing green fluorescence protein. Fluorescence-based screening was then performed in the presence of various aromatic compounds. A total of 12 clones were isolated that fluoresced in response to salicylate, 3-methyl catechol, 4-chlorocatechol and chlorohydroquinone. Sequence analysis revealed at least 1 putative transcriptional regulator, excluding 1 clone (CHLO8F. Deletion analysis identified compound-specific transcriptional regulators; namely, 8 LysR-types, 2 two-component-types and 1 AraC-type. Of these, 9 representative clones were selected and their reaction specificities to 18 aromatic compounds were investigated. Overall, our transcriptional regulators were functionally diverse in terms of both specificity and induction rates. LysR- and AraC- type regulators had relatively narrow specificities with high induction rates (5-50 fold, whereas two-component-types had wide specificities with low induction rates (3 fold. Numerous transcriptional regulators have been deposited in sequence databases, but their functions remain largely unknown. Thus, our results add valuable information regarding the sequence-function relationship of transcriptional regulators.

Reciprocal Regulation of GlnR and PhoP in Response to Nitrogen and Phosphate Limitations in Saccharopolyspora erythraea

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Yao, Li-li

2015-01-01

Nitrogen and phosphate source sensing, uptake, and assimilation are essential for the growth and development of microorganisms. In this study, we demonstrated that SACE_6965 encodes the phosphate regulator PhoP, which controls the transcription of genes involved in phosphate metabolism in the erythromycin-producing Saccharopolyspora erythraea. We found that PhoP and the nitrogen regulator GlnR both regulate the transcription of glnR as well as other nitrogen metabolism-related genes. Interestingly, both GlnR- and PhoP-binding sites were identified in the phoP promoter region. Unlike the nonreciprocal regulation of GlnR and PhoP observed in Streptomyces coelicolor and Streptomyces lividans, GlnR negatively controls the transcription of the phoP gene in S. erythraea. This suggests that GlnR directly affects phosphate metabolism and demonstrates that the cross talk between GlnR and PhoP is reciprocal. Although GlnR and PhoP sites in the glnR and phoP promoter regions are located in close proximity to one another (separated by only 2 to 4 bp), the binding of both regulators to their respective region was independent and noninterfering. These results indicate that two regulators could separately bind to their respective binding sites and control nitrogen and phosphate metabolism in response to environmental changes. The reciprocal cross talk observed between GlnR and PhoP serves as a foundation for understanding the regulation of complex primary and secondary metabolism in antibiotic-producing actinomycetes. PMID:26519391

Regulating Children's Television Advertising: Reassessing Parental Responsibility.

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Reid, Leonard N.

In response to public concern over the effects of television commercials on children, the Federal Trade Commission formulated regulatory proposals that would ban certain advertising from children's television and regulate advertising intended for the eight year old to the eleven year old age group. However, in the light of two recent research…

Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp.

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Morgan E. Milton

2018-02-01

Full Text Available 2-aminoimidazole (2-AI compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown. Response regulators are one part of two-component systems (TCS. TCSs allow cells to respond to changes in their environment, and are used to trigger quorum sensing, virulence factors, and antibiotic resistance. Drugs that target the TCS signaling process can inhibit pathogenic behavior, making this a potent new therapeutic approach that has not yet been fully exploited. We previously laid the groundwork for the interaction of the Acinetobacter baumannii response regulator BfmR with an early 2-AI derivative. Here, we further investigate the response regulator/2-AI interaction and look at a wider library of 2-AI compounds. By combining molecular modeling with biochemical and cellular studies, we expand on a potential mechanism for interaction between response regulators and 2-AIs. We also establish that Francisella tularensis/novicida, encoding for only three known response regulators, can be a model system to study the interaction between 2-AIs and response regulators. We show that knowledge gained from studying Francisella can be applied to the more complex A. baumannii system, which contains over 50 response regulators. Understanding the impact of 2-AIs on response regulators and their mechanism of interaction will lead to the development of more potent compounds that will serve as adjuvant therapies to broad-range antibiotics.

Neuroanatomical heterogeneity of essential tremor according to propranolol response.

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Seok Jong Chung

Full Text Available BACKGROUND: Recent studies have suggested that essential tremor (ET is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET. METHODS: A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18 and a non-responder group (n = 14. We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters. RESULTS: There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration. CONCLUSIONS: The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity.

Ethylene and the Regulation of Physiological and Morphological Responses to Nutrient Deficiencies

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García, María José; Romera, Francisco Javier; Lucena, Carlos; Alcántara, Esteban; Pérez-Vicente, Rafael

2015-01-01

To cope with nutrient deficiencies, plants develop both morphological and physiological responses. The regulation of these responses is not totally understood, but some hormones and signaling substances have been implicated. It was suggested several years ago that ethylene participates in the regulation of responses to iron and phosphorous deficiency. More recently, its role has been extended to other deficiencies, such as potassium, sulfur, and others. The role of ethylene in so many deficiencies suggests that, to confer specificity to the different responses, it should act through different transduction pathways and/or in conjunction with other signals. In this update, the data supporting a role for ethylene in the regulation of responses to different nutrient deficiencies will be reviewed. In addition, the results suggesting the action of ethylene through different transduction pathways and its interaction with other hormones and signaling substances will be discussed. PMID:26175512

Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae.

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Boyle, Keith B; Gyori, David; Sindrilaru, Anca; Scharffetter-Kochanek, Karin; Taylor, Philip R; Mócsai, Attila; Stephens, Len R; Hawkins, Phillip T

2011-03-01

An effective immune response to the ubiquitous fungus Aspergillus fumigatus is dependent upon production of reactive oxygen species (ROS) by the NADPH oxidase. This is evidenced by the acute sensitivity of oxidase-deficient humans and mice to invasive aspergillosis. Neutrophils are recruited to the lungs shortly postinfection and respond by phagocytosing conidia and mediating extracellular killing of germinated hyphae in a ROS-dependent manner. However, the signaling mechanisms regulating the generation of ROS in response to hyphae are poorly understood. PI3Ks are important regulators of numerous cellular processes, with much recent work describing unique roles for the different class I PI3K isoforms. We showed by live-cell imaging that the lipid products of class I PI3Ks accumulated at the hyphal-bound neutrophil plasma membrane. Further, we used pharmacological and genetic approaches to demonstrate essential, but overlapping, roles for PI3Kβ and PI3Kδ in the ROS and spreading responses of murine neutrophils to Aspergillus hyphae. Hyphal-induced ROS responses were substantially inhibited by deletion of the common β2-integrin subunit CD18, with only a minor, redundant role for Dectin-1. However, addition of soluble algal glucans plus the genetic deletion of CD18 were required to significantly inhibit activation of the PI3K-effector protein kinase B. Hyphal ROS responses were also totally dependent on the presence of Syk, but not its ITAM-containing adaptor proteins FcRγ or DAP12, and the Vav family of Rac-guanine nucleotide exchange factors. These results start to define the signaling network controlling neutrophil ROS responses to A. fumigatus hyphae.

The MurC Ligase Essential for Peptidoglycan Biosynthesis Is Regulated by the Serine/Threonine Protein Kinase PknA in Corynebacterium glutamicum*

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Fiuza, Maria; Canova, Marc J.; Patin, Delphine; Letek, Michal; Zanella-Cléon, Isabelle; Becchi, Michel; Mateos, Luís M.; Mengin-Lecreulx, Dominique; Molle, Virginie; Gil, José A.

2008-01-01

The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (l-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recently emerged as a major physiological mechanism of regulation in prokaryotes. Herein, the hypothesis of a phosphorylation-dependent mechanism of regulation of the MurC activity was investigated in Corynebacterium glutamicum. We showed that MurC was phosphorylated in vitro by the PknA protein kinase. An analysis of the phosphoamino acid content indicated that phosphorylation exclusively occurred on threonine residues. Six phosphoacceptor residues were identified by mass spectrometry analysis, and we confirmed that mutagenesis to alanine residues totally abolished PknA-dependent phosphorylation of MurC. In vitro and in vivo ligase activity assays showed that the catalytic activity of MurC was impaired following mutation of these threonine residues. Further in vitro assays revealed that the activity of the MurC-phosphorylated isoform was severely decreased compared with the non-phosphorylated protein. To our knowledge, this is the first demonstration of a MurC ligase phosphorylation in vitro. The finding that phosphorylation is correlated with a decrease in MurC enzymatic activity could have significant consequences in the regulation of peptidoglycan biosynthesis. PMID:18974047

Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine.

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Biswas, Amlan; Wilmanski, Jeanette; Forsman, Huamei; Hrncir, Tomas; Hao, Liming; Tlaskalova-Hogenova, Helena; Kobayashi, Koichi S

2011-01-01

A healthy intestinal tract is characterized by controlled homeostasis due to the balanced interaction between commensal bacteria and the host mucosal immune system. Human and animal model studies have supported the hypothesis that breakdown of this homeostasis may underlie the pathogenesis of inflammatory bowel diseases. However, it is not well understood how intestinal microflora stimulate the intestinal mucosal immune system and how such activation is regulated. Using a spontaneous, commensal bacteria-dependent colitis model in IL-10-deficient mice, we investigated the role of TLR and their negative regulation in intestinal homeostasis. In addition to IL-10(-/-) MyD88(-/-) mice, IL-10(-/-) TLR4(-/-) mice exhibited reduced colitis compared to IL-10(-/-) mice, indicating that TLR4 signaling plays an important role in inducing colitis. Interestingly, the expression of IRAK-M, a negative regulator of TLR signaling, is dependent on intestinal commensal flora, as IRAK-M expression was reduced in mice re-derived into a germ-free environment, and introduction of commensal bacteria into germ-free mice induced IRAK-M expression. IL-10(-/-) IRAK-M(-/-) mice exhibited exacerbated colitis with increased inflammatory cytokine gene expression. Therefore, this study indicates that intestinal microflora stimulate the colitogenic immune system through TLR and negative regulation of TLR signaling is essential in maintaining intestinal homeostasis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The significance of translation regulation in the stress response

OpenAIRE

Picard, Flora; Loubière, Pascal; Girbal, Laurence; Bousquet, Muriel

2013-01-01

Background: The stress response in bacteria involves the multistage control of gene expression but is not entirely understood. To identify the translational response of bacteria in stress conditions and assess its contribution to the regulation of gene expression, the translational states of all mRNAs were compared under optimal growth condition and during nutrient (isoleucine) starvation. Results: A genome-scale study of the translational response to nutritional limitation was performed in t...

Locomotory and physiological responses induced by clove and cinnamon essential oils in the maize weevil Sitophilus zeamais.

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Gonzales Correa, Yenis Del Carmen; Faroni, Lêda R A; Haddi, Khalid; Oliveira, Eugênio E; Pereira, Eliseu José G

2015-11-01

Plant essential oils have been suggested as a suitable alternative for controlling stored pests worldwide. However, very little is known about the physiological or behavioral responses induced by these compounds in insect populations that are resistant to traditional insecticides. Thus, this investigation evaluated the toxicity (including the impacts on population growth) as well as the locomotory and respiratory responses induced by clove, Syzygium aromaticum L., and cinnamon, Cinnamomum zeylanicum L., essential oils in Brazilian populations of the maize weevil Sitophilus zeamais. We used populations that are resistant to phosphine and pyrethroids (PyPhR), only resistant to pyrethroids (PyR1 and PyR2) or susceptible to both insecticide types (SUS). The PyPhR population was more tolerant to cinnamon essential oil, and its population growth rate was less affected by both oil types. Insects from this population reduced their respiratory rates (i.e., CO2 production) after being exposed to both oil types and avoided (in free choice-experiments) or reduced their mobility on essential oil-treated surfaces. The PyR1 and PyR2 populations reduced their respiratory rates, avoided (without changing their locomotory behavior in no-choice experiments) essential oil-treated surfaces and their population growth rates were severely affected by both oil types. Individuals from SUS population increased their mobility on surfaces that were treated with both oil types and showed the highest levels of susceptibility to these oils. Our findings indicate that S. zeamais populations that are resistant to traditional insecticides might have distinct but possibly overlapping mechanisms to mitigate the actions of essential oils and traditional insecticides. Copyright © 2015 Elsevier Inc. All rights reserved.

Growth rate regulated genes and their wide involvement in the Lactococcus lactis stress responses

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Redon Emma

2008-07-01

Full Text Available Abstract Background The development of transcriptomic tools has allowed exhaustive description of stress responses. These responses always superimpose a general response associated to growth rate decrease and a specific one corresponding to the stress. The exclusive growth rate response can be achieved through chemostat cultivation, enabling all parameters to remain constant except the growth rate. Results We analysed metabolic and transcriptomic responses of Lactococcus lactis in continuous cultures at different growth rates ranging from 0.09 to 0.47 h-1. Growth rate was conditioned by isoleucine supply. Although carbon metabolism was constant and homolactic, a widespread transcriptomic response involving 30% of the genome was observed. The expression of genes encoding physiological functions associated with biogenesis increased with growth rate (transcription, translation, fatty acid and phospholipids metabolism. Many phages, prophages and transposon related genes were down regulated as growth rate increased. The growth rate response was compared to carbon and amino-acid starvation transcriptomic responses, revealing constant and significant involvement of growth rate regulations in these two stressful conditions (overlap 27%. Two regulators potentially involved in the growth rate regulations, llrE and yabB, have been identified. Moreover it was established that genes positively regulated by growth rate are preferentially located in the vicinity of replication origin while those negatively regulated are mainly encountered at the opposite, thus indicating the relationship between genes expression and their location on chromosome. Although stringent response mechanism is considered as the one governing growth deceleration in bacteria, the rigorous comparison of the two transcriptomic responses clearly indicated the mechanisms are distinct. Conclusion This work of integrative biology was performed at the global level using transcriptomic analysis

Functional link between DNA damage responses and transcriptional regulation by ATM in response to a histone deacetylase inhibitor TSA.

Science.gov (United States)

Lee, Jong-Soo

2007-09-01

Mutations in the ATM (ataxia-telangiectasia mutated) gene, which encodes a 370 kd protein with a kinase catalytic domain, predisposes people to cancers, and these mutations are also linked to ataxia-telangiectasia (A-T). The histone acetylaion/deacetylation- dependent chromatin remodeling can activate the ATM kinase-mediated DNA damage signal pathway (in an accompanying work, Lee, 2007). This has led us to study whether this modification can impinge on the ATM-mediated DNA damage response via transcriptional modulation in order to understand the function of ATM in the regulation of gene transcription. To identify the genes whose expression is regulated by ATM in response to histone deaceylase (HDAC) inhibition, we performed an analysis of oligonucleotide microarrays with using the appropriate cell lines, isogenic A-T (ATM(-)) and control (ATM(+)) cells, following treatment with a HDAC inhibitor TSA. Treatment with TSA reprograms the differential gene expression profile in response to HDAC inhibition in ATM(-) cells and ATM(+) cells. We analyzed the genes that are regulated by TSA in the ATM-dependent manner, and we classified these genes into different functional categories, including those involved in cell cycle/DNA replication, DNA repair, apoptosis, growth/differentiation, cell- cell adhesion, signal transduction, metabolism and transcription. We found that while some genes are regulated by TSA without regard to ATM, the patterns of gene regulation are differentially regulated in an ATM-dependent manner. Taken together, these finding indicate that ATM can regulate the transcription of genes that play critical roles in the molecular response to DNA damage, and this response is modulated through an altered HDAC inhibition-mediated gene expression.

Regulation of bitter taste responses by tumor necrosis factor.

Science.gov (United States)

Feng, Pu; Jyotaki, Masafumi; Kim, Agnes; Chai, Jinghua; Simon, Nirvine; Zhou, Minliang; Bachmanov, Alexander A; Huang, Liquan; Wang, Hong

2015-10-01

Inflammatory cytokines are important regulators of metabolism and food intake. Over production of inflammatory cytokines during bacterial and viral infections leads to anorexia and reduced food intake. However, it remains unclear whether any inflammatory cytokines are involved in the regulation of taste reception, the sensory mechanism governing food intake. Previously, we showed that tumor necrosis factor (TNF), a potent proinflammatory cytokine, is preferentially expressed in a subset of taste bud cells. The level of TNF in taste cells can be further induced by inflammatory stimuli. To investigate whether TNF plays a role in regulating taste responses, in this study, we performed taste behavioral tests and gustatory nerve recordings in TNF knockout mice. Behavioral tests showed that TNF-deficient mice are significantly less sensitive to the bitter compound quinine than wild-type mice, while their responses to sweet, umami, salty, and sour compounds are comparable to those of wild-type controls. Furthermore, nerve recording experiments showed that the chorda tympani nerve in TNF knockout mice is much less responsive to bitter compounds than that in wild-type mice. Chorda tympani nerve responses to sweet, umami, salty, and sour compounds are similar between TNF knockout and wild-type mice, consistent with the results from behavioral tests. We further showed that taste bud cells express the two known TNF receptors TNFR1 and TNFR2 and, therefore, are potential targets of TNF. Together, our results suggest that TNF signaling preferentially modulates bitter taste responses. This mechanism may contribute to taste dysfunction, particularly taste distortion, associated with infections and some chronic inflammatory diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

14 CFR 272.5 - Determination of essential air service.

Science.gov (United States)

2010-01-01

... (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS ESSENTIAL AIR SERVICE TO THE FREELY ASSOCIATED STATES § 272.5 Determination of essential air service. Procedures for the determination of essential air service under this... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Determination of essential air service. 272...

Response to NII review of the PCSR July 1982 - protection and essential safety systems

International Nuclear Information System (INIS)

Burton, R.J.

1982-12-01

The design provisions of the systems are summarised, and response is made to the detailed concerns of the Nuclear Installations Inspectorate as expressed in their review of the pre-construction safety report (PCSR). Further clarification is provided of work done on protection and essential safety systems since presentation of the PCSR, and the ongoing work programme is described. (U.K.)

Improving the regulation of safety at DOE nuclear facilities. Final report: Appendices

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-12-01

The report strongly recommends that, with the end of the Cold War, safety and health at DOE facilities should be regulated by outside agencies rather than by any regulatory scheme, DOE must maintain a strong internal safety management system; essentially all aspects of safety at DOE`s nuclear facilities should be externally regulated; and existing agencies rather than a new one should be responsible for external regulation.

Improving the regulation of safety at DOE nuclear facilities. Final report: Appendices

International Nuclear Information System (INIS)

1995-12-01

The report strongly recommends that, with the end of the Cold War, safety and health at DOE facilities should be regulated by outside agencies rather than by any regulatory scheme, DOE must maintain a strong internal safety management system; essentially all aspects of safety at DOE's nuclear facilities should be externally regulated; and existing agencies rather than a new one should be responsible for external regulation

Neutron flux response to regulating rod random vibrations

International Nuclear Information System (INIS)

Dach, K.; Nemec, J.; Pecinka, L.

The relation is presented for the mean square value of the deflection of the rod for the n-th vibration shape on an arbitrary site. The relation may serve the obtaining of a variable which may be used both in a mechanical, i.e., stress analysis and in the determination of neutron flux fluctuations. It is demonstrated that the vibration frequency introduced in the reactor by the regulating rod has the same response in the neutron flux. This effect was used in the localization of an enormously vibrating regulating rod. (J.P.)

Vascular Function and Regulation of Blood Flow in Resting and Contracting Skeletal Muscle

DEFF Research Database (Denmark)

Nyberg, Michael Permin

importance. The present work provides new insight in to vasodilator interactions important for exercise hyperemia and sheds light on mechanisms important for vascular function and regulation of skeletal muscle blood flow in essential hypertension (high blood pressure) and aging and identifies mechanisms......The precise matching of blood flow, oxygen delivery and metabolism is essential as it ensures that any increase in muscle work is precisely matched by increases in oxygen delivery. Therefore, understanding the control mechanisms of skeletal muscle blood flow regulation is of great biological...... in the regulation of exercise hyperemia. Furthermore, blood flow to contracting leg skeletal muscles is reduced both in essential hypertension and with aging. The potential difference in vasoactive system(s) responsible for the reduction in blood flow in the two conditions is in agreement with the suggestion...

A CRE1- regulated cluster is responsible for light dependent production of dihydrotrichotetronin in Trichoderma reesei.

Directory of Open Access Journals (Sweden)

Alberto Alonso Monroy

Full Text Available Changing light conditions, caused by the rotation of earth resulting in day and night or growth on the surface or within a substrate, result in considerably altered physiological processes in fungi. For the biotechnological workhorse Trichoderma reesei, regulation of glycoside hydrolase gene expression, especially cellulase expression was shown to be a target of light dependent gene regulation. Analysis of regulatory targets of the carbon catabolite repressor CRE1 under cellulase inducing conditions revealed a secondary metabolite cluster to be differentially regulated in light and darkness and by photoreceptors. We found that this cluster is involved in production of trichodimerol and that the two polyketide synthases of the cluster are essential for biosynthesis of dihydrotrichotetronine (syn. bislongiquinolide or bisorbibutenolide. Additionally, an indirect influence on production of the peptaibol antibiotic paracelsin was observed. The two polyketide synthetase genes as well as the monooxygenase gene of the cluster were found to be connected at the level of transcription in a positive feedback cycle in darkness, but negative feedback in light, indicating a cellular sensing and response mechanism for the products of these enzymes. The transcription factor TR_102497/YPR2 residing within the cluster regulates the cluster genes in a light dependent manner. Additionally, an interrelationship of this cluster with regulation of cellulase gene expression was detected. Hence the regulatory connection between primary and secondary metabolism appears more widespread than previously assumed, indicating a sophisticated distribution of resources either to degradation of substrate (feed or to antagonism of competitors (fight, which is influenced by light.

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

Quantitative variations in the essential oil of Minthostachys mollis (Kunth.) Griseb. in response to insects with different feeding habits.

Science.gov (United States)

Banchio, Erika; Zygadlo, Julio; Valladares, Graciela R

2005-08-24

Plants display a diverse array of inducible changes in secondary metabolites following insect herbivory. Herbivores differ in their feeding behavior, physiology, and mode of attachment to the leaf surface, and such variations might be reflected in the induced responses of damaged plants. Induced changes were analyzed for Minthostachys mollis, a Lamiaceae with medicinal and aromatic uses, and four species of folivore insects with different feeding habits (chewing, scraping, sap-sucking, and puncturing). In M. mollis leaves experimentally exposed to the insects, levels of the two dominant monoterpenes pulegone and menthone were assessed 24 and 48 h after wounding. Menthone content generally decreased in the essential oil of damaged leaves, whereas pulegone concentration increased in all treatments. These changes occurred also in the adjacent undamaged leaves, suggesting a systemic response. The relatively uniform response to different kinds of damage could be attributable to the presence of such a strongly active compound as pulegone in the essential oil of M. mollis. The effects of wounding on essential oil concentration may be significant from a commercial point of view.

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.

Assessing the Value of Regulation Resources Based on Their Time Response Characteristics

Energy Technology Data Exchange (ETDEWEB)

Makarov, Yuri V.; Lu, Shuai; Ma, Jian; Nguyen, Tony B.

2008-06-01

Fast responsive regulation resources are potentially more valuable as a power system regulation resource (more efficient) because they allow applying controls at the exact moment and in the exact amount as needed. Faster control is desirable because it facilitates more reliable compliance with the NERC Control Performance Standards at relatively lesser regulation capacity procurements. The current California ISO practices and markets do not provide a differentiation among the regulation resources based on their speed of response (with the exception of some minimum ramping capabilities). Some demand response technologies, including some generation and energy storage resources, can provide quicker control actions. California ISO practices and markets could be updated to welcome more fast regulation resources into the California ISO service area. The project work reported in this work was pursuing the following objectives: • Develop methodology to assess the relative value of generation resources used for regulation and load following California ISO functions • This assessment should be done based on physical characteristics including the ability to quickly change their output following California ISO signals • Evaluate what power is worth on different time scales • Analyze the benefits of new regulation resources to provide effective compliance with the mandatory NERC Control Performance Standards • Evaluate impacts of the newly proposed BAAL and FRR standards on the potential value of fast regulation and distributed regulation resources • Develop a scope for the follow-up projects to pave a road for the new efficient types of balancing resources in California. The work included the following studies: • Analysis of California ISO regulating units characteristics • California ISO automatic generation system (AGC) analysis • California ISO regulation procurement and market analysis • Fast regulation efficiency analysis • Projection of the

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...

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.

Effect of two active compounds obtained from the essential oil of Cordia verbenacea on the acute inflammatory responses elicited by LPS in the rat paw.

Science.gov (United States)

Medeiros, R; Passos, G F; Vitor, C E; Koepp, J; Mazzuco, T L; Pianowski, L F; Campos, M M; Calixto, J B

2007-07-01

alpha-Humulene and trans-caryophyllene are sesquiterpene compounds identified in the essential oil of Cordia verbenacea which display topical and systemic anti-inflammatory effects in different experimental models. However, the molecular mechanisms through which they exert their anti-inflammatory activity still remain unclear. Here, we evaluate the effects of alpha-humulene and trans-caryophyllene on the acute inflammatory responses elicited by LPS. The biological activities of alpha-humulene and trans-caryophyllene were investigated in a model of acute inflammation in rat paw, induced by LPS and characterized by paw oedema, neutrophil recruitment, cytokine production, activation of MAP kinases and NF-kappaB and up-regulated expression of kinin B(1) receptors. Treatment with either alpha-humulene or trans-caryophyllene effectively reduced neutrophil migration and activation of NF-kappaB induced by LPS in the rat paw. However, only alpha-humulene significantly reduced the increase in TNF-alpha and IL-1beta levels, paw oedema and the up-regulation of B(1) receptors following treatment with LPS. Both compounds failed to interfere with the activation of the MAP kinases, ERK, p38 and JNK. Both alpha-humulene and trans-caryophyllene inhibit the LPS-induced NF-kappaB activation and neutrophil migration, although only alpha-humulene had the ability to prevent the production of pro-inflammatory cytokines TNF-alpha and IL-1beta and the in vivo up-regulation of kinin B(1) receptors. These data provide additional molecular and functional insights into the beneficial effects of the sesquiterpenes alpha-humulene and trans-caryophyllene isolated from the essential oil of Cordia verbenacea as agents for the management of inflammatory diseases.

Mechanisms and pathways of innate immune activation and regulation in health and cancer.

Science.gov (United States)

Cui, Jun; Chen, Yongjun; Wang, Helen Y; Wang, Rong-Fu

2014-01-01

Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.

Improving the regulation of safety at DOE nuclear facilities. Final report

International Nuclear Information System (INIS)

1995-12-01

The report strongly recommends that, with the end of the Cold War, safety and health at DOE facilities should be regulated by outside agencies rather than by DOE itself. The three major recommendations are: under any regulatory scheme, DOE must maintain a strong internal safety management system; essentially all aspects of safety at DOE's nuclear facilities should be externally regulated; and existing agencies rather than a new one should be responsible for external regulation

An essential role for the circadian-regulated gene nocturnin in osteogenesis: the importance of local timekeeping in skeletal homeostasis.

Science.gov (United States)

Guntur, Anyonya R; Kawai, Masanobu; Le, Phuong; Bouxsein, Mary L; Bornstein, Sheila; Green, Carla B; Rosen, Clifford J

2011-11-01

The role of circadian proteins in regulating whole-body metabolism and bone turnover has been studied in detail and has led to the discovery of an elemental system for timekeeping involving the core genes Clock, Bmal1, Per, and Cry. Nocturnin (Noc; Ccrn4l), a peripheral circadian-regulated gene has been shown to play a very important role in regulating adipogenesis by deadenylation of key mRNAs and intracytoplasmic transport of PPARγ. The role that it plays in osteogenesis has previously not been studied in detail. In this report we examined in vitro and in vivo osteogenesis in the presence and absence of Noc and show that loss of Noc enhances bone formation and can rescue rosiglitazone-induced bone loss in mice. The circadian rhythm of Noc is likely to be an essential element of marrow stromal cell fate. © 2011 New York Academy of Sciences.

Calcium, essential for health

Science.gov (United States)

Martínez de Victoria, Emilio

2016-07-12

Calcium (Ca) is the most abundant mineral element in our body. It accounts for about 2% of body weight. The functions of calcium are: a) functions skeletal and b) regulatory functions. Bone consists of a protein matrix that mineralizes mainly with calcium (the most abundant), phosphate and magnesium, for it is essential an adequate dietary intake of Ca, phosphorus and vitamin D. The ionic Ca (Ca2+) is essential to maintain and / or perform different specialized functions of, virtually, all body cells cellular. Because of its important functions Ca2+ must be closely regulated, keeping plasma concentrations within narrow ranges. For this reason there is an accurate response against hypocalcemia or hypercalcemia in which the parathormone, calcitriol, calcitonin and vitamin K are involved. Ca intakes in the Spanish population are low in a significant percentage of the older adult’s population, especially in women. The main source of Ca in the diet is milk and milk derivatives. Green leafy vegetables, fruits and legumes can be important sources of Ca in a Mediterranean dietary pattern. The bioavailability of dietary Ca depends on physiological and dietary factors. Physiological include age, physiological status (gestation and lactation) Ca and vitamin D status and disease. Several studies relate Ca intake in the diet and various diseases, such as osteoporosis, cancer, cardiovascular disease and obesity.

Access to essential medicines in Pakistan: policy and health systems research concerns.

Directory of Open Access Journals (Sweden)

Shehla Zaidi

Full Text Available INTRODUCTION: Inadequate access to essential medicines is a common issue within developing countries. Policy response is constrained, amongst other factors, by a dearth of in-depth country level evidence. We share here i gaps related to access to essential medicine in Pakistan; and ii prioritization of emerging policy and research concerns. METHODS: An exploratory research was carried out using a health systems perspective and applying the WHO Framework for Equitable Access to Essential Medicine. Methods involved key informant interviews with policy makers, providers, industry, NGOs, experts and development partners, review of published and grey literature, and consultative prioritization in stakeholder's Roundtable. FINDINGS: A synthesis of evidence found major gaps in essential medicine access in Pakistan driven by weaknesses in the health care system as well as weak pharmaceutical regulation. 7 major policy concerns and 11 emerging research concerns were identified through consultative Roundtable. These related to weaknesses in medicine registration and quality assurance systems, unclear and counterproductive pricing policies, irrational prescribing and sub-optimal drug availability. Available research, both locally and globally, fails to target most of the identified policy concerns, tending to concentrate on irrational prescriptions. It overlooks trans-disciplinary areas of policy effectiveness surveillance, consumer behavior, operational pilots and pricing interventions review. CONCLUSION: Experience from Pakistan shows that policy concerns related to essential medicine access need integrated responses across various components of the health systems, are poorly addressed by existing evidence, and require an expanded health systems research agenda.

CCR6-dependent positioning of memory B cells is essential for their ability to mount a recall response to antigen.

Science.gov (United States)

Elgueta, Raul; Marks, Ellen; Nowak, Elizabeth; Menezes, Shinelle; Benson, Micah; Raman, Vanitha S; Ortiz, Carla; O'Connell, Samuel; Hess, Henry; Lord, Graham M; Noelle, Randolph

2015-01-15

Chemokine-dependent localization of specific B cell subsets within the immune microarchitecture is essential to ensure successful cognate interactions. Although cognate interactions between T cells and memory B cells (B(mem)) are essential for the secondary humoral immune responses, the chemokine response patterns of B(mem) cells are largely unknown. In contrast to naive B cells, this study shows that Ag-specific B(mem) cells have heightened expression of CCR6 and a selective chemotactic response to the CCR6 ligand, CCL20. Although CCR6 appears be nonessential for the initial clonal expansion and maintenance of B(mem), CCR6 is essential for the ability of B(mem) to respond to a recall response to their cognate Ag. This dependency was deemed intrinsic by studies in CCR6-deficient mice and in bone marrow chimeric mice where CCR6 deficiency was limited to the B cell lineage. Finally, the mis-positioning of CCR6-deficient B(mem) was revealed by immunohistological analysis with an altered distribution of CCR6-deficient B(mem) from the marginal and perifollicular to the follicular/germinal center area. Copyright © 2015 by The American Association of Immunologists, Inc.

Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis

Science.gov (United States)

Garcia-Barros, Monica; Paris, Francois; Cordon-Cardo, Carlos; Lyden, David; Rafii, Shahin; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard

2003-05-01

About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

Arabidopsis YAK1 regulates abscisic acid response and drought resistance.

Science.gov (United States)

Kim, Dongjin; Ntui, Valentine Otang; Xiong, Liming

2016-07-01

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.

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.

Chromatin changes in response to drought, salinity, heat, and cold stresses in plants

Directory of Open Access Journals (Sweden)

Jong-Myong eKim

2015-03-01

Full Text Available Chromatin regulation is essential to regulate genes and genome activities. In plants, the alteration of histone modification and DNA methylation are coordinated with changes in the expression of stress-responsive genes to adapt to environmental changes. Several chromatin regulators have been shown to be involved in the regulation of stress-responsive gene networks under abiotic stress conditions. Specific histone modification sites and the histone modifiers that regulate key stress-responsive genes have been identified by genetic and biochemical approaches, revealing the importance of chromatin regulation in plant stress responses. Recent studies have also suggested that histone modification plays an important role in plant stress memory. In this review, we summarize recent progress on the regulation and alteration of histone modification (acetylation, methylation, phosphorylation, and SUMOylation in response to the abiotic stresses, drought, high-salinity, heat, and cold in plants.

Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.

Science.gov (United States)

Weisman, Ronit

2016-10-01

All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.

Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling.

Science.gov (United States)

Lisse, Thomas S; Hewison, Martin; Adams, John S

2011-03-01

Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

Who regulates food? Australians' perceptions of responsibility for food safety.

Science.gov (United States)

Henderson, Julie; Coveney, John; Ward, Paul

2010-01-01

Food scares have diminished trust in public institutions to guarantee food safety. Food governance after the food scare era is concerned with institutional independence and transparency leading to a hybrid of public and private sector management and to mechanisms for consumer involvement in food governance. This paper explores Australian consumers' perceptions of who is, and should be responsible for food safety. Forty-seven participants were interviewed as part of a larger study on trust in the food system. Participants associate food governance with government, industry, and the individual. While few participants can name the national food regulator, there is a strong belief that the government is responsible for regulating the quality and safety of food. Participants are wary of the role of the food industry in food safety, believing that profit motives will undermine effective food regulation. Personal responsibility for food safety practices was also identified. While there are fewer mechanisms for consumer involvement and transparency built into the food governance system, Australian consumers display considerable trust in government to protect food safety. There is little evidence of the politicisation of food, reflecting a level of trust in the Australian food governance system that may arise from a lack of exposure to major food scares.

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.

Regulation of gene expression in Streptococcus pneumoniae by response regulator 09 is strain dependent

NARCIS (Netherlands)

W.T. Hendriksen (Wouter); N. Silva (Nuno); H.J. Bootsma (Hester); C.E. Blue (Clare); G.K. Paterson (Gavin); A.R. Kerr (Alison); A.S. de Jong (Arjan); O.P. Kuipers (Oscar); P.W.M. Hermans (Peter); T.J. Mitchell

2007-01-01

textabstractRecent murine studies have demonstrated that the role of response regulator 09 (RR09) of Streptococcus pneumoniae in virulence is different in different strains. In the present study, we used a murine pneumonia model of infection to assess the virulence of a TIGR4 rr09 mutant, and we

Regulation of gene expression in Streptococcus pneumoniae by response regulator 09 is strain dependent

NARCIS (Netherlands)

Hendriksen, Wouter T.; Silva, Nuno; Bootsma, Hester J.; Blue, Clare E.; Paterson, Gavin K.; Kerr, Alison R.; de Jong, Anne; Kuipers, Oscar P.; Hermans, Peter W. M.; Mitchell, Tim J.

Recent murine studies have demonstrated that the role of response regulator 09 (RR09) of Streptococcus pneumoniae in virulence is different in different strains. In the present study, we used a murine pneumonia model of infection to assess the virulence of a TIGR4 rr09 mutant, and we found that

Thyme and Savory Essential Oil Efficacy and Induction of Resistance against Botrytis cinerea through Priming of Defense Responses in Apple.

Science.gov (United States)

Banani, Houda; Olivieri, Leone; Santoro, Karin; Garibaldi, Angelo; Gullino, Maria Lodovica; Spadaro, Davide

2018-01-23

The efficacy of thyme and savory essential oils were investigated against Botrytis cinerea on apple fruit. Apples treated with thyme and savory essential oils showed significantly lower gray mold severity and incidence. Thyme essential oil at 1% concentration showed the highest efficacy, with lower disease incidence and smaller lesion diameter. The expression of specific pathogenesis-related (PR) genes PR-8 and PR-5 was characterized in apple tissues in response to thyme oil application and B. cinerea inoculation. After 6 h of pathogen inoculation, thyme essential oil induced a 2.5-fold increase of PR-8 gene expression compared to inoculated fruits. After 24 h of inoculation, PR-8 was highly induced (7-fold) in both thyme oil-treated and untreated apples inoculated with B. cinerea . After 48 h of inoculation, PR-8 expression in thyme-treated and inoculated apples was 4- and 6-fold higher than in inoculated and water-treated apples. Neither thyme oil application nor B. cinerea inoculation markedly affected PR-5 expression. These results suggest that thyme oil induces resistance against B. cinerea through the priming of defense responses in apple fruit, and the PR-8 gene of apple may play a key role in the mechanism by which thyme essential oil effectively inhibits gray mold in apple fruit.

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. Copyright © 2016. Published by Elsevier B.V.

Foliar treatments with Gaultheria procumbens essential oil induce defence responses and resistance against a fungal pathogen in Arabidopsis

Directory of Open Access Journals (Sweden)

Sophie eVergnes

2014-09-01

Full Text Available Essential oil from Gaultheria procumbens is mainly composed of methylsalicylate (>96%, a compound which can be metabolized in plant tissues to salicylic acid, a phytohormone inducing plant immunity against microbial pathogens. The potential use of G. procumbens essential oil as a biocontrol agent was evaluated on the model plant Arabidopsis thaliana. Expression of a selection of defence genes was detected 1, 6 and 24 hours after essential oil treatment (0.1 ml/L using a high-throughput qPCR-based microfluidic technology. Control treatments included methyl jasmonate and a commercialized salicylic acid analog, benzo(1,2,3-thiadiazole-7carbothiolic acid (BTH. Strong induction of defence markers known to be regulated by the salicylic acid pathway was observed after the treatment with G. procumbens essential oil. Treatment induced the accumulation of total salicylic acid in the wild -type Arabidopsis line Col-0 and analysis of the Arabidopsis line sid2, mutated in a salicylic acid biosynthetic gene, revealed that approximately 30% of methylsalicylate sprayed on the leaves penetrated inside plant tissues and was demethylated by endogenous esterases. Induction of plant resistance by G. procumbens essential oil was tested following inoculation with a GFP-expressing strain of the Arabidopsis fungal pathogen Colletotrichum higginsianum. Flurorescence measurement of infected tissues revealed that treatments led to a strong reduction (60% of pathogen development and that the efficacy of the G. procumbens essential oil was similar to the commercial product BION®. Together, these results show that the G. procubens essential oil is a natural source of methylsalicylate which can be formulated to develop new biocontrol products.

Transcription factor FoxO1 is essential for enamel biomineralization.

Directory of Open Access Journals (Sweden)

Ross A Poché

Full Text Available The Transforming growth factor β (Tgf-β pathway, by signaling via the activation of Smad transcription factors, induces the expression of many diverse downstream target genes thereby regulating a vast array of cellular events essential for proper development and homeostasis. In order for a specific cell type to properly interpret the Tgf-β signal and elicit a specific cellular response, cell-specific transcriptional co-factors often cooperate with the Smads to activate a discrete set of genes in the appropriate temporal and spatial manner. Here, via a conditional knockout approach, we show that mice mutant for Forkhead Box O transcription factor FoxO1 exhibit an enamel hypomaturation defect which phenocopies that of the Smad3 mutant mice. Furthermore, we determined that both the FoxO1 and Smad3 mutant teeth exhibit changes in the expression of similar cohort of genes encoding enamel matrix proteins required for proper enamel development. These data raise the possibility that FoxO1 and Smad3 act in concert to regulate a common repertoire of genes necessary for complete enamel maturation. This study is the first to define an essential role for the FoxO family of transcription factors in tooth development and provides a new molecular entry point which will allow researchers to delineate novel genetic pathways regulating the process of biomineralization which may also have significance for studies of human tooth diseases such as amelogenesis imperfecta.

MAP Kinase Cascades Regulate the Cold Response by Modulating ICE1 Protein Stability.

Science.gov (United States)

Zhao, Chunzhao; Wang, Pengcheng; Si, Tong; Hsu, Chuan-Chih; Wang, Lu; Zayed, Omar; Yu, Zheping; Zhu, Yingfang; Dong, Juan; Tao, W Andy; Zhu, Jian-Kang

2017-12-04

Mitogen-activated protein kinase cascades are important signaling modules that convert environmental stimuli into cellular responses. We show that MPK3, MPK4, and MPK6 are rapidly activated after cold treatment. The mpk3 and mpk6 mutants display increased expression of CBF genes and enhanced freezing tolerance, whereas constitutive activation of the MKK4/5-MPK3/6 cascade in plants causes reduced expression of CBF genes and hypersensitivity to freezing, suggesting that the MKK4/5-MPK3/6 cascade negatively regulates the cold response. MPK3 and MPK6 can phosphorylate ICE1, a basic-helix-loop-helix transcription factor that regulates the expression of CBF genes, and the phosphorylation promotes the degradation of ICE1. Interestingly, the MEKK1-MKK2-MPK4 pathway constitutively suppresses MPK3 and MPK6 activities and has a positive role in the cold response. Furthermore, the MAPKKK YDA and two calcium/calmodulin-regulated receptor-like kinases, CRLK1 and CRLK2, negatively modulate the cold activation of MPK3/6. Our results uncover important roles of MAPK cascades in the regulation of plant cold response. Copyright © 2017 Elsevier Inc. All rights reserved.

Swelling-activated ion channels: functional regulation in cell-swelling, proliferation and apoptosis

DEFF Research Database (Denmark)

Stutzin, A; Hoffmann, E K

2006-01-01

Cell volume regulation is one of the most fundamental homeostatic mechanisms and essential for normal cellular function. At the same time, however, many physiological mechanisms are associated with regulatory changes in cell size meaning that the set point for cell volume regulation is under phys...... as key players in the maintenance of normal steady-state cell volume, with particular emphasis on the intracellular signalling pathways responsible for their regulation during hypotonic stress, cell proliferation and apoptosis....

mTORC1 directly phosphorylates and regulates human MAF1.

OpenAIRE

Michels Annemieke A; Robitaille Aaron M; Buczynski-Ruchonnet Diane; Hodroj Wassim; Reina Jaime H; Hall Michael N; Hernandez Nouria

2010-01-01

mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated and represses pol III transcription after various stresses, but neither the significance of the p...

Regulation of water, salinity, and cold stress responses by salicylic acid

Directory of Open Access Journals (Sweden)

Kenji eMiura

2014-01-01

Full Text Available Salicylic acid (SA is a naturally occurring phenolic compound. SA plays an important role in the regulation of plant growth, development, ripening, and defense responses. The role of SA in the plant-pathogen relationship has been extensively investigated. In addition to defense responses, SA plays an important role in the response to abiotic stresses, including drought, low temperature, and salinity stresses. It has been suggested that SA has great agronomic potential to improve the stress tolerance of agriculturally important crops. However, the utility of SA is dependent on the concentration of the applied SA, the mode of application, and the state of the plants (e.g., developmental stage and acclimation. Generally, low concentrations of applied SA alleviate the sensitivity to abiotic stresses, and high concentrations of applied induce high levels of oxidative stress, leading to a decreased tolerance to abiotic stresses. In this chapter, the effects of SA on the water stress responses and regulation of stomatal closure are reviewed.

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. Copyright © 2014 Elsevier Inc. All rights reserved.

Characterization of a type-A response regulator differentially expressed during adventitious caulogenesis in Pinus pinaster.

Science.gov (United States)

Alvarez, José M; Cortizo, Millán; Ordás, Ricardo J

2012-12-15

The molecular cloning and characterization of PipsRR1, a type-A response regulator in Pinus pinaster, is reported here. Type-A response regulators mediate downstream responses to cytokinin and act as negative feedback regulators of the signal transduction pathway. Some type-A response regulators in Arabidopsis have been related to de novo meristem formation. However, little information exists in Pinus spp. The PipsRR1 gene contains 5 exons, as do all type-A response regulators in Arabidopsis, and the deduced protein contains a receiver domain with the conserved DDK residues and a short C terminal extension. Expression analysis showed that the PipsRR1 gene is differentially expressed during the first phases of adventitious caulogenesis induced by benzyladenine in P. pinaster cotyledons, suggesting that PipsRR1 plays a role in caulogenesis in conifers. Additionally, a binary vector carrying the PipsRR1 promoter driving GFP:GUS expression was constructed to analyze the promoter activity in P. pinaster somatic embryos. The results of genetic transformation showed GUS activity during somatic embryo mass proliferation and embryo maturation. Copyright © 2012 Elsevier GmbH. All rights reserved.

Nitric oxide-activated hydrogen sulfide is essential for cadmium stress response in bermudagrass (Cynodon dactylon (L). Pers.).

Science.gov (United States)

Shi, Haitao; Ye, Tiantian; Chan, Zhulong

2014-01-01

Nitric oxide (NO) and hydrogen sulfide (H2S) are important gaseous molecules, serving as important secondary messengers in plant response to various biotic and abiotic stresses. However, the interaction between NO and H2S in plant stress response was largely unclear. In this study, endogenous NO and H2S were evidently induced by cadmium stress treatment in bermudagrass, and exogenous applications of NO donor (sodium nitroprusside, SNP) or H2S donor (sodium hydrosulfide, NaHS) conferred improved cadmium stress tolerance. Additionally, SNP and NaHS treatments alleviated cadmium stress-triggered plant growth inhibition, cell damage and reactive oxygen species (ROS) burst, partly via modulating enzymatic and non-enzymatic antioxidants. Moreover, SNP and NaHS treatments also induced the productions of both NO and H2S in the presence of Cd. Interestingly, combined treatments with inhibitors and scavengers of NO and H2S under cadmium stress condition showed that NO signal could be blocked by both NO and H2S inhibitors and scavengers, while H2S signal was specifically blocked by H2S inhibitors and scavengers, indicating that NO-activated H2S was essential for cadmium stress response. Taken together, we assigned the protective roles of endogenous and exogenous NO and H2S in bermudagrass response to cadmium stress, and speculated that NO-activated H2S might be essential for cadmium stress response in bermudagrass. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

VLDL hydrolysis by hepatic lipase regulates PPARδ transcriptional responses.

Directory of Open Access Journals (Sweden)

Jonathan D Brown

Full Text Available 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.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.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 into specific lipid mediators and pathways of lipid

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 bacteriallipopolysaccharide. Qur...e The Lps locus: genetic regulation of host responses to bacteriallipopolysaccharide. Authors Qur

Modelling the regulation of thermal adaptation in Candida albicans, a major fungal pathogen of humans.

Directory of Open Access Journals (Sweden)

Michelle D Leach

Full Text Available Eukaryotic cells have evolved mechanisms to sense and adapt to dynamic environmental changes. Adaptation to thermal insults, in particular, is essential for their survival. The major fungal pathogen of humans, Candida albicans, is obligately associated with warm-blooded animals and hence occupies thermally buffered niches. Yet during its evolution in the host it has retained a bona fide heat shock response whilst other stress responses have diverged significantly. Furthermore the heat shock response is essential for the virulence of C. albicans. With a view to understanding the relevance of this response to infection we have explored the dynamic regulation of thermal adaptation using an integrative systems biology approach. Our mathematical model of thermal regulation, which has been validated experimentally in C. albicans, describes the dynamic autoregulation of the heat shock transcription factor Hsf1 and the essential chaperone protein Hsp90. We have used this model to show that the thermal adaptation system displays perfect adaptation, that it retains a transient molecular memory, and that Hsf1 is activated during thermal transitions that mimic fever. In addition to providing explanations for the evolutionary conservation of the heat shock response in this pathogen and the relevant of this response to infection, our model provides a platform for the analysis of thermal adaptation in other eukaryotic cells.

Homeodomain-Interacting Protein Kinase (HPK-1) regulates stress responses and ageing in C. elegans.

Science.gov (United States)

Berber, Slavica; Wood, Mallory; Llamosas, Estelle; Thaivalappil, Priya; Lee, Karen; Liao, Bing Mana; Chew, Yee Lian; Rhodes, Aaron; Yucel, Duygu; Crossley, Merlin; Nicholas, Hannah R

2016-01-21

Proteins of the Homeodomain-Interacting Protein Kinase (HIPK) family regulate an array of processes in mammalian systems, such as the DNA damage response, cellular proliferation and apoptosis. The nematode Caenorhabditis elegans has a single HIPK homologue called HPK-1. Previous studies have implicated HPK-1 in longevity control and suggested that this protein may be regulated in a stress-dependent manner. Here we set out to expand these observations by investigating the role of HPK-1 in longevity and in the response to heat and oxidative stress. We find that levels of HPK-1 are regulated by heat stress, and that HPK-1 contributes to survival following heat or oxidative stress. Additionally, we show that HPK-1 is required for normal longevity, with loss of HPK-1 function leading to a faster decline of physiological processes that reflect premature ageing. Through microarray analysis, we have found that HPK-1-regulated genes include those encoding proteins that serve important functions in stress responses such as Phase I and Phase II detoxification enzymes. Consistent with a role in longevity assurance, HPK-1 also regulates the expression of age-regulated genes. Lastly, we show that HPK-1 functions in the same pathway as DAF-16 to regulate longevity and reveal a new role for HPK-1 in development.

Autocrine regulation of ecdysone synthesis by β3-octopamine receptor in the prothoracic gland is essential for Drosophila metamorphosis.

Science.gov (United States)

Ohhara, Yuya; Shimada-Niwa, Yuko; Niwa, Ryusuke; Kayashima, Yasunari; Hayashi, Yoshiki; Akagi, Kazutaka; Ueda, Hitoshi; Yamakawa-Kobayashi, Kimiko; Kobayashi, Satoru

2015-02-03

In Drosophila, pulsed production of the steroid hormone ecdysone plays a pivotal role in developmental transitions such as metamorphosis. Ecdysone production is regulated in the prothoracic gland (PG) by prothoracicotropic hormone (PTTH) and insulin-like peptides (Ilps). Here, we show that monoaminergic autocrine regulation of ecdysone biosynthesis in the PG is essential for metamorphosis. PG-specific knockdown of a monoamine G protein-coupled receptor, β3-octopamine receptor (Octβ3R), resulted in arrested metamorphosis due to lack of ecdysone. Knockdown of tyramine biosynthesis genes expressed in the PG caused similar defects in ecdysone production and metamorphosis. Moreover, PTTH and Ilps signaling were impaired by Octβ3R knockdown in the PG, and activation of these signaling pathways rescued the defect in metamorphosis. Thus, monoaminergic autocrine signaling in the PG regulates ecdysone biogenesis in a coordinated fashion on activation by PTTH and Ilps. We propose that monoaminergic autocrine signaling acts downstream of a body size checkpoint that allows metamorphosis to occur when nutrients are sufficiently abundant.

An Sfp-type PPTase and associated polyketide and nonribosomal peptide synthases in Agrobacterium vitis are essential for induction of tobacco hypersensitive response and grape necrosis.

Science.gov (United States)

Zheng, Desen; Burr, Thomas J

2013-07-01

An Sfp-type phosphopantetheinyl transferase (PPTase) encoding gene F-avi5813 in Agrobacterium vitis F2/5 was found to be required for the induction of a tobacco hypersensitive response (HR) and grape necrosis. Sfp-type PPTases are post-translation modification enzymes that activate acyl-carry protein (ACP) domains in polyketide synthases (PKS) and peptidyl-carrier protein (PCP) domains of nonribosomal peptide synthases (NRPS). Mutagenesis of PKS and NRPS genes in A. vitis led to the identification of a PKS gene (F-avi4330) and NRPS gene (F-avi3342) that are both required for HR and necrosis. The gene immediately downstream of F-avi4330 (F-avi4329) encoding a predicted aminotransferase was also found to be required for HR and necrosis. Regulation of F-avi4330 and F-avi3342 by quorum-sensing genes avhR, aviR, and avsR and by a lysR-type regulator, lhnR, was investigated. It was determined that F-avi4330 expression is positively regulated by avhR, aviR, and lhnR and negatively regulated by avsR. F-avi3342 was found to be positively regulated by avhR, aviR, and avsR and negatively regulated by lhnR. Our results suggest that a putative hybrid peptide-polyketide metabolite synthesized by F-avi4330 and F-avi3342 is associated with induction of tobacco HR and grape necrosis. This is the first report that demonstrates that NRPS and PKS play essential roles in conferring the unique ability of A. vitis to elicit a non-host-specific HR and host-specific necrosis.

Thyme and Savory Essential Oil Efficacy and Induction of Resistance against Botrytis cinerea through Priming of Defense Responses in Apple

Directory of Open Access Journals (Sweden)

Houda Banani

2018-01-01

Full Text Available The efficacy of thyme and savory essential oils were investigated against Botrytis cinerea on apple fruit. Apples treated with thyme and savory essential oils showed significantly lower gray mold severity and incidence. Thyme essential oil at 1% concentration showed the highest efficacy, with lower disease incidence and smaller lesion diameter. The expression of specific pathogenesis-related (PR genes PR-8 and PR-5 was characterized in apple tissues in response to thyme oil application and B. cinerea inoculation. After 6 h of pathogen inoculation, thyme essential oil induced a 2.5-fold increase of PR-8 gene expression compared to inoculated fruits. After 24 h of inoculation, PR-8 was highly induced (7-fold in both thyme oil-treated and untreated apples inoculated with B. cinerea. After 48 h of inoculation, PR-8 expression in thyme-treated and inoculated apples was 4- and 6-fold higher than in inoculated and water-treated apples. Neither thyme oil application nor B. cinerea inoculation markedly affected PR-5 expression. These results suggest that thyme oil induces resistance against B. cinerea through the priming of defense responses in apple fruit, and the PR-8 gene of apple may play a key role in the mechanism by which thyme essential oil effectively inhibits gray mold in apple fruit.

Jamb and jamc are essential for vertebrate myocyte fusion.

Directory of Open Access Journals (Sweden)

Gareth T Powell

2011-12-01

Full Text Available Cellular fusion is required in the development of several tissues, including skeletal muscle. In vertebrates, this process is poorly understood and lacks an in vivo-validated cell surface heterophilic receptor pair that is necessary for fusion. Identification of essential cell surface interactions between fusing cells is an important step in elucidating the molecular mechanism of cellular fusion. We show here that the zebrafish orthologues of JAM-B and JAM-C receptors are essential for fusion of myocyte precursors to form syncytial muscle fibres. Both jamb and jamc are dynamically co-expressed in developing muscles and encode receptors that physically interact. Heritable mutations in either gene prevent myocyte fusion in vivo, resulting in an overabundance of mononuclear, but otherwise overtly normal, functional fast-twitch muscle fibres. Transplantation experiments show that the Jamb and Jamc receptors must interact between neighbouring cells (in trans for fusion to occur. We also show that jamc is ectopically expressed in prdm1a mutant slow muscle precursors, which inappropriately fuse with other myocytes, suggesting that control of myocyte fusion through regulation of jamc expression has important implications for the growth and patterning of muscles. Our discovery of a receptor-ligand pair critical for fusion in vivo has important implications for understanding the molecular mechanisms responsible for myocyte fusion and its regulation in vertebrate myogenesis.

NLRC5: a key regulator of MHC class I-dependent immune responses.

Science.gov (United States)

Kobayashi, Koichi S; van den Elsen, Peter J

2012-12-01

The expression of MHC class I molecules is crucial for the initiation and regulation of adaptive immune responses against pathogens. NOD-, LRR- and CARD-containing 5 (NLRC5) was recently identified as a specific transactivator of MHC class I genes (CITA). NLRC5 and the master regulator for MHC class II genes, class II transactivator (CIITA), interact with similar MHC promoter-bound factors. Here, we provide a broad overview of the molecular mechanisms behind MHC class I transcription and the role of the class I transactivator NLRC5 in MHC class I-dependent immune responses.

Autographa californica multiple nucleopolyhedrovirus PK-1 is essential for nucleocapsid assembly

Energy Technology Data Exchange (ETDEWEB)

Liang, Changyong, E-mail: cyliang@yzu.edu.cn [College of Bioscience and Biotechnology, Yangzhou University, Yangzhou 225009 (China); Li, Min; Dai, Xuejuan; Zhao, Shuling; Hou, Yanling; Zhang, Yongli; Lan, Dandan [College of Bioscience and Biotechnology, Yangzhou University, Yangzhou 225009 (China); Wang, Yun; Chen, Xinwen [State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071 (China)

2013-09-01

PK-1 (Ac10) is a baculovirus-encoded serine/threonine kinase and its function is unclear. Our results showed that a pk-1 knockout AcMNPV failed to produce infectious progeny, while the pk-1 repair virus could rescue this defect. qPCR analysis demonstrated that pk-1 deletion did not affect viral DNA replication. Analysis of the repaired recombinants with truncated pk-1 mutants demonstrated that the catalytic domain of protein kinases of PK-1 was essential to viral infectivity. Moreover, those PK-1 mutants that could rescue the infectious BV production defect exhibited kinase activity in vitro. Therefore, it is suggested that the kinase activity of PK-1 is essential in regulating viral propagation. Electron microscopy revealed that pk-1 deletion affected the formation of normal nucleocapsids. Masses of electron-lucent tubular structures were present in cell transfected with pk-1 knockout bacmid. Therefore, PK-1 appears to phosphorylate some viral or cellular proteins that are essential for DNA packaging to regulate nucleocapsid assembly. - Highlights: • A pk-1 knockout AcMNPV failed to produce infectious progeny. • The pk-1 deletion did not affect viral DNA replication. • The catalytic domain of protein kinases (PKc) of PK-1 was essential to viral infectivity. • The kinase activity of PK-1 is essential in regulating viral propagation. • PK-1 appears to phosphorylate some viral proteins that are essential for DNA packaging to regulate nucleocapsid assembly.

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

International Nuclear Information System (INIS)

Perochon, Alexandre; Dieterle, Stefan; Pouzet, Cecile; Aldon, Didier; Galaud, Jean-Philippe; Ranty, Benoit

2010-01-01

Research highlights: → The pseudo-response regulator PRR2 specifically binds CML9, a calmodulin-like protein → The interaction is confirmed in plant cell nuclei → 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.

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.

Understanding the Posttranscriptional Regulation of Plant Responses to Abiotic Stress

KAUST Repository

Alshareef, Sahar

2017-01-01

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

Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of Clostridium difficile

Directory of Open Access Journals (Sweden)

Charles Darkoh

2016-08-01

Full Text Available Clostridium difficile infection (CDI is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients. C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr quorum signaling system. Some C. difficile strains encode two Agr loci in their genomes, designated agr1 and agr2. The agr1 locus is present in all of the C. difficile strains sequenced to date, whereas the agr2 locus is present in a few strains. The functional roles of agr1 and agr2 in C. difficile toxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of both agr loci and examined the mutants for toxin production and virulence. The results showed that the agr1 mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-type agr1. Furthermore, the agr1 mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease.

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

The Essential Role of Mbd5 in the Regulation of Somatic Growth and Glucose Homeostasis in Mice

Science.gov (United States)

Du, Yarui; Liu, Bo; Guo, Fan; Xu, Guifang; Ding, Yuqiang; Liu, Yong; Sun, Xin; Xu, Guoliang

2012-01-01

Methyl-CpG binding domain protein 5 (MBD5) belongs to the MBD family proteins, which play central roles in transcriptional regulation and development. The significance of MBD5 function is highlighted by recent studies implicating it as a candidate gene involved in human 2q23.1 microdeletion syndrome. To investigate the physiological role of Mbd5, we generated knockout mice. The Mbd5-deficient mice showed growth retardation, wasting and pre-weaning lethality. The observed growth retardation was associated with the impairment of GH/IGF-1 axis in Mbd5-null pups. Conditional knockout of Mbd5 in the brain resulted in the similar phenotypes as whole body deletion, indicating that Mbd5 functions in the nervous system to regulate postnatal growth. Moreover, the mutant mice also displayed enhanced glucose tolerance and elevated insulin sensitivity as a result of increased insulin signaling, ultimately resulting in disturbed glucose homeostasis and hypoglycemia. These results indicate Mbd5 as an essential factor for mouse postnatal growth and maintenance of glucose homeostasis. PMID:23077600

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

The acute-phase response is a catabolic event involving increased waste of amino-nitrogen (N) via hepatic urea synthesis, despite an increased need for amino-N incorporation into acute-phase proteins. This study aimed to clarify the regulation of N elimination via urea during different phases...... 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...

Mondo/ChREBP-Mlx-Regulated Transcriptional Network Is Essential for Dietary Sugar Tolerance in Drosophila

Science.gov (United States)

Havula, Essi; Teesalu, Mari; Hyötyläinen, Tuulia; Seppälä, Heini; Hasygar, Kiran; Auvinen, Petri; Orešič, Matej; Sandmann, Thomas; Hietakangas, Ville

2013-01-01

Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources. PMID:23593032

The Specific Roles of Vitamins in the Regulation of Immunosurveillance and Maintenance of Immunologic Homeostasis in the Gut

OpenAIRE

Hosomi, Koji; Kunisawa, Jun

2017-01-01

Vitamins are micronutrients which are essential for the maintenance of biological responses including immune system. Hence, vitamin deficiency increases a risk of infectious, allergic, and inflammatory diseases. Accumulating evidence has recently revealed the molecular and cellular mechanisms of vitamin-mediated regulation in the active and quiescent immune responses. In this review, we focus on the immunologic roles of vitamins in the regulation of homeostasis and surveillance in the gut.

Wheat TILLING mutants show that the vernalization gene VRN1 down-regulates the flowering repressor VRN2 in leaves but is not essential for flowering.

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Andrew Chen

Full Text Available Most of the natural variation in wheat vernalization response is determined by allelic differences in the MADS-box transcription factor VERNALIZATION1 (VRN1. Extended exposures to low temperatures during the winter (vernalization induce VRN1 expression and promote the transition of the apical meristem to the reproductive phase. In contrast to its Arabidopsis homolog (APETALA1, which is mainly expressed in the apical meristem, VRN1 is also expressed at high levels in the leaves, but its function in this tissue is not well understood. Using tetraploid wheat lines with truncation mutations in the two homoeologous copies of VRN1 (henceforth vrn1-null mutants, we demonstrate that a central role of VRN1 in the leaves is to maintain low transcript levels of the VRN2 flowering repressor after vernalization. Transcript levels of VRN2 were gradually down-regulated during vernalization in both mutant and wild-type genotypes, but were up-regulated after vernalization only in the vrn1-null mutants. The up-regulation of VRN2 delayed flowering by repressing the transcription of FT, a flowering-integrator gene that encodes a mobile protein that is transported from the leaves to the apical meristem to induce flowering. The role of VRN2 in the delayed flowering of the vrn1-null mutant was confirmed using double vrn1-vrn2-null mutants, which flowered two months earlier than the vrn1-null mutants. Both mutants produced normal flowers and seeds demonstrating that VRN1 is not essential for wheat flowering, which contradicts current flowering models. This result does not diminish the importance of VRN1 in the seasonal regulation of wheat flowering. The up-regulation of VRN1 during winter is required to maintain low transcript levels of VRN2, accelerate the induction of FT in the leaves, and regulate a timely flowering in the spring. Our results also demonstrate the existence of redundant wheat flowering genes that may provide new targets for engineering wheat

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.

Apple and quince peroxidase activity in response to essential oils ...

African Journals Online (AJOL)

Enzymatic browning arises by peroxidase in fruits. However, essential oils are recognized as natural antioxidant agents. So in this study, the effect of thyme, coriander and rosemary essential oils were evaluated on the reduction of peroxidase activity in apples (Malus domestica Mill. cv Golden delicious), (M. domestica Mill.

[Mechanism and implication of regulation of the pricing of essential medicines in the private pharmaceutical sector in Mali].

Science.gov (United States)

Maïga, D; Maïga, S; Maïga, M D

2010-04-01

The healthcare and pharmaceutical professions in Mali were privatized in 1985. Privatization led to swift expansion of the private sector and upset the balance that had existed between the public and private sectors. A national pharmaceutical policy did not emerge until a decade later. Its purpose was to promote a system ensuring fair access to essential generic medicines for all. It was hoped that synergy between the two sectors would promote that objective. However, the policy calling for distribution of essential generic medicine through the private sector was not accompanied by an adequate system for pricing. This problem led the government to adopt a price regulation policy to realign market dynamics with public health goals. This experience shows that a sustained effort from public policy makers is necessary to prevail against the professional and business interests that can conflict with the public interest. Analysis of this experience also demonstrates the need to improve, restructure, and control the pharmaceutical industry. The government must continue to play its crucial role in the context of limited resources and inequality between consumers and pharmaceutical companies.

Antioxidant response elements: Discovery, classes, regulation and potential applications

Directory of Open Access Journals (Sweden)

Azhwar Raghunath

2018-07-01

Full Text Available Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs, which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress. Keywords: Antioxidant response elements, Antioxidant genes, ARE-reporter constructs, ARE SNPs, Keap1/Nrf2/ARE pathway, Oxidative stress

14 CFR 204.4 - Carriers proposing to provide essential air service.

Science.gov (United States)

2010-01-01

... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Carriers proposing to provide essential air... (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS DATA TO SUPPORT FITNESS DETERMINATIONS Filing Requirements § 204.4 Carriers proposing to provide essential air service. Applicants proposing to provide essential air...

Providers perspectives on self-regulation impact their use of responsive feeding practices in child care.

Science.gov (United States)

Dev, Dipti A; Speirs, Katherine E; Williams, Natalie A; Ramsay, Samantha; McBride, Brent A; Hatton-Bowers, Holly

2017-11-01

Supporting children's self-regulation in eating through caregivers' practice of responsive feeding is paramount to obesity prevention, and while much attention has been given to supporting children's self-regulation in eating through parents' responsive feeding practices in the home setting, little attention has been given to this issue in childcare settings. This qualitative study examines childcare providers' perspectives on using responsive feeding practices with young children (2-5years). Individual semi-structured interviews were conducted with providers until saturation was reached. Data was analyzed using thematic analysis. The final sample included 18 providers who were employed full-time in Head Start or state-licensed center-based childcare programs, cared for children (2-5y), and were directly responsible for serving meals and snacks. Providers were primarily (67%) employed in childcare programs that served children from low-income families and received reimbursement for meals and snacks from the US Department of Agriculture's Child and Adult Care Food Program. Three factors emerged that shaped childcare providers' experiences using responsive feeding practices: the providers' perspectives about whether or not young children can self-regulate food intake, their understanding of Child and Adult Care Food Program (CACFP) portion size regulations, and the availability of food at the center where they worked. Future research should examine how childcare providers' understanding of children's ability to self-regulate their food intake, the appropriate use of the CACFP regulations in relationship to serving sizes, and having food available to offer seconds promotes providers' use of responsive feeding practices in center-based childcare programs and children's dietary behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations.

Science.gov (United States)

Qing, Xiao-Yu; Steenackers, Hans; Venken, Tom; De Maeyer, Marc; Voet, Arnout

2017-11-01

The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the α4-β5-α5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Response Regulator YycF Inhibits Expression of the Fatty Acid Biosynthesis Repressor FabT in Streptococcus pneumoniae

Science.gov (United States)

Mohedano, Maria L.; Amblar, Mónica; de la Fuente, Alicia; Wells, Jerry M.; López, Paloma

2016-01-01

The YycFG (also known as WalRK, VicRK, MicAB, or TCS02) two-component system (TCS) is highly conserved among Gram-positive bacteria with a low G+C content. In Streptococcus pneumoniae the YycF response regulator has been reported to be essential due to its control of pcsB gene expression. Previously we showed that overexpression of yycF in S. pneumoniae TIGR4 altered the transcription of genes involved in cell wall metabolism and fatty acid biosynthesis, giving rise to anomalous cell division and increased chain length of membrane fatty acids. Here, we have overexpressed the yycFG system in TIGR4 wild-type strain and yycF in a TIGR4 mutant depleted of YycG, and analyzed their effects on expression of proteins involved in fatty acid biosynthesis during activation of the TCS. We demonstrate that transcription of the fab genes and levels of their products were only altered in the YycF overexpressing strain, indicating that the unphosphorylated form of YycF is involved in the regulation of fatty acid biosynthesis. In addition, DNA-binding assays and in vitro transcription experiments with purified YycF and the promoter region of the FabTH-acp operon support a direct inhibition of transcription of the FabT repressor by YycF, thus confirming the role of the unphosphorylated form in transcriptional regulation. PMID:27610104

DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses.

Science.gov (United States)

Bruneau, Sarah; Nakayama, Hironao; Woda, Craig B; Flynn, Evelyn A; Briscoe, David M

2013-09-05

The maintenance of normal tissue homeostasis and the prevention of chronic inflammatory disease are dependent on the active process of inflammation resolution. In endothelial cells (ECs), proinflammation results from the activation of intracellular signaling responses and/or the inhibition of endogenous regulatory/pro-resolution signaling networks that, to date, are poorly defined. In this study, we find that DEP domain containing mTOR interacting protein (DEPTOR) is expressed in different microvascular ECs in vitro and in vivo, and using a small interfering RNA (siRNA) knockdown approach, we find that it regulates mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 1 activation in part through independent mechanisms. Moreover, using limited gene arrays, we observed that DEPTOR regulates EC activation including mRNA expression of the T-cell chemoattractant chemokines CXCL9, CXCL10, CXCL11, CX3CL1, CCL5, and CCL20 and the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (P < .05). DEPTOR siRNA-transfected ECs also bound increased numbers of peripheral blood mononuclear cells (P < .005) and CD3+ T cells (P < .005) in adhesion assays in vitro and had increased migration and angiogenic responses in spheroid sprouting (P < .01) and wound healing (P < .01) assays. Collectively, these findings define DEPTOR as a critical upstream regulator of EC activation responses and suggest that it plays an important role in endogenous mechanisms of anti-inflammation and pro-resolution.

Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution.

Science.gov (United States)

Burgon, Joseph; Robertson, Anne L; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R; Walker, Paul; Hoggett, Emily E; Ward, Jonathan R; Farrow, Stuart N; Zuercher, William J; Jeffrey, Philip; Savage, Caroline O; Ingham, Philip W; Hurlstone, Adam F; Whyte, Moira K B; Renshaw, Stephen A

2014-02-15

The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid-regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.

Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

OpenAIRE

Judith A. Smith; Judith A. Smith

2018-01-01

Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defen...

Presenilins Regulate Neurotrypsin Gene Expression and Neurotrypsin-dependent Agrin Cleavage via Cyclic AMP Response Element-binding Protein (CREB) Modulation*

Science.gov (United States)

Almenar-Queralt, Angels; Kim, Sonia N.; Benner, Christopher; Herrera, Cheryl M.; Kang, David E.; Garcia-Bassets, Ivan; Goldstein, Lawrence S. B.

2013-01-01

Presenilins, the catalytic components of the γ-secretase complex, are upstream regulators of multiple cellular pathways via regulation of gene transcription. However, the underlying mechanisms and the genes regulated by these pathways are poorly characterized. In this study, we identify Tequila and its mammalian ortholog Prss12 as genes negatively regulated by presenilins in Drosophila larval brains and mouse embryonic fibroblasts, respectively. Prss12 encodes the serine protease neurotrypsin, which cleaves the heparan sulfate proteoglycan agrin. Altered neurotrypsin activity causes serious synaptic and cognitive defects; despite this, the molecular processes regulating neurotrypsin expression and activity are poorly understood. Using γ-secretase drug inhibitors and presenilin mutants in mouse embryonic fibroblasts, we found that a mature γ-secretase complex was required to repress neurotrypsin expression and agrin cleavage. We also determined that PSEN1 endoproteolysis or processing of well known γ-secretase substrates was not essential for this process. At the transcriptional level, PSEN1/2 removal induced cyclic AMP response element-binding protein (CREB)/CREB-binding protein binding, accumulation of activating histone marks at the neurotrypsin promoter, and neurotrypsin transcriptional and functional up-regulation that was dependent on GSK3 activity. Upon PSEN1/2 reintroduction, this active epigenetic state was replaced by a methyl CpG-binding protein 2 (MeCP2)-containing repressive state and reduced neurotrypsin expression. Genome-wide analysis revealed hundreds of other mouse promoters in which CREB binding is similarly modulated by the presence/absence of presenilins. Our study thus identifies Tequila and neurotrypsin as new genes repressed by presenilins and reveals a novel mechanism used by presenilins to modulate CREB signaling based on controlling CREB recruitment. PMID:24145027

Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation.

Science.gov (United States)

Almenar-Queralt, Angels; Kim, Sonia N; Benner, Christopher; Herrera, Cheryl M; Kang, David E; Garcia-Bassets, Ivan; Goldstein, Lawrence S B

2013-12-06

Presenilins, the catalytic components of the γ-secretase complex, are upstream regulators of multiple cellular pathways via regulation of gene transcription. However, the underlying mechanisms and the genes regulated by these pathways are poorly characterized. In this study, we identify Tequila and its mammalian ortholog Prss12 as genes negatively regulated by presenilins in Drosophila larval brains and mouse embryonic fibroblasts, respectively. Prss12 encodes the serine protease neurotrypsin, which cleaves the heparan sulfate proteoglycan agrin. Altered neurotrypsin activity causes serious synaptic and cognitive defects; despite this, the molecular processes regulating neurotrypsin expression and activity are poorly understood. Using γ-secretase drug inhibitors and presenilin mutants in mouse embryonic fibroblasts, we found that a mature γ-secretase complex was required to repress neurotrypsin expression and agrin cleavage. We also determined that PSEN1 endoproteolysis or processing of well known γ-secretase substrates was not essential for this process. At the transcriptional level, PSEN1/2 removal induced cyclic AMP response element-binding protein (CREB)/CREB-binding protein binding, accumulation of activating histone marks at the neurotrypsin promoter, and neurotrypsin transcriptional and functional up-regulation that was dependent on GSK3 activity. Upon PSEN1/2 reintroduction, this active epigenetic state was replaced by a methyl CpG-binding protein 2 (MeCP2)-containing repressive state and reduced neurotrypsin expression. Genome-wide analysis revealed hundreds of other mouse promoters in which CREB binding is similarly modulated by the presence/absence of presenilins. Our study thus identifies Tequila and neurotrypsin as new genes repressed by presenilins and reveals a novel mechanism used by presenilins to modulate CREB signaling based on controlling CREB recruitment.

A Novel PCR Assay for Listeria welshimeri Targeting Transcriptional Regulator Gene lwe1801

Science.gov (United States)

Transcriptional regulator genes encode a group of specialized molecules that play essential roles in microbial responses to changing external conditions. These genes have been shown to possess species or group specificity and are useful as detection targets for diagnostic application. The present st...

Drosophila UTX coordinates with p53 to regulate ku80 expression in response to DNA damage.

Directory of Open Access Journals (Sweden)

Chengwan Zhang

Full Text Available UTX is known as a general factor that activates gene transcription during development. Here, we demonstrate an additional essential role of UTX in the DNA damage response, in which it upregulates the expression of ku80 in Drosophila, both in cultured cells and in third instar larvae. We further showed that UTX mediates the expression of ku80 by the demethylation of H3K27me3 at the ku80 promoter upon exposure to ionizing radiation (IR in a p53-dependent manner. UTX interacts physically with p53, and both UTX and p53 are recruited to the ku80 promoter following IR exposure in an interdependent manner. In contrast, the loss of utx has little impact on the expression of ku70, mre11, hid and reaper, suggesting the specific regulation of ku80 expression by UTX. Thus, our findings further elucidate the molecular function of UTX.

Shigella Iron Acquisition Systems and their Regulation.

Science.gov (United States)

Wei, Yahan; Murphy, Erin R

2016-01-01

Survival of Shigella within the host is strictly dependent on the ability of the pathogen to acquire essential nutrients, such as iron. As an innate immune defense against invading pathogens, the level of bio-available iron within the human host is maintained at exceeding low levels, by sequestration of the element within heme and other host iron-binding compounds. In response to sequestration mediated iron limitation, Shigella produce multiple iron-uptake systems that each function to facilitate the utilization of a specific host-associated source of nutrient iron. As a mechanism to balance the essential need for iron and the toxicity of the element when in excess, the production of bacterial iron acquisition systems is tightly regulated by a variety of molecular mechanisms. This review summarizes the current state of knowledge on the iron-uptake systems produced by Shigella species, their distribution within the genus, and the molecular mechanisms that regulate their production.

Delicate regulation of the cGAS-MITA-mediated innate immune response.

Science.gov (United States)

Luo, Wei-Wei; Shu, Hong-Bing

2018-02-19

Although it has long been demonstrated that cytosolic DNA is a potent immune stimulant, it is only in recent years that the molecular mechanisms of DNA-stimulated innate immune responses have emerged. Studies have established critical roles for the DNA sensor cyclic GMP-AMP synthase (cGAS) and the adapter protein MITA/STING in the innate immune response to cytosolic DNA or DNA viruses. Although the regulation of cGAS-MITA/STING-mediated signaling remains to be fully investigated, understanding the processes involved may help to explain the mechanisms of innate immune signaling events and perhaps autoinflammatory diseases and to provide potential therapeutic targets for drug intervention. In this review, we summarize recent progress on the regulation of the cGAS-MITA/STING-mediated innate immune response to DNA viruses at the organelle-trafficking, post-translational and transcriptional levels.Cellular & Molecular Immunology advance online publication, 19 February 2018; doi:10.1038/cmi.2016.51.

Regulation and Turnover of Nitric Oxide by Phytoglobins in Plant Cell Responses

DEFF Research Database (Denmark)

Igamberdiev, Abir U; Hebelstrup, Kim; Stasolla, Claudio

2016-01-01

The involvement of phytoglobins in the metabolism of nitric oxide (NO) and reactive nitrogen species (RNS) produced during stress, plant growth, and development is discussed. The action of phytoglobin expression upon NO leads to the maintenance of redox status, minimization of the damage from...... to the mobility of both NO and phytohormones, plants developed strategies to regulate specific cell hormonal actions to permit differentiation during development and to respond to stress. Phytoglobins are the agents responsible for differential cellular responses to hormones that use NO as a signal transduction...... reactive oxygen and nitrogen species in the cytoplasm of the cell, and regulation of hormonal and stress responses. NO scavenging is achieved via phytoglobins, and it can also involve S-nitrosoglutathione reductase and a direct interaction of NO with superoxide anion followed by detoxification of formed...

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Science.gov (United States)

Lee, Hong-Jen; Lan, Li; Peng, Guang; Chang, Wei-Chao; Hsu, Ming-Chuan; Wang, Ying-Nai; Cheng, Chien-Chia; Wei, Leizhen; Nakajima, Satoshi; Chang, Shih-Shin; Liao, Hsin-Wei; Chen, Chung-Hsuan; Lavin, Martin; Ang, K Kian; Lin, Shiaw-Yih; Hung, Mien-Chie

2015-01-01

Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition. PMID:25601159

Deletion of the Ustilago maydis ortholog of the Aspergillus sporulation regulator medA affects mating and virulence through pheromone response

Science.gov (United States)

Mating of compatible haploid cells of Ustilago maydis is essential for infection and disease development in the host. For mating and subsequent filamentous growth and pathogenicity, the transcription factor, prf1 is necessary. Prf1 is in turn regulated by the cAMP and MAPK pathways and other regul...

Innate scavenger receptor-A regulates adaptive T helper cell responses to pathogen infection

Science.gov (United States)

Xu, Zhipeng; Xu, Lei; Li, Wei; Jin, Xin; Song, Xian; Chen, Xiaojun; Zhu, Jifeng; Zhou, Sha; Li, Yong; Zhang, Weiwei; Dong, Xiaoxiao; Yang, Xiaowei; Liu, Feng; Bai, Hui; Chen, Qi; Su, Chuan

2017-01-01

The pattern recognition receptor (PRR) scavenger receptor class A (SR-A) has an important function in the pathogenesis of non-infectious diseases and in innate immune responses to pathogen infections. However, little is known about the role of SR-A in the host adaptive immune responses to pathogen infection. Here we show with mouse models of helminth Schistosoma japonicum infection and heat-inactivated Mycobacterium tuberculosis stimulation that SR-A is regulated by pathogens and suppresses IRF5 nuclear translocation by direct interaction. Reduced abundance of nuclear IRF5 shifts macrophage polarization from M1 towards M2, which subsequently switches T-helper responses from type 1 to type 2. Our study identifies a role for SR-A as an innate PRR in regulating adaptive immune responses. PMID:28695899

Structure of the Francisella response regulator QseB receiver domain, and characterization of QseB inhibition by antibiofilm 2-aminoimidazole-based compounds: Inhibition of response regulator QseB by antibiofilm compounds

Energy Technology Data Exchange (ETDEWEB)

Milton, Morgan E.; Allen, C. Leigh; Feldmann, Erik A.; Bobay, Benjamin G.; Jung, David K.; Stephens, Matthew D.; Melander, Roberta J.; Theisen, Kelly E.; Zeng, Daina; Thompson, Richele J.; Melander, Christian; Cavanagh, John (NCSU)

2017-08-16

With antibiotic resistance increasing at alarming rates, targets for new antimicrobial therapies must be identified. A particularly promising target is the bacterial two-component system. Two-component systems allow bacteria to detect, evaluate and protect themselves against changes in the environment, such as exposure to antibiotics and also to trigger production of virulence factors. Drugs that target the response regulator portion of two-component systems represent a potent new approach so far unexploited. Here, we focus efforts on the highly virulent bacterium Francisella tularensis tularensis. Francisella contains only three response regulators, making it an ideal system to study. In this study, we initially present the structure of the N-terminal domain of QseB, the response regulator responsible for biofilm formation. Subsequently, using binding assays, computational docking and cellular studies, we show that QseB interacts with2-aminoimidazole based compounds that impede its function. This information will assist in tailoring compounds to act as adjuvants that will enhance the effect of antibiotics.

14 CFR 272.3 - Places eligible for guaranteed essential air service.

Science.gov (United States)

2010-01-01

... TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS ESSENTIAL AIR SERVICE TO THE FREELY ASSOCIATED STATES § 272.3 Places eligible for guaranteed essential air service. (a) Subject to the provisions of this part... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Places eligible for guaranteed essential...

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.

DNA demethylases target promoter transposable elements to positively regulate stress responsive genes in Arabidopsis.

Science.gov (United States)

Le, Tuan-Ngoc; Schumann, Ulrike; Smith, Neil A; Tiwari, Sameer; Au, Phil Chi Khang; Zhu, Qian-Hao; Taylor, Jennifer M; Kazan, Kemal; Llewellyn, Danny J; Zhang, Ren; Dennis, Elizabeth S; Wang, Ming-Bo

2014-09-17

DNA demethylases regulate DNA methylation levels in eukaryotes. Arabidopsis encodes four DNA demethylases, DEMETER (DME), REPRESSOR OF SILENCING 1 (ROS1), DEMETER-LIKE 2 (DML2), and DML3. While DME is involved in maternal specific gene expression during seed development, the biological function of the remaining DNA demethylases remains unclear. We show that ROS1, DML2, and DML3 play a role in fungal disease resistance in Arabidopsis. A triple DNA demethylase mutant, rdd (ros1 dml2 dml3), shows increased susceptibility to the fungal pathogen Fusarium oxysporum. We identify 348 genes differentially expressed in rdd relative to wild type, and a significant proportion of these genes are downregulated in rdd and have functions in stress response, suggesting that DNA demethylases maintain or positively regulate the expression of stress response genes required for F. oxysporum resistance. The rdd-downregulated stress response genes are enriched for short transposable element sequences in their promoters. Many of these transposable elements and their surrounding sequences show localized DNA methylation changes in rdd, and a general reduction in CHH methylation, suggesting that RNA-directed DNA methylation (RdDM), responsible for CHH methylation, may participate in DNA demethylase-mediated regulation of stress response genes. Many of the rdd-downregulated stress response genes are downregulated in the RdDM mutants nrpd1 and nrpe1, and the RdDM mutants nrpe1 and ago4 show enhanced susceptibility to F. oxysporum infection. Our results suggest that a primary function of DNA demethylases in plants is to regulate the expression of stress response genes by targeting promoter transposable element sequences.

Fitting into the Harsh Reality: Regulation of Irondeficiency Responses in Dicotyledonous Plants

Institute of Scientific and Technical Information of China (English)

Rumen Ivanov; Tzvetina Brumbarova; Petra Bauer

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 ironresponsive 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.

Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide

Science.gov (United States)

Fomenko, Dmitri E.; Koc, Ahmet; Agisheva, Natalia; Jacobsen, Michael; Kaya, Alaattin; Malinouski, Mikalai; Rutherford, Julian C.; Siu, Kam-Leung; Jin, Dong-Yan; Winge, Dennis R.; Gladyshev, Vadim N.

2011-01-01

Hydrogen peroxide is thought to regulate cellular processes by direct oxidation of numerous cellular proteins, whereas antioxidants, most notably thiol peroxidases, are thought to reduce peroxides and inhibit H2O2 response. However, thiol peroxidases have also been implicated in activation of transcription factors and signaling. It remains unclear if these enzymes stimulate or inhibit redox regulation and whether this regulation is widespread or limited to a few cellular components. Herein, we found that Saccharomyces cerevisiae cells lacking all eight thiol peroxidases were viable and withstood redox stresses. They transcriptionally responded to various redox treatments, but were unable to activate and repress gene expression in response to H2O2. Further studies involving redox transcription factors suggested that thiol peroxidases are major regulators of global gene expression in response to H2O2. The data suggest that thiol peroxidases sense and transfer oxidative signals to the signaling proteins and regulate transcription, whereas a direct interaction between H2O2 and other cellular proteins plays a secondary role. PMID:21282621

Stress responses during ageing: molecular pathways regulating protein homeostasis.

Science.gov (United States)

Kyriakakis, Emmanouil; Princz, Andrea; Tavernarakis, Nektarios

2015-01-01

The ageing process is characterized by deterioration of physiological function accompanied by frailty and ageing-associated diseases. The most broadly and well-studied pathways influencing ageing are the insulin/insulin-like growth factor 1 signaling pathway and the dietary restriction pathway. Recent studies in diverse organisms have also delineated emerging pathways, which collectively or independently contribute to ageing. Among them the proteostatic-stress-response networks, inextricably affect normal ageing by maintaining or restoring protein homeostasis to preserve proper cellular and organismal function. In this chapter, we survey the involvement of heat stress and endoplasmic reticulum stress responses in the regulation of longevity, placing emphasis on the cross talk between different response mechanisms and their systemic effects. We further discuss novel insights relevant to the molecular pathways mediating these stress responses that may facilitate the development of innovative interventions targeting age-related pathologies such as diabetes, cancer, cardiovascular and neurodegenerative diseases.

Nrf2, the Master Regulator of Anti-Oxidative Responses

Directory of Open Access Journals (Sweden)

Sandra Vomund

2017-12-01

Full Text Available Tight regulation of inflammation is very important to guarantee a balanced immune response without developing chronic inflammation. One of the major mediators of the resolution of inflammation is the transcription factor: the nuclear factor erythroid 2-like 2 (Nrf2. Stabilized following oxidative stress, Nrf2 induces the expression of antioxidants as well as cytoprotective genes, which provoke an anti-inflammatory expression profile, and is crucial for the initiation of healing. In view of this fundamental modulatory role, it is clear that both hyper- or hypoactivation of Nrf2 contribute to the onset of chronic diseases. Understanding the tight regulation of Nrf2 expression/activation and its interaction with signaling pathways, known to affect inflammatory processes, will facilitate development of therapeutic approaches to prevent Nrf2 dysregulation and ameliorate chronic inflammatory diseases. We discuss in this review the principle mechanisms of Nrf2 regulation with a focus on inflammation and autophagy, extending the role of dysregulated Nrf2 to chronic diseases and tumor development.

microRNA regulation of the embryonic hypoxic response in Caenorhabditis elegans

DEFF Research Database (Denmark)

Kagias, Konstantinos; Pocock, Roger

2015-01-01

Layered strategies to combat hypoxia provide flexibility in dynamic oxygen environments. Here we show that multiple miRNAs are required for hypoxic survival responses during C. elegans embryogenesis. Certain miRNAs promote while others antagonize the hypoxic survival response. We found...... of the full mRNA target repertoire of these miRNAs will reveal the miRNA-regulated network of hypoxic survival mechanisms in C. elegans....

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.

Locus coeruleus phasic discharge is essential for stimulus-induced gamma oscillations in the prefrontal cortex.

Science.gov (United States)

Neves, Ricardo M; van Keulen, Silvia; Yang, Mingyu; Logothetis, Nikos K; Eschenko, Oxana

2018-03-01

The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We previously reported that LC microstimulation caused a transient desynchronization of population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest modulation in the gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, an α 2 -adrenoreceptor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the PFC and is essential for mediating sensory information along an ascending noxious pathway. NEW & NOTEWORTHY Our study shows linear relationships between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory information

Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing.

Directory of Open Access Journals (Sweden)

Olivier J Becherel

2013-04-01

Full Text Available Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2, plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI. Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops, and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx⁻/⁻ revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.

Essential role of RSK2 in c-Fos-dependent osteosarcoma development.

Science.gov (United States)

David, Jean-Pierre; Mehic, Denis; Bakiri, Latifa; Schilling, Arndt F; Mandic, Vice; Priemel, Matthias; Idarraga, Maria Helena; Reschke, Markus O; Hoffmann, Oskar; Amling, Michael; Wagner, Erwin F

2005-03-01

Inactivation of the growth factor-regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities. Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation. The phenotype is associated with decreased expression of Phex, an endopeptidase regulating bone mineralization. This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus. However, in the absence of RSK2, c-Fos-dependent osteosarcoma formation is impaired. The lack of c-Fos phosphorylation leads to reduced c-Fos protein levels, which are thought to be responsible for decreased proliferation and increased apoptosis of transformed osteoblasts. Therefore, RSK2-dependent stabilization of c-Fos is essential for osteosarcoma formation in mice and may also be important for human osteosarcomas.

Demonstration of Essential Reliability Services by a 300-MW Solar Photovoltaic Power Plant

Energy Technology Data Exchange (ETDEWEB)

Loutan, Clyde; Klauer, Peter; Chowdhury, Sirajul; Hall, Stephen; Morjaria, Mahesh; Chadliev, Vladimir; Milam, Nick; Milan, Christopher; Gevorgian, Vahan

2017-03-24

The California Independent System Operator (CAISO), First Solar, and the National Renewable Energy Laboratory (NREL) conducted a demonstration project on a large utility-scale photovoltaic (PV) power plant in California to test its ability to provide essential ancillary services to the electric grid. With increasing shares of solar- and wind-generated energy on the electric grid, traditional generation resources equipped with automatic governor control (AGC) and automatic voltage regulation controls -- specifically, fossil thermal -- are being displaced. The deployment of utility-scale, grid-friendly PV power plants that incorporate advanced capabilities to support grid stability and reliability is essential for the large-scale integration of PV generation into the electric power grid, among other technical requirements. A typical PV power plant consists of multiple power electronic inverters and can contribute to grid stability and reliability through sophisticated 'grid-friendly' controls. In this way, PV power plants can be used to mitigate the impact of variability on the grid, a role typically reserved for conventional generators. In August 2016, testing was completed on First Solar's 300-MW PV power plant, and a large amount of test data was produced and analyzed that demonstrates the ability of PV power plants to use grid-friendly controls to provide essential reliability services. These data showed how the development of advanced power controls can enable PV to become a provider of a wide range of grid services, including spinning reserves, load following, voltage support, ramping, frequency response, variability smoothing, and frequency regulation to power quality. Specifically, the tests conducted included various forms of active power control such as AGC and frequency regulation; droop response; and reactive power, voltage, and power factor controls. This project demonstrated that advanced power electronics and solar generation can be

Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension

DEFF Research Database (Denmark)

Damkjaer, M.; Jensen, Pia Hønnerup; Schwämmle, Veit

2014-01-01

AimIn essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein...... patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion. MethodsAfter 2-week drug washout and 4-day diet, systemic and renal hemodynamics, cardio-renal hormones, glomerular filtration and renal excretion were studied in male patients during saline loading (SL...

Reducing Conservatism in Aircraft Engine Response Using Conditionally Active Min-Max Limit Regulators

Science.gov (United States)

May, Ryan D.; Garg, Sanjay

2012-01-01

Current aircraft engine control logic uses a Min-Max control selection structure to prevent the engine from exceeding any safety or operational limits during transients due to throttle commands. This structure is inherently conservative and produces transient responses that are slower than necessary. In order to utilize the existing safety margins more effectively, a modification to this architecture is proposed, referred to as a Conditionally Active (CA) limit regulator. This concept uses the existing Min-Max architecture with the modification that limit regulators are active only when the operating point is close to a particular limit. This paper explores the use of CA limit regulators using a publicly available commercial aircraft engine simulation. The improvement in thrust response while maintaining all necessary safety limits is demonstrated in a number of cases.

Specific microRNAs Regulate Heat Stress Responses in Caenorhabditis elegans

DEFF Research Database (Denmark)

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

2015-01-01

have identified additional functions for already known players (mir-71 and mir-239) as well as identifying mir-80 and the mir-229 mir-64-66 cluster as important regulators of the heat stress response in C. elegans. These findings uncover an additional layer of complexity to the regulation of stress...... to heat stress in Caenorhabditis elegans and show that a discrete subset of miRNAs is thermoregulated. Using in-depth phenotypic analyses of miRNA deletion mutant strains we reveal multiple developmental and post-developmental survival and behavioral functions for specific miRNAs during heat stress. We...

The external PASTA domain of the essential serine/threonine protein kinase PknB regulates mycobacterial growth.

Science.gov (United States)

Turapov, Obolbek; Loraine, Jessica; Jenkins, Christopher H; Barthe, Philippe; McFeely, Daniel; Forti, Francesca; Ghisotti, Daniela; Hesek, Dusan; Lee, Mijoon; Bottrill, Andrew R; Vollmer, Waldemar; Mobashery, Shahriar; Cohen-Gonsaud, Martin; Mukamolova, Galina V

2015-07-01

PknB is an essential serine/threonine protein kinase required for mycobacterial cell division and cell-wall biosynthesis. Here we demonstrate that overexpression of the external PknB_PASTA domain in mycobacteria results in delayed regrowth, accumulation of elongated bacteria and increased sensitivity to β-lactam antibiotics. These changes are accompanied by altered production of certain enzymes involved in cell-wall biosynthesis as revealed by proteomics studies. The growth inhibition caused by overexpression of the PknB_PASTA domain is completely abolished by enhanced concentration of magnesium ions, but not muropeptides. Finally, we show that the addition of recombinant PASTA domain could prevent regrowth of Mycobacterium tuberculosis, and therefore offers an alternative opportunity to control replication of this pathogen. These results suggest that the PknB_PASTA domain is involved in regulation of peptidoglycan biosynthesis and maintenance of cell-wall architecture.

Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress

Directory of Open Access Journals (Sweden)

Stephanie Munk

2017-10-01

Full Text Available The mechanisms that protect eukaryotic DNA during the cumbersome task of replication depend on the precise coordination of several post-translational modification (PTM-based signaling networks. Phosphorylation is a well-known regulator of the replication stress response, and recently an essential role for SUMOs (small ubiquitin-like modifiers has also been established. Here, we investigate the global interplay between phosphorylation and SUMOylation in response to replication stress. Using SUMO and phosphoproteomic technologies, we identify thousands of regulated modification sites. We find co-regulation of central DNA damage and replication stress responders, of which the ATR-activating factor TOPBP1 is the most highly regulated. Using pharmacological inhibition of the DNA damage response kinases ATR and ATM, we find that these factors regulate global protein SUMOylation in the protein networks that protect DNA upon replication stress and fork breakage, pointing to integration between phosphorylation and SUMOylation in the cellular systems that protect DNA integrity.

Energy regulation in China: Objective selection, potential assessment and responsibility sharing by partial frontier analysis

International Nuclear Information System (INIS)

Xia, X.H.; Chen, Y.B.; Li, J.S.; Tasawar, H.; Alsaedi, A.; Chen, G.Q.

2014-01-01

To cope with the excessive growth of energy consumption, the Chinese government has been trying to strengthen the energy regulation system by introducing new initiatives that aim at controlling the total amount of energy consumption. A partial frontier analysis is performed in this paper to make a comparative assessment of the combinations of possible energy conservation objectives, new constraints and regulation strategies. According to the characteristics of the coordination of existing regulation structure and the optimality of regulation strategy, four scenarios are constructed and regional responsibilities are reasonably divided by fully considering the production technology in the economy. The relative importance of output objectives and the total amount controlling is compared and the impacts on the regional economy caused by the changes of regulation strategy are also evaluated for updating regulation policy. - Highlights: • New initiatives to control the total amount of energy consumption are evaluated. • Twenty-four regulation strategies and four scenarios are designed and compared. • Crucial regions for each sector and regional potential are identified. • The national goals of energy abatement are decomposed into regional responsibilities. • The changes of regulation strategy are evaluated for updating regulation policy

14 CFR 272.6 - Considerations in the determination of essential air service.

Science.gov (United States)

2010-01-01

... essential air service. 272.6 Section 272.6 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS ESSENTIAL AIR SERVICE TO THE FREELY ASSOCIATED STATES § 272.6 Considerations in the determination of essential air service. (a) In the determination of...

Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Regulates Neutrophil Clearance During Inflammation Resolution

Science.gov (United States)

Burgon, Joseph; Robertson, Anne L.; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R.; Walker, Paul; Hoggett, Emily E.; Ward, Jonathan R.; Farrow, Stuart N.; Zuercher, William J.; Jeffrey, Philip; Savage, Caroline O.; Ingham, Philip W.; Hurlstone, Adam F.; Whyte, Moira K. B.; Renshaw, Stephen A.

2013-01-01

The inflammatory response is integral to maintaining health, by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralise invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein Serum and Glucocorticoid Regulated Kinase 1 (SGK1). We have characterised the expression patterns and regulation of SGK family members in human neutrophils, and shown that inhibition of SGK activity completely abrogates the anti-apoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signalling, and thus may prove a valuable therapeutic target for the treatment of inflammatory disease. PMID:24431232

49 CFR 40.11 - What are the general responsibilities of employers under this regulation?

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false What are the general responsibilities of employers... PROCEDURES FOR TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Employer Responsibilities § 40.11 What are the general responsibilities of employers under this regulation? (a) As an employer, you are...

Does the renin-angiotensin system determine the renal and systemic hemodynamic response to sodium in patients with essential hypertension?

NARCIS (Netherlands)

vanPaassen, P; deZeeuw, D; Navis, G; deJong, PE

Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the

Stress responsiveness of the hypothalamic-pituitary-adrenal axis: age-related features of the vasopressinergic regulation

Directory of Open Access Journals (Sweden)

Nadezhda Dmitrievna Goncharova

2013-03-01

Full Text Available The hypothalamic-pituitary-adrenal (HPA axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH and arginine vasopressin (AVP into pituitary portal system; CRH and AVP stimulate ACTH release through specific G protein-coupled membrane receptors on pituitary corticotrophs, CRH1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.

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

NapA Mediates a Redox Regulation of the Antioxidant Response, Carbon Utilization and Development in Aspergillus nidulans

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Ariann E. Mendoza-Martínez

2017-03-01

Full Text Available The redox-regulated transcription factors (TFs of the bZIP AP1 family, such as yeast Yap1 and fission yeast Pap1, are activated by peroxiredoxin proteins (Prxs to regulate the antioxidant response. Previously, Aspergillus nidulans mutants lacking the Yap1 ortholog NapA have been characterized as sensitive to H2O2 and menadione. Here we study NapA roles in relation to TFs SrrA and AtfA, also involved in oxidant detoxification, showing that these TFs play different roles in oxidative stress resistance, catalase gene regulation and development, during A. nidulans life cycle. We also uncover novel NapA roles in repression of sexual development, normal conidiation, conidial mRNA accumulation, and carbon utilization. The phenotypic characterization of ΔgpxA, ΔtpxA, and ΔtpxB single, double and triple peroxiredoxin mutants in wild type or ΔnapA backgrounds shows that none of these Prxs is required for NapA function in H2O2 and menadione resistance. However, these Prxs participate in a minor NapA-independent H2O2 resistance pathway and NapA and TpxA appear to regulate conidiation along the same route. Using transcriptomic analysis we show that during conidial development NapA-dependent gene expression pattern is different from canonical oxidative stress patterns. In the course of conidiation, NapA is required for regulation of at least 214 genes, including ethanol utilization genes alcR, alcA and aldA, and large sets of genes encoding proteins involved in transcriptional regulation, drug detoxification, carbohydrate utilization and secondary metabolism, comprising multiple oxidoreductases, membrane transporters and hydrolases. In agreement with this, ΔnapA mutants fail to grow or grow very poorly in ethanol, arabinose or fructose as sole carbon sources. Moreover, we show that NapA nuclear localization is induced not only by oxidative stress but also by growth in ethanol and by carbon starvation. Together with our previous work, these results show

Melanopsin Regulates Both Sleep-Promoting and Arousal-Promoting Responses to Light.

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Violetta Pilorz

2016-06-01

Full Text Available Light plays a critical role in the regulation of numerous aspects of physiology and behaviour, including the entrainment of circadian rhythms and the regulation of sleep. These responses involve melanopsin (OPN4-expressing photosensitive retinal ganglion cells (pRGCs in addition to rods and cones. Nocturnal light exposure in rodents has been shown to result in rapid sleep induction, in which melanopsin plays a key role. However, studies have also shown that light exposure can result in elevated corticosterone, a response that is not compatible with sleep. To investigate these contradictory findings and to dissect the relative contribution of pRGCs and rods/cones, we assessed the effects of light of different wavelengths on behaviourally defined sleep. Here, we show that blue light (470 nm causes behavioural arousal, elevating corticosterone and delaying sleep onset. By contrast, green light (530 nm produces rapid sleep induction. Compared to wildtype mice, these responses are altered in melanopsin-deficient mice (Opn4-/-, resulting in enhanced sleep in response to blue light but delayed sleep induction in response to green or white light. We go on to show that blue light evokes higher Fos induction in the SCN compared to the sleep-promoting ventrolateral preoptic area (VLPO, whereas green light produced greater responses in the VLPO. Collectively, our data demonstrates that nocturnal light exposure can have either an arousal- or sleep-promoting effect, and that these responses are melanopsin-mediated via different neural pathways with different spectral sensitivities. These findings raise important questions relating to how artificial light may alter behaviour in both the work and domestic setting.

Relationship between cognitive emotion regulation, social support, resilience and acute stress responses in Chinese soldiers: Exploring multiple mediation model.

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Cai, Wen-Peng; Pan, Yu; Zhang, Shui-Miao; Wei, Cun; Dong, Wei; Deng, Guang-Hui

2017-10-01

The current study aimed to explore the association of cognitive emotion regulation, social support, resilience and acute stress responses in Chinese soldiers and to understand the multiple mediation effects of social support and resilience on the relationship between cognitive emotion regulation and acute stress responses. A total of 1477 male soldiers completed mental scales, including the cognitive emotion regulation questionnaire-Chinese version, the perceived social support scale, the Chinese version of the Connor-Davidson resilience scale, and the military acute stress scale. As hypothesized, physiological responses, psychological responses, and acute stress were associated with negative-focused cognitive emotion regulation, and negatively associated with positive-focused cognitive emotion regulation, social supports and resilience. Besides, positive-focused cognitive emotion regulation, social support, and resilience were significantly associated with one another, and negative-focused cognitive emotion regulation was negatively associated with social support. Regression analysis and bootstrap analysis showed that social support and resilience had partly mediating effects on negative strategies and acute stress, and fully mediating effects on positive strategies and acute stress. These results thus indicate that military acute stress is significantly associated with cognitive emotion regulation, social support, and resilience, and that social support and resilience have multiple mediation effects on the relationship between cognitive emotion regulation and acute stress responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Regulation of Neurotransmitter Responses in the Central Nervous System.

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1987-05-01

and identify by block number) FIELD GROUP SUB-GROUP J’-aminobutyric acid; yclic AM’P; neuromodulation ; brain 1ABTAT(Continue on reverse if necessary and...crucial enzyme for regulating neuromodulation in brain. Given the ultimate goal of developing novel pharmacological agents for N! manipulating...central nervous system function, the discovery of a biochemical response to a neuromodulator can be considered a major step in that direction. Thus, up to

Iron deficiency regulated OsOPT7 is essential for iron homeostasis in rice.

Science.gov (United States)

Bashir, Khurram; Ishimaru, Yasuhiro; Itai, Reiko Nakanishi; Senoura, Takeshi; Takahashi, Michiko; An, Gynheung; Oikawa, Takaya; Ueda, Minoru; Sato, Aiko; Uozumi, Nobuyuki; Nakanishi, Hiromi; Nishizawa, Naoko K

2015-05-01

The molecular mechanism of iron (Fe) uptake and transport in plants are well-characterized; however, many components of Fe homeostasis remain unclear. We cloned iron-deficiency-regulated oligopeptide transporter 7 (OsOPT7) from rice. OsOPT7 localized to the plasma membrane and did not transport Fe(III)-DMA or Fe(II)-NA and GSH in Xenopus laevis oocytes. Furthermore OsOPT7 did not complement the growth of yeast fet3fet4 mutant. OsOPT7 was specifically upregulated in response to Fe-deficiency. Promoter GUS analysis revealed that OsOPT7 expresses in root tips, root vascular tissue and shoots as well as during seed development. Microarray analysis of OsOPT7 knockout 1 (opt7-1) revealed the upregulation of Fe-deficiency-responsive genes in plants grown under Fe-sufficient conditions, despite the high Fe and ferritin concentrations in shoot tissue indicating that Fe may not be available for physiological functions. Plants overexpressing OsOPT7 do not exhibit any phenotype and do not accumulate more Fe compared to wild type plants. These results indicate that OsOPT7 may be involved in Fe transport in rice.

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

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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.

The ethylene response factor AtERF4 negatively regulates the iron deficiency response in Arabidopsis thaliana.

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Wei Liu

Full Text Available Iron (Fe deficiency is one of many conditions that can seriously damage crops. Low levels of photosynthesis can lead to the degradation of chlorophyll content and impaired respiration in affected plants, which together cause poor growth and reduce quality. Although ethylene plays an important role in responses to Fe deficiency, a limited number of studies have been carried out on ethylene response factor (ERFs as components of plant regulation mechanisms. Thus, this study aimed to investigate the role of AtERF4 in plant responses to Fe deficiency. Results collected when Arabidopsis thaliana was grown under Fe deficient conditions as well as in the presence of 1-aminocyclopropane-1-carboxylic acid (ACC revealed that leaf chlorosis did not occur over short timescales and that chloroplast structural integrity was retained. At the same time, expression of the chlorophyll degradation-related genes AtPAO and AtCLH1 was inhibited and net H+ root flux was amplified. Our results show that chlorophyll content was enhanced in the mutant erf4, while expression of the chlorophyll degradation gene AtCLH1 was reduced. Ferric reductase activity in roots was also significantly higher in the mutant than in wild type plants, while erf4 caused high levels of expression of the genes AtIRT1 and AtHA2 under Fe deficient conditions. We also utilized yeast one-hybrid technology in this study to determine that AtERF4 binds directly to the AtCLH1 and AtITR1 promoter. Observations show that transient over-expression of AtERF4 resulted in rapid chlorophyll degradation in the leaves of Nicotiana tabacum and the up-regulation of gene AtCLH1 expression. In summary, AtERF4 plays an important role as a negative regulator of Fe deficiency responses, we hypothesize that AtERF4 may exert a balancing effect on plants subject to nutrition stress.

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 ...

Transcriptional regulation of dimethyl sulfoxide respiration in a haloarchaeon, Haloferax volcanii.

Science.gov (United States)

Qi, Qiuzi; Ito, Yoshiyasu; Yoshimatsu, Katsuhiko; Fujiwara, Taketomo

2016-01-01

The halophilic euryarchaeon Haloferax volcanii can grow anaerobically by DMSO respiration. DMSO reductase was induced by DMSO respiration not only under anaerobic growth conditions but also in denitrifying cells of H. volcanii. Deletion of the dmsR gene, encoding a putative regulator for the DMSO reductase, resulted in the loss of anaerobic growth by DMSO respiration. Reporter experiments revealed that only the anaerobic condition was essential for transcription of the dmsEABCD genes encoding DMSO reductase and that transcription was enhanced threefold by supplementation of DMSO. In the ∆dmsR mutant, transcription of the dmsEABCD genes induced by the anaerobic condition was not enhanced by DMSO, suggesting that DmsR is a DMSO-responsive regulator. Transcriptions of the dmsR and mgd genes for Mo-bisMGD biosynthesis were regulated in the same manner as the dmsEABCD genes. These results suggest that the genetic regulation of DMSO respiration in H. volcanii is controlled by at least two systems: one is the DMSO-responsive DmsR, and the other is an unknown anaerobic regulator.

Letter to the Editor: License Portability for Occupational Audiologists is Essential

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George R. Cook

2017-11-01

Full Text Available Occupational audiologists have a crisis in their profession and need advocates. These audiologists are primarily responsible for industrial hearing conservation programs and their compliance with multiple regulations, such as Occupational Safety and Health Administration (OSHA, Mine Safety and Health Administration (MSHA and the Federal Railroad Administration.  Occupational hearing programs, for the most part, are multi-state programs as companies and corporations are national organizations. Also, companies may contract services across state lines as local services may not be desired or available. Individual state telepractice regulations require audiologists who are professionally supervising these programs via the internet and phone, to secure licensure in each state. For this licensure redundancy, the cost in time and tracking are enormous.  It is imperative that the American Speech-Language-Hearing Association (ASHA, secure multistate licensure for speech-language pathologists and audiologists. For the profession of occupational audiology, it is essential. Keywords: Licensure, Occupational audiologists, Telehealth, Telepractice

Budding yeast ATM/ATR control meiotic double-strand break (DSB levels by down-regulating Rec114, an essential component of the DSB-machinery.

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Jesús A Carballo

2013-06-01

Full Text Available An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs. Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks.

Budding Yeast ATM/ATR Control Meiotic Double-Strand Break (DSB) Levels by Down-Regulating Rec114, an Essential Component of the DSB-machinery

Science.gov (United States)

Carballo, Jesús A.; Panizza, Silvia; Serrentino, Maria Elisabetta; Johnson, Anthony L.; Geymonat, Marco; Borde, Valérie; Klein, Franz; Cha, Rita S.

2013-01-01

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or “DSB homeostasis”, might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks. PMID:23825959

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. (c) 2015 APA, all rights reserved).

Membrane-localized ubiquitin ligase ATL15 functions in sugar-responsive growth regulation in Arabidopsis.

Science.gov (United States)

Aoyama, Shoki; Terada, Saki; Sanagi, Miho; Hasegawa, Yoko; Lu, Yu; Morita, Yoshie; Chiba, Yukako; Sato, Takeo; Yamaguchi, Junji

2017-09-09

Ubiquitin ligases play important roles in regulating various cellular processes by modulating the protein function of specific ubiquitination targets. The Arabidopsis Tóxicos en Levadura (ATL) family is a group of plant-specific RING-type ubiquitin ligases that localize to membranes via their N-terminal transmembrane-like domains. To date, 91 ATL isoforms have been identified in the Arabidopsis genome, with several ATLs reported to be involved in regulating plant responses to environmental stresses. However, the functions of most ATLs remain unknown. This study, involving transcriptome database analysis, identifies ATL15 as a sugar responsive ATL gene in Arabidopsis. ATL15 expression was rapidly down-regulated in the presence of sugar. The ATL15 protein showed ubiquitin ligase activity in vitro and localized to plasma membrane and endomembrane compartments. Further genetic analyses demonstrated that the atl15 knockout mutants are insensitive to high glucose concentrations, whereas ATL15 overexpression depresses plant growth. In addition, endogenous glucose and starch amounts were reciprocally affected in the atl15 knockout mutants and the ATL15 overexpressors. These results suggest that ATL15 protein plays a significant role as a membrane-localized ubiquitin ligase that regulates sugar-responsive plant growth in Arabidopsis. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Study on the Effectiveness of Responsive Aggression Regulation Therapy (Re-ART)

NARCIS (Netherlands)

Hoogsteder, L.; Kuijpers, N N; Stams, G.J.J.M.; van Horn, J.; 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

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

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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.

Two anomalous cardiovascular responses to active standing in essential hypertension.

Science.gov (United States)

Bettencourt, M Joaquina; Pinto, Basílio Gomes; de Oliveira, E Infante; Silva-Carvalho, L

2008-05-01

In a previous work we studied, non-invasively, autonomic nervous system control of circulation in healthy subjects, observing the hemodynamic reaction to active standing. We now propose to extend this analysis to essential hypertension (EH), investigating possible autonomic dysfunction. The cardiovascular response to postural change from the supine position to active standing of 48 EH patients, of both sexes, with and without medication, was compared with that obtained for healthy subjects. We evaluated arterial systolic (SBP) and diastolic (DBP) blood pressure, stroke volume (SV), inotropic index (INOI), total vascular resistance (TVR), cardiac work (W), stroke work (SW), arterial compliance (AC) and heart rate (HR), using the entirely non-invasive BoMed NCCOM3 thoracic electrical bioimpedance monitor and sphygmomanometry. We found two patient groups characterized by different linear relationships between values of cardiovascular variables in active standing and in supine positions. Except for HR, in both groups these regression lines differed from normal. Compared to the supine position, in active standing, one group (EH-I) presented increased TVR, diminished SV, INOI, W, SW, and AC, and normal HR; the other group (EH-II) presented diminished TVR and HR and increased SV, INOI, W, SW and AC. The two patient groups could be separated on the basis of their age, but not on the basis of their systolic, diastolic and mean arterial blood pressures, gender or medication. The younger patient group (EH-I) included 28 subjects aged 24 to 69 years (50+/-10), of whom 11 were unmedicated, and the older patient group (EH-II) included 20 subjects aged 35 to 75 years (62+/-11), of whom 7 were unmedicated. Our results show a depressed response in postural change for older patients, which in the autonomic control of circulation expresses carotid baroreflex impairment, and conversely an enhanced response for younger patients, which can be caused by a maladjustment of the influence

Role of nitric oxide and prostanoids in the regulation of leg blood flow and blood pressure in humans with essential hypertension: effect of high-intensity aerobic training

DEFF Research Database (Denmark)

Nyberg, Michael Permin; Jensen, Lasse Gliemann; Thaning, Pia

2012-01-01

We examined the role of nitric oxide (NO) and prostanoids in the regulation of leg blood flow and systemic blood pressure before and after 8 weeks of aerobic high-intensity training in individuals with essential hypertension (n=10) and matched healthy control subjects (n=11). Hypertensive subjects...

Responses of grapevine rootstocks to drought through altered root system architecture and root transcriptomic regulations.

Science.gov (United States)

Yıldırım, Kubilay; Yağcı, Adem; Sucu, Seda; Tunç, Sümeyye

2018-06-01

Roots are the major interface between the plant and various stress factors in the soil environment. Alteration of root system architecture (RSA) (root length, spread, number and length of lateral roots) in response to environmental changes is known to be an important strategy for plant adaptation and productivity. In light of ongoing climate changes and global warming predictions, the breeding of drought-tolerant grapevine cultivars is becoming a crucial factor for developing a sustainable viticulture. Root-trait modeling of grapevine rootstock for drought stress scenarios, together with high-throughput phenotyping and genotyping techniques, may provide a valuable background for breeding studies in viticulture. Here, tree grafted grapevine rootstocks (110R, 5BB and 41B) having differential RSA regulations and drought tolerance were investigated to define their drought dependent root characteristics. Root area, root length, ramification and number of root tips reduced less in 110R grafted grapevines compared to 5BB and 41B grafted ones during drought treatment. Root relative water content as well as total carbohydrate and nitrogen content were found to be much higher in the roots of 110R than it was in the roots of other rootstocks under drought. Microarray-based root transcriptome profiling was also conducted on the roots of these rootstocks to identify their gene regulation network behind drought-dependent RSA alterations. Transcriptome analysis revealed totally 2795, 1196 and 1612 differentially expressed transcripts at the severe drought for the roots of 110R, 5BB and 41B, respectively. According to this transcriptomic data, effective root elongation and enlargement performance of 110R were suggested to depend on three transcriptomic regulations. First one is the drought-dependent induction in sugar and protein transporters genes (SWEET and NRT1/PTR) in the roots of 110R to facilitate carbohydrate and nitrogen accumulation. In the roots of the same rootstock

Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress.

Science.gov (United States)

Deegan, Shane; Saveljeva, Svetlana; Gorman, Adrienne M; Samali, Afshin

2013-07-01

Macroautophagy (autophagy) is a cellular catabolic process which can be described as a self-cannibalism. It serves as an essential protective response during conditions of endoplasmic reticulum (ER) stress through the bulk removal and degradation of unfolded proteins and damaged organelles; in particular, mitochondria (mitophagy) and ER (reticulophagy). Autophagy is genetically regulated and the autophagic machinery facilitates removal of damaged cell components and proteins; however, if the cell stress is acute or irreversible, cell death ensues. Despite these advances in the field, very little is known about how autophagy is initiated and how the autophagy machinery is transcriptionally regulated in response to ER stress. Some three dozen autophagy genes have been shown to be required for the correct assembly and function of the autophagic machinery; however; very little is known about how these genes are regulated by cellular stress. Here, we will review current knowledge regarding how ER stress and the unfolded protein response (UPR) induce autophagy, including description of the different autophagy-related genes which are regulated by the UPR.

Photomorphogenic responses to ultraviolet-B light.

Science.gov (United States)

Jenkins, Gareth I

2017-11-01

Exposure to ultraviolet B (UV-B) light regulates numerous aspects of plant metabolism, morphology and physiology through the differential expression of hundreds of genes. Photomorphogenic responses to UV-B are mediated by the photoreceptor UV RESISTANCE LOCUS8 (UVR8). Considerable progress has been made in understanding UVR8 action: the structural basis of photoreceptor function, how interaction with CONSTITUTIVELY PHOTOMORPHOGENIC 1 initiates signaling and how REPRESSOR OF UV-B PHOTOMORPHOGENESIS proteins negatively regulate UVR8 action. In addition, recent research shows that UVR8 mediates several responses through interaction with other signaling pathways, in particular auxin signaling. Nevertheless, many aspects of UVR8 action remain poorly understood. Most research to date has been undertaken with Arabidopsis, and it is important to explore the functions and regulation of UVR8 in diverse plant species. Furthermore, it is essential to understand how UVR8, and UV-B signaling in general, regulates processes under natural growth conditions. Ultraviolet B regulates the expression of many genes through UVR8-independent pathways, but the activity and importance of these pathways in plants growing in sunlight are poorly understood. © 2017 John Wiley & Sons Ltd.

Digitalising the General Data Protection Regulation with Dynamic Condition Response Graphs

DEFF Research Database (Denmark)

Heuck, Emil; Hildebrandt, Thomas; Kiærulff Lerche, Rasmus

2017-01-01

We describe how the declarative Dynamic Condition Response (DCR) Graphs proces notation can be used to digitalise the General Data Protection Regulation (GDPR) and make a first evaluation to what extend the formalisation and associated tool for end-user modelling and simulation can be used to cla...

Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR.

Science.gov (United States)

Sato, Shogo; Jung, Hunmin; Nakagawa, Tsutomu; Pawlosky, Robert; Takeshima, Tomomi; Lee, Wan-Ru; Sakiyama, Haruhiko; Laxman, Sunil; Wynn, R Max; Tu, Benjamin P; MacMillan, John B; De Brabander, Jef K; Veech, Richard L; Uyeda, Kosaku

2016-05-13

The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Regulating corporate social and human rights responsibilities at the UN plane

DEFF Research Database (Denmark)

Buhmann, Karin

2009-01-01

Globalisation's unprecedented growth and transborder activities of business coupled with increasing awareness of the impact of business on societies and human rights has resulted in demands for the international society to regulate corporate social and human rights responsibilities. This not only...... challenges traditional notions of duty bearers under international law, but also calls for novel approaches for the United Nations (UN) to implement central parts of the Charter's human rights aims and to address corporate behaviour in a state-centred international law-making order that lacks the willingness...... businesses' impact on human rights. The pattern of using these forms suggests an institutionalisation of reflexive regulation as a regulatory process drawing on public-private regulation, and of an emerging UN based 'Global Administrative Law' in order to meet regulatory challenges in living up to the human...

Branching of the PIF3 regulatory network in Arabidopsis: roles of PIF3-regulated MIDAs in seedling development in the dark and in response to light.

Science.gov (United States)

Sentandreu, Maria; Leivar, Pablo; Martín, Guiomar; Monte, Elena

2012-04-01

Plants need to accurately adjust their development after germination in the underground darkness to ensure survival of the seedling, both in the dark and in the light upon reaching the soil surface. Recent studies have established that the photoreceptors phytochromes and the bHLH phytochrome interacting factors PIFs regulate seedling development to adjust it to the prevailing light environment during post-germinative growth. However, complete understanding of the downstream regulatory network implementing these developmental responses is still lacking. In a recent work, published in The Plant Cell, we report a subset of PIF3-regulated genes in dark-grown seedlings that we have named MIDAs (MISREGULATED IN DARK). Analysis of their functional relevance using mutants showed that four of them present phenotypic alterations in the dark, and that each affected a particular facet of seedling development, suggesting organ-specific branching in the signal that PIF3 relays downstream. Furthermore, our results also showed an altered response to light in seedlings with an impaired PIF3/MIDA regulatory network, indicating that these factors might also be essential to initiate and optimize the developmental adjustment of the seedling to the light environment.

Pricing regulations in Great Britain

International Nuclear Information System (INIS)

Cicoletti, G.

1993-01-01

This paper briefly describes the structure and functions of Great Britain's essential electric power regulatory authority institutionalized by the 1989 British Electricity Act, i.e., the Office of Electricity Regulation, OFFER, and the responsibilities and tasks of the head of OFFER -the Director General of Electricity Supply (DGES). In particular, with regard to the latter, the paper describes how the DGES works together with regional electricity commissions to ensure the respect, by the various utilities, of consumer price caps and compliance with overall quality of service standards, as well as, to oversee 'pooling' activities by producers and distributors

Pricing regulations in Great Britain

International Nuclear Information System (INIS)

Cicoletti, G.

1993-01-01

This paper briefly describes the structure and functions of Great Britain's essential electric power regulatory authority institutionalized by the 1989 British Electricity Act, i.e., the Office of Electricity Regulation, OFFER, and the responsibilities and tasks of the head of OFFER - the Director General of Electricity Supply (DGES). In particular, with regard to the latter, the paper describes how the DGES works together with regional electricity commissions to ensure the respect, by the various utilities, of consumer price caps and compliance with overall quality of service standards, as well as, to oversee 'pooling' activities by producers and distributors

Sexual self-regulation and cognitive absorption as factors of sexual response toward virtual characters.

Science.gov (United States)

Renaud, Patrice; Trottier, Dominique; Nolet, Kevin; Rouleau, Joanne L; Goyette, Mathieu; Bouchard, Stéphane

2014-04-01

The eye movements and penile responses of 20 male participants were recorded while they were immersed with virtual sexual stimuli. These participants were divided into two groups according to their capacity to focus their attention in immersion (high and low focus). In order to understand sexual self-regulation better, we subjected participants to three experimental conditions: (a) immersion with a preferred sexual stimulus, without sexual inhibition; (b) immersion with a preferred sexual stimulus, with sexual inhibition; and (c) immersion with a neutral stimulus. A significant difference was observed between the effects of each condition on erectile response and scanpath. The groups differed on self-regulation of their erectile responses and on their scanpath patterns. High focus participants had more difficulties than low focus participants with inhibiting their sexual responses and displayed less scattered eye movement trajectories over the critical areas of the virtual sexual stimuli. Results are interpreted in terms of sexual self-regulation and cognitive absorption in virtual immersion. In addition, the use of validated virtual sexual stimuli is presented as a methodological improvement over static and moving pictures, since it paves the way for the study of the role of social interaction in an ecologically valid and well-controlled way.

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

NARCIS (Netherlands)

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

2017-01-01

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

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

FOXL2 Is an Essential Activator of SF-1-Induced Transcriptional Regulation of Anti-Müllerian Hormone in Human Granulosa Cells.

Directory of Open Access Journals (Sweden)

Hanyong Jin

Full Text Available Anti-Müllerian hormone (AMH is required for proper sexual differentiation by regulating the regression of the Müllerian ducts in males. Recent studies indicate that AMH could be an important factor for maintaining the ovarian reserve. However, the mechanisms of AMH regulation in the ovary are largely unknown. Here, we provide evidence that AMH is an ovarian target gene of steroidogenic factor-1 (SF-1, an orphan nuclear receptor required for proper follicle development. FOXL2 is an evolutionally conserved transcription factor, and its mutations cause blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES, wherein affected females display eyelid defects and premature ovarian failure (POF. Notably, we found that functional FOXL2 is essential for SF-1-induced AMH regulation, via protein-protein interactions between FOXL2 and SF-1. A BPES-inducing mutant of FOXL2 (290-291delCA was unable to interact with SF-1 and failed to mediate the association between SF-1 and the AMH promoter. Therefore, this study identified a novel regulatory circuit for ovarian AMH production; specifically, through the coordinated interplay between FOXL2 and SF-1 that could control ovarian follicle development.

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

Science.gov (United States)

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

2014-01-01

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

MicroRNA regulated defense responses in Triticum aestivum L. during Puccinia graminis f.sp. tritici infection.

Science.gov (United States)

Gupta, Om Prakash; Permar, Vipin; Koundal, Vikas; Singh, Uday Dhari; Praveen, Shelly

2012-02-01

Plants have evolved diverse mechanism to recognize pathogen attack and triggers defense responses. These defense responses alter host cellular function regulated by endogenous, small, non-coding miRNAs. To understand the mechanism of miRNAs regulated cellular functions during stem rust infection in wheat, we investigated eight different miRNAs viz. miR159, miR164, miR167, miR171, miR444, miR408, miR1129 and miR1138, involved in three different independent cellular defense response to infection. The investigation reveals that at the initiation of disease, accumulation of miRNAs might be playing a key role in hypersensitive response (HR) from host, which diminishes at the maturation stage. This suggests a possible host-fungal synergistic relation leading to susceptibility. Differential expression of these miRNAs in presence and absence of R gene provides a probable explanation of miRNA regulated R gene mediated independent pathways.

Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.

Science.gov (United States)

Li, LiQi; Jothi, Raja; Cui, Kairong; Lee, Jan Y; Cohen, Tsadok; Gorivodsky, Marat; Tzchori, Itai; Zhao, Yangu; Hayes, Sandra M; Bresnick, Emery H; Zhao, Keji; Westphal, Heiner; Love, Paul E

2011-02-01

The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

Conformational dynamism for DNA interaction in the Salmonella RcsB response regulator.

Science.gov (United States)

Casino, Patricia; Miguel-Romero, Laura; Huesa, Juanjo; García, Pablo; García-Del Portillo, Francisco; Marina, Alberto

2018-01-09

The RcsCDB phosphorelay system controls an extremely large regulon in Enterobacteriaceae that involves processes such as biofilm formation, flagella production, synthesis of extracellular capsules and cell division. Therefore, fine-tuning of this system is essential for virulence in pathogenic microorganisms of this group. The final master effector of the RcsCDB system is the response regulator (RR) RcsB, which activates or represses multiple genes by binding to different promoter regions. This regulatory activity of RcsB can be done alone or in combination with additional transcriptional factors in phosphorylated or dephosphorylated states. The capacity of RcsB to interact with multiple promoters and partners, either dephosphorylated or phosphorylated, suggests an extremely conformational dynamism for this RR. To shed light on the activation mechanism of RcsB and its implication on promoter recognition, we solved the crystal structure of full-length RcsB from Salmonella enterica serovar Typhimurium in the presence and absence of a phosphomimetic molecule BeF3-. These two novel structures have guided an extensive site-directed mutagenesis study at the structural and functional level that confirms RcsB conformational plasticity and dynamism. Our data allowed us to propose a β5-T switch mechanism where phosphorylation is coupled to alternative DNA binding ways and which highlights the conformational dynamism of RcsB to be so pleiotropic. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Structural transitions in conserved, ordered Beclin 1 domains essential to regulating autophagy

Energy Technology Data Exchange (ETDEWEB)

Glover, Karen; Li, Yue; Mukhopadhyay, Shreya; Leuthner, Zoe; Chakravarthy, Srinivas; Colbert, Christopher L.; Sinha, Sangita C. (NDSU); (IIT)

2017-08-10

Beclin 1 (BECN1) is a key regulator of autophagy, a critical catabolic homeostasis pathway that involves sequestration of selected cytoplasmic components by multilayered vesicles called autophagosomes, followed by lysosomal fusion and degradation. BECN1 is a core component of class III phosphatidylinositol-3-kinase complexes responsible for autophagosome nucleation. Without heterologous binding partners, BECN1 forms an antiparallel homodimer via its coiled-coil domain (CCD). However, the last 16 CCD residues, composing an “overlap helix” (OH), have been crystallized in two mutually exclusive states: either as part of the CCD or packed against the C-terminal β-α repeated, autophagy-specific domain (BARAD). Here, using CD spectroscopy, isothermal titration calorimetry, and small-angle X-ray scattering, we show that in the homodimeric state, the OH transitions between these two different packing states, with the predominant state comprising the OH packed against the BARAD, contrary to expectations based on known BECN1 interactions with heterologous partners. We confirmed this observation by comparing the impact of mutating four residues that mediate packing of the OH against both the CCD and BARAD on structure and stability of the CCD, the OH+BARAD, and the two-domain CCD–BARAD. Last, we used cellular assays to demonstrate that mutation of these OH-interface residues abrogates starvation-induced up-regulation of autophagy but does not affect basal autophagy. In summary, we have identified a BECN1 helical region that transitions between packing as part of either one of two conserved domains (i.e. the CCD or the BARAD). Our findings have important implications for the relative stability of autophagy-inactive and autophagy-active BECN1 complexes.

QTL analysis of internode elongation in response to gibberellin in deepwater rice

OpenAIRE

Nagai, Keisuke; Kondo, Yuma; Kitaoka, Takuya; Noda, Tomonori; Kuroha, Takeshi; Angeles-Shim, Rosalyn B.; Yasui, Hideshi; Yoshimura, Atsushi; Ashikari, Motoyuki

2014-01-01

Gibberellin (GA) is a plant hormone that has important roles in numerous plant developmental phases. Rice plants known as deepwater rice respond to flooding by elongating their internodes to avoid anoxia. Previous studies reported that GA is essential for internode elongation in deepwater rice. Quantitative trait locus (QTL) analyses identified QTLs regulating internode elongation in response to deepwater conditions. However, the interaction between internode elongation and regulators of GA s...

AMPK regulates metabolism and survival in response to ionizing radiation

International Nuclear Information System (INIS)

Zannella, Vanessa E.; Cojocari, Dan; Hilgendorf, Susan; Vellanki, Ravi N.; Chung, Stephen; Wouters, Bradly G.; Koritzinsky, Marianne

2011-01-01

Background and purpose: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. Methods: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK α1/α2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK α1/α2 shRNA mediated knockdown. Results: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. Conclusions: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.

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

On regulation of environmental responsibility in the final stage of the nuclear fuel cycle. - Parallel regulation within the framework of Euratom and the Lisbon-treaty

International Nuclear Information System (INIS)

Erhag, Thomas

2010-09-01

In Sweden, the responsibility for the disposal of spent nuclear fuel is regulated in various laws and regulations. This means that there is an overlap between laws providing a sometimes vague and weak legal situation. Although attempts have been made to coordinate environmental and nuclear law these attempts have not succeeded. Recently, several Swedish reports have again described the fact that we have a parallel system of legal rules for the handling of spent nuclear fuel and the consequences of this. Foremost attention has been drawn to the fact that the licensing of a repository must be made both under the Nuclear Safety Act and the Environmental Code. The regulation referred to above is Swedish, and both the parallel regulation of nuclear safety-, radiation protection- and environmental- responsibility, and the relationship between such legislation, has its own Swedish history. However, Swedish legislation in all these areas is also under the influence of international regulations. This article describes the parallel regulation of nuclear safety and radiation protection issues on a European level. It shows that the division and logic found in the relationship between the Swedish laws is only partially reflected at European level. First treated is the relationship between the EC-treaty and Euratom. The article then turns to examples of regulatory responsibility for waste management and communication of information relating to license applications (environmental impact assessments) for the final disposal of spent nuclear fuel within the framework of Euratom and the EC-treaty. Finally, it discusses the implications of this type of parallel regulation for the Swedish licensing procedure

On regulation of environmental responsibility in the final stage of the nuclear fuel cycle. - Parallel regulation within the framework of Euratom and the Lisbon-treaty

Energy Technology Data Exchange (ETDEWEB)

Erhag, Thomas (Dept. of Law, Univ. of Goeteborg, Goeteborg (Sweden)), e-mail: thomas.erhag@law.gu.se

2010-09-15

In Sweden, the responsibility for the disposal of spent nuclear fuel is regulated in various laws and regulations. This means that there is an overlap between laws providing a sometimes vague and weak legal situation. Although attempts have been made to coordinate environmental and nuclear law these attempts have not succeeded. Recently, several Swedish reports have again described the fact that we have a parallel system of legal rules for the handling of spent nuclear fuel and the consequences of this. Foremost attention has been drawn to the fact that the licensing of a repository must be made both under the Nuclear Safety Act and the Environmental Code. The regulation referred to above is Swedish, and both the parallel regulation of nuclear safety-, radiation protection- and environmental- responsibility, and the relationship between such legislation, has its own Swedish history. However, Swedish legislation in all these areas is also under the influence of international regulations. This article describes the parallel regulation of nuclear safety and radiation protection issues on a European level. It shows that the division and logic found in the relationship between the Swedish laws is only partially reflected at European level. First treated is the relationship between the EC-treaty and Euratom. The article then turns to examples of regulatory responsibility for waste management and communication of information relating to license applications (environmental impact assessments) for the final disposal of spent nuclear fuel within the framework of Euratom and the EC-treaty. Finally, it discusses the implications of this type of parallel regulation for the Swedish licensing procedure

Two novel transcriptional regulators are essential for infection-related morphogenesis and pathogenicity of the rice blast fungus Magnaporthe oryzae.

Directory of Open Access Journals (Sweden)

Xia Yan

2011-12-01

Full Text Available The cyclic AMP-dependent protein kinase A signaling pathway plays a major role in regulating plant infection by the rice blast fungus Magnaporthe oryzae. Here, we report the identification of two novel genes, MoSOM1 and MoCDTF1, which were discovered in an insertional mutagenesis screen for non-pathogenic mutants of M. oryzae. MoSOM1 or MoCDTF1 are both necessary for development of spores and appressoria by M. oryzae and play roles in cell wall differentiation, regulating melanin pigmentation and cell surface hydrophobicity during spore formation. MoSom1 strongly interacts with MoStu1 (Mstu1, an APSES transcription factor protein, and with MoCdtf1, while also interacting more weakly with the catalytic subunit of protein kinase A (CpkA in yeast two hybrid assays. Furthermore, the expression levels of MoSOM1 and MoCDTF1 were significantly reduced in both Δmac1 and ΔcpkA mutants, consistent with regulation by the cAMP/PKA signaling pathway. MoSom1-GFP and MoCdtf1-GFP fusion proteins localized to the nucleus of fungal cells. Site-directed mutagenesis confirmed that nuclear localization signal sequences in MoSom1 and MoCdtf1 are essential for their sub-cellular localization and biological functions. Transcriptional profiling revealed major changes in gene expression associated with loss of MoSOM1 during infection-related development. We conclude that MoSom1 and MoCdtf1 functions downstream of the cAMP/PKA signaling pathway and are novel transcriptional regulators associated with cellular differentiation during plant infection by the rice blast fungus.

Short term responses in feed intake and yield during concentrate regulation in dairy cows

DEFF Research Database (Denmark)

Schmidt Henriksen, Julie Cherono; Munksgaard, Lene; Weisbjerg, Martin Riis

at the onset of the experiment. The 83 cows (42 Jersey, 41 Holstein) were balanced between treatments according to breed, parity and lactation stage. The mixed ration was fed ad libitum. The change in response during regulation was analyzed as a linear regression and reported as daily change (slope......,β). The concentrate intake increased during the week of up regulation in daily concentrate offer, and decreased during down regulation (β=0.3 kg/day, β=-0.3 kg/day; Pchange in concentrate offer affected the mixed ration intake with a decrease during up...... regulation, and an increase during down regulation (β=-0.3 kg DM/day, β0.06 kg DM/day; Pration decrease during up regulation of concentrate and increase during down regulation W=-1.1 min/day; P=0.06; β= 1.3 min/day; P

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...

The amoebal MAP kinase response to Legionella pneumophila is regulated by DupA.

Science.gov (United States)

Li, Zhiru; Dugan, Aisling S; Bloomfield, Gareth; Skelton, Jason; Ivens, Alasdair; Losick, Vicki; Isberg, Ralph R

2009-09-17

The amoeba Dictyostelium discoideum can support replication of Legionella pneumophila. Here we identify the dupA gene, encoding a putative tyrosine kinase/dual-specificity phosphatase, in a screen for D. discoideum mutants altered in allowing L. pneumophila intracellular replication. Inactivation of dupA resulted in depressed L. pneumophila growth and sustained hyperphosphorylation of the amoebal MAP kinase ERK1, consistent with loss of a phosphatase activity. Bacterial challenge of wild-type amoebae induced dupA expression and resulted in transiently increased ERK1 phosphorylation, suggesting that dupA and ERK1 are part of a response to bacteria. Indeed, over 500 of the genes misregulated in the dupA(-) mutant were regulated in response to L. pneumophila infection, including some thought to have immune-like functions. MAP kinase phosphatases are known to be highly upregulated in macrophages challenged with L. pneumophila. Thus, DupA may regulate a MAP kinase response to bacteria that is conserved from amoebae to mammals.

The Ihh signal is essential for regulating proliferation and hypertrophy of cultured chicken chondrocytes.

Science.gov (United States)

Ma, R S; Zhou, Z L; Luo, J W; Zhang, H; Hou, J F

2013-10-01

The Indian hedgehog (Ihh) signal plays a vital role in regulating proliferation and hypertrophy of chondrocytes. To investigate its function in postnatal chicken (Gallus gallus) chondrocytes, cyclopamine was used to inhibit Ihh signaling. The MTT and ALP assays revealed the downgrade-proliferation and upgrade-differentiation of chondrocytes. To further elucidate the mechanism, the mRNA expression levels of Ihh, parathyroid hormone related protein (PTHrP), Gli-2, Bcl-2, Bone Morphogenetic Protein 6 (BMP-6), type X collagen (Col X) and type II collagen (Col II) were detected by quantitative real-time RT-PCR analysis, and the protein expressions of Ihh, Col X, and Col II were determined using Western blot analysis. After the Ihh signal was blocked, chondrocytes demonstrated high expression levels of PTHrP and Col X and low levels of Gli-2, BMP-6, Bcl-2 and Col II although Ihh expression was increased. Based on these results, the Ihh signal is essential for balancing chicken chondrocyte proliferation and hypertrophy, and the regulatory function of PTHrP acts in an Ihh-dependent manner. Furthermore, BMP-6 and Bcl-2 played roles in maintaining the development of chondrocytes and may be downstream regulatory factors of Ihh signaling. © 2013.

Toll-8/Tollo negatively regulates antimicrobial response in the Drosophila respiratory epithelium.

Directory of Open Access Journals (Sweden)

Idir Akhouayri

2011-10-01

Full Text Available Barrier epithelia that are persistently exposed to microbes have evolved potent immune tools to eliminate such pathogens. If mechanisms that control Drosophila systemic responses are well-characterized, the epithelial immune responses remain poorly understood. Here, we performed a genetic dissection of the cascades activated during the immune response of the Drosophila airway epithelium i.e. trachea. We present evidence that bacteria induced-antimicrobial peptide (AMP production in the trachea is controlled by two signalling cascades. AMP gene transcription is activated by the inducible IMD pathway that acts non-cell autonomously in trachea. This IMD-dependent AMP activation is antagonized by a constitutively active signalling module involving the receptor Toll-8/Tollo, the ligand Spätzle2/DNT1 and Ect-4, the Drosophila ortholog of the human Sterile alpha and HEAT/ARMadillo motif (SARM. Our data show that, in addition to Toll-1 whose function is essential during the systemic immune response, Drosophila relies on another Toll family member to control the immune response in the respiratory epithelium.

Chk2 regulates transcription-independent p53-mediated apoptosis in response to DNA damage

International Nuclear Information System (INIS)

Chen Chen; Shimizu, Shigeomi; Tsujimoto, Yoshihide; Motoyama, Noboru

2005-01-01

The tumor suppressor protein p53 plays a central role in the induction of apoptosis in response to genotoxic stress. The protein kinase Chk2 is an important regulator of p53 function in mammalian cells exposed to ionizing radiation (IR). Cells derived from Chk2-deficient mice are resistant to the induction of apoptosis by IR, and this resistance has been thought to be a result of the defective transcriptional activation of p53 target genes. It was recently shown, however, that p53 itself and histone H1.2 translocate to mitochondria and thereby induces apoptosis in a transcription-independent manner in response to IR. We have now examined whether Chk2 also regulates the transcription-independent induction of apoptosis by p53 and histone H1.2. The reduced ability of IR to induce p53 stabilization in Chk2-deficient thymocytes was associated with a marked impairment of p53 and histone H1 translocation to mitochondria. These results suggest that Chk2 regulates the transcription-independent mechanism of p53-mediated apoptosis by inducing stabilization of p53 in response to IR

Hate crimes and normative regulation

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Kovačević Milica

2011-01-01

Full Text Available This paper is primarily devoted to issues related to the normative regulation of hate crimes, with special reference to the regulations of the Republic of Serbia, which are indirectly related to this matter. This kind of crimes are characterized by prejudices that perpetrators have towards injured parties, as members of certain, mostly, minority groups, due to which many hate crimes could be also called crimes of prejudice. In comparative law there are two different basic directions when it comes to regulating hate crimes: separation of hate crimes in a separate category on the one hand, and punishment of perpetrators of criminal acts with the detriment of minority groups through the usual charges of a given criminal justice system, on the other. The author finds that, regardless of the formal response forms, real life suggests that hate crimes can be essentially suppressed only by promoting values such as equality, respect for diversity and tolerance, and by continuous education of public about the danger of hate crimes.

Iron-binding haemerythrin RING ubiquitin ligases regulate plant iron responses and accumulation

Science.gov (United States)

Kobayashi, Takanori; Nagasaka, Seiji; Senoura, Takeshi; Itai, Reiko Nakanishi; Nakanishi, Hiromi; Nishizawa, Naoko K.

2013-01-01

Iron is essential for most living organisms. Plants transcriptionally induce genes involved in iron acquisition under conditions of low iron availability, but the nature of the deficiency signal and its sensors are unknown. Here we report the identification of new iron regulators in rice, designated Oryza sativa Haemerythrin motif-containing Really Interesting New Gene (RING)- and Zinc-finger protein 1 (OsHRZ1) and OsHRZ2. OsHRZ1, OsHRZ2 and their Arabidopsis homologue BRUTUS bind iron and zinc, and possess ubiquitination activity. OsHRZ1 and OsHRZ2 are susceptible to degradation in roots irrespective of iron conditions. OsHRZ-knockdown plants exhibit substantial tolerance to iron deficiency, and accumulate more iron in their shoots and grains irrespective of soil iron conditions. The expression of iron deficiency-inducible genes involved in iron utilization is enhanced in OsHRZ-knockdown plants, mostly under iron-sufficient conditions. These results suggest that OsHRZ1 and OsHRZ2 are iron-binding sensors that negatively regulate iron acquisition under conditions of iron sufficiency. PMID:24253678

Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

Directory of Open Access Journals (Sweden)

Xin Sun

2018-01-01

Full Text Available How chromatin-remodeling complexes modulate gene networks to control organ-specific properties is not well understood. For example, Baf60c (Smarcd3 encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex, but its role in heart development is not fully understood. We found that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes resulted in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD. In a yeast two-hybrid screen, we identified MYOCD as a BAF60c interacting factor; we showed that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

The VELVET A Orthologue VEL1 of Trichoderma reesei Regulates Fungal Development and Is Essential for Cellulase Gene Expression

Science.gov (United States)

Atanasova, Lea; Fekete, Erzsébet; Paholcsek, Melinda; Sándor, Erzsébet; Aquino, Benigno; Druzhinina, Irina S.; Karaffa, Levente; Kubicek, Christian P.

2014-01-01

Trichoderma reesei is the industrial producer of cellulases and hemicellulases for biorefinery processes. Their expression is obligatorily dependent on the function of the protein methyltransferase LAE1. The Aspergillus nidulans orthologue of LAE1 - LaeA - is part of the VELVET protein complex consisting of LaeA, VeA and VelB that regulates secondary metabolism and sexual as well as asexual reproduction. Here we have therefore investigated the function of VEL1, the T. reesei orthologue of A. nidulans VeA. Deletion of the T. reesei vel1 locus causes a complete and light-independent loss of conidiation, and impairs formation of perithecia. Deletion of vel1 also alters hyphal morphology towards hyperbranching and formation of thicker filaments, and with consequently reduced growth rates. Growth on lactose as a sole carbon source, however, is even more strongly reduced and growth on cellulose as a sole carbon source eliminated. Consistent with these findings, deletion of vel1 completely impaired the expression of cellulases, xylanases and the cellulase regulator XYR1 on lactose as a cellulase inducing carbon source, but also in resting mycelia with sophorose as inducer. Our data show that in T. reesei VEL1 controls sexual and asexual development, and this effect is independent of light. VEL1 is also essential for cellulase gene expression, which is consistent with the assumption that their regulation by LAE1 occurs by the VELVET complex. PMID:25386652

ABF2, an ABRE-binding bZIP factor, is an essential component of glucose signaling and its overexpression affects multiple stress tolerance.

Science.gov (United States)

Kim, Sunmi; Kang, Jung-Youn; Cho, Dong-Im; Park, Ji Hye; Kim, Soo Young

2004-10-01

Phytohormone abscisic acid (ABA) regulates stress-responsive gene expression during vegetative growth, which is mediated largely by cis-elements sharing the ACGTGGC consensus. Although many transcription factors are known to bind the elements in vitro, only a few have been demonstrated to have in vivo functions and their specific roles in ABA/stress responses are mostly unknown. Here, we report that ABF2, an ABF subfamily member of bZIP proteins interacting with the ABA-responsive elements, is involved in ABA/stress responses. Its overexpression altered ABA sensitivity, dehydration tolerance, and the expression levels of ABA/stress-regulated genes. Furthermore, ABF2 overexpression promoted glucose-induced inhibition of seedling development, whereas its mutation impaired glucose response. The reduced sugar sensitivity was not observed with mutants of two other ABF family members, ABF3 and ABF4. Instead, these mutants displayed defects in ABA, salt, and dehydration responses, which were not observed with the abf2 mutant. Our data indicate distinct roles of ABF family members: whereas ABF3 and ABF4 play essential roles in ABA/stress responses, ABF2 is required for normal glucose response. We also show that ABF2 overexpression affects multiple stress tolerance.

A Disulfide Bond in the Membrane Protein IgaA Is Essential for Repression of the RcsCDB System

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M. Graciela Pucciarelli

2017-12-01

Full Text Available IgaA is an integral inner membrane protein that was discovered as repressor of the RcsCDB phosphorelay system in the intracellular pathogen Salmonella enterica serovar Typhimurium. The RcsCDB system, conserved in many members of the family Enterobacteriaceae, regulates expression of varied processes including motility, biofilm formation, virulence and response to envelope stress. IgaA is an essential protein to which, in response to envelope perturbation, the outer membrane lipoprotein RcsF has been proposed to bind in order to activate the RcsCDB phosphorelay. Envelope stress has also been reported to be sensed by a surface exposed domain of RcsF. These observations support a tight control of the RcsCDB system by RcsF and IgaA via mechanisms that, however, remain unknown. Interestingly, RcsF and IgaA have four conserved cysteine residues in loops exposed to the periplasmic space. Two non-consecutive disulfide bonds were shown to be required for RcsF function. Here, we report mutagenesis studies supporting the presence of one disulfide bond (C404-C425 in the major periplasmic loop of IgaA that is essential for repression of the RcsCDB phosphorelay. Our data therefore suggest that the redox state of the periplasm may be critical for the control of the RcsCDB system by its two upstream regulators, RcsF and IgaA.

Three Pairs of Protease-Serpin Complexes Cooperatively Regulate the Insect Innate Immune Responses*

OpenAIRE

Jiang, Rui; Kim, Eun-Hye; Gong, Ji-Hee; Kwon, Hyun-Mi; Kim, Chan-Hee; Ryu, Kyoung-Hwa; Park, Ji-Won; Kurokawa, Kenji; Zhang, Jinghai; Gubb, David; Lee, Bok-Luel

2009-01-01

Serpins are known to be necessary for the regulation of several serine protease cascades. However, the mechanisms of how serpins regulate the innate immune responses of invertebrates are not well understood due to the uncertainty of the identity of the serine proteases targeted by the serpins. We recently reported the molecular activation mechanisms of three serine protease-mediated Toll and melanin synthesis cascades in a large beetle, Tenebrio molitor. Here, we purified three novel serpins ...

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

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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.

The role of beneficial bacteria wall elasticity in regulating innate immune response

OpenAIRE

?okrozub, Viktoria V.; Lazarenko, Liudmyla M.; Sichel, Liubov M.; Babenko, Lidia P.; Lytvyn, Petro M.; Demchenko, Olga M.; Melnichenko, Yulia O.; Boyko, Nadiya V.; Biavati, Bruno; DiGioia, Diana; Bubnov, Rostyslav V.; Spivak, Mykola Ya

2015-01-01

Background Probiotics have great potential to contribute to development of healthy dietary regimes, preventive care, and an integrated approach to immunity-related disease management. The bacterial wall is a dynamic entity, depending on many components and playing an essential role in modulating immune response. The impact of cell wall elasticity on the beneficial effects of probiotic strains has not been sufficiently studied. The aim was to investigate the effect of lactic acid bacteria (LAB...

FIN5 positively regulates far-red light responses in Arabidopsis thaliana

International Nuclear Information System (INIS)

Cho, D.S.; Hong, S.H.; Nam, H.G.; Soh, M.S.

2003-01-01

We report the characterization of a semi-dominant mutation fin5-1 (far-red insensitive 5-1) of Arabidopsis, which was isolated from genetic screening of phytochrome A (phyA) signaling components. Plants with the fin5-1 mutation exhibited a long hypocotyl phenotype when grown under far-red (FR) light, but not under red light. Physiological analyses implied that FIN5 might be differentially involved in diverse responses that are regulated by phyA under continuous FR light. Anthocyanin accumulation, gravitropic response of hypocotyl growth, and FR light-preconditioned blocking of greening were also impaired in the fin5-1 mutant, whereas photoperiodic floral induction was not, if at all, significantly affected. Moreover, light-regulated expression of the CHS, PORA and PsbS genes was attenuated in fin5-1 mutant plants, while the light-induced expression of CAB was normal. The mutation exhibited semi-dominance regarding control of hypocotyl growth in FR light. We suggest that FIN5 defines a novel branch in the network of phyA signaling in Arabidopsis. (author)

Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

Science.gov (United States)

Kang, Jian; Kusnadi, Eric P.; Ogden, Allison J.; Hicks, Rodney J.; Bammert, Lukas; Kutay, Ulrike; Hung, Sandy; Sanij, Elaine; Hannan, Ross D.; Hannan, Katherine M.; Pearson, Richard B.

2016-01-01

Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer. PMID:27385002

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.

Regulation of phosphate starvation responses in higher plants.

Science.gov (United States)

Yang, Xiao Juan; Finnegan, Patrick M

2010-04-01

Phosphorus (P) is often a limiting mineral nutrient for plant growth. Many soils worldwide are deficient in soluble inorganic phosphate (P(i)), the form of P most readily absorbed and utilized by plants. A network of elaborate developmental and biochemical adaptations has evolved in plants to enhance P(i) acquisition and avoid starvation. Controlling the deployment of adaptations used by plants to avoid P(i) starvation requires a sophisticated sensing and regulatory system that can integrate external and internal information regarding P(i) availability. In this review, the current knowledge of the regulatory mechanisms that control P(i) starvation responses and the local and long-distance signals that may trigger P(i) starvation responses are discussed. Uncharacterized mutants that have P(i)-related phenotypes and their potential to give us additional insights into regulatory pathways and P(i) starvation-induced signalling are also highlighted and assessed. An impressive list of factors that regulate P(i) starvation responses is now available, as is a good deal of knowledge regarding the local and long-distance signals that allow a plant to sense and respond to P(i) availability. However, we are only beginning to understand how these factors and signals are integrated with one another in a regulatory web able to control the range of responses demonstrated by plants grown in low P(i) environments. Much more knowledge is needed in this agronomically important area before real gains can be made in improving P(i) acquisition in crop plants.

Transcriptional feedback regulation of YUCCA genes in response to auxin levels in Arabidopsis.

Science.gov (United States)

Suzuki, Masashi; Yamazaki, Chiaki; Mitsui, Marie; Kakei, Yusuke; Mitani, Yuka; Nakamura, Ayako; Ishii, Takahiro; Soeno, Kazuo; Shimada, Yukihisa

2015-08-01

The IPyA pathway, the major auxin biosynthesis pathway, is transcriptionally regulated through a negative feedback mechanism in response to active auxin levels. The phytohormone auxin plays an important role in plant growth and development, and levels of active free auxin are determined by biosynthesis, conjugation, and polar transport. Unlike conjugation and polar transport, little is known regarding the regulatory mechanism of auxin biosynthesis. We discovered that expression of genes encoding indole-3-pyruvic acid (IPyA) pathway enzymes is regulated by elevated or reduced active auxin levels. Expression levels of TAR2, YUC1, YUC2, YUC4, and YUC6 were downregulated in response to synthetic auxins [1-naphthaleneacetic acid (NAA) and 2,4-dichlorophenoxyacetic acid (2,4-D)] exogenously applied to Arabidopsis thaliana L. seedlings. Concomitantly, reduced levels of endogenous indole-3-acetic acid (IAA) were observed. Alternatively, expression of these YUCCA genes was upregulated by the auxin biosynthetic inhibitor kynurenine in Arabidopsis seedlings, accompanied by reduced IAA levels. These results indicate that expression of YUCCA genes is regulated by active auxin levels. Similar results were also observed in auxin-overproduction and auxin-deficient mutants. Exogenous application of IPyA to Arabidopsis seedlings preincubated with kynurenine increased endogenous IAA levels, while preincubation with 2,4-D reduced endogenous IAA levels compared to seedlings exposed only to IPyA. These results suggest that in vivo conversion of IPyA to IAA was enhanced under reduced auxin levels, while IPyA to IAA conversion was depressed in the presence of excess auxin. Based on these results, we propose that the IPyA pathway is transcriptionally regulated through a negative feedback mechanism in response to active auxin levels.

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

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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.

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

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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.

Essential Oils for Alternative Teak Rust Control

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Pedro Raymundo Argüelles Osorio

2018-03-01

Full Text Available ABSTRACT The objectives of this study were to evaluate the effect of lemon grass, citronella grass, Mexican-tea and noni essential oils on urediniospore germination of Olivea neotectonae , the agent responsible for rust in Teak (Tectona grandis L.f.; to evaluate the phytotoxic effect of these essential oils on teak seedlings; and to evaluate the use of essential oils to control rust in teak plants when preventively and curatively applied. We found that the noni and lemon grass essential oils inhibited 100% of urediniospore germination. On the other hand, the essential oils from noni and lemon grass caused phytotoxicity when applied to seedlings at concentrations of 2000 and 1500 μL L-1, respectively. The major constituents found in lemon grass essential oil were Geranial and Neral, while Octanoic Acid was found in noni oil. Lower values in the area below the rust progress curve were observed with the preventive application of lemon grass and noni essential oils.

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 ...

Structure and Chromosomal Organization of Yeast Genes Regulated by Topoisomerase II.

Science.gov (United States)

Joshi, Ricky S; Nikolaou, Christoforos; Roca, Joaquim

2018-01-03

Cellular DNA topoisomerases (topo I and topo II) are highly conserved enzymes that regulate the topology of DNA during normal genome transactions, such as DNA transcription and replication. In budding yeast, topo I is dispensable whereas topo II is essential, suggesting fundamental and exclusive roles for topo II, which might include the functions of the topo IIa and topo IIb isoforms found in mammalian cells. In this review, we discuss major findings of the structure and chromosomal organization of genes regulated by topo II in budding yeast. Experimental data was derived from short (10 min) and long term (120 min) responses to topo II inactivation in top-2 ts mutants. First, we discuss how short term responses reveal a subset of yeast genes that are regulated by topo II depending on their promoter architecture. These short term responses also uncovered topo II regulation of transcription across multi-gene clusters, plausibly by common DNA topology management. Finally, we examine the effects of deactivated topo II on the elongation of RNA transcripts. Each study provides an insight into the particular chromatin structure that interacts with the activity of topo II. These findings are of notable clinical interest as numerous anti-cancer therapies interfere with topo II activity.

Essential medicine policy in China: pros and cons.

Science.gov (United States)

Hu, Shanlian

2013-01-01

To analyze the achievements, issues and policy recommendations for implementing essential medicine system in China after a 3-year effort. Policy documents analysis and Literature reviews are conducted. From 2009-2011, a series of national essential medicine (EM) policies has been established which contain EM list, organizing production, quality assurance, pricing, tendering and procurement, distribution, rational use, monitoring and evaluation, etc. About 98.8% government-run primary healthcare institutions and 41.5% village health posts are conducting zero-mark-up policy while buying EMs. The average cost per visit, per admission, and per description in outpatient and inpatient departments has declined. The issues with the national EM list cannot meet the requirements of clinical practice at the local level, all provinces have to increase additional 64-455 EMs in their local supplementary list; the limitation of EML in primary healthcare institutions causes patients to transfer directly to secondary or tertiary hospitals to search appropriate treatment; there is no defined regulation or legislation regarding the responsibility and accountability of government to compensate for the financial loss after implementing a zero mark-up policy in primary healthcare institutions. In the future, some innovative reform should be taken into account, such as revising EML, quality assurance, control margins within the distribution system, differential pricing and internal reference-based pricing, waive taxes and import duties of EMs, and separation between prescribing and dispensing in public hospital reform. Establishing a national essential medicine system is a difficult task to accomplish. The role of the zero-mark-up policy of EMs is to cut off the economic profit chain among different stakeholders. Using pharmaceutical profit to subsidize hospital revenue will be gradually eliminated in China.

Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide

OpenAIRE

Fomenko, Dmitri E.; Koc, Ahmet; Agisheva, Natalia; Jacobsen, Michael; Kaya, Alaattin; Malinouski, Mikalai; Rutherford, Julian C.; Siu, Kam-Leung; Jin, Dong-Yan; Winge, Dennis R.; Gladyshev, Vadim N.

2011-01-01

Hydrogen peroxide is thought to regulate cellular processes by direct oxidation of numerous cellular proteins, whereas antioxidants, most notably thiol peroxidases, are thought to reduce peroxides and inhibit H2O2 response. However, thiol peroxidases have also been implicated in activation of transcription factors and signaling. It remains unclear if these enzymes stimulate or inhibit redox regulation and whether this regulation is widespread or limited to a few cellular components. Herein, w...

Antioxidant response elements: Discovery, classes, regulation and potential applications.

Science.gov (United States)

Raghunath, Azhwar; Sundarraj, Kiruthika; Nagarajan, Raju; Arfuso, Frank; Bian, Jinsong; Kumar, Alan P; Sethi, Gautam; Perumal, Ekambaram

2018-07-01

Exposure to antioxidants and xenobiotics triggers the expression of a myriad of genes encoding antioxidant proteins, detoxifying enzymes, and xenobiotic transporters to offer protection against oxidative stress. This articulated universal mechanism is regulated through the cis-acting elements in an array of Nrf2 target genes called antioxidant response elements (AREs), which play a critical role in redox homeostasis. Though the Keap1/Nrf2/ARE system involves many players, AREs hold the key in transcriptional regulation of cytoprotective genes. ARE-mediated reporter constructs have been widely used, including xenobiotics profiling and Nrf2 activator screening. The complexity of AREs is brought by the presence of other regulatory elements within the AREs. The diversity in the ARE sequences not only bring regulatory selectivity of diverse transcription factors, but also confer functional complexity in the Keap1/Nrf2/ARE pathway. The different transcription factors either homodimerize or heterodimerize to bind the AREs. Depending on the nature of partners, they may activate or suppress the transcription. Attention is required for deeper mechanistic understanding of ARE-mediated gene regulation. The computational methods of identification and analysis of AREs are still in their infancy. Investigations are required to know whether epigenetics mechanism plays a role in the regulation of genes mediated through AREs. The polymorphisms in the AREs leading to oxidative stress related diseases are warranted. A thorough understanding of AREs will pave the way for the development of therapeutic agents against cancer, neurodegenerative, cardiovascular, metabolic and other diseases with oxidative stress. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

The response regulator expM is essential for the virulence of Erwinia carotovora subsp. carotovora and acts negatively on the sigma factor RpoS (sigma s).

Science.gov (United States)

Andersson, R A; Palva, E T; Pirhonen, M

1999-07-01

The main virulence factors of Erwinia carotovora subsp. carotovora, the secreted, extracellular cell-wall-degrading enzymes, are controlled by several regulatory mechanisms. We have isolated transposon mutants with reduced virulence on tobacco. One of these mutants, with a mutation in a gene designated expM, was characterized in this study. This mutant produces slightly reduced amounts of extracellular enzymes in vitro and the secretion of the enzymes is also affected. The expM wild-type allele was cloned together with an upstream gene, designated expL, that has an unknown function. The expM gene was sequenced and found to encode a protein with similarity to the RssB/SprE protein of Escherichia coli and the MviA protein of Salmonella typhimurium. These proteins belong to a new type of two-component response regulators that negatively regulate the stability of the Sigma factor RpoS (sigma s) at the protein level. The results of this study suggest that ExpM has a similar function in E. carotovora subsp. carotovora. We also provide evidence that the overproduction of RpoS in the expM mutant is an important factor for the reduced virulence phenotype and that it partly causes the observed phenotype seen in vitro. However, an expM/rpoS double mutant is still affected in secretion of extracellular enzymes, suggesting that ExpM in addition to RpoS also acts on other targets.

Actin is an essential component of plant gravitropic signaling pathways

Science.gov (United States)

Braun, Markus; Hauslage, Jens; Limbach, Christoph

2003-08-01

A role of the actin cytoskeleton in the different phases of gravitropism in higher plant organs seems obvious, but experimental evidence is still inconclusive and contradictory. In gravitropically tip-growing rhizoids and protonemata, however, it is well documented that actin is an essential component of the tip-growth machinery and is involved either in the cellular mechanisms that lead to gravity sensing and in the processes of the graviresponses that result in the reorientation of the growth direction. All these processes depend on a complexly organized and highly dynamic organization of actin filaments whose diverse functions are coordinated by numerous associated proteins. Actin filaments and myosins mediate the transport of secretory vehicles to the growing tip and precisely control the delivery of cell wall material. In addition, both cell types use a very efficient actomyosin-based system to control and correct the position of their statoliths and to direct sedimenting statoliths to confined graviperception sites at the plasma membrane. The studies presented in this paper provide evidence for the essential role of actin in plant gravity sensing and the gravitropic responses. A unique actin-organizing center exists in the tip of characean rhizoids and protonemata which is associated with and dynamically regulated by a specific set of actin-dynamizing proteins. It is concluded that this highly dynamic apical actin array is an essential prerequisite for gravity sensing and gravity-oriented tip growth.

GPR68 Senses Flow and Is Essential for Vascular Physiology.

Science.gov (United States)

Xu, Jie; Mathur, Jayanti; Vessières, Emilie; Hammack, Scott; Nonomura, Keiko; Favre, Julie; Grimaud, Linda; Petrus, Matt; Francisco, Allain; Li, Jingyuan; Lee, Van; Xiang, Fu-Li; Mainquist, James K; Cahalan, Stuart M; Orth, Anthony P; Walker, John R; Ma, Shang; Lukacs, Viktor; Bordone, Laura; Bandell, Michael; Laffitte, Bryan; Xu, Yan; Chien, Shu; Henrion, Daniel; Patapoutian, Ardem

2018-04-19

Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Regulation of Homologous Recombination by SUMOylation

DEFF Research Database (Denmark)

Pinela da Silva, Sonia Cristina

factors such as the homologous recombination (HR) machinery. HR constitutes the main DSB repair pathway in Saccharomyces cerevisiae and despite being largely considered an error-free process and essential for genome stability, uncontrolled recombination can lead to loss of heterozygosity, translocations......, deletions, and genome rearrangements that can lead to cell death or cancer in humans. The post-translational modification by SUMO (small ubiquitinlike modifier) has proven to be an important regulator of HR and genome integrity, but the molecular mechanisms responsible for these roles are still unclear....... In this study I present new insights for the role of SUMOylation in regulating HR by dissecting the role of SUMO in the interaction between the central HR-mediator protein Rad52 and its paralogue Rad59 and the outcome of recombination. This data provides evidence for the importance of SUMO in promoting protein...

Protein Kinase A Regulatory Subunit Isoforms Regulate Growth and Differentiation in Mucor circinelloides: Essential Role of PKAR4

Science.gov (United States)

Ocampo, J.; McCormack, B.; Navarro, E.; Moreno, S.; Garre, V.

2012-01-01

The protein kinase A (PKA) signaling pathway plays a role in regulating growth and differentiation in the dimorphic fungus Mucor circinelloides. PKA holoenzyme is comprised of two catalytic (C) and two regulatory (R) subunits. In M. circinelloides, four genes encode the PKAR1, PKAR2, PKAR3, and PKAR4 isoforms of R subunits. We have constructed null mutants and demonstrate that each isoform has a different role in growth and differentiation. The most striking finding is that pkaR4 is an essential gene, because only heterokaryons were obtained in knockout experiments. Heterokaryons with low levels of wild-type nuclei showed an impediment in the emission of the germ tube, suggesting a pivotal role of this gene in germ tube emergence. The remaining null strains showed different alterations in germ tube emergence, sporulation, and volume of the mother cell. The pkaR2 null mutant showed an accelerated germ tube emission and was the only mutant that germinated under anaerobic conditions when glycine was used as a nitrogen source, suggesting that pkaR2 participates in germ tube emergence by repressing it. From the measurement of the mRNA and protein levels of each isoform in the wild-type and knockout strains, it can be concluded that the expression of each subunit has its own mechanism of differential regulation. The PKAR1 and PKAR2 isoforms are posttranslationally modified by ubiquitylation, suggesting another regulation point in the specificity of the signal transduction. The results indicate that each R isoform has a different role in M. circinelloides physiology, controlling the dimorphism and contributing to the specificity of cyclic AMP (cAMP)-PKA pathway. PMID:22635921

c-Myb Regulates the T-Bet-Dependent Differentiation Program in B Cells to Coordinate Antibody Responses

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Dana Piovesan

2017-04-01

Full Text Available Summary: Humoral immune responses are tailored to the invading pathogen through regulation of key transcription factors and their networks. This is critical to establishing effective antibody-mediated responses, yet it is unknown how B cells integrate pathogen-induced signals to drive or suppress transcriptional programs specialized for each class of pathogen. Here, we detail the key role of the transcription factor c-Myb in regulating the T-bet-mediated anti-viral program. Deletion of c-Myb in mature B cells significantly increased serum IgG2c and CXCR3 expression by upregulating T-bet, normally suppressed during Th2-cell-mediated responses. Enhanced expression of T-bet resulted in aberrant plasma cell differentiation within the germinal center, mediated by CXCR3 expression. These findings identify a dual role for c-Myb in limiting inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Identifying such intrinsic regulators of specialized antibody responses can assist in vaccine design and therapeutic intervention in B-cell-mediated immune disorders. : Piovesan et al. examine how B cells establish transcriptional programs that result in tailored responses to invading pathogens. The authors find that the transcription factor c-Myb represses the T-bet-mediated anti-viral program in B cells. c-Myb limits inappropriate effector responses while coordinating plasma cell differentiation with germinal center egress. Keywords: B cells, c-Myb, T-bet, immunoglobulin, CXCR3, plasma cell, germinal center

The dynamic regulation of NAD metabolism in mitochondria

Science.gov (United States)

Stein, Liana Roberts; Imai, Shin-ichiro

2012-01-01

Mitochondria are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. While the maintenance of an optimal NAD/NADH ratio is essential for mitochondrial function, it has recently become apparent that the maintenance of the mitochondrial NAD pool also has critical importance. The biosynthesis, transport, and catabolism of NAD and its key intermediates play an important role in the regulation of NAD-consuming mediators, such as sirtuins, poly-ADP-ribose polymerases, and CD38/157 ectoenzymes, in intra- and extracellular compartments. Mitochondrial NAD biosynthesis is also modulated in response to nutritional and environmental stimuli. In this article, we discuss this dynamic regulation of NAD metabolism in mitochondria to shed light on the intimate connection between NAD and mitochondrial function. PMID:22819213

CLE peptides regulate lateral root development in response to nitrogen nutritional status of plants.

Science.gov (United States)

Araya, Takao; von Wirén, Nicolaus; Takahashi, Hideki

2014-01-01

CLE (CLAVATA3/embryo surrounding region (ESR)) peptides control meristem functions in plants. Our recent study highlights the critical role of a peptide-receptor signaling module composed of nitrogen (N)-responsive CLE peptides and the CLAVATA1 (CLV1) leucine-rich repeat receptor-like kinase in controlling lateral root development in Arabidopsis thaliana. CLE1, -3, -4 and -7 are expressed in root pericycle cells in Arabidopsis roots under N-limited growth conditions. Overexpression of these CLE genes inhibits lateral root emergence from the primary root. The inhibitory action of N-responsive CLE peptides on lateral root development requires the function of CLV1 expressed in phloem companion cells in roots, suggesting that downstream signals are transferred through phloem for systemic regulation of root system architecture. An additional mechanism downstream of CLV1 feedback-regulates transcript levels of N-responsive CLE genes in roots for fine-tuning the signal amplitude.

PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

Science.gov (United States)

Yang, Jason H.; Polanowska-Grabowska, Renata K.; Smith, Jeffrey S.; Shields, Charles W.; Saucerman, Jeffrey J.

2014-01-01

β-adrenergic signaling is spatiotemporally heterogeneous in the cardiac myocyte, conferring exquisite control to sympathetic stimulation. Such heterogeneity drives the formation of protein kinase A (PKA) signaling microdomains, which regulate Ca2+ handling and contractility. Here, we test the hypothesis that the nucleus independently comprises a PKA signaling microdomain regulating myocyte hypertrophy. Spatially-targeted FRET reporters for PKA activity identified slower PKA activation and lower isoproterenol sensitivity in the nucleus (t50 = 10.60±0.68 min; EC50 = 89.00 nmol/L) than in the cytosol (t50 = 3.71±0.25 min; EC50 = 1.22 nmol/L). These differences were not explained by cAMP or AKAP-based compartmentation. A computational model of cytosolic and nuclear PKA activity was developed and predicted that differences in nuclear PKA dynamics and magnitude are regulated by slow PKA catalytic subunit diffusion, while differences in isoproterenol sensitivity are regulated by nuclear expression of protein kinase inhibitor (PKI). These were validated by FRET and immunofluorescence. The model also predicted differential phosphorylation of PKA substrates regulating cell contractility and hypertrophy. Ca2+ and cell hypertrophy measurements validated these predictions and identified higher isoproterenol sensitivity for contractile enhancements (EC50 = 1.84 nmol/L) over cell hypertrophy (EC50 = 85.88 nmol/L). Over-expression of spatially targeted PKA catalytic subunit to the cytosol or nucleus enhanced contractile and hypertrophic responses, respectively. We conclude that restricted PKA catalytic subunit diffusion is an important PKA compartmentation mechanism and the nucleus comprises a novel PKA signaling microdomain, insulating hypertrophic from contractile β-adrenergic signaling responses. PMID:24225179

The Response Regulator ResD Plays a Role in Metabolism of Listeria monocytogenes

DEFF Research Database (Denmark)

Larsen, Marianne Halberg; Sørensen, Martine; Ingmer, Hanne

to be transmitted to food processing plants from where it can establish and survive for extended periods of time contaminating processed food products. Recently we have identified the response regulator ResD of L. monocytogenes and showed that it is important for growth in laboratory media and for sugar uptake...... in the upstream regulatory region of several genes of L. monocytogenes and the binding of the ResD protein to some of these regulatory regions upstream putative target genes is analysed by electrophoretic mobility shift assays (EMSAs). In conclusion, the response regulator ResD act is important for metabolisme...

Essential versus potentially toxic dietary substances: A seasonal comparison of essential fatty acids and methyl mercury concentrations in the planktonic food web

Energy Technology Data Exchange (ETDEWEB)

Kainz, Martin [Aquatic Ecosystem Management Research Division, National Water Research Institute, Environment Canada, 867 Lakeshore Road, P.O. Box 505, Burlington, ON L7R 4A6 (Canada)], E-mail: martin.kainz@donau-uni.ac.at; Arts, Michael T. [Water and Aquatic Sciences Research Program, University of Victoria, Department of Biology, P.O. Box 3020, Stn. CSC, Victoria, BC V8W 3N5 (Canada); Mazumder, Asit [Aquatic Ecosystem Management Research Division, National Water Research Institute, Environment Canada, 867 Lakeshore Road, P.O. Box 505, Burlington, ON L7R 4A6 (Canada)

2008-09-15

We investigated seasonal variability of essential fatty acids (EFA) and methyl mercury (MeHg) concentrations in four size categories of planktonic organisms in two coastal lakes. MeHg concentrations increased significantly with increasing plankton size and were independent of plankton taxonomy. However, total EFA increased from seston to mesozooplankton, but decreased in the cladoceran-dominated macrozooplankton size-class. Analysis of EFA patterns revealed that linoleic, alpha-linolenic, arachidonic, and eicosapentaenoic acids increased with increasing zooplankton size, but docosahexaenoic acid (DHA) in the cladoceran-dominated macrozooplankton was generally lower than in seston. This consistent pattern demonstrates that cladocerans, although bioaccumulating MeHg, convey less DHA than similar-sized copepods to their consumers. It is thus evident that fish consuming cladocerans have restricted access to DHA, yet unrestricted dietary access to MeHg. Thus, the structure of planktonic food webs clearly affects the composition of EFA and regulates dietary supply of these essential nutrients, while MeHg bioaccumulates with increasing zooplankton size. - The structure of planktonic food webs largely regulates the composition and dietary supply of essential fatty acids, while MeHg bioaccumulates with zooplankton size.

Essential versus potentially toxic dietary substances: A seasonal comparison of essential fatty acids and methyl mercury concentrations in the planktonic food web

International Nuclear Information System (INIS)

Kainz, Martin; Arts, Michael T.; Mazumder, Asit

2008-01-01

We investigated seasonal variability of essential fatty acids (EFA) and methyl mercury (MeHg) concentrations in four size categories of planktonic organisms in two coastal lakes. MeHg concentrations increased significantly with increasing plankton size and were independent of plankton taxonomy. However, total EFA increased from seston to mesozooplankton, but decreased in the cladoceran-dominated macrozooplankton size-class. Analysis of EFA patterns revealed that linoleic, alpha-linolenic, arachidonic, and eicosapentaenoic acids increased with increasing zooplankton size, but docosahexaenoic acid (DHA) in the cladoceran-dominated macrozooplankton was generally lower than in seston. This consistent pattern demonstrates that cladocerans, although bioaccumulating MeHg, convey less DHA than similar-sized copepods to their consumers. It is thus evident that fish consuming cladocerans have restricted access to DHA, yet unrestricted dietary access to MeHg. Thus, the structure of planktonic food webs clearly affects the composition of EFA and regulates dietary supply of these essential nutrients, while MeHg bioaccumulates with increasing zooplankton size. - The structure of planktonic food webs largely regulates the composition and dietary supply of essential fatty acids, while MeHg bioaccumulates with zooplankton size

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

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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.

Structural Basis for DNA Recognition by the Two-Component Response Regulator RcsB.

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Filippova, Ekaterina V; Zemaitaitis, Bozena; Aung, Theint; Wolfe, Alan J; Anderson, Wayne F

2018-02-27

RcsB is a highly conserved transcription regulator of the Rcs phosphorelay system, a complex two-component signal transduction system (N. Majdalani and S. Gottesman, Annu Rev Microbiol 59:379-405, 2005; A. J. Wolfe, Curr Opin Microbiol 13:204-209, 2010, https://doi.org/10.1016/j.mib.2010.01.002; D. J. Clarke, Future Microbiol 5:1173-1184, 2010, https://doi.org/10.2217/fmb.10.83). RcsB plays an important role in virulence and pathogenicity in human hosts by regulating biofilm formation. RcsB can regulate transcription alone or together with its auxiliary transcription regulators by forming heterodimers. This complexity allows RcsB to regulate transcription of more than 600 bacterial genes in response to different stresses (D. Wang et al., Mol Plant Microbe Interact 25:6-17, 2012, https://doi.org/10.1094/MPMI-08-11-0207). Despite increasing knowledge of RcsB importance, molecular mechanisms that drive the ability of RcsB to control transcription of a large number of genes remain unclear. Here, we present crystal structures of unphosphorylated RcsB in complex with the consensus DNA-binding sequence of 22-mer (DNA22) and 18-mer (DNA18) of the flhDC operon from Escherichia coli determined at 3.15- and 3.37-Å resolution, respectively. The results of our structural analysis combined with the results of in vitro binding assays provide valuable insights to the protein regulatory mechanism, demonstrate how RcsB recognizes target DNA sequences, and reveal a unique oligomeric state that allows RcsB to form homo- and heterodimers. This information will help us understand the complex mechanisms of transcriptional regulation by RcsB in bacteria. IMPORTANCE RcsB is a well-studied two-component response regulator of the Rcs phosphorelay system, conserved within the family Enterobacteriaceae , which includes many pathogens. It is a global regulator, controlling more than 5% of bacterial genes associated with capsule biosynthesis, flagellar biogenesis, cell wall biosynthesis

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...

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

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Yanyan Yang

2014-01-01

Full Text Available Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α and cyclooxygenase-2 (COX-2. p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

The phosducin-like protein PhLP1 impacts regulation of glycoside hydrolases and light response in Trichoderma reesei

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Tisch Doris

2011-12-01

Full Text Available Abstract Background In the biotechnological workhorse Trichoderma reesei (Hypocrea jecorina transcription of cellulase genes as well as efficiency of the secreted cellulase mixture are modulated by light. Components of the heterotrimeric G-protein pathway interact with light-dependent signals, rendering this pathway a key regulator of cellulase gene expression. Results As regulators of heterotrimeric G-protein signaling, class I phosducin-like proteins, are assumed to act as co-chaperones for G-protein beta-gamma folding and exert their function in response to light in higher eukaryotes. Our results revealed light responsive transcription of the T. reesei class I phosducin-like protein gene phlp1 and indicate a light dependent function of PhLP1 also in fungi. We showed the functions of PhLP1, GNB1 and GNG1 in the same pathway, with one major output being the regulation of transcription of glycoside hydrolase genes including cellulase genes in T. reesei. We found no direct correlation between the growth rate and global regulation of glycoside hydrolases, which suggests that regulation of growth does not occur only at the level of substrate degradation efficiency. Additionally, PhLP1, GNB1 and GNG1 are all important for proper regulation of light responsiveness during long term exposure. In their absence, the amount of light regulated genes increased from 2.7% in wild type to 14% in Δphlp1. Besides from the regulation of degradative enzymes, PhLP1 was also found to impact on the transcription of genes involved in sexual development, which was in accordance with decreased efficiency of fruiting body formation in Δphlp1. The lack of GNB1 drastically diminished ascospore discharge in T. reesei. Conclusions The heterotrimeric G-protein pathway is crucial for the interconnection of nutrient signaling and light response of T. reesei, with the class I phosducin-like protein PhLP1, GNB1 and GNG1 acting as important nodes, which influence light

Functional characterization of MAT1-1-specific mating-type genes in the homothallic ascomycete Sordaria macrospora provides new insights into essential and nonessential sexual regulators.

Science.gov (United States)

Klix, V; Nowrousian, M; Ringelberg, C; Loros, J J; Dunlap, J C; Pöggeler, S

2010-06-01

Mating-type genes in fungi encode regulators of mating and sexual development. Heterothallic ascomycete species require different sets of mating-type genes to control nonself-recognition and mating of compatible partners of different mating types. Homothallic (self-fertile) species also carry mating-type genes in their genome that are essential for sexual development. To analyze the molecular basis of homothallism and the role of mating-type genes during fruiting-body development, we deleted each of the three genes, SmtA-1 (MAT1-1-1), SmtA-2 (MAT1-1-2), and SmtA-3 (MAT1-1-3), contained in the MAT1-1 part of the mating-type locus of the homothallic ascomycete species Sordaria macrospora. Phenotypic analysis of deletion mutants revealed that the PPF domain protein-encoding gene SmtA-2 is essential for sexual reproduction, whereas the alpha domain protein-encoding genes SmtA-1 and SmtA-3 play no role in fruiting-body development. By means of cross-species microarray analysis using Neurospora crassa oligonucleotide microarrays hybridized with S. macrospora targets and quantitative real-time PCR, we identified genes expressed under the control of SmtA-1 and SmtA-2. Both genes are involved in the regulation of gene expression, including that of pheromone genes.

A Unique Fungal Two-Component System Regulates Stress Responses, Drug Sensitivity, Sexual Development, and Virulence of Cryptococcus neoformans

Science.gov (United States)

Bahn, Yong-Sun; Kojima, Kaihei; Cox, Gary M.

2006-01-01

The stress-activated mitogen-activated protein kinase (MAPK) pathway is widely used by eukaryotic organisms as a central conduit via which cellular responses to the environment effect growth and differentiation. The basidiomycetous human fungal pathogen Cryptococcus neoformans uniquely uses the stress-activated Pbs2-Hog1 MAPK system to govern a plethora of cellular events, including stress responses, drug sensitivity, sexual reproduction, and virulence. Here, we characterized a fungal “two-component” system that controls these fundamental cellular functions via the Pbs2-Hog1 MAPK cascade. A typical response regulator, Ssk1, modulated all Hog1-dependent phenotypes by controlling Hog1 phosphorylation, indicating that Ssk1 is the major upstream signaling component of the Pbs2-Hog1 pathway. A second response regulator, Skn7, governs sensitivity to Na+ ions and the antifungal agent fludioxonil, negatively controls melanin production, and functions independently of Hog1 regulation. To control these response regulators, C. neoformans uses multiple sensor kinases, including two-component–like (Tco) 1 and Tco2. Tco1 and Tco2 play shared and distinct roles in stress responses and drug sensitivity through the Hog1 MAPK system. Furthermore, each sensor kinase mediates unique cellular functions for virulence and morphological differentiation. Our findings highlight unique adaptations of this global two-component MAPK signaling cascade in a ubiquitous human fungal pathogen. PMID:16672377

HSF1 and HSF3 cooperatively regulate the heat shock response in lizards.

Science.gov (United States)

Takii, Ryosuke; Fujimoto, Mitsuaki; Matsuura, Yuki; Wu, Fangxu; Oshibe, Namiko; Takaki, Eiichi; Katiyar, Arpit; Akashi, Hiroshi; Makino, Takashi; Kawata, Masakado; Nakai, Akira

2017-01-01

Cells cope with temperature elevations, which cause protein misfolding, by expressing heat shock proteins (HSPs). This adaptive response is called the heat shock response (HSR), and it is regulated mainly by heat shock transcription factor (HSF). Among the four HSF family members in vertebrates, HSF1 is a master regulator of HSP expression during proteotoxic stress including heat shock in mammals, whereas HSF3 is required for the HSR in birds. To examine whether only one of the HSF family members possesses the potential to induce the HSR in vertebrate animals, we isolated cDNA clones encoding lizard and frog HSF genes. The reconstructed phylogenetic tree of vertebrate HSFs demonstrated that HSF3 in one species is unrelated with that in other species. We found that the DNA-binding activity of both HSF1 and HSF3 in lizard and frog cells was induced in response to heat shock. Unexpectedly, overexpression of lizard and frog HSF3 as well as HSF1 induced HSP70 expression in mouse cells during heat shock, indicating that the two factors have the potential to induce the HSR. Furthermore, knockdown of either HSF3 or HSF1 markedly reduced HSP70 induction in lizard cells and resistance to heat shock. These results demonstrated that HSF1 and HSF3 cooperatively regulate the HSR at least in lizards, and suggest complex mechanisms of the HSR in lizards as well as frogs.

Interagency Transition Team Development and Facilitation. Essential Tools.

Science.gov (United States)

Stodden, Robert A.; Brown, Steven E.; Galloway, L. M.; Mrazek, Susan; Noy, Liora

2005-01-01

The purpose of this Essential Tool is to assist state-level transition coordinators and others responsible for forming, conducting, and evaluating the performance of interagency transition teams that are focused upon the school and post-school needs of youth with disabilities. This Essential Tool is designed to guide the coordination efforts of…

RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

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Toshinori Ozaki

2013-01-01

Full Text Available A proper DNA damage response (DDR, which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such as p21WAF1, BAX, and PUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

Economic demand and essential value.

Science.gov (United States)

Hursh, Steven R; Silberberg, Alan

2008-01-01

The strength of a rat's eating reflex correlates with hunger level when strength is measured by the response frequency that precedes eating (B. F. Skinner, 1932a, 1932b). On the basis of this finding, Skinner argued response frequency could index reflex strength. Subsequent work documented difficulties with this notion because responding was affected not only by the strengthening properties of the reinforcer but also by the rate-shaping effects of the schedule. This article obviates this problem by measuring strength via methods from behavioral economics. This approach uses demand curves to map how reinforcer consumption changes with changes in the "price" different ratio schedules impose. An exponential equation is used to model these demand curves. The value of this exponential's rate constant is used to scale the strength or essential value of a reinforcer, independent of the scalar dimensions of the reinforcer. Essential value determines the consumption level to be expected at particular prices and the response level that will occur to support that consumption. This approach permits comparing reinforcers that differ in kind, contributing toward the goal of scaling reinforcer value. (c) 2008 APA, all rights reserved

Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions.

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Norihisa Mikami

Full Text Available Dendritic cells (DCs play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP, is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1 results in higher cytokine production in response to LPS (lipopolysaccharide. On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2(+ DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2(+ DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2(- DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs.

[Regulation of heat shock gene expression in response to stress].

Science.gov (United States)

Garbuz, D G

2017-01-01

Heat shock (HS) genes, or stress genes, code for a number of proteins that collectively form the most ancient and universal stress defense system. The system determines the cell capability of adaptation to various adverse factors and performs a variety of auxiliary functions in normal physiological conditions. Common stress factors, such as higher temperatures, hypoxia, heavy metals, and others, suppress transcription and translation for the majority of genes, while HS genes are upregulated. Transcription of HS genes is controlled by transcription factors of the HS factor (HSF) family. Certain HSFs are activated on exposure to higher temperatures or other adverse factors to ensure stress-induced HS gene expression, while other HSFs are specifically activated at particular developmental stages. The regulation of the main mammalian stress-inducible factor HSF1 and Drosophila melanogaster HSF includes many components, such as a variety of early warning signals indicative of abnormal cell activity (e.g., increases in intracellular ceramide, cytosolic calcium ions, or partly denatured proteins); protein kinases, which phosphorylate HSFs at various Ser residues; acetyltransferases; and regulatory proteins, such as SUMO and HSBP1. Transcription factors other than HSFs are also involved in activating HS gene transcription; the set includes D. melanogaster GAF, mammalian Sp1 and NF-Y, and other factors. Transcription of several stress genes coding for molecular chaperones of the glucose-regulated protein (GRP) family is predominantly regulated by another stress-detecting system, which is known as the unfolded protein response (UPR) system and is activated in response to massive protein misfolding in the endoplasmic reticulum and mitochondrial matrix. A translational fine tuning of HS protein expression occurs via changing the phosphorylation status of several proteins involved in translation initiation. In addition, specific signal sequences in the 5'-UTRs of some HS

Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha

Science.gov (United States)

Hall, J.A.; Cannons, J.L.; Grainger, J.R.; Santos, L.M. Dos; Hand, T.W.; Naik, S.; Wohlfert, E.A.; Chou, D.B.; Oldenhove, G.; Robinson, M.; Grigg, M.E.; Kastenmayer, R.; Schwartzberg, P.L.; Belkaid, Y.

2012-01-01

SUMMARY Vitamin A and its metabolite, retinoic acid (RA), have recently been implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we show that RA is also required to elicit proinflammatory CD4+ helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) is the critical mediator of these effects. Strikingly, antagonism of RAR signaling and deficiency in RARα(Rara−/−) results in a cell autonomous CD4+ T cell activation defect. Altogether, these findings reveal a fundamental role for the RA/RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses. PMID:21419664

Mathematical model of the SOS response regulation in wild-type Escherichia coli

International Nuclear Information System (INIS)

Aksenov, S.V.

1997-01-01

Regulation of the SOS response in Escherichia coli, which is a set of inducible cellular reactions introduced after DNA damage, is due to specific interaction of LexA and RecA proteins. LexA protein is a common repressor of the genes of the SOS system, and RecA protein, once transiently activated by the so-called SOS-inducing signal, promotes LexA protein destruction. We have described the SOS regulation by means of differential equations with regard to LexA and RecA concentrations elsewhere. The 'input' function for model equations is the level of the SOS-inducing signal against time. Here we present a means for calculating the concentration of single-stranded DNA (SOS-inducing signal) as a function of time in wild-type cells after ultraviolet irradiation. With model equations one can simulate kinetic curves of SOS regulatory proteins after DNA damage to survey the SOS response kinetics. Simulation of LexA protein kinetics agrees with experimental data. We compare simulated LexA kinetic curves in wild-type and uνr - mutant bacteria, which is useful in investigating the way uνrABC-dependent excision repair modulates the SOS response kinetics. Possible applications of the model to investigating various aspects of the SOS induction are discussed

Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature.

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Makoto Horikawa

2015-04-01

Full Text Available Temperature potently modulates various physiologic processes including organismal motility, growth rate, reproduction, and ageing. In ectotherms, longevity varies inversely with temperature, with animals living shorter at higher temperatures. Thermal effects on lifespan and other processes are ascribed to passive changes in metabolic rate, but recent evidence also suggests a regulated process. Here, we demonstrate that in response to temperature, daf-41/ZC395.10, the C. elegans homolog of p23 co-chaperone/prostaglandin E synthase-3, governs entry into the long-lived dauer diapause and regulates adult lifespan. daf-41 deletion triggers constitutive entry into the dauer diapause at elevated temperature dependent on neurosensory machinery (daf-10/IFT122, insulin/IGF-1 signaling (daf-16/FOXO, and steroidal signaling (daf-12/FXR. Surprisingly, daf-41 mutation alters the longevity response to temperature, living longer than wild-type at 25°C but shorter than wild-type at 15°C. Longevity phenotypes at 25°C work through daf-16/FOXO and heat shock factor hsf-1, while short lived phenotypes converge on daf-16/FOXO and depend on the daf-12/FXR steroid receptor. Correlatively daf-41 affected expression of DAF-16 and HSF-1 target genes at high temperature, and nuclear extracts from daf-41 animals showed increased occupancy of the heat shock response element. Our studies suggest that daf-41/p23 modulates key transcriptional changes in longevity pathways in response to temperature.

Bmp indicator mice reveal dynamic regulation of transcriptional response.

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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.

Leptin regulates dopamine responses to sustained stress in humans.

Science.gov (United States)

Burghardt, Paul R; Love, Tiffany M; Stohler, Christian S; Hodgkinson, Colin; Shen, Pei-Hong; Enoch, Mary-Anne; Goldman, David; Zubieta, Jon-Kar

2012-10-31

Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.

Rifampin Resistance rpoB Alleles or Multicopy Thioredoxin/Thioredoxin Reductase Suppresses the Lethality of Disruption of the Global Stress Regulator spx in Staphylococcus aureus

DEFF Research Database (Denmark)

Villanueva, Maite; Jousselin, Ambre; Baek, Kristoffer T

2016-01-01

is a thiol/oxidative stress sensor that interacts with the C-terminal domain of the RNA polymerase RpoA subunit, leading to changes in gene expression that help sustain viability under various conditions. Using genetic and deep-sequencing methods, we show that spx is essential in S. aureus...... discovered that Spx, an RNA polymerase-interacting stress regulator implicated in many stress responses in S. aureus, including responses to oxidative and cell wall antibiotics, is essential. We describe two mechanisms that suppress the lethality of spx disruption. One mechanism highlights how only certain...... rifampin resistance-encoding alleles of RpoB confer new properties on RNA polymerase, with important mechanistic implications. We describe additional stress conditions where the loss of spx is deleterious, thereby highlighting Spx as a multifaceted regulator and attractive drug discovery target....

History of river regulation of the Noce River (NE Italy) and related bio-morphodynamic responses

Science.gov (United States)

Serlet, Alyssa; Scorpio, Vittoria; Mastronunzio, Marco; Proto, Matteo; Zen, Simone; Zolezzi, Guido; Bertoldi, Walter; Comiti, Francesco; Prà, Elena Dai; Surian, Nicola; Gurnell, Angela

2016-04-01

The Noce River is a hydropower-regulated Alpine stream in Northern-East Italy and a major tributary of the Adige River, the second longest Italian river. The objective of the research is to investigate the response of the lower course of the Noce to two main stages of hydromorphological regulation; channelization/ diversion and, one century later, hydropower regulation. This research uses a historical reconstruction to link the geomorphic response with natural and human-induced factors by identifying morphological and vegetation features from historical maps and airborne photogrammetry and implementing a quantitative analysis of the river response to channelization and flow / sediment supply regulation related to hydropower development. A descriptive overview is presented. The concept of evolutionary trajectory is integrated with predictions from morphodynamic theories for river bars that allow increased insight to investigate the river response to a complex sequence of regulatory events such as development of bars, islands and riparian vegetation. Until the mid-19th century the river had a multi-thread channel pattern. Thereafter (1852) the river was straightened and diverted. Upstream of Mezzolombardo village the river was constrained between embankments of approximately 100 m width while downstream they are of approximately 50 m width. Since channelization some interesting geomorphic changes have appeared in the river e.g. the appearance of alternate bars in the channel. In 1926 there was a breach in the right bank of the downstream part that resulted in a multi-thread river reach which can be viewed as a recovery to the earlier multi-thread pattern. After the 1950's the flow and sediment supply became strongly regulated by hydropower development. The analysis of aerial images reveals that the multi-thread reach became progressively stabilized by vegetation development over the bars, though signs of some dynamics can still be recognizable today, despite the

Essential Medicines in National Constitutions

Science.gov (United States)

Toebes, Brigit; Hogerzeil, Hans

2016-01-01

Abstract A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states’ legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID:27781006

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

Directory of Open Access Journals (Sweden)

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.

TG2 regulates the heat-shock response by the post-translational modification of HSF1.

Science.gov (United States)

Rossin, Federica; Villella, Valeria Rachela; D'Eletto, Manuela; Farrace, Maria Grazia; Esposito, Speranza; Ferrari, Eleonora; Monzani, Romina; Occhigrossi, Luca; Pagliarini, Vittoria; Sette, Claudio; Cozza, Giorgio; Barlev, Nikolai A; Falasca, Laura; Fimia, Gian Maria; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi; Piacentini, Mauro

2018-05-11

Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter. We show that the inhibition of TG2 restores the unbalance in HSF1-HSP70 pathway in cystic fibrosis (CF), a human disorder characterized by deregulation of proteostasis. The absence of TG2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG2. Altogether, these results indicate that TG2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat-shock response. © 2018 The Authors.

33 CFR 165.838 - Regulated Navigation Area; New Orleans Area of Responsibility, New Orleans, LA.

Science.gov (United States)

2010-07-01

... Orleans Area of Responsibility, New Orleans, LA. 165.838 Section 165.838 Navigation and Navigable Waters... Guard District § 165.838 Regulated Navigation Area; New Orleans Area of Responsibility, New Orleans, LA... Ponchartrain and to the Mississippi River in New Orleans, LA; (2) The Harvey Canal, between the Lapalco...

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

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Stephen L. McDaniel

2017-06-01

Full Text Available Set2-mediated histone methylation at H3K36 regulates diverse activities, including DNA repair, mRNA splicing, and suppression of inappropriate (cryptic transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased lifespan, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found that the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.

Differences in Sirtuin Regulation in Response to Calorie Restriction in Cryptococcus neoformans.

Science.gov (United States)

Bouklas, Tejas; Masone, Lindsey; Fries, Bettina C

2018-02-18

Cryptococcus neoformans successfully replicates in low glucose in infected patients. In the serotype A strain, H99, growth in this condition prolongs lifespan regulated by SIR2, and can be modulated with SIR2-specific drugs. Previous studies show that lifespan modulation of a cryptococcal population affects its sensitivity to antifungals, and survival in an infection model. Sirtuins and their role in longevity are conserved among fungi; however, the effect of glucose starvation is not confirmed even in Saccharomyces cerevisiae. Lifespan analysis of C. neoformans strains in low glucose showed that 37.5% exhibited pro-longevity, and lifespan of a serotype D strain, RC2, was shortened. Transcriptome comparison of H99 and RC2 under calorie restriction demonstrated differences, confirmed by real-time PCR showing that SIR2 , TOR1 , SCH9 , and PKA1 expression correlated with lifespan response to calorie restriction. As expected, RC2 -sir2 Δ cells exhibited a shortened lifespan, which was reconstituted. However, shortened lifespan from calorie restriction was independent of SIR2 . In contrast to H99 but consistent with altered SIR2 regulation, SIR2 -specific drugs did not affect outcome of RC2 infection. These data suggest that SIR2 regulation and response to calorie restriction varies in C. neoformans, which should be considered when Sirtuins are investigated as potential therapy targets for fungal infections.

Disrupted-in-Schizophrenia-1 is essential for normal hypothalamic-pituitary-interrenal (HPI) axis function.

Science.gov (United States)

Eachus, Helen; Bright, Charlotte; Cunliffe, Vincent T; Placzek, Marysia; Wood, Jonathan D; Watt, Penelope J

2017-06-01

Psychiatric disorders arise due to an interplay of genetic and environmental factors, including stress. Studies in rodents have shown that mutants for Disrupted-In-Schizophrenia-1 (DISC1), a well-accepted genetic risk factor for mental illness, display abnormal behaviours in response to stress, but the mechanisms through which DISC1 affects stress responses remain poorly understood. Using two lines of zebrafish homozygous mutant for disc1, we investigated behaviour and functioning of the hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that the role of DISC1 in stress responses is evolutionarily conserved and that DISC1 is essential for normal functioning of the HPI axis. Adult zebrafish homozygous mutant for disc1 show aberrant behavioural responses to stress. Our studies reveal that in the embryo, disc1 is expressed in neural progenitor cells of the hypothalamus, a conserved region of the vertebrate brain that centrally controls responses to environmental stressors. In disc1 mutant embryos, proliferating rx3+ hypothalamic progenitors are not maintained normally and neuronal differentiation is compromised: rx3-derived ff1b+ neurons, implicated in anxiety-related behaviours, and corticotrophin releasing hormone (crh) neurons, key regulators of the stress axis, develop abnormally, and rx3-derived pomc+ neurons are disorganised. Abnormal hypothalamic development is associated with dysfunctional behavioural and neuroendocrine stress responses. In contrast to wild type siblings, disc1 mutant larvae show altered crh levels, fail to upregulate cortisol levels when under stress and do not modulate shoal cohesion, indicative of abnormal social behaviour. These data indicate that disc1 is essential for normal development of the hypothalamus and for the correct functioning of the HPA/HPI axis. © The Author 2017. Published by Oxford University Press.

The MurC Ligase Essential for Peptidoglycan Biosynthesis Is Regulated by the Serine/Threonine Protein Kinase PknA in Corynebacterium glutamicum*

OpenAIRE

Fiuza, Maria; Canova, Marc J.; Patin, Delphine; Letek, Michal; Zanella-Cléon, Isabelle; Becchi, Michel; Mateos, Luís M.; Mengin-Lecreulx, Dominique; Molle, Virginie; Gil, José A.

2008-01-01

The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (l-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recen...

Nuclear regulation - the Canadian approach

International Nuclear Information System (INIS)

Jennekens, J.

1981-09-01

Although the Atomic Energy Control Board was established 35 years ago the basic philosophy of nuclear regulation in Canada and the underlying principles of the regulatory process remain essentially unchanged. This paper outlines the Canadian approach to nuclear regulation and explains in practical terms how the principles of regulation are applied. (author)

Regulating hedge funds.

OpenAIRE

Daníelsson, J.; Zigrand, JP.

2007-01-01

Due to the ever-increasing amounts under management and their unregulated and opaque nature, hedge funds have emerged as a key concern for policymakers. While until now, hedge funds have been left essentially unregulated, we are seeing increasing calls for regulation for both microprudential and macroprudential reasons. In our view, most calls for the regulation of hedge funds are based on a misperception of the effectiveness of financial regulations, perhaps coupled with a lack of understand...

Leptin regulates the pro-inflammatory response in human epidermal keratinocytes.

Science.gov (United States)

Lee, Moonyoung; Lee, Eunyoung; Jin, Sun Hee; Ahn, Sungjin; Kim, Sae On; Kim, Jungmin; Choi, Dalwoong; Lim, Kyung-Min; Lee, Seung-Taek; Noh, Minsoo

2018-05-01

The role of leptin in cutaneous wound healing process has been suggested in genetically obese mouse studies. However, the molecular and cellular effects of leptin on human epidermal keratinocytes are still unclear. In this study, the whole-genome-scale microarray analysis was performed to elucidate the effect of leptin on epidermal keratinocyte functions. In the leptin-treated normal human keratinocytes (NHKs), we identified the 151 upregulated and 53 downregulated differentially expressed genes (DEGs). The gene ontology (GO) enrichment analysis with the leptin-induced DEGs suggests that leptin regulates NHKs to promote pro-inflammatory responses, extracellular matrix organization, and angiogenesis. Among the DEGs, the protein expression of IL-8, MMP-1, fibronectin, and S100A7, which play roles in which is important in the regulation of cutaneous inflammation, was confirmed in the leptin-treated NHKs. The upregulation of the leptin-induced proteins is mainly regulated by the STAT3 signaling pathway in NHKs. Among the downregulated DEGs, the protein expression of nucleosome assembly-associated centromere protein A (CENPA) and CENPM was confirmed in the leptin-treated NHKs. However, the expression of CENPA and CENPM was not coupled with those of other chromosome passenger complex like Aurora A kinase, INCENP, and survivin. In cell growth kinetics analysis, leptin had no significant effect on the cell growth curves of NHKs in the normal growth factor-enriched condition. Therefore, leptin-dependent downregulation of CENPA and CENPM in NHKs may not be directly associated with mitotic regulation during inflammation.

The effect of mandatory regulation on corporate social responsibility reporting quality: evidence from China

OpenAIRE

Wang, Jianling; Tian, Gaoliang; Fan, Weiguo; Luo, Dan

2017-01-01

Corporate Social Responsibility (CSR) disclosure has attracted attention from regulatory bodies and academics over the past few decades. Due to the unreliability resulted from CSR voluntary disclosure, an increasing number of researchers are calling for more government regulation on CSR disclosure. Based on 1830 standalone CSR reports disclosed by the Chinese-listed firms during 2009-2012, we examine the effect of mandatory regulation on CSR\\ud reporting quality. We further hypothesize and te...

mTORC1 directly phosphorylates and regulates human MAF1.

Science.gov (United States)

Michels, Annemieke A; Robitaille, Aaron M; Buczynski-Ruchonnet, Diane; Hodroj, Wassim; Reina, Jaime H; Hall, Michael N; Hernandez, Nouria

2010-08-01

mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated and represses pol III transcription after various stresses, but neither the significance of the phosphorylations nor the kinase involved is known. We find that human MAF1 is absolutely required for pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. The protein is phosphorylated mainly on residues S60, S68, and S75, and this inhibits its pol III repression function. The responsible kinase is mTORC1, which phosphorylates MAF1 directly. Our results describe molecular mechanisms by which mTORC1 controls human MAF1, a key repressor of RNA polymerase III transcription, and add a new branch to the signal transduction cascade immediately downstream of TORC1.

Flexibility in the face of fear: Hippocampal-prefrontal regulation of fear and avoidance.

Science.gov (United States)

Moscarello, Justin M; Maren, Stephen

2018-02-01

Generating appropriate defensive behaviors in the face of threat is essential to survival. Although many of these behaviors are 'hard-wired', they are also flexible. For example, Pavlovian fear conditioning generates learned defensive responses, such as conditioned freezing, that can be suppressed through extinction. The expression of extinguished responses is highly context-dependent, allowing animals to engage behavioral responses appropriate to the contexts in which threats are encountered. Likewise, animals and humans will avoid noxious outcomes if given the opportunity. In instrumental avoidance learning, for example, animals overcome conditioned defensive responses, including freezing, in order to actively avoid aversive stimuli. Recent work has greatly advanced understanding of the neural basis of these phenomena and has revealed common circuits involved in the regulation of fear. Specifically, the hippocampus and medial prefrontal cortex play pivotal roles in gating fear reactions and instrumental actions, mediated by the amygdala and nucleus accumbens, respectively. Because an inability to adaptively regulate fear and defensive behavior is a central component of many anxiety disorders, the brain circuits that promote flexible responses to threat are of great clinical significance.

Actin retrograde flow controls natural killer cell response by regulating the conformation state of SHP-1.

Science.gov (United States)

Matalon, Omri; Ben-Shmuel, Aviad; Kivelevitz, Jessica; Sabag, Batel; Fried, Sophia; Joseph, Noah; Noy, Elad; Biber, Guy; Barda-Saad, Mira

2018-03-01

Natural killer (NK) cells are a powerful weapon against viral infections and tumor growth. Although the actin-myosin (actomyosin) cytoskeleton is crucial for a variety of cellular processes, the role of mechanotransduction, the conversion of actomyosin mechanical forces into signaling cascades, was never explored in NK cells. Here, we demonstrate that actomyosin retrograde flow (ARF) controls the immune response of primary human NK cells through a novel interaction between β-actin and the SH2-domain-containing protein tyrosine phosphatase-1 (SHP-1), converting its conformation state, and thereby regulating NK cell cytotoxicity. Our results identify ARF as a master regulator of the NK cell immune response. Since actin dynamics occur in multiple cellular processes, this mechanism might also regulate the activity of SHP-1 in additional cellular systems. © 2018 The Authors.

Post-translational regulation of Oct4 transcriptional activity.

Directory of Open Access Journals (Sweden)

Jonathan P Saxe

Full Text Available Oct4 is a key component of the molecular circuitry which regulates embryonic stem cell proliferation and differentiation. It is essential for maintenance of undifferentiated, pluripotent cell populations, and accomplishes these tasks by binding DNA in multiple heterodimer and homodimer configurations. Very little is known about how formation of these complexes is regulated, or the mechanisms through which Oct4 proteins respond to complex extracellular stimuli which regulate pluripotency. Here, we provide evidence for a phosphorylation-based mechanism which regulates specific Oct4 homodimer conformations. Point mutations of a putative phosphorylation site can specifically abrogate transcriptional activity of a specific homodimer assembly, with little effect on other configurations. Moreover, we performed bioinformatic predictions to identify a subset of Oct4 target genes which may be regulated by this specific assembly, and show that altering Oct4 protein levels affects transcription of Oct4 target genes which are regulated by this assembly but not others. Finally, we identified several signaling pathways which may mediate this phosphorylation and act in combination to regulate Oct4 transcriptional activity and protein stability. These results provide a mechanism for rapid and reversible alteration of Oct4 transactivation potential in response to extracellular signals.

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.

translin Is Required for Metabolic Regulation of Sleep.

Science.gov (United States)

Murakami, Kazuma; Yurgel, Maria E; Stahl, Bethany A; Masek, Pavel; Mehta, Aradhana; Heidker, Rebecca; Bollinger, Wesley; Gingras, Robert M; Kim, Young-Joon; Ja, William W; Suter, Beat; DiAngelo, Justin R; Keene, Alex C

2016-04-04

Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the identification of translin (trsn), a highly conserved RNA/DNA binding protein, as essential for starvation-induced sleep suppression. Strikingly, trsn does not appear to regulate energy stores, free glucose levels, or feeding behavior suggesting the sleep phenotype of trsn mutant flies is not a consequence of general metabolic dysfunction or blunted response to starvation. While broadly expressed in all neurons, trsn is transcriptionally upregulated in the heads of flies in response to starvation. Spatially restricted rescue or targeted knockdown localizes trsn function to neurons that produce the tachykinin family neuropeptide Leucokinin. Manipulation of neural activity in Leucokinin neurons revealed these neurons to be required for starvation-induced sleep suppression. Taken together, these findings establish trsn as an essential integrator of sleep and metabolic state, with implications for understanding the neural mechanism underlying sleep disruption in response to environmental perturbation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antispasmodic activity of essential oil from Lippia dulcis Trev.

Science.gov (United States)

Görnemann, T; Nayal, R; Pertz, H H; Melzig, M F

2008-04-17

To investigate the essential oil of Lippia dulcis Trev. (Verbenaceae) that is traditionally used in the treatment of cough, colds, bronchitis, asthma, and colic in Middle America for antispasmodic activity. We used a porcine bronchial bioassay to study contractile responses to carbachol and histamine in the absence or presence of the essential oil. The essential oil showed anti-histaminergic and anti-cholinergic activities at 100 microg/ml. The anti-histaminergic and anti-cholinergic activities of the essential oil of Lippia dulcis support the rational use of the plant or plant extracts to treat bronchospasm.

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

Science.gov (United States)

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

2014-01-01

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

Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

International Nuclear Information System (INIS)

Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

2016-01-01

The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

2016-02-12

The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

Homeodomain Transcription Factor Msx-2 Regulates Uterine Progenitor Cell Response to Diethylstilbestrol.

Science.gov (United States)

Yin, Yan; Lin, Congxing; Zhang, Ivy; Fisher, Alexander V; Dhandha, Maulik; Ma, Liang

The fate of mouse uterine epithelial progenitor cells is determined between postnatal days 5 to 7. Around this critical time window, exposure to an endocrine disruptor, diethylstilbestrol (DES), can profoundly alter uterine cytodifferentiation. We have shown previously that a homeo domain transcription factor MSX-2 plays an important role in DES-responsiveness in the female reproductive tract (FRT). Mutant FRTs exhibited a much more severe phenotype when treated with DES, accompanied by gene expression changes that are dependent on Msx2 . To better understand the role that MSX-2 plays in uterine response to DES, we performed global gene expression profiling experiment in mice lacking Msx2 By comparing this result to our previously published microarray data performed on wild-type mice, we extracted common and differentially regulated genes in the two genotypes. In so doing, we identified potential downstream targets of MSX-2, as well as genes whose regulation by DES is modulated through MSX-2. Discovery of these genes will lead to a better understanding of how DES, and possibly other endocrine disruptors, affects reproductive organ development.

Increasing intake of essential fatty acids from milk replacer benefits performance, immune responses, and health of preweaned Holstein calves.

Science.gov (United States)

Garcia, M; Shin, J H; Schlaefli, A; Greco, L F; Maunsell, F P; Thatcher, W W; Santos, J E P; Staples, C R

2015-01-01

The objective was to evaluate the effect of feeding increasing amounts of essential fatty acids (FA) in milk replacer (MR) during the first 60 d of life on growth, health, and immunity of Holstein calves. Calves were born from dams fed low concentrations of total and essential FA during the lasT2 mo of pregnancy. Newborn calves were blocked by sex and parity of the dam and assigned randomly to receive 1 of 4 MR treatments (T). Hydrogenated coconut oil and soybean oil were mixed with emulsifier and commercial MR powder to prepare the following 4 MR containing 0.119 and 0.007 (T1), 0.187 and 0.017 (T2), 0.321 and 0.036 (T3), and 0.593 and 0.076 (T4) g of intake per kg of metabolic body weight (BW(0.75)) of linoleic acid and α-linolenic acid, respectively. At 30 d of life, concentrations of essential FA (linoleic acid and α-linolenic acid) in liver increased, whereas concentrations of C12:0, C14:0, C16:0, and C20:3n-9 decreased linearly with increasing intake of essential FA. Body weight gain and feed efficiency were optimized when male calves consumed T2, whereas gain by female calves tended to increase linearly with increasing intake of essential FA during the first 30 d of age. However, these responses to treatment were not maintained after initiation of concentrate feeding at 31 d of life. Over the 60-d preweaning period, wither and hip heights were improved in both sexes as intake of essential FA increased up to T3. Some measures of health and immunity were affected by replacing some coconut oil with soybean oil. Severity of diarrhea tended to decrease linearly; plasma concentrations of haptoglobin during diarrhea were lower in T2, T3, and T4; phagocytosis by blood neutrophils tended to peak for calves fed T2; in vitro proliferation of stimulated blood lymphocytes was greater for calves fed T2; in vitro stimulated blood cells produced more IFN-γ (up to T3 for males and T2 for females), concentrations of serum IgG against ovalbumin injections were increased in

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

DEFF Research Database (Denmark)

Andreasson, E.; Jenkins, T.; Brodersen, P.

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...

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

Directory of Open Access Journals (Sweden)

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.

Regulation of Specialized Metabolism by WRKY Transcription Factors

Science.gov (United States)

Schluttenhofer, Craig; Yuan, Ling

2015-01-01

WRKY transcription factors (TFs) are well known for regulating plant abiotic and biotic stress tolerance. However, much less is known about how WRKY TFs affect plant-specialized metabolism. Analysis of WRKY TFs regulating the production of specialized metabolites emphasizes the values of the family outside of traditionally accepted roles in stress tolerance. WRKYs with conserved roles across plant species seem to be essential in regulating specialized metabolism. Overall, the WRKY family plays an essential role in regulating the biosynthesis of important pharmaceutical, aromatherapy, biofuel, and industrial components, warranting considerable attention in the forthcoming years. PMID:25501946

Exercise improves mitochondrial and redox-regulated stress responses in the elderly: better late than never!

Science.gov (United States)

Cobley, James N; Moult, Peter R; Burniston, Jatin G; Morton, James P; Close, Graeme L

2015-04-01

Ageing is associated with several physiological declines to both the cardiovascular (e.g. reduced aerobic capacity) and musculoskeletal system (muscle function and mass). Ageing may also impair the adaptive response of skeletal muscle mitochondria and redox-regulated stress responses to an acute exercise bout, at least in mice and rodents. This is a functionally important phenomenon, since (1) aberrant mitochondrial and redox homeostasis are implicated in the pathophysiology of musculoskeletal ageing and (2) the response to repeated exercise bouts promotes exercise adaptations and some of these adaptations (e.g. improved aerobic capacity and exercise-induced mitochondrial remodelling) offset age-related physiological decline. Exercise-induced mitochondrial remodelling is mediated by upstream signalling events that converge on downstream transcriptional co-factors and factors that orchestrate a co-ordinated nuclear and mitochondrial transcriptional response associated with mitochondrial remodelling. Recent translational human investigations have demonstrated similar exercise-induced mitochondrial signalling responses in older compared with younger skeletal muscle, regardless of training status. This is consistent with data indicating normative mitochondrial remodelling responses to long-term exercise training in the elderly. Thus, human ageing is not accompanied by diminished mitochondrial plasticity to acute and chronic exercise stimuli, at least for the signalling pathways measured to date. Exercise-induced increases in reactive oxygen and nitrogen species promote an acute redox-regulated stress response that manifests as increased heat shock protein and antioxidant enzyme content. In accordance with previous reports in rodents and mice, it appears that sedentary ageing is associated with a severely attenuated exercise-induced redox stress response that might be related to an absent redox signal. In this regard, regular exercise training affords some protection

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 the complex hormonal crosstalk of classical growth stimulating plant hormones within the naturally occurring biotic and abiotic multistress environment of higher plants. The MAPK- and phytohormone-cascades which comprise a multitude of single molecules on different signalling levels, as well as interactions...

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.

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.

Effect of Lavender (Lavandula angustifolia) Essential Oil on Acute Inflammatory Response

Science.gov (United States)

Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Cassarotti, Larissa Laila; Salvadego, Valter Eduardo Cocco; Spironello, Ricardo Alexandre; Bersani-Amado, Ciomar Aparecida

2018-01-01

Lavandula angustifolia is a plant of Lamiaceae family, with many therapeutic properties and biological activities, such as anticonvulsant, anxiolytic, antioxidant, anti-inflammatory, and antimicrobial activities. The aim of this study was to evaluate the effect of Lavandula angustifolia Mill. essential oil (LEO) on acute inflammatory response. LEO was analyzed using gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR) methods and showed predominance of 1,8-cineole (39.83%), borneol (22.63%), and camphor (22.12%). LEO at concentrations of 0.5, 1, 3, and 10 μg/ml did not present in vitro cytotoxicity. Additionally, LEO did not stimulate the leukocyte chemotaxis in vitro. The LEO topical application at concentrations of 0.25, 0.5, and 1 mg/ear reduced edema formation, myeloperoxidase (MPO) activity, and nitric oxide (NO) production in croton oil-induced ear edema model. In carrageenan-induced paw edema model, LEO treatment at doses of 75, 100, and 250 mg/kg reduced edema formation, MPO activity, and NO production. In dextran-induced paw edema model, LEO at doses of 75 and 100 mg/kg reduced paw edema and MPO activity. In conclusion, LEO presented anti-inflammatory activity, and the mechanism proposed of LEO seems to be, at least in part, involving the participation of prostanoids, NO, proinflammatory cytokines, and histamine. PMID:29743918

A response regulator from a soil metagenome enhances resistance to the β-lactam antibiotic carbenicillin in Escherichia coli.

Directory of Open Access Journals (Sweden)

Heather K Allen

Full Text Available Functional metagenomic analysis of soil metagenomes is a method for uncovering as-yet unidentified mechanisms for antibiotic resistance. Here we report an unconventional mode by which a response regulator derived from a soil metagenome confers resistance to the β-lactam antibiotic carbenicillin in Escherichia coli. A recombinant clone (βlr16 harboring a 5,169 bp DNA insert was selected from a metagenomic library previously constructed from a remote Alaskan soil. The βlr16 clone conferred specific resistance to carbenicillin, with limited increases in resistance to other tested antibiotics, including other β-lactams (penicillins and cephalosporins, rifampin, ciprofloxacin, erythromycin, chloramphenicol, nalidixic acid, fusidic acid, and gentamicin. Resistance was more pronounced at 24°C than at 37°C. Zone-of-inhibition assays suggested that the mechanism of carbenicillin resistance was not due to antibiotic inactivation. The DNA insert did not encode any genes known to confer antibiotic resistance, but did have two putative open reading frames (ORFs that were annotated as a metallopeptidase and a two-component response regulator. Transposon mutagenesis and subcloning of the two ORFs followed by phenotypic assays showed that the response regulator gene was necessary and sufficient to confer the resistance phenotype. Quantitative reverse transcriptase PCR showed that the response regulator suppressed expression of the ompF porin gene, independently of the small RNA regulator micF, and enhanced expression of the acrD, mdtA, and mdtB efflux pump genes. This work demonstrates that antibiotic resistance can be achieved by the modulation of gene regulation by heterologous DNA. Functional analyses such as these can be important for making discoveries in antibiotic resistance gene biology and ecology.

Oral Administration of N-Acetyl-D Glucosamine Polymer Particles Down-Regulates Airway Allergic Responses

National Research Council Canada - National Science Library

Shibata, Yoshimi

2006-01-01

... (IL-12, IL-18 and TNFo) that down-regulate allergic immune responses. We also found that administration of chitin particles resulted in less likely induce the production of IL-10 and prostaglandin E2 (PGE2...

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.

Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

DEFF Research Database (Denmark)

Storkebaum, Erik; Ruiz de Almodovar, Carmen; Meens, Merlijn

2010-01-01

BACKGROUND: Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. METHODS AND RESULTS: Here, we report that VEGF( ...

Histone H2A.Z is essential for estrogen receptor signaling

Science.gov (United States)

Gévry, Nicolas; Hardy, Sara; Jacques, Pierre-Étienne; Laflamme, Liette; Svotelis, Amy; Robert, François; Gaudreau, Luc

2009-01-01

Incorporation of H2A.Z into the chromatin of inactive promoters has been shown to poise genes for their expression. Here we provide strong evidence that H2A.Z is incorporated into the promoter regions of estrogen receptor (ERα) target genes only upon gene induction, and that, in a cyclic pattern. Moreover, members of the human H2A.Z-depositing complex, p400, also follow the same gene recruitment kinetics as H2A.Z. Importantly, cellular depletion of H2A.Z or p400 leads to a severe defect in estrogen signaling, including loss of estrogen-specific cell proliferation. We find that incorporation of H2A.Z within TFF1 promoter chromatin allows nucleosomes to adopt preferential positions along the DNA translational axis. Finally, we provide evidence that H2A.Z is essential to allow estrogen-responsive enhancer function. Taken together, our results provide strong mechanistic insight into how H2A.Z regulates ERα-mediated gene expression and provide a novel link between H2A.Z–p400 and ERα-dependent gene regulation and enhancer function. PMID:19515975

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.

Using principles from emergency management to improve emergency response plans for research animals.

Science.gov (United States)

Vogelweid, Catherine M

2013-10-01

Animal research regulatory agencies have issued updated requirements for emergency response planning by regulated research institutions. A thorough emergency response plan is an essential component of an institution's animal care and use program, but developing an effective plan can be a daunting task. The author provides basic information drawn from the field of emergency management about best practices for developing emergency response plans. Planners should use the basic principles of emergency management to develop a common-sense approach to managing emergencies in their facilities.

Tumor PDT-associated immune response: relevance of sphingolipids

Science.gov (United States)

Korbelik, Mladen; Merchant, Soroush; Separovic, Duska M.

2010-02-01

Sphingolipids have become recognized as essential effector molecules in signal transduction with involvement in various aspects of cell function and death, immune response and cancer treatment response. Major representatives of sphingolipids family, ceramide, sphingosine and sphingosine-1-phosphate (S1P), have attracted interest in their relevance to tumor response to photodynamic therapy (PDT) because of their roles as enhancers of apoptosis, mediators of cell growth and vasculogenesis, and regulators of immune response. Our recent in vivo studies with mouse tumor models have confirmed that PDT treatment has a pronounced impact on sphingolipid profile in the targeted tumor and that significant advances in therapeutic gain with PDT can be attained by combining this modality with adjuvant treatment with ceramide analog LCL29.

Regulation of Burkholderia cenocepacia biofilm formation by RpoN and the c-di-GMP effector BerB

DEFF Research Database (Denmark)

Fazli, Mustafa; Rybtke, Morten Levin; Steiner, Elisabeth

2017-01-01

Knowledge about the molecular mechanisms that are involved in the regulation of biofilm formation is essential for the development of biofilm-control measures. It is well established that the nucleotide second messenger cyclic diguanosine monophosphate (c-di-GMP) is a positive regulator of biofilm...... formation in many bacteria, but more knowledge about c-di-GMP effectors is needed. We provide evidence that c-di-GMP, the alternative sigma factor RpoN (σ54), and the enhancer-binding protein BerB play a role in biofilm formation of Burkholderia cenocepacia by regulating the production of a biofilm......-stabilizing exopolysaccharide. Our findings suggest that BerB binds c-di-GMP, and activates RpoN-dependent transcription of the berA gene coding for a c-di-GMP-responsive transcriptional regulator. An increased level of the BerA protein in turn induces the production of biofilm-stabilizing exopolysaccharide in response to high...

The polyketide synthase gene pks4 is essential for sexual development and regulates fruiting body morphology in Sordaria macrospora.

Science.gov (United States)

Schindler, Daniel; Nowrousian, Minou

2014-07-01

Filamentous ascomycetes have long been known as producers of a variety of secondary metabolites, many of which have toxic effects on other organisms. However, the role of these metabolites in the biology of the fungi that produce them remains in most cases enigmatic. A major group of fungal secondary metabolites are polyketides. They are chemically diverse, but have in common that their chemical scaffolds are synthesized by polyketide synthases (PKSs). In a previous study, we analyzed development-dependent expression of pks genes in the filamentous ascomycete Sordaria macrospora. Here, we show that a deletion mutant of the pks4 gene is sterile, producing only protoperithecia but no mature perithecia, whereas overexpression of pks4 leads to enlarged, malformed fruiting bodies. Thus, correct expression levels of pks4 are essential for wild type-like perithecia formation. The predicted PKS4 protein has a domain structure that is similar to homologs in other fungi, but conserved residues of a methyl transferase domain present in other fungi are mutated in PKS4. Expression of several developmental genes is misregulated in the pks4 mutant. Surprisingly, the development-associated app gene is not downregulated in the mutant, in contrast to all other previously studied mutants with a block at the protoperithecial stage. Our data show that the polyketide synthase gene pks4 is essential for sexual development and plays a role in regulating fruiting body morphology. Copyright © 2014 Elsevier Inc. All rights reserved.

Gene expression and stress response mediated by the epigenetic regulation of a transposable element small RNA.

Directory of Open Access Journals (Sweden)

Andrea D McCue

2012-02-01

Full Text Available The epigenetic activity of transposable elements (TEs can influence the regulation of genes; though, this regulation is confined to the genes, promoters, and enhancers that neighbor the TE. This local cis regulation of genes therefore limits the influence of the TE's epigenetic regulation on the genome. TE activity is suppressed by small RNAs, which also inhibit viruses and regulate the expression of genes. The production of TE heterochromatin-associated endogenous small interfering RNAs (siRNAs in the reference plant Arabidopsis thaliana is mechanistically distinct from gene-regulating small RNAs, such as microRNAs or trans-acting siRNAs (tasiRNAs. Previous research identified a TE small RNA that potentially regulates the UBP1b mRNA, which encodes an RNA-binding protein involved in stress granule formation. We demonstrate that this siRNA, siRNA854, is under the same trans-generational epigenetic control as the Athila family LTR retrotransposons from which it is produced. The epigenetic activation of Athila elements results in a shift in small RNA processing pathways, and new 21-22 nucleotide versions of Athila siRNAs are produced by protein components normally not responsible for processing TE siRNAs. This processing results in siRNA854's incorporation into ARGONAUTE1 protein complexes in a similar fashion to gene-regulating tasiRNAs. We have used reporter transgenes to demonstrate that the UPB1b 3' untranslated region directly responds to the epigenetic status of Athila TEs and the accumulation of siRNA854. The regulation of the UPB1b 3' untranslated region occurs both on the post-transcriptional and translational levels when Athila TEs are epigenetically activated, and this regulation results in the phenocopy of the ubp1b mutant stress-sensitive phenotype. This demonstrates that a TE's epigenetic activity can modulate the host organism's stress response. In addition, the ability of this TE siRNA to regulate a gene's expression in trans blurs

Transcription factor genes essential for cell proliferation and replicative lifespan in budding yeast

Energy Technology Data Exchange (ETDEWEB)

Kamei, Yuka; Tai, Akiko; Dakeyama, Shota; Yamamoto, Kaori; Inoue, Yamato; Kishimoto, Yoshifumi; Ohara, Hiroya; Mukai, Yukio, E-mail: y_mukai@nagahama-i-bio.ac.jp

2015-07-31

Many of the lifespan-related genes have been identified in eukaryotes ranging from the yeast to human. However, there is limited information available on the longevity genes that are essential for cell proliferation. Here, we investigated whether the essential genes encoding DNA-binding transcription factors modulated the replicative lifespan of Saccharomyces cerevisiae. Heterozygous diploid knockout strains for FHL1, RAP1, REB1, and MCM1 genes showed significantly short lifespan. {sup 1}H-nuclear magnetic resonance analysis indicated a characteristic metabolic profile in the Δfhl1/FHL1 mutant. These results strongly suggest that FHL1 regulates the transcription of lifespan related metabolic genes. Thus, heterozygous knockout strains could be the potential materials for discovering further novel lifespan genes. - Highlights: • Involvement of yeast TF genes essential for cell growth in lifespan was evaluated. • The essential TF genes, FHL1, RAP1, REB1, and MCM1, regulate replicative lifespan. • Heterozygous deletion of FHL1 changes cellular metabolism related to lifespan.

mTORC1 Directly Phosphorylates and Regulates Human MAF1▿

Science.gov (United States)

Michels, Annemieke A.; Robitaille, Aaron M.; Buczynski-Ruchonnet, Diane; Hodroj, Wassim; Reina, Jaime H.; Hall, Michael N.; Hernandez, Nouria

2010-01-01

mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated and represses pol III transcription after various stresses, but neither the significance of the phosphorylations nor the kinase involved is known. We find that human MAF1 is absolutely required for pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. The protein is phosphorylated mainly on residues S60, S68, and S75, and this inhibits its pol III repression function. The responsible kinase is mTORC1, which phosphorylates MAF1 directly. Our results describe molecular mechanisms by which mTORC1 controls human MAF1, a key repressor of RNA polymerase III transcription, and add a new branch to the signal transduction cascade immediately downstream of TORC1. PMID:20516213

On the "essential condition" of intellectual capital: labour!

DEFF Research Database (Denmark)

O'Donnell, David; Tracey, Mairead; Henriksen, Lars Bo

2006-01-01

Following Marx and Engels' identification of the "essential condition of capital", the purpose of this paper is to begin an initial critical exploration of the essential condition of intellectual capital, particularly the ownership rights of labor. Adopting a critically modernist stance on unitar......, reducing reported accounting expense in order to boost reported earnings, deferring taxes, and attracting, retaining and exploiting key elements of labor....... on unitarist HR and OB discourse, and contextualized within a background on the stock option phenomenon and recent accounting regulation, the paper argues that the fundamental nature of capital-labor relation continues resiliently into the IC labor (intellectual capital-labor) relation. There is strong...

Depolarization-mediated regulation of alternative splicing

Directory of Open Access Journals (Sweden)

Alok eSharma

2011-12-01

Full Text Available Alternative splicing in eukaryotes plays an important role in regulating gene expression by selectively including alternative exons. A wealth of information has been accumulated that explains how alternative exons are selected in a developmental stage- or tissue-specific fashion. However, our knowledge of how cells respond to environmental changes to alter alternative splicing is very limited. For example, although a number of alternative exons have been shown to be regulated by calcium level alterations, the underlying mechanisms are not well understood. As calcium signaling in neurons plays a crucial role in essential neuronal functions such as learning and memory formation, it is important to understand how this process is regulated at every level in gene expression. The significance of the dynamic control of alternative splicing in response to changes of calcium levels has been largely unappreciated. In this communication, we will summarize the recent advances in calcium signaling-mediated alternative splicing that have provided some insights into the important regulatory mechanisms. In addition to describing the cis-acting RNA elements on the pre-mRNA molecules that respond to changes of intracellular calcium levels, we will summarize how splicing regulators change and affect alternative splicing in this process. We will also discuss a novel mode of calcium-mediated splicing regulation at the level of chromatin structure and transcription.

[The role of gut microbiota in the regulation of the immune response].

Science.gov (United States)

Alarcón, Pedro; González, Margarita; Castro, Érica

2016-07-01

The gastrointestinal tract hosts around 10(14) bacterial microorganisms, in a constantly growing density from the stomach to the distal colon. This microbiota is composed by more than 500 species of bacteria, which are quickly acquired after birth, fairly stable during the host’s life, and essential for human homeostasis. These bacteria have important functions, such as stimulating the immune system, protecting the host from invading bacteria and viruses, and improving digestion, especially of complex carbohydrates. Also, the gut microbiota interacts directly with the immune system. However, the interaction of the intestinal epithelium and its microbiota with the immune system has yet to be fully understood. Secretory immunoglobulin A, produced by the plasma cells in Peyer’s patches and in the lamina propria, maintains non-invasive commensal bacteria and neutralize invasive pathogens. Dendritic cells migrate from the lamina propria of the secondary lymphoid organs to regulate gut immunity. They also have a key role maintaining luminal IgA and inducing the growth of regulatory T cells. Dendritic cells supervise the gut microenvironment too, keeping an immunological equilibrium and tolerance. The importance of the gut microbiota in regulating the immune system lies mostly in the homeostasis-or positive equilibrium. Thus, many diseases are a consequence of poor interactions or a loss of this equilibrium.

Autonomy promotion, responsiveness, and emotion regulation promote effective social support in times of stress.

Science.gov (United States)

Cutrona, Carolyn E; Russell, Daniel W

2017-02-01

Adult attachment theory provides guidance for providing optimal social support in intimate relationships. According to attachment theory, facilitating autonomy (secure base support) sometimes is more important than providing nurturance (safe haven support). In addition, it is important that couples celebrate one another's triumphs and successes (another form of secure base support). A key construct that explains the development of attachment is responsiveness to the individual's needs. Support that is delivered in a responsive manner (i.e., that leads the individual to feel understood, validated, and cared for) is more likely to enhance the relationship and less likely to damage self-esteem than assistance that is not responsive. A responsive exchange is more likely if emotion dysregulation can be prevented. Attachment theory offers explanations for why people vary in their effectiveness at emotion regulation. Appropriate emotion regulation is more likely if disclosures of current difficulties can be made in a way that is not defensive or accusatory, an ability that varies as a function of attachment orientation. Attachment theory also offers guidance regarding the optimal forms of social support for specific individuals. All these insights from adult attachment theory can be integrated into interventions to help couples become more effective support providers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunosuppressive Effect of Litsea cubeba L. Essential Oil on Dendritic Cell and Contact Hypersensitivity Responses

Directory of Open Access Journals (Sweden)

Hsin-Chun Chen

2016-08-01

Full Text Available Litsea cubeba L., also named as Makauy, is a traditional herb and has been used as cooking condiment or tea brewing to treat diseases for aborigines. The present study was undertaken to explore the chemical compositions of the fruit essential oil of L. cubeba (LCEO and the immunomodulatory effect of LCEO on dendritic cells and mice. The LCEO was analyzed using gas chromatography (GC and gas chromatography/mass spectrometry (GC/MS with direct injection (DI/GC or headspace-solid phase microextraction (HS-SPME/GC. In total, 56 components were identified, of which 48 were detected by DI/GC and 49 were detected by HS-SPME/GC. The principal compounds were citral (neral and geranial. An immunosuppressive activity of LCEO was investigated with bone marrow-derived dendritic cells (DCs which have a critical role to trigger the adaptive immunity. Additionally, the inhibitory effect of LCEO on immune response was elucidated by performing the contact hypersensitivity (CHS responses in mice. Our results clearly showed that LCEO decreases the production of TNF-α and cytokine IL-12 in a dose-dependent manner in lipopolysaccharide (LPS-stimulated DCs. CHS response and the infiltrative T cells were inhibited in the tested ears of the mice co-treated with LCEO. We demonstrate, for the first time, that the LCEO mainly containing citral exhibits an immunosuppressive effect on DCs and mice, indicating that LCEO can potentially be applied in the treatment of CHS, inflammatory diseases, and autoimmune diseases.

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations.

Science.gov (United States)

Verger, Emmanuelle; Cassinat, Bruno; Chauveau, Aurélie; Dosquet, Christine; Giraudier, Stephane; Schlageter, Marie-Hélène; Ianotto, Jean-Christophe; Yassin, Mohammed A; Al-Dewik, Nader; Carillo, Serge; Legouffe, Eric; Ugo, Valerie; Chomienne, Christine; Kiladjian, Jean-Jacques

2015-12-10

Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy. © 2015 by The American Society of Hematology.

Experimentally observed responses to humour are related to individual differences in emotion perception and regulation in everyday life.

OpenAIRE

Papousek I.; Schulter G.; Lackner H. K.; Samson A. C.; Freudenthaler H. H.

2014-01-01

This study aimed to investigate the relevance of an individual's typical emotion perception and emotion regulation behavior to his or her responsiveness to humor. This was studied behaviorally by examining responses to different types of humorous stimuli in an experimental paradigm, in a sample of n = 54 participants aged between 18 to 41 years (29 women, 25 men). Individual differences in emotion perception and regulation were assessed by relevant subscales of an established self-report inst...

The Mediator complex and transcription regulation

Science.gov (United States)

Poss, Zachary C.; Ebmeier, Christopher C.

2013-01-01

The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module. PMID:24088064

The cell wall and endoplasmic reticulum stress responses are coordinately regulated in Saccharomyces cerevisiae

OpenAIRE

Krysan, Damian J

2009-01-01

The unfolded protein response (UPR) is an intracellular signaling pathway that regulates the cellular response to the accumulation of misfolded proteins in eukaryotes. Our group has demonstrated that cell wall stress activates UPR in yeast through signals transmitted by the cell wall integrity (CWI) mitogen-activated protein (MAP) kinase cascade. The UPR is required to maintain cell wall integrity; mutants lacking a functional UPR have defects in cell wall biosynthesis and are hypersensitive ...

TRX-1 Regulates SKN-1 Nuclear Localization Cell Non-autonomously in Caenorhabditis elegans.

Science.gov (United States)

McCallum, Katie C; Liu, Bin; Fierro-González, Juan Carlos; Swoboda, Peter; Arur, Swathi; Miranda-Vizuete, Antonio; Garsin, Danielle A

2016-05-01

The Caenorhabditis elegans oxidative stress response transcription factor, SKN-1, is essential for the maintenance of redox homeostasis and is a functional ortholog of the Nrf family of transcription factors. The numerous levels of regulation that govern these transcription factors underscore their importance. Here, we add a thioredoxin, encoded by trx-1, to the expansive list of SKN-1 regulators. We report that loss of trx-1 promotes nuclear localization of intestinal SKN-1 in a redox-independent, cell non-autonomous fashion from the ASJ neurons. Furthermore, this regulation is not general to the thioredoxin family, as two other C. elegans thioredoxins, TRX-2 and TRX-3, do not play a role in this process. Moreover, TRX-1-dependent regulation requires signaling from the p38 MAPK-signaling pathway. However, while TRX-1 regulates SKN-1 nuclear localization, classical SKN-1 transcriptional activity associated with stress response remains largely unaffected. Interestingly, RNA-Seq analysis revealed that loss of trx-1 elicits a general, organism-wide down-regulation of several classes of genes; those encoding for collagens and lipid transport being most prevalent. Together, these results uncover a novel role for a thioredoxin in regulating intestinal SKN-1 nuclear localization in a cell non-autonomous manner, thereby contributing to the understanding of the processes involved in maintaining redox homeostasis throughout an organism. Copyright © 2016 by the Genetics Society of America.

Determining the essential skill requirements for construction managers' practice in Nigeria

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Olabode E Ogunsanmi

2016-12-01

Full Text Available The study investigates the essential skill requirements for construction managers in Nigeria. The objective is to determine the most important skill requirements for construction managers. A structured questionnaire was administered to construction professionals who worked recently with construction managers in their recently completed projects. Snowballing sampling technique was used to select seventy (70 respondents, however only forty (40 responses were used for the data analysis. The results indicate that essential skills required by the construction managers for their jobs include: procedural-industrial skills, quality assurance/management, listening skills, knowledge of codes and regulations, sustainable skills and ability to learn skills. These skills are important for the construction manager to practice effectively in Nigeria and other developing countries. These findings have seven practical implications to professional bodies, Universities and other trainers of construction managers, whose present curricula may be deficient in knowledge areas in industry (business, managerial, personal and technical. These institutions may need to re-orientate and improve the curricula for newly trained construction managers to cope with current skill requirements. On the other hand, recruiting agencies should ensure that job applicants with the right hard and soft skills are engaged as construction managers. Consequently efficient and effective management of future construction projects in Nigeria and other developing countries can be ensured.

Two-stage gene regulation of the superoxide stress response soxRS system in Escherichia coli.

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Nunoshiba, T

1996-01-01

All organisms have adapted to environmental changes by acquiring various functions controlled by gene regulation. In bacteria, a number of specific responses have been found to confer cell survival in various nutrient-limited conditions, and under physiological stresses such as high or low temperature, extreme pH, radiation, and oxidation (for review, see Neidhardt et al., 1987). In this article, I introduce an Escherichia coli (E. coli) global response induced by superoxide stress, the soxRS regulon. The functions controlled by this system consist of a wide variety of enzymes such as manganese-containing SOD (Mn-SOD); glucose 6-phosphate dehydrogenase (G6PD), the DNA repair enzyme endonuclease IV, fumarase C, NADPH:ferredoxin oxidoreductase, and aconitase. This response is positively regulated by a two-stage control system in which SoxR iron-sulfur protein senses exposure to superoxide and nitric oxide, and then activates transcription of the soxS gene, whose product stimulates the expression of the regulon genes. Our recent finding indicates that soxS transcription is initiated in a manner dependent on the rpoS gene encoding RNA polymerase sigma factor, theta s, in response to entering the stationary phase of growth. With this information, mechanisms for prokaryotic coordinating gene expression in response to superoxide stress and in stationary phase are discussed.

The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation

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Rodgers, Mary A.; Bowman, James W.; Fujita, Hiroaki; Orazio, Nicole; Shi, Mude; Liang, Qiming; Amatya, Rina; Kelly, Thomas J.; Iwai, Kazuhiro; Ting, Jenny

2014-01-01

Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB–mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow–derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L−/− mice have reduced IL-1β secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients. PMID:24958845

V-ATPase Is Involved in Silkworm Defense Response against Bombyx mori Nucleopolyhedrovirus.

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Peng Lü

Full Text Available Silkworms are usually susceptible to the infection of Bombyx mori (B. mori nucleopolyhedrovirus (BmNPV, which can cause significant economic loss. However, some silkworm strains are identified to be highly resistant to BmNPV. To explore the silkworm genes involved in this resistance in the present study, we performed comparative real-time PCR, ATPase assay, over-expression and sub-cellular localization experiments. We found that when inoculated with BmNPV both the expression and activity of V-ATPase were significantly up-regulated in the midgut column cells (not the goblet cells of BmNPV-resistant strains (NB and BC8, the main sites for the first step of BmNPV invasion, but not in those of a BmNPV-susceptible strain 306. Furthermore, this up-regulation mainly took place during the first 24 hours post inoculation (hpi, the essential period required for establishment of virus infection, and then was down-regulated to normal levels. Amazingly, transient over-expression of V-ATPase c subunit in BmNPV-infected silkworm cells could significantly inhibit BmNPV proliferation. To our knowledge this is the first report demonstrating clearly that V-ATPase is indeed involved in the defense response against BmNPV. Our data further suggests that prompt and potent regulation of V-ATPase may be essential for execution of this response, which may enable fast acidification of endosomes and/or lysosomes to render them competent for degradation of invading viruses.

Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis.

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Klose, Christoph S N; Artis, David

2016-06-21

Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.

Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

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Julianna Han

2018-04-01

Full Text Available Summary: The emergence of influenza A viruses (IAVs from zoonotic reservoirs poses a great threat to human health. As seasonal vaccines are ineffective against zoonotic strains, and newly transmitted viruses can quickly acquire drug resistance, there remains a need for host-directed therapeutics against IAVs. Here, we performed a genome-scale CRISPR/Cas9 knockout screen in human lung epithelial cells with a human isolate of an avian H5N1 strain. Several genes involved in sialic acid biosynthesis and related glycosylation pathways were highly enriched post-H5N1 selection, including SLC35A1, a sialic acid transporter essential for IAV receptor expression and thus viral entry. Importantly, we have identified capicua (CIC as a negative regulator of cell-intrinsic immunity, as loss of CIC resulted in heightened antiviral responses and restricted replication of multiple viruses. Therefore, our study demonstrates that the CRISPR/Cas9 system can be utilized for the discovery of host factors critical for the replication of intracellular pathogens. : Using a genome-wide CRISPR/Cas9 screen, Han et al. demonstrate that the major hit, the sialic acid transporter SLC35A1, is an essential host factor for IAV entry. In addition, they identify the DNA-binding transcriptional repressor CIC as a negative regulator of cell-intrinsic immunity. Keywords: CRISPR/Cas9 screen, GeCKO, influenza virus, host factors, sialic acid pathway, SLC35A1, Capicua, CIC, cell-intrinsic immunity, H5N1

14 CFR 272.9 - Selection of a carrier to provide essential air service and payment of compensation.

Science.gov (United States)

2010-01-01

... SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) ECONOMIC REGULATIONS ESSENTIAL AIR SERVICE TO THE FREELY ASSOCIATED STATES § 272.9 Selection of a carrier to provide essential air service and... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Selection of a carrier to provide essential...

Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

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Alecia Seliga

2018-02-01

Full Text Available The Kallikrein–Kinin System (KKS, comprised of kallikreins (klks, bradykinins (BKs angiotensin-converting enzyme (ACE, and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand, R848 (TLR7 ligand, or recombinant IFN-α to induce interferon-stimulated genes (ISGs and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein, or captopril (an ACE inhibitor. BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice, and in human PBMCs, especially the induction of Irf7 gene (p < 0.05, the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs. BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10, the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2, suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

Essential oil extraction with concentrating solar thermal energy

OpenAIRE

Veynandt, François

2015-01-01

Material complementari del cas estudi "Essential oil extraction with concentrating solar thermal energy”, part component del llibre "Case studies for developing globally responsible engineers" Peer Reviewed

Autoinhibitory Regulation of Plasma Membrane H⁺-ATPases

DEFF Research Database (Denmark)

Pedersen, Jesper Torbøl

Electrochemical gradients across cell membranes are essential for nutrient uptake. In plant and fungal cells the electrochemical gradient across the plasma membrane (PM) can build much higher than in mammalian cells. The protein responsible for this gradient is the essential PM H+-ATPase that uses...... resolution 3D structure the mechanism behind is only poorly understood. This thesis aimed at illuminating the autoinhibitory mechanism in plant and yeast PM H+-ATPases and below some of our main findings will be highlighted. The two terminal domains of the PM H+-ATPases have several amino acid residues...... that can be phosphorylated, and it has been demonstrated that these phosphorylation sites in both plant and yeast are highly involved in the regulation of terminal autoinhibition. In this study we used a phylogenetic analysis to investigate the evolutionary development of these phosphorylation sites...

A G-protein β subunit, AGB1, negatively regulates the ABA response and drought tolerance by down-regulating AtMPK6-related pathway in Arabidopsis.

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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.

Regulation of immune responses and tolerance: the microRNA perspective

Science.gov (United States)

Chen, Chang-Zheng; Schaffert, Steven; Fragoso, Rita; Loh, Christina

2013-01-01

Summary Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNA (miRNA) genes, an abundant class of non-coding RNA genes that produce characteristic approximately 22 nucleotides small RNAs, play important roles in immune cells. In this article, we discuss emerging knowledge regarding the functions of miRNA genes in the immune system. We delve into the roles of miRNAs in regulating signaling strength and threshold, homeostasis, and the dynamics of the immune response and tolerance during normal and pathogenic immunological conditions. We also present observations based on analyzes of miR-181 family genes that indicate the potential functions of primary and/ or precursor miRNAs in target recognition and explore the impact of these findings on target identification. Finally, we illustrate that despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses. Tuning miRNA functions in immune cells, through gain- and loss-of-function approaches in mice, may reveal novel approach to restore immune equilibrium from pathogenic conditions, such as autoimmune disease and leukemia, without significant toxicity. PMID:23550642

Regulation of immune responses and tolerance: the microRNA perspective.

Science.gov (United States)

Chen, Chang-Zheng; Schaffert, Steven; Fragoso, Rita; Loh, Christina

2013-05-01

Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNA (miRNA) genes, an abundant class of non-coding RNA genes that produce characteristic approximately 22 nucleotides small RNAs, play important roles in immune cells. In this article, we discuss emerging knowledge regarding the functions of miRNA genes in the immune system. We delve into the roles of miRNAs in regulating signaling strength and threshold, homeostasis, and the dynamics of the immune response and tolerance during normal and pathogenic immunological conditions. We also present observations based on analyzes of miR-181 family genes that indicate the potential functions of primary and/or precursor miRNAs in target recognition and explore the impact of these findings on target identification. Finally, we illustrate that despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses. Tuning miRNA functions in immune cells, through gain- and loss-of-function approaches in mice, may reveal novel approach to restore immune equilibrium from pathogenic conditions, such as autoimmune disease and leukemia, without significant toxicity. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses

International Nuclear Information System (INIS)

Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi; Kataoka, Kosuke; Markham, Jonathan D.; Irwin, Allyson R.; Moon, Grace H.; Tokuhara, Yuka; Fujihashi, Keiko; Davydova, Julia; Yamamoto, Masato; Gilbert, Rebekah S.; Fujihashi, Kohtaro

2012-01-01

Highlights: ► Nasal Ad-FL effectively up-regulates APC function by CD11c + DCs in mucosal tissues. ► Nasal Ad-FL induces Notch ligand (L)-expressing CD11c + DCs. ► Notch L-expressing DCs support the induction of Th1- and Th2-type cytokine responses. -- Abstract: Our previous studies showed that an adenovirus (Ad) serotype 5 vector expressing Flt3 ligand (Ad-FL) as nasal adjuvant activates CD11c + dendritic cells (DCs) for the enhancement of antigen (Ag)-specific IgA antibody (Ab) responses. In this study, we examined the molecular mechanism for activation of CD11c + DCs and their roles in induction of Ag-specific Th1- and Th2-cell responses. Ad-FL activated CD11c + DCs expressed increased levels of the Notch ligand (L)-expression and specific mRNA. When CD11c + DCs from various mucosal and systemic lymphoid tissues of mice given nasal OVA plus Ad-FL were cultured with CD4 + T cells isolated from non-immunized OVA TCR-transgenic (OT II) mice, significantly increased levels of T cell proliferative responses were noted. Furthermore, Ad-FL activated DCs induced IFN-γ, IL-2 and IL-4 producing CD4 + T cells. Of importance, these APC functions by Ad-FL activated DCs were down-regulated by blocking Notch–Notch-L pathway. These results show that Ad-FL induces CD11c + DCs to the express Notch-ligands and these activated DCs regulate the induction of Ag-specific Th1- and Th2-type cytokine responses.

Somatic insulin signaling regulates a germline starvation response in Drosophila egg chambers

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Burn, K. Mahala; Shimada, Yuko; Ayers, Kathleen; Lu, Feiyue; Hudson, Andrew M.; Cooley, Lynn

2014-01-01

Egg chambers from starved Drosophila females contain large aggregates of processing (P) bodies and cortically enriched microtubules. As this response to starvation is rapidly reversed upon re-feeding females or culturing egg chambers with exogenous bovine insulin, we examined the role of endogenous insulin signaling in mediating the starvation response. We found that systemic Drosophila insulin-like peptides (dILPs) activate the insulin pathway in follicle cells, which then regulate both microtubule and P body organization in the underlying germline cells. This organization is modulated by the motor proteins Dynein and Kinesin. Dynein activity is required for microtubule and P body organization during starvation, while Kinesin activity is required during nutrient-rich conditions. Blocking the ability of egg chambers to form P body aggregates in response to starvation correlated with reduced progeny survival. These data suggest a potential mechanism to maximize fecundity even during periods of poor nutrient availability, by mounting a protective response in immature egg chambers. PMID:25481758

Design of protein-responsive micro-sized hydrogels for self-regulating microfluidic systems

Science.gov (United States)

Hirayama, Mayu; Tsuruta, Kazuhiro; Kawamura, Akifumi; Ohara, Masayuki; Shoji, Kan; Kawano, Ryuji; Miyata, Takashi

2018-03-01

Diagnosis sensors using micro-total analysis systems (µ-TAS) have been developed for detecting target biomolecules such as proteins and saccharides because they are signal biomolecules for monitoring body conditions and diseases. In this study, biomolecularly stimuli-responsive micro-sized hydrogels that exhibited quick shrinkage in response to lectin concanavalinA (ConA) were prepared in a microchannel by photopolymerization using a fluorescence microscope. In preparing the micro-size hydrogels, glycosyloxyethyl methacrylate (GEMA) as a ligand monomer was copolymerized with a crosslinker in the presence of template ConA in molecular imprinting. The ConA-imprinted micro-hydrogel showed greater shrinkage in response to target ConA than nonimprinted micro-hydrogel. When a buffer solution was switched to an aqueous ConA solution in the Y-shaped microchannel, the flow rates changed quickly because of the responsive shrinkage of the micro-hydrogel prepared in the microchannel. These results suggest that the ConA-imprinted micro-hydrogel acted as a self-regulated microvalve in microfluidic systems.

Differential RNA-seq, Multi-Network Analysis and Metabolic Regulation Analysis of Kluyveromyces marxianus Reveals a Compartmentalised Response to Xylose.

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Du Toit W P Schabort

Full Text Available We investigated the transcriptomic response of a new strain of the yeast Kluyveromyces marxianus, in glucose and xylose media using RNA-seq. The data were explored in a number of innovative ways using a variety of networks types, pathway maps, enrichment statistics, reporter metabolites and a flux simulation model, revealing different aspects of the genome-scale response in an integrative systems biology manner. The importance of the subcellular localisation in the transcriptomic response is emphasised here, revealing new insights. As was previously reported by others using a rich medium, we show that peroxisomal fatty acid catabolism was dramatically up-regulated in a defined xylose mineral medium without fatty acids, along with mechanisms to activate fatty acids and transfer products of β-oxidation to the mitochondria. Notably, we observed a strong up-regulation of the 2-methylcitrate pathway, supporting capacity for odd-chain fatty acid catabolism. Next we asked which pathways would respond to the additional requirement for NADPH for xylose utilisation, and rationalised the unexpected results using simulations with Flux Balance Analysis. On a fundamental level, we investigated the contribution of the hierarchical and metabolic regulation levels to the regulation of metabolic fluxes. Metabolic regulation analysis suggested that genetic level regulation plays a major role in regulating metabolic fluxes in adaptation to xylose, even for the high capacity reactions, which is unexpected. In addition, isozyme switching may play an important role in re-routing of metabolic fluxes in subcellular compartments in K. marxianus.

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.

Selenium as an essential micronutrient: roles in cell cycle and apoptosis.

Science.gov (United States)

Zeng, Huawei

2009-03-23

Selenium is an essential trace element for humans and animals, and selenium deficiency is associated with several disease conditions such as immune impairment. In addition, selenium intakes that are greater than the recommended daily allowance (RDA) appear to protect against certain types of cancers. In humans and animals, cell proliferation and death must be regulated to maintain tissue homeostasis, and it has been well documented that numerous human diseases are directly related to the control of cell cycle progression and apoptosis. Thus, the elucidation of the mechanisms by which selenium regulates the cell cycle and apoptosis can lead to a better understanding of the nature of selenium's essentiality and its role in disease prevention. This article reviews the status of knowledge concerning the effect of selenium on cell cycle and apoptosis.

Function and Regulation of Yeast Ribonucleotide Reductase: Cell Cycle, Genotoxic Stress, and Iron Bioavailability

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Nerea Sanvisens

2013-04-01

Full Text Available Ribonucleotide reductases (RNRs are essential enzymes that catalyze the reduction of ribonucleotides to desoxyribonucleotides, thereby providing the building blocks required for de novo DNA biosynthesis. The RNR function is tightly regulated because an unbalanced or excessive supply of deoxyribonucleoside triphosphates (dNTPs dramatically increases the mutation rates during DNA replication and repair that can lead to cell death or genetic anomalies. In this review, we focus on Saccharomyces cerevisiae class Ia RNR as a model to understand the different mechanisms controlling RNR function and regulation in eukaryotes. Many studies have contributed to our current understanding of RNR allosteric regulation and, more recently, to its link to RNR oligomerization. Cells have developed additional mechanisms that restrict RNR activity to particular periods when dNTPs are necessary, such as the S phase or upon genotoxic stress. These regulatory strategies include the transcriptional control of the RNR gene expression, inhibition of RNR catalytic activity, and the subcellular redistribution of RNR subunits. Despite class Ia RNRs requiring iron as an essential cofactor for catalysis, little is known about RNR function regulation depending on iron bioavailability. Recent studies into yeast have deciphered novel strategies for the delivery of iron to RNR and for its regulation in response to iron deficiency. Taken together, these studies open up new possibilities to explore in order to limit uncontrolled tumor cell proliferation via RNR.

Retinoic Acid Is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program

Science.gov (United States)

Brown, Chrysothemis C.; Esterhazy, Daria; Sarde, Aurelien; London, Mariya; Pullabhatla, Venu; Osma-Garcia, Ines; al-Bader, Raya; Ortiz, Carla; Elgueta, Raul; Arno, Matthew; de Rinaldis, Emanuele; Mucida, Daniel; Lord, Graham M.; Noelle, Randolph J.

2015-01-01

Summary CD4+ T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells. PMID:25769610

Mechanisms of iron sensing and regulation in the yeast Saccharomyces cerevisiae.

Science.gov (United States)

Martínez-Pastor, María Teresa; Perea-García, Ana; Puig, Sergi

2017-04-01

Iron is a redox active element that functions as an essential cofactor in multiple metabolic pathways, including respiration, DNA synthesis and translation. While indispensable for eukaryotic life, excess iron can lead to oxidative damage of macromolecules. Therefore, living organisms have developed sophisticated strategies to optimally regulate iron acquisition, storage and utilization in response to fluctuations in environmental iron bioavailability. In the yeast Saccharomyces cerevisiae, transcription factors Aft1/Aft2 and Yap5 regulate iron metabolism in response to low and high iron levels, respectively. In addition to producing and assembling iron cofactors, mitochondrial iron-sulfur (Fe/S) cluster biogenesis has emerged as a central player in iron sensing. A mitochondrial signal derived from Fe/S synthesis is exported and converted into an Fe/S cluster that interacts directly with Aft1/Aft2 and Yap5 proteins to regulate their transcriptional function. Various conserved proteins, such as ABC mitochondrial transporter Atm1 and, for Aft1/Aft2, monothiol glutaredoxins Grx3 and Grx4 are implicated in this iron-signaling pathway. The analysis of a wide range of S. cerevisiae strains of different geographical origins and sources has shown that yeast strains adapted to high iron display growth defects under iron-deficient conditions, and highlighted connections that exist in the response to both opposite conditions. Changes in iron accumulation and gene expression profiles suggest differences in the regulation of iron homeostasis genes.

Regulation of T Cell Homeostasis and Responses by Pten

Directory of Open Access Journals (Sweden)

Ryan H. Newton

2012-06-01

Full Text Available The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, costimulatory, cytokine and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K reaction, directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages of T cell development.

Regulation of Cell Wall Biogenesis in Saccharomyces cerevisiae: The Cell Wall Integrity Signaling Pathway

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Levin, David E.

2011-01-01

The yeast cell wall is a strong, but elastic, structure that is essential not only for the maintenance of cell shape and integrity, but also for progression through the cell cycle. During growth and morphogenesis, and in response to environmental challenges, the cell wall is remodeled in a highly regulated and polarized manner, a process that is principally under the control of the cell wall integrity (CWI) signaling pathway. This pathway transmits wall stress signals from the cell surface to the Rho1 GTPase, which mobilizes a physiologic response through a variety of effectors. Activation of CWI signaling regulates the production of various carbohydrate polymers of the cell wall, as well as their polarized delivery to the site of cell wall remodeling. This review article centers on CWI signaling in Saccharomyces cerevisiae through the cell cycle and in response to cell wall stress. The interface of this signaling pathway with other pathways that contribute to the maintenance of cell wall integrity is also discussed. PMID:22174182

The Escherichia coli Cpx envelope stress response regulates genes of diverse function that impact antibiotic resistance and membrane integrity.

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Raivio, Tracy L; Leblanc, Shannon K D; Price, Nancy L

2013-06-01

The Cpx envelope stress response mediates adaptation to stresses that cause envelope protein misfolding. Adaptation is partly conferred through increased expression of protein folding and degradation factors. The Cpx response also plays a conserved role in the regulation of virulence determinant expression and impacts antibiotic resistance. We sought to identify adaptive mechanisms that may be involved in these important functions by characterizing changes in the transcriptome of two different Escherichia coli strains when the Cpx response is induced. We show that, while there is considerable strain- and condition-specific variability in the Cpx response, the regulon is enriched for proteins and functions that are inner membrane associated under all conditions. Genes that were changed by Cpx pathway induction under all conditions were involved in a number of cellular functions and included several intergenic regions, suggesting that posttranscriptional regulation is important during Cpx-mediated adaptation. Some Cpx-regulated genes are centrally involved in energetics and play a role in antibiotic resistance. We show that a number of small, uncharacterized envelope proteins are Cpx regulated and at least two of these affect phenotypes associated with membrane integrity. Altogether, our work suggests new mechanisms of Cpx-mediated envelope stress adaptation and antibiotic resistance.

O-GlcNAc regulates NEDD4-1 stability via caspase-mediated pathway

International Nuclear Information System (INIS)

Jiang, Kuan; Bai, Bingyang; Ta, Yajie; Zhang, Tingling; Xiao, Zikang; Wang, Peng George; Zhang, Lianwen

2016-01-01

O-GlcNAc modification of cytosolic and nuclear proteins regulates essential cellular processes such as stress responses, transcription, translation, and protein degradation. Emerging evidence indicates O-GlcNAcylation has a dynamic interplay with ubiquitination in cellular regulation. Here, we report that O-GlcNAc indirectly targets a vital E3 ubiquitin ligase enzyme of NEDD4-1. The protein level of NEDD4-1 is accordingly decreased following an increase of overall O-GlcNAc level upon PUGNAc or glucosamine stimulation. O-GlcNAc transferase (OGT) knockdown, overexpression and mutation results confirm that the stability of NEDD4-1 is negatively regulated by cellular O-GlcNAc. Moreover, the NEDD4-1 degradation induced by PUGNAc or GlcN is significantly inhibited by the caspase inhibitor. Our study reveals a regulation mechanism of NEDD4-1 stability by O-GlcNAcylation. - Highlights: • Reduced NEDD4-1 correlates with increased overall O-GlcNAc level. • OGT negatively regulates NEDD4-1 stability. • O-GlcNAc regulates NEDD4-1 through caspase-mediated pathway.

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

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Cory A. Rubel

2016-10-01

Full Text Available Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2 are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.

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

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

2016-01-01

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

Innate-Type and Acquired-Type Allergy Regulated by IL-33

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Tomohiro Yoshimoto

2014-01-01

Full Text Available We propose two types of allergic response: IgE-dependent and IgE-independent, and designate these as 'acquired-type allergy' and 'innate-type allergy', respectively. IL-33 stimulates both innate (basophils, mast cells, or group 2 innate lymphoid cells and acquired (Th2 cells allergy-related cells to induce and/or augment Th2 cytokine production, which leads to eosinophilic inflammation in vivo. Thus, IL-33 is an essential regulator for both 'innate-type allergy' and 'acquired-type allergy', and might be an attractive therapeutic target for allergic diseases.

Chloroplast Translation: Structural and Functional Organization, Operational Control, and Regulation[OPEN

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2018-01-01

Chloroplast translation is essential for cellular viability and plant development. Its positioning at the intersection of organellar RNA and protein metabolism makes it a unique point for the regulation of gene expression in response to internal and external cues. Recently obtained high-resolution structures of plastid ribosomes, the development of approaches allowing genome-wide analyses of chloroplast translation (i.e., ribosome profiling), and the discovery of RNA binding proteins involved in the control of translational activity have greatly increased our understanding of the chloroplast translation process and its regulation. In this review, we provide an overview of the current knowledge of the chloroplast translation machinery, its structure, organization, and function. In addition, we summarize the techniques that are currently available to study chloroplast translation and describe how translational activity is controlled and which cis-elements and trans-factors are involved. Finally, we discuss how translational control contributes to the regulation of chloroplast gene expression in response to developmental, environmental, and physiological cues. We also illustrate the commonalities and the differences between the chloroplast and bacterial translation machineries and the mechanisms of protein biosynthesis in these two prokaryotic systems. PMID:29610211

A complex regulatory network controls aerobic ethanol oxidation in Pseudomonas aeruginosa: indication of four levels of sensor kinases and response regulators.

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Mern, Demissew S; Ha, Seung-Wook; Khodaverdi, Viola; Gliese, Nicole; Görisch, Helmut

2010-05-01

In addition to the known response regulator ErbR (former AgmR) and the two-component regulatory system EraSR (former ExaDE), three additional regulatory proteins have been identified as being involved in controlling transcription of the aerobic ethanol oxidation system in Pseudomonas aeruginosa. Two putative sensor kinases, ErcS and ErcS', and a response regulator, ErdR, were found, all of which show significant similarity to the two-component flhSR system that controls methanol and formaldehyde metabolism in Paracoccus denitrificans. All three identified response regulators, EraR (formerly ExaE), ErbR (formerly AgmR) and ErdR, are members of the luxR family. The three sensor kinases EraS (formerly ExaD), ErcS and ErcS' do not contain a membrane domain. Apparently, they are localized in the cytoplasm and recognize cytoplasmic signals. Inactivation of gene ercS caused an extended lag phase on ethanol. Inactivation of both genes, ercS and ercS', resulted in no growth at all on ethanol, as did inactivation of erdR. Of the three sensor kinases and three response regulators identified thus far, only the EraSR (formerly ExaDE) system forms a corresponding kinase/regulator pair. Using reporter gene constructs of all identified regulatory genes in different mutants allowed the hierarchy of a hypothetical complex regulatory network to be established. Probably, two additional sensor kinases and two additional response regulators, which are hidden among the numerous regulatory genes annotated in the genome of P. aeruginosa, remain to be identified.

Essential oil from leaves of Liquidambar formosana ameliorates inflammatory response in lipopolysaccharide-activated mouse macrophages.

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Hua, Kuo-Feng; Yang, Tzu-Jung; Chiu, Huan-Wen; Ho, Chen-Lung

2014-06-01

The essential oil from Liquidambar formosana leaves (EOLF) was demonstrated to exhibit anti-inflammatory activity in mouse macrophages. EOLF reduced nitrite oxide generation, secretion levels of tumor necrosis factor-alpha and interleukin-6, and expression levels of prointerleukin-beta, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide (LPS)-activated mouse macrophages. EOLF also reduced NLRP3 inflammasome-derived interleukin-1beta secretion. The underlying mechanisms for the EOLF-mediated anti-inflammatory activity were (1) reduction of LPS-induced reactive oxygen species generation; (2) reduction of LPS-induced activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 MAP kinase; (3) reduction of LPS-induced nuclear factor-kappaBeta activation. Furthermore, 25 compounds were identified in the EOLF using GC-FID and GC-MS and the major compounds were terpinen-4-ol (32.0%), beta-pinene (18.0%), gamma-terpinene (13.8%), and alpha-terpinene (9.7%). We found that LPS-induced nitrite oxide generation was inhibited significantly by terpinen-4-ol. Our results indicated that EOLF has anti-inflammatory activity and may provide a molecular rationale for future therapeutic interventions in immune modulation.

Effect Mechanism of Penstock on Stability and Regulation Quality of Turbine Regulating System

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Wencheng Guo

2014-01-01

Full Text Available This paper studies the effect mechanism of water inertia and head loss of penstock on stability and regulation quality of turbine regulating system with surge tank or not and proposes the construction method of equivalent model of regulating system. Firstly, the complete linear mathematical model of regulating system is established. Then, the free oscillation equation and time response of the frequency that describe stability and regulation quality, respectively, are obtained. Finally, the effects of penstock are analysed by using stability region and response curves. The results indicate that the stability and regulation quality of system without surge tank are determined by time response of frequency which only depends on water hammer wave in penstock, while, for system with surge tank, the time response of frequency depending on water hammer wave in penstock and water-level fluctuation in surge tank jointly determines the stability and regulation quality. Water inertia of penstock mainly affects the stability and time response of frequency of system without surge tank as well as the stability and head wave of time response of frequency with surge tank. Head loss of penstock mainly affects the stability and tail wave of time response of frequency with surge tank.

Nitric Oxide Regulates Seedling Growth and Mitochondrial Responses in Aged Oat Seeds

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Chunli Mao

2018-04-01

Full Text Available Mitochondria are the source of reactive oxygen species (ROS in plant cells and play a central role in the mitochondrial electron transport chain (ETC and tricarboxylic acid cycle (TCA cycles; however, ROS production and regulation for seed germination, seedling growth, as well as mitochondrial responses to abiotic stress, are not clear. This study was conducted to obtain basic information on seed germination, embryo mitochondrial antioxidant responses, and protein profile changes in artificial aging in oat seeds (Avena sativa L. exposed to exogenous nitric oxide (NO treatment. The results showed that the accumulation of H2O2 in mitochondria increased significantly in aged seeds. Artificial aging can lead to a loss of seed vigor, which was shown by a decline in seed germination and the extension of mean germination time (MGT. Seedling growth was also inhibited. Some enzymes, including catalase (CAT, glutathione reductase (GR, dehydroascorbate reductase (DHAR, and monodehydroascorbate reductase (MDHAR, maintained a lower level in the ascorbate-glutathione (AsA-GSH scavenging system. Proteomic analysis revealed that the expression of some proteins related to the TCA cycle were down-regulated and several enzymes related to mitochondrial ETC were up-regulated. With the application of 0.05 mM NO in aged oat seeds, a protective effect was observed, demonstrated by an improvement in seed vigor and increased H2O2 scavenging ability in mitochondria. There were also higher activities of CAT, GR, MDHAR, and DHAR in the AsA-GSH scavenging system, enhanced TCA cycle-related enzymes (malate dehydrogenase, succinate-CoA ligase, fumarate hydratase, and activated alternative pathways, as the cytochrome pathway was inhibited. Therefore, our results indicated that seedling growth and seed germinability could retain a certain level in aged oat seeds, predominantly depending on the lower NO regulation of the TCA cycle and AsA-GSH. Thus, it could be concluded that the

Francisella tularensis subsp. tularensis induces a unique pulmonary inflammatory response: role of bacterial gene expression in temporal regulation of host defense responses.

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Kathie-Anne Walters

Full Text Available Pulmonary exposure to Francisella tularensis is associated with severe lung pathology and a high mortality rate. The lack of induction of classical inflammatory mediators, including IL1-β and TNF-α, during early infection has led to the suggestion that F. tularensis evades detection by host innate immune surveillance and/or actively suppresses inflammation. To gain more insight into the host response to Francisella infection during the acute stage, transcriptomic analysis was performed on lung tissue from mice exposed to virulent (Francisella tularensis ssp tularensis SchuS4. Despite an extensive transcriptional response in the lungs of animals as early as 4 hrs post-exposure, Francisella tularensis was associated with an almost complete lack of induction of immune-related genes during the initial 24 hrs post-exposure. This broad subversion of innate immune responses was particularly evident when compared to the pulmonary inflammatory response induced by other lethal (Yersinia pestis and non-lethal (Legionella pneumophila, Pseudomonas aeruginosa pulmonary infections. However, the unique induction of a subset of inflammation-related genes suggests a role for dysregulation of lymphocyte function and anti-inflammatory pathways in the extreme virulence of Francisella. Subsequent activation of a classical inflammatory response 48 hrs post-exposure was associated with altered abundance of Francisella-specific transcripts, including those associated with bacterial surface components. In summary, virulent Francisella induces a unique pulmonary inflammatory response characterized by temporal regulation of innate immune pathways correlating with altered bacterial gene expression patterns. This study represents the first simultaneous measurement of both host and Francisella transcriptome changes that occur during in vivo infection and identifies potential bacterial virulence factors responsible for regulation of host inflammatory pathways.

Three transcription regulators of the Nss family mediate the adaptive response induced by nitrate, nitric oxide or nitrous oxide in Wolinella succinogenes.

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Kern, Melanie; Simon, Jörg

2016-09-01

Sensing potential nitrogen-containing respiratory substrates such as nitrate, nitrite, hydroxylamine, nitric oxide (NO) or nitrous oxide (N2 O) in the environment and subsequent upregulation of corresponding catabolic enzymes is essential for many microbial cells. The molecular mechanisms of such adaptive responses are, however, highly diverse in different species. Here, induction of periplasmic nitrate reductase (Nap), cytochrome c nitrite reductase (Nrf) and cytochrome c N2 O reductase (cNos) was investigated in cells of the Epsilonproteobacterium Wolinella succinogenes grown either by fumarate, nitrate or N2 O respiration. Furthermore, fumarate respiration in the presence of various nitrogen compounds or NO-releasing chemicals was examined. Upregulation of each of the Nap, Nrf and cNos enzyme systems was found in response to the presence of nitrate, NO-releasers or N2 O, and the cells were shown to employ three transcription regulators of the Crp-Fnr superfamily (homologues of Campylobacter jejuni NssR), designated NssA, NssB and NssC, to mediate the upregulation of Nap, Nrf and cNos. Analysis of single nss mutants revealed that NssA controls production of the Nap and Nrf systems in fumarate-grown cells, while NssB was required to induce the Nap, Nrf and cNos systems specifically in response to NO-generators. NssC was indispensable for cNos production under any tested condition. The data indicate dedicated signal transduction routes responsive to nitrate, NO and N2 O and imply the presence of an N2 O-sensing mechanism. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.