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Hasan, Naimul, Ibrahim Alsaidan, Mohammad Sajid, Shahida Khatoon und Shuaib Farooq. „Hybrid MPC-Based Automatic Generation Control for Dominant Wind Energy Penetrated Multisource Power System“. Modelling and Simulation in Engineering 2022 (17.01.2022): 1–10. http://dx.doi.org/10.1155/2022/5526827.
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This paper presents hybrid model predictive control-based automatic generation regulator design for dominant wind energy penetrated multisource power system. The other power generation sources hydro and thermal are also considered in each area. The proposed AGC regulator is designed for each independent area considering only local power system states to ensure the stability of closed-loop system under small perturbation. The performance of the proposed AGC regulator has been validated for 2% step load perturbation. Furthermore, system parameter is varied to 20% of nominal value to assess the robust performance of the regulator. Performance evaluation between the hybrid MPC, conventional MPC, and traditional AGC regulators considering the dominant participation of the DFIG wind turbines is presented to demonstrate the superior performance of the hybrid MPC AGC regulator.
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HAJIBARAT, Zohreh, und Abbas SAIDI. „Genome wide identification of AGC kinase genes and their expression in response to heat and cold stresses in barley“. Acta agriculturae Slovenica 118, Nr. 3 (20.10.2022): 1. http://dx.doi.org/10.14720/aas.2022.118.3.2589.
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<p class="042abstractstekst">AGC kinases are highly conserved regulators in a variety of cellular processes such as differentiation, proliferation, and growth. They are known to play important roles in stress and hormonal responses, including ROS signaling. AGC kinases are the main class of protein kinases in plants, having central functions in different stages of plant growth. In the present study, the analysis of phylogenetic relationships, gene structures, chromosomal locations, synteny analysis, gene ontology, subcellular localization, and gene expression of AGC kinase identified 28 AGC kinase<em> </em>genes in barley<em>.</em> Phylogenetic tree grouped them into seven subfamilies, as supported by exon-intron organization. Gene duplication and synteny indicated that tandom and block duplication events played an essential role in the expansion of AGC kinase gene families in barley. The Real-time quantitative reverse transcription PCR (qRT-PCR) analysis performed for <em>HvAGC kinase gene </em>were largely expressed in different tissues of roots, stems, and leaves in Azaran<em> </em>and Jolgeh cultivars under heat and cold stresses. The results of chromosomal localization showed that the AGC kinases were located on all chromosomes of barley except chromosome 1. Genome evolution of species was surveyed using identification of orthologous and paralogous genes. Identifying overlaps between orthologous clusters can enable us to study the function and evolution of proteins in different species. To our knowledge, this is the first detailed report of using AGC kinases for bioinformatics analysis in barley. Results revealed a broad understanding of the AGC kinase<em> </em>gene family in barley, which will be valuable for improving barley varieties’ response to heat and cold stresses. Also, <em>HvNDR6.2 </em>gene can utilized as molecular markers under cold stress in the three organs.</p>
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Tamaskovic, Rastislav, Samuel J. Bichsel und Brian A. Hemmings. „NDR family of AGC kinases - essential regulators of the cell cycle and morphogenesis“. FEBS Letters 546, Nr. 1 (13.05.2003): 73–80. http://dx.doi.org/10.1016/s0014-5793(03)00474-5.
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Ćalović, M. S., P. Č. Stefanov und N. M. Obradović. „Automatic correction of the systematic error on AGC regulators due to tie-line losses“. European Transactions on Electrical Power 18, Nr. 3 (2008): 281–95. http://dx.doi.org/10.1002/etep.176.
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Egido, I., F. Fernández-Bernal und L. Rouco. „Evaluation of Automatic Generation Control (AGC) regulators by performance indices using data from real operation“. IET Generation, Transmission & Distribution 1, Nr. 2 (2007): 294. http://dx.doi.org/10.1049/iet-gtd:20060173.
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Liu, K., X. Zhang, C. Sumanasekera, R. L. Lester und R. C. Dickson. „Signalling functions for sphingolipid long-chain bases in Saccharomyces cerevisiae“. Biochemical Society Transactions 33, Nr. 5 (26.10.2005): 1170–73. http://dx.doi.org/10.1042/bst0331170.
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Over the past several years, studies of sphingolipid functions in the baker's yeast Saccharomyces cerevisiae have revealed that the sphingoid LCBs (long-chain bases), dihydrosphingosine and PHS (phytosphingosine), are important signalling molecules or second messengers under heat stress and during non-stressed conditions. LCBs are now recognized as regulators of AGC-type protein kinase (where AGC stands for protein kinases A, G and C) Pkh1 and Pkh2, which are homologues of mammalian phosphoinositide-dependent protein kinase 1. LCBs were previously shown to activate Pkh1 and Pkh2, which then activate the downstream protein kinase Pkc1. We have recently demonstrated that PHS stimulates Pkh1 to activate additional downstream kinases including Ypk1, Ypk2 and Sch9. We have also found that PHS acts downstream of Pkh1 and partially activates Ypk1, Ypk2 and Sch9. These kinases control a wide range of cellular processes including growth, cell wall integrity, stress resistance, endocytosis and aging. As we learn more about the cellular processes controlled by Ypk1, Ypk2 and Sch9, we will have a far greater appreciation of LCBs as second messengers.
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Gupta, Esha, und Akash Saxena. „Performance Evaluation of Antlion Optimizer Based Regulator in Automatic Generation Control of Interconnected Power System“. Journal of Engineering 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/4570617.
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This paper presents an application of the recently introduced Antlion Optimizer (ALO) to find the parameters of primary governor loop of thermal generators for successful Automatic Generation Control (AGC) of two-area interconnected power system. Two standard objective functions, Integral Square Error (ISE) and Integral Time Absolute Error (ITAE), have been employed to carry out this parameter estimation process. The problem is transformed in optimization problem to obtain integral gains, speed regulation, and frequency sensitivity coefficient for both areas. The comparison of the regulator performance obtained from ALO is carried out with Genetic Algorithm (GA), Particle Swarm Optimization (PSO), and Gravitational Search Algorithm (GSA) based regulators. Different types of perturbations and load changes are incorporated to establish the efficacy of the obtained design. It is observed that ALO outperforms all three optimization methods for this real problem. The optimization performance of ALO is compared with other algorithms on the basis of standard deviations in the values of parameters and objective functions.
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Chen, Chien-Hung, Vladimir Kiyan, Assylbek A. Zhylkibayev, Dubek Kazyken, Olga Bulgakova, Kent E. Page, Rakhmet I. Bersimbaev, Eric Spooner und Dos D. Sarbassov. „Autoregulation of the Mechanistic Target of Rapamycin (mTOR) Complex 2 Integrity Is Controlled by an ATP-dependent Mechanism“. Journal of Biological Chemistry 288, Nr. 38 (08.08.2013): 27019–30. http://dx.doi.org/10.1074/jbc.m113.498055.
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Nutrients are essential for living organisms because they fuel biological processes in cells. Cells monitor nutrient abundance and coordinate a ratio of anabolic and catabolic reactions. Mechanistic target of rapamycin (mTOR) signaling is the essential nutrient-sensing pathway that controls anabolic processes in cells. The central component of this pathway is mTOR, a highly conserved and essential protein kinase that exists in two distinct functional complexes. The nutrient-sensitive mTOR complex 1 (mTORC1) controls cell growth and cell size by phosphorylation of the regulators of protein synthesis S6K1 and 4EBP1, whereas its second complex, mTORC2, regulates cell proliferation by functioning as the regulatory kinase of Akt and other members of the AGC kinase family. The regulation of mTORC2 remains poorly characterized. Our study shows that the cellular ATP balance controls a basal kinase activity of mTORC2 that maintains the integrity of mTORC2 and phosphorylation of Akt on the turn motif Thr-450 site. We found that mTOR stabilizes SIN1 by phosphorylation of its hydrophobic and conserved Ser-260 site to maintain the integrity of mTORC2. The optimal kinase activity of mTORC2 requires a concentration of ATP above 1.2 mm and makes this kinase complex highly sensitive to ATP depletion. We found that not amino acid but glucose deprivation of cells or acute ATP depletion prevented the mTOR-dependent phosphorylation of SIN1 on Ser-260 and Akt on Thr-450. In a low glucose medium, the cells carrying a substitution of SIN1 with its phosphomimetic mutant show an increased rate of cell proliferation related to a higher abundance of mTORC2 and phosphorylation of Akt. Thus, the homeostatic ATP sensor mTOR controls the integrity of mTORC2 and phosphorylation of Akt on the turn motif site.
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Cheng, Jing, Peter C. Lucas und Linda M. McAllister-Lucas. „Canonical and Non-Canonical Roles of GRK2 in Lymphocytes“. Cells 10, Nr. 2 (03.02.2021): 307. http://dx.doi.org/10.3390/cells10020307.
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G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2′s canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.
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BIONDI, Ricardo M., und Angel R. NEBREDA. „Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions“. Biochemical Journal 372, Nr. 1 (15.05.2003): 1–13. http://dx.doi.org/10.1042/bj20021641.
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Signal transduction pathways use protein kinases for the modification of protein function by phosphorylation. A major question in the field is how protein kinases achieve the specificity required to regulate multiple cellular functions. Here we review recent studies that illuminate the mechanisms used by three families of Ser/Thr protein kinases to achieve substrate specificity. These kinases rely on direct docking interactions with substrates, using sites distinct from the phospho-acceptor sequences. Docking interactions also contribute to the specificity and regulation of protein kinase activities. Mitogen-activated protein kinase (MAPK) family members can associate with and phosphorylate specific substrates by virtue of minor variations in their docking sequences. Interestingly, the same MAPK docking pocket that binds substrates also binds docking sequences of positive and negative MAPK regulators. In the case of glycogen synthase kinase 3 (GSK3), the presence of a phosphate-binding site allows docking of previously phosphorylated (primed) substrates; this docking site is also required for the mechanism of GSK3 inhibition by phosphorylation. In contrast, non-primed substrates interact with a different region of GSK3. Phosphoinositide-dependent protein kinase-1 (PDK1) contains a hydrophobic pocket that interacts with a hydrophobic motif present in all known substrates, enabling their efficient phosphorylation. Binding of the substrate hydrophobic motifs to the pocket in the kinase domain activates PDK1 and other members of the AGC family of protein kinases. Finally, the analysis of protein kinase structures indicates that the sites used for docking substrates can also bind N- and C-terminal extensions to the kinase catalytic core and participate in the regulation of its activity.
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Sharma, Gulshan. „Optimal AGC Design for Diverse Sources of Power Generations in each Area Using Output Vector Feedback Control Technique“. International Journal of Engineering Research in Africa 45 (November 2019): 99–114. http://dx.doi.org/10.4028/www.scientific.net/jera.45.99.
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In this paper an attempt is made to design the regulator for automatic generation control (AGC) of an interconnected energy delivery system to regulate the frequency and tie-power to original value for sudden change in the energy demand of the customers. The considered energy delivery system is having the power generation via thermal, hydro and gas sources and connected via means of parallel AC/DC tie-lines. Further, most of AGC studies focussed on regulator design using application of control theory such as optimal control to manage the balance between generation and load demand considering all system states. However, inreality it is hard enough to measure all system states and design effective regulator for AGC action. Hence in this paper efforts are made to design regulator for AGC problem using few states which are easily measurable and available in real situation of the system i.e. output vector feedback. The feasibility & stability of proposed AGC is tested for 1% change in power demand and compared with optimal AGC which is based on all system states using obtained system responses, feedback gains of control as well as closed loop eigenvalues.
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Zhang, Weibin, Junhua Ma, Chengyuan Zang, Yingying Song und Peipei Liu. „The Fur Transcription Regulator and Fur-Regulated Genes inClostridium botulinumA ATCC 3502“. Journal of Biomedicine and Biotechnology 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/934756.
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Clostridium botulinumis a spore-forming bacterium that can produce a very powerful neurotoxin that causes botulism. In this study, we have investigated the Fur transcription regulators inClostridium botulinumand Fur-regulated genes inClostridium botulinumA ATCC 3502. We found that gene loss may be the main cause leading to the different numbers of Fur transcription regulators in differentClostridium botulinumstrains. Meanwhile, 46 operons were found to be regulated by the Fur transcription regulator inClostridium botulinumA ATCC 3502, involved in several functional classifications, including iron acquisition, iron utilization, iron transport, and transcription regulator. Under an iron-restricted medium, we experimentally found that a Fur transcription regulator (CBO1372) and two operons (DedA, CBO2610–CBO2614 and ABC transporter, CBO0845–CBO0847) are shown to be differentially expressed inClostridium botulinumA ATCC 3502. This study has provided-us novel insights into the diversity of Fur transcription regulators in differentClostridium botulinumstrains and diversity of Fur-targeted genes, as well as a better understanding of the dynamic changes in iron restriction occurring in response to this stress.
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Knutsen, Eivind, Ola Ween und Leiv Sigve Håvarstein. „Two Separate Quorum-Sensing Systems Upregulate Transcription of the Same ABC Transporter in Streptococcus pneumoniae“. Journal of Bacteriology 186, Nr. 10 (15.05.2004): 3078–85. http://dx.doi.org/10.1128/jb.186.10.3078-3085.2004.
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ABSTRACT Streptococcus pneumoniae secretes two different peptide pheromones used for intercellular communication. These peptides, which have completely unrelated primary structures, activate two separate signal transduction pathways, ComABCDE and BlpABCSRH, which regulate natural genetic transformation and bacteriocin production, respectively. Each signal transduction pathway contains a response regulator (ComE and BlpR, respectively) that activates transcription of target genes by binding to similar, but not identical, imperfect direct repeat motifs. In general the direct repeat binding sites are specific for one or the other of the two response regulators, ensuring that competence development and bacteriocin production are regulated separately. However, in the present study we show that the rate of transcription of an operon, encoding an ABC transporter of unknown function, can be stimulated by both peptide pheromones. We also show that this cross-induction is due to a hybrid direct repeat motif that can respond to both ComE and BlpR. To our knowledge this kind of convergent gene regulation by two separate two-component regulatory systems has not been described before in bacteria.
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Veleba, Mark, Paul G. Higgins, Gerardo Gonzalez, Harald Seifert und Thamarai Schneiders. „Characterization of RarA, a Novel AraC Family Multidrug Resistance Regulator in Klebsiella pneumoniae“. Antimicrobial Agents and Chemotherapy 56, Nr. 8 (29.05.2012): 4450–58. http://dx.doi.org/10.1128/aac.00456-12.
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ABSTRACTTranscriptional regulators, such as SoxS, RamA, MarA, and Rob, which upregulate the AcrAB efflux pump, have been shown to be associated with multidrug resistance in clinically relevant Gram-negative bacteria. In addition to the multidrug resistance phenotype, these regulators have also been shown to play a role in the cellular metabolism and possibly the virulence potential of microbial cells. As such, the increased expression of these proteins is likely to cause pleiotropic phenotypes.Klebsiella pneumoniaeis a major nosocomial pathogen which can express the SoxS, MarA, Rob, and RamA proteins, and the accompanying paper shows that the increased transcription oframAis associated with tigecycline resistance (M. Veleba and T. Schneiders, Antimicrob. Agents Chemother. 56:4466–4467, 2012). Bioinformatic analyses of the availableKlebsiellagenome sequences show that an additional AraC-type regulator is encoded chromosomally. In this work, we characterize this novel AraC-type regulator, hereby called RarA (Regulator of antibiotic resistance A), which is encoded inK. pneumoniae,Enterobactersp. 638,Serratia proteamaculans568, andEnterobacter cloacae. We show that the overexpression ofrarAresults in a multidrug resistance phenotype which requires a functional AcrAB efflux pump but is independent of the other AraC regulators. Quantitative real-time PCR experiments show thatrarA(MGH 78578 KPN_02968) and its neighboring efflux pump operonoqxAB(KPN_02969_02970) are consistently upregulated in clinical isolates collected from various geographical locations (Chile, Turkey, and Germany). Our results suggest thatrarAoverexpression upregulates theoqxABefflux pump. Additionally, it appears thatoqxR, encoding a GntR-type regulator adjacent to theoqxABoperon, is able to downregulate the expression of theoqxABefflux pump, where OqxR complementation resulted in reductions to olaquindox MICs.
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Macvanin, Mirjana, Johanna Björkman, Sofia Eriksson, Mikael Rhen, Dan I. Andersson und Diarmaid Hughes. „Fusidic Acid-Resistant Mutants of Salmonella enterica Serovar Typhimurium with Low Fitness In Vivo Are Defective in RpoS Induction“. Antimicrobial Agents and Chemotherapy 47, Nr. 12 (Dezember 2003): 3743–49. http://dx.doi.org/10.1128/aac.47.12.3743-3749.2003.
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ABSTRACT Mutants of Salmonella enterica serovar Typhimurium resistant to fusidic acid (Fusr) have mutations in fusA, the gene encoding translation elongation factor G (EF-G). Most Fusr mutants have reduced fitness in vitro and in vivo, in part explained by mutant EF-G slowing the rate of protein synthesis and growth. However, some Fusr mutants with normal rates of protein synthesis still suffer from reduced fitness in vivo. As shown here, Fusr mutants could be similarly ranked in their relative fitness in mouse infection models, in a macrophage infection model, in their relative hypersensitivity to hydrogen peroxide in vivo and in vitro, and in the amount of RpoS production induced upon entry into the stationary phase. We identify a reduced ability to induce production of RpoS (σs) as a defect associated with Fusr strains. Because RpoS is a regulator of the general stress response, and an important virulence factor in Salmonella, an inability to produce RpoS in appropriate amounts can explain the low fitness of Fusr strains in vivo. The unfit Fusr mutants also produce reduced levels of the regulatory molecule ppGpp in response to starvation. Because ppGpp is a positive regulator of RpoS production, we suggest that a possible cause of the reduced levels of RpoS is the reduction in ppGpp production associated with mutant EF-G. The low fitness of Fusr mutants in vivo suggests that drugs that can alter the levels of global regulators of gene expression deserve attention as potential antimicrobial agents.
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Bettiol, Esther, Jeffrey D. Wetherington, Nicola Schmitt und Stephan Harbarth. „Challenges and Solutions for Clinical Development of New Antibacterial Agents: Results of a Survey among Pharmaceutical Industry Professionals“. Antimicrobial Agents and Chemotherapy 59, Nr. 7 (27.04.2015): 3695–99. http://dx.doi.org/10.1128/aac.00638-15.
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ABSTRACTAs the number of antibacterial medicines in the pipeline remains low, we anonymously surveyed pharmaceutical industry professionals on challenges and solutions for clinical development of these agents. Challenges were reported primarily as financial and regulatory. For multidrug-resistant organisms, there are needs for rapid diagnostic tests, new regulatory guidance, and adaptation of endpoints/trial designs. Regulators and public/private initiatives are addressing these challenges to help ensure that proposed solutions have the support of all involved stakeholders.
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Yoon, Eun-Jeong, Patrice Courvalin und Catherine Grillot-Courvalin. „RND-Type Efflux Pumps in Multidrug-Resistant Clinical Isolates of Acinetobacter baumannii: Major Role for AdeABC Overexpression and AdeRS Mutations“. Antimicrobial Agents and Chemotherapy 57, Nr. 7 (15.04.2013): 2989–95. http://dx.doi.org/10.1128/aac.02556-12.
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ABSTRACTIncreased expression of chromosomal genes for resistance-nodulation-cell division (RND)-type efflux systems plays a major role in the multidrug resistance (MDR) ofAcinetobacter baumannii. However, the relative contributions of the three most prevalent pumps, AdeABC, AdeFGH, and AdeIJK, have not been evaluated in clinical settings. We have screened 14 MDR clinical isolates shown to be distinct on the basis of multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) for the presence and overexpression of the three Ade efflux systems and analyzed the sequences of the regulators AdeRS, a two-component system, for AdeABC and AdeL, a LysR-type regulator, for AdeFGH. GeneadeBwas detected in 13 of 14 isolates, andadeGand the intrinsicadeJgene were detected in all strains. Significant overexpression ofadeBwas observed in 10 strains, whereas only 7 had moderately increased levels of expression of AdeFGH, and none overexpressed AdeIJK. Thirteen strains had reduced susceptibility to tigecycline, but there was no correlation between tigecycline MICs and the levels of AdeABC expression, suggesting the presence of other mechanisms for tigecycline resistance. No mutations were found in the highly conserved LysR regulator of the nine strains expressing AdeFGH. In contrast, functional mutations were found in conserved domains of AdeRS in all the strains that overexpressed AdeABC with two mutational hot spots, one in AdeS near histidine 149 suggesting convergent evolution and the other in the DNA binding domain of AdeR compatible with horizontal gene transfer. This report outlines the high incidence of AdeABC efflux pump overexpression in MDRA. baumanniias a result of a variety of single mutations in the corresponding two-component regulatory system.
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Mora, Alfonso, David Komander, Daan M. F. van Aalten und Dario R. Alessi. „PDK1, the master regulator of AGC kinase signal transduction“. Seminars in Cell & Developmental Biology 15, Nr. 2 (April 2004): 161–70. http://dx.doi.org/10.1016/j.semcdb.2003.12.022.
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Muzzi, João C. D., Jéssica M. Magno, Jean S. Souza, Larissa M. Alvarenga, Juliana F. de Moura, Bonald C. Figueiredo und Mauro A. A. Castro. „Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis“. Cancers 14, Nr. 21 (27.10.2022): 5279. http://dx.doi.org/10.3390/cancers14215279.
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We reconstructed a transcriptional regulatory network for adrenocortical carcinoma (ACC) using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)-ACC cohort. We investigated the association of transcriptional regulatory units (regulons) with overall survival, molecular phenotypes, and immune signatures. We annotated the ACC regulons with cancer hallmarks and assessed single sample regulon activities in the European Network for the Study of Adrenal Tumors (ENSAT) cohort. We found 369 regulons associated with overall survival and subdivided them into four clusters: RC1 and RC2, associated with good prognosis, and RC3 and RC4, associated with worse outcomes. The RC1 and RC3 regulons were highly correlated with the ‘Steroid Phenotype,’ while the RC2 and RC4 regulons were highly correlated with a molecular proliferation signature. We selected two regulons, NR5A1 (steroidogenic factor 1, SF-1) and CENPA (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The CENPA regulon was the primary regulator of MKI-67 (a marker of proliferation KI-67), while the NR5A1 regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the ZBTB4 (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with CENPA in our transcriptional regulatory network, is also a druggable anti-tumorigenic TF. We anticipate that the ACC regulons may be used as a reference for further investigations concerning the complex molecular interactions in ACC tumors.
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Aryal, Bibek, Christophe Laurent und Markus Geisler. „Learning from each other: ABC transporter regulation by protein phosphorylation in plant and mammalian systems“. Biochemical Society Transactions 43, Nr. 5 (01.10.2015): 966–74. http://dx.doi.org/10.1042/bst20150128.
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The ABC (ATP-binding cassette) transporter family in higher plants is highly expanded compared with those of mammalians. Moreover, some members of the plant ABC subfamily B (ABCB) display very high substrate specificity compared with their mammalian counterparts that are often associated with multi-drug resistance phenomena. In this review, we highlight prominent functions of plant and mammalian ABC transporters and summarize our knowledge on their post-transcriptional regulation with a focus on protein phosphorylation. A deeper comparison of regulatory events of human cystic fibrosis transmembrane conductance regulator (CFTR) and ABCB1 from the model plant Arabidopsis reveals a surprisingly high degree of similarity. Both physically interact with orthologues of the FK506-binding proteins that chaperon both transporters to the plasma membrane in an action that seems to involve heat shock protein (Hsp)90. Further, both transporters are phosphorylated at regulatory domains that connect both nt-binding folds. Taken together, it appears that ABC transporters exhibit an evolutionary conserved but complex regulation by protein phosphorylation, which apparently is, at least in some cases, tightly connected with protein–protein interactions (PPI).
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Wang, Jie, Qijun Yi, Tingting Liu, Yi Yao, Ian Loveless, Kalpana Subedi, Indra Adrianto, Howard Crawford, Li Zhou und Qing-Sheng Mi. „Abstract 2108: ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 2108. http://dx.doi.org/10.1158/1538-7445.am2022-2108.
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Abstract Background: Liver metastasis is a common feature of pancreatic tumor and associated with a poor outcome. Invariant natural killer cells (iNKT) are innate-like T cells that are important regulators of innate and adaptive immune responses in cancer and is the largest subset of lymphocytes within liver. However, the role of iNKT cells in pancreatic tumor liver metastasis (PTLM) is still not clear. Hypothesis: activated liver iNKT cells could play a role in PTLM. Method: We established a PTLM mouse model by hemi-spleen murine pancreatic tumor cells (CF1242) injection. We combined single-cell RNA sequencing, flow cytometry analysis, and imaging mass cytometry analysis to landscape the immune profile of tumor microenvironment during PTLM with or without iNKT cell activator α-galactosylceramide (αGC) treatment. Results: αGC treatment significantly blocked PTLM development based on liver weight compared to control group(P<0.001). We sequenced total 6,728 CD45+ infiltrating immune cells in PTLM with/without αGC treatment and identified total 12 immune subpopulations that were present in both samples at different frequencies. Post αGC treatment, activated iNKT cells in liver appeared robust population expansion and enriched in cytotoxic signaling pathway. Alternatively, activated iNKT cells promoted infiltrating CD4 T cells to a Th1 profile shift, and promoted infiltrating CD8 T cells toward an effector/memory phenotype (upregulation of the CD44, T-bet, and IFN-γ; P<0.001), and increased NK cell cytotoxic activity (P<0.001). In addition, we observed that aGC treatment blocked infiltrating CD8 T cell exhaustion by downregulating the immune checkpoint TIGIT, Lag3, and PD-1 (P<0.001). Analysis of tumor-infiltrating myeloid clusters revealed that macrophage skewed to M1 phenotype compared to the control group(P<0.05). Conclusion: αGC treatment can expand and activate liver iNKT cells, which may directly increase tumor cell killing ability, recruit immune cells to tumor sites, and orchestrate the anti-tumor function through boost both innate and adaptive tumor immunity to inhibit PTLM. Our results indicate that iNKT cells may serve as a new immunotherapeutic target for PTLM. (Funded by HFCI and NIH/NIAID) Citation Format: Jie Wang, Qijun Yi, Tingting Liu, Yi Yao, Ian Loveless, Kalpana Subedi, Indra Adrianto, Howard Crawford, Li Zhou, Qing-Sheng Mi. ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2108.
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Li, Jiping, und Bernard R. Glick. „Transcriptional regulation of the Enterobacter cloacae UW4 1-aminocyclopropane-1-carboxylate (ACC) deaminase gene (acdS)“. Canadian Journal of Microbiology 47, Nr. 4 (01.04.2001): 359–67. http://dx.doi.org/10.1139/w01-009.
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Based on DNA sequence analysis and 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity, the region of DNA immediately upstream of the Enterobacter cloacae UW4 ACC deaminase gene (acdS) contains several features that appear to be involved in its transcriptional regulation. In the present study, the 5' upstream region of acdS was cloned into the promoter-probe vector, pQF70, which carries the promoterless luciferase gene (luxAB), and luciferase expression was monitored. The data obtained from studying the expression of the luciferase gene showed that (i) a leucine responsive regulatory protein (LRP)-like protein encoded within the upstream region is located on the opposite strand from acdS under the control of a promoter stronger than the one responsible for acdS transcription, (ii) luciferase gene expression required both ACC and the LRP-like protein, (iii) luciferase expression was increased three-fold under anaerobic conditions, consistent with the involvement of a fumarate-nitrate reduction (FNR)-like regulatory protein box within the upstream region, and (iv) the addition of leucine to the growth medium decreased luciferase activity in the presence of ACC and increased luciferase activity in the absence of ACC, consistent with leucine acting as a regulator of the expression of the LRP-like protein.Key words: plant growth promotion, ethylene, ACC deaminase, regulation, Enterobacter cloacae.
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Vasudeva-Rao, Hema M., und Kathleen A. McDonough. „Expression of the Mycobacterium tuberculosis acr-Coregulated Genes from the DevR (DosR) Regulon Is Controlled by Multiple Levels of Regulation“. Infection and Immunity 76, Nr. 6 (07.04.2008): 2478–89. http://dx.doi.org/10.1128/iai.01443-07.
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ABSTRACT Little is known about how Mycobacterium tuberculosis regulates gene expression in response to its host environment, despite its importance as a pathogen. We previously characterized 10 a cr-coregulated genes (ACGs), all of which belong to the DevR (DosR) “dormancy” regulon, and identified one to three copies of a conserved 18-bp palindromic DNA motif in the promoter of each ACG family member. In the present study, we used base substitution analyses to assess the importance of individual motif copies and to identify additional regulatory sequences in five ACG promoters. Regulation of acr, acg, Rv2623, narK2, and Rv1738 was examined by using single-copy M. tuberculosis promoter-lacZ reporter constructs in Mycobacterium bovis BCG under conditions of ambient air versus hypoxia, each in shaking versus standing shallow culture conditions. We found that regulation of these ACG promoters is more heterogeneous than expected and is controlled at multiple levels. In addition to the positive regulation previously associated with DevR (DosR) and the 18-bp ACG motif, we identified negative regulation associated with sequences in the 5′ untranslated regions of acg and Rv2623 and positive regulation associated with far upstream regulatory regions of narK2 and Rv1738. The importance of individual ACG motifs varied among the promoters examined, and Rv1738 was exceptional in that its ACG motif copies were associated with negative, rather than positive, regulation under some conditions. Further understanding of this important regulon requires the identification of additional regulators that compete and/or collaborate with DevR (DosR) to regulate its individual gene members.
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Pérez-Martínez, Isabel, und Dieter Haas. „Azithromycin Inhibits Expression of the GacA-Dependent Small RNAs RsmY and RsmZ in Pseudomonas aeruginosa“. Antimicrobial Agents and Chemotherapy 55, Nr. 7 (02.05.2011): 3399–405. http://dx.doi.org/10.1128/aac.01801-10.
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ABSTRACTAzithromycin at clinically relevant doses does not inhibit planktonic growth of the opportunistic pathogenPseudomonas aeruginosabut causes markedly reduced formation of biofilms and quorum-sensing-regulated extracellular virulence factors. In the Gac/Rsm signal transduction pathway, which acts upstream of the quorum-sensing machinery inP. aeruginosa, the GacA-dependent untranslated small RNAs RsmY and RsmZ are key regulatory elements. As azithromycin treatment and mutational inactivation ofgacAhave strikingly similar phenotypic consequences, the effect of azithromycin onrsmYandrsmZexpression was investigated. In planktonically growing cells, the antibiotic strongly inhibited the expression of both small RNA genes but did not affect the expression of the housekeeping geneproC. The azithromycin treatment resulted in reduced expression ofgacAandrsmA, which are known positive regulators ofrsmYandrsmZ, and of the PA0588-PA0584 gene cluster, which was discovered as a novel positive regulatory element involved inrsmYandrsmZexpression. Deletion of this cluster resulted in diminished ability ofP. aeruginosato produce pyocyanin and to swarm. The results of this study indicate that azithromycin inhibitsrsmYandrsmZtranscription indirectly by lowering the expression of positive regulators of these small RNA genes.
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Gao, Rongsui, Jingxia Lin, Han Zhang und Youjun Feng. „Transcriptional Repression of the VC2105 Protein by Vibrio FadR Suggests that It Is a New Auxiliary Member of thefadRegulon“. Applied and Environmental Microbiology 82, Nr. 9 (04.03.2016): 2819–32. http://dx.doi.org/10.1128/aem.00293-16.
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ABSTRACTRecently, our group along with others reported that theVibrioFadR regulatory protein is unusual in that, unlike the prototypicalfadRproduct ofEscherichia coli, which has only one ligand-binding site,VibrioFadR has two ligand-binding sites and represents a new mechanism for fatty acid sensing. The promoter region of thevc2105gene, encoding a putative thioesterase, was mapped, and a putative FadR-binding site (AA CTG GTA AGA GCA CTT) was proposed. Different versions of the FadR regulatory proteins were prepared and purified to homogeneity. Both electrophoretic mobility shift assay (EMSA) and surface plasmon resonance (SPR) determined the direct interaction of thevc2105gene with FadR proteins of various origins. Further, EMSAs illustrated that the addition of long-chain acyl-coenzyme A (CoA) species efficiently dissociates thevc2105promoter from the FadR regulator. The expression level of theVibrio cholerae vc2105gene was elevated 2- to 3-fold in afadRnull mutant strain, validating that FadR is a repressor for thevc2105gene. The β-galactosidase activity of avc2105-lacZtranscriptional fusion was increased over 2-fold upon supplementation of growth medium with oleic acid. Unlike thefadDgene, a member of theVibrio fadregulon, the VC2105 protein played no role in bacterial growth and virulence-associated gene expression ofctxAB(cholera toxin A/B) andtcpA(toxin coregulated pilus A). Given that the transcriptional regulation ofvc2105fits the criteria for fatty acid degradation (fad) genes, we suggested that it is a new member of theVibrio fadregulon.IMPORTANCETheVibrioFadR regulator is unusual in that it has two ligand-binding sites. Different versions of the FadR regulatory proteins were prepared and characterizedin vitroandin vivo. An auxiliaryfadgene (vc2105) fromVibriowas proposed that encodes a putative thioesterase and has a predicted FadR-binding site (AAC TGG TA A GAG CAC TT). The function of this putative binding site was proved using both EMSA and SPR. Furtherin vitroandin vivoexperiments revealed that theVibrioFadR is a repressor for thevc2105gene. UnlikefadD, a member of theVibrio fadregulon, VC2105 played no role in bacterial growth and expression of the two virulence-associated genes (ctxABandtcpA). Therefore, since transcriptional regulation ofvc2105fits the criteria forfadgenes, it seems likely thatvc2105acts as a new auxiliary member of theVibrio fadregulon.
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Aryal, Bibek, Christophe Laurent und Markus Geisler. „Correction: Learning from each other: ABC transporter regulation by protein phosphorylation in plant and mammalian systems“. Biochemical Society Transactions 44, Nr. 2 (11.04.2016): 663–73. http://dx.doi.org/10.1042/bst20150128_2.
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The ABC (ATP-binding cassette) transporter family in higher plants is highly expanded compared with those of mammalians. Moreover, some members of the plant ABCB subfamily display very high substrate specificity compared with their mammalian counterparts that are often associated with multidrug resistance (MDR) phenomena. In this review we highlight prominent functions of plant and mammalian ABC transporters and summarize our knowledge on their post-transcriptional regulation with a focus on protein phosphorylation. A deeper comparison of regulatory events of human cystic fibrosis transmembrane conductance regulator (CFTR) and ABCB1 from the model plant Arabidopsis reveals a surprisingly high degree of similarity. Both physically interact with orthologues of the FK506-binding proteins (FKBPs) that chaperon both transporters to the plasma membrane in an action that seems to involve Hsp90. Further both transporters are phosphorylated at regulatory domains that connect both nucleotide-binding folds. Taken together it appears that ABC transporters exhibit an evolutionary conserved but complex regulation by protein phosphorylation, which apparently is, at least in some cases, tightly connected with protein–protein interactions (PPI).
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Geddes, Barney A., Brad S. Pickering, Nathan J. Poysti, Heather Collins, Harry Yudistira und Ivan J. Oresnik. „A locus necessary for the transport and catabolism of erythritol in Sinorhizobium meliloti“. Microbiology 156, Nr. 10 (01.10.2010): 2970–81. http://dx.doi.org/10.1099/mic.0.041905-0.
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In this work we have genetically defined an erythritol utilization locus in Sinorhizobium meliloti. A cosmid containing the locus was isolated by complementation of a transposon mutant and was subsequently mutagenized using Tn5 : : B20. The locus was found to consist of five transcriptional units, each of which was necessary for the utilization of erythritol. Genetic complementation experiments using genes putatively annotated as erythritol catabolic genes clearly showed that, of the 17 genes at this locus, six genes are not necessary for the utilization of erythritol as a sole carbon source. The remaining genes encode EryA, EryB, EryC and TpiB as well as an uncharacterized ABC-type transporter. Transport experiments using labelled erythritol showed that components of the ABC transporter are necessary for the uptake of erythritol. The locus also contains two regulators: EryD, a SorC class regulator, and SMc01615, a DeoR class regulator. Quantitative RT-PCR experiments showed that each of these regulators negatively regulates its own transcription. In addition, induction of the erythritol locus was dependent upon EryD and a product of erythritol catabolism. Further characterization of polar mutations revealed that in addition to erythritol, the locus contains determinants for adonitol and l-arabitol utilization. The context of the mutations suggests that the locus is important for both the transport and catabolism of adonitol and l-arabitol.
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Nentwich, Svenja S., Karina Brinkrolf, Lars Gaigalat, Andrea T. Hüser, Daniel A. Rey, Tobias Mohrbach, Kay Marin, Alfred Pühler, Andreas Tauch und Jörn Kalinowski. „Characterization of the LacI-type transcriptional repressor RbsR controlling ribose transport in Corynebacterium glutamicum ATCC 13032“. Microbiology 155, Nr. 1 (01.01.2009): 150–64. http://dx.doi.org/10.1099/mic.0.020388-0.
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The gene products of the rbsRACBD (rbs) operon of C. glutamicum (cg1410–cg1414) encode a ribose-specific ATP-binding cassette (ABC) transport system and its corresponding regulatory protein (RbsR). Deletion of the structural genes rbsACBD prohibited ribose uptake. Deletion of the regulatory gene rbsR resulted in an increased mRNA level of the whole operon. Analysis of the promoter region of the rbs operon by electrophoretic mobility shift assays identified a catabolite-responsive element (cre)-like sequence as the RbsR-binding site. Additional RbsR-binding sites were identified in front of the recently characterized uriR operon (uriR-rbsK1-uriT-uriH) and the ribokinase gene rbsK2. In vitro, the repressor RbsR bound to its targets in the absence of an effector. A probable negative effector of RbsR in vivo is ribose 5-phosphate or a derivative thereof, since in a ribokinase (rbsK1 rbsK2) double mutant, no derepression of the rbs operon in the presence of ribose was observed. Analysis of the ribose stimulon in the C. glutamicum wild-type revealed transcriptional induction of the uriR and rbs operons as well as of the rbsK2 gene. The inconsistency between the existence of functional RbsR-binding sites upstream of the ribokinase genes, their transcriptional induction during growth on ribose, and the missing induction in the rbsR mutant suggested the involvement of a second transcriptional regulator. Simultaneous deletion of the regulatory genes rbsR and uriR finally demonstrated a transcriptional co-control of the rbs and uriR operons and the rbsK2 gene by both regulators, RbsR and UriR, which were furthermore shown to recognize the same cognate DNA sequences in the operators of their target genes.
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El-Din, Ashraf Zein, und Awad El-Sabbe. „A Novel A.C. Voltage Regulator“. EPE Journal 9, Nr. 3-4 (Januar 2000): 47–51. http://dx.doi.org/10.1080/09398368.2000.11463450.
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Lee, Heon-Myung, Gabsik Yang, Tae-Gue Ahn, Myung-Dong Kim, Agung Nugroho, Hee-Juhn Park, Kyung-Tae Lee, Wansu Park und Hyo-Jin An. „Antiadipogenic Effects ofAster glehniExtract: In Vivo and In Vitro Effects“. Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/859624.
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Aster glehni(AG) is a Korean traditional herb that grows in Ulleungdo Island, Republic of Korea. None of the several reports on AG include a determination of the effect of AG on adipogenesis. The primary aim of this study was to determine whether AG attenuates adipogenesis in mouse 3T3-L1 cells and epididymal fat tissue. AG blocked the differentiation of 3T3-L1 preadipocytes in a concentration-dependent manner and suppressed the expression of adipogenesis-related genes such asPPARγ,C/EBPα, andSREBP1c, the master regulators of adipogenesis. Male C57BL/6J mice were divided randomly and equally into 4 diet groups: control diet (CON), high-fat diet (HFD), HFD with 1% AG extract added (AG1), and HFD with 5% AG extract added (AG5). The experimental animals were fed HFD and the 2 combinations for 10 weeks. Mice fed HFD with AG gained less body weight and visceral fat-pad weight than did the mice fed HFD alone. Moreover, AG inhibited the expression of important adipogenic genes such asPPARγ,C/EBPα,SREBP1c,LXR, and leptin in the epididymal adipose tissue of the mice treated with AG1 and AG5. These findings indicate antiadipogenic and antiobesity effects of AG and suggest its therapeutic potential in obesity and obesity-related diseases.
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Smolik, Magdalena, Joanna Suraj, Anna Kurpinska und Maria Walczak. „ABC membrane transporters and their multifunctional nature“. Postępy Higieny i Medycyny Doświadczalnej 72 (16.07.2018): 606–22. http://dx.doi.org/10.5604/01.3001.0012.1966.
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ABC transporters are the largest family of transport proteins, which mediate the active translocation of a wide spectrum of molecules through the cell membrane, using energy from hydrolysis of ATP. They can act as importers (in Procaryota exclusively) or exporters (in both Procaryota and Eucaryota) of specified substrates. Despite a quite conservative structure model, ABC transporters are diverse in terms of functions performed in the body. These proteins are important elements of the blood-organ barriers, they maintain lipid homeostasis, participate in cellular immune response but also are involved in the development of multidrug resistance as well as affect the biology of tumour cells. Additionally, they play the role of ion channels or regulators of their activity. The activity of ABC transporters is also correlated with the occurrence of certain disease entities, such as cystic fibrosis, Dubin-Johnson syndrome, Tangier disease, persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and neoplasia. Due to their therapeutic potential, ABC transporters are becoming increasingly popular. Knowledge of the mechanisms of action of ABC transporters and their regulatory systems will provide the basis for the development of personalized medicine, which may be significant especially in the context of cancer treatment.
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Willett, Robert E. „Regulatory Strategy AGA Looks at 1989“. Natural Gas 5, Nr. 4 (11.09.2007): 16–17. http://dx.doi.org/10.1002/gas.3410050406.
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Boucher, Isabelle, Christian Vadeboncoeur und Sylvain Moineau. „Characterization of Genes Involved in the Metabolism of α-Galactosides by Lactococcus raffinolactis“. Applied and Environmental Microbiology 69, Nr. 7 (Juli 2003): 4049–56. http://dx.doi.org/10.1128/aem.69.7.4049-4056.2003.
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ABSTRACT Lactococcus raffinolactis, unlike most lactococci, is able to ferment α-galactosides, such as melibiose and raffinose. More than 12 kb of chromosomal DNA from L. raffinolactis ATCC 43920 was sequenced, including the α-galactosidase gene and genes involved in the Leloir pathway of galactose metabolism. These genes are organized into an operon containing aga (α-galactosidase), galK (galactokinase), and galT (galactose 1-phosphate uridylyltransferase). Northern blotting experiments revealed that this operon was induced by galactosides, such as lactose, melibiose, raffinose, and, to a lesser extent, galactose. Similarly, α-galactosidase activity was higher in lactose-, melibiose-, and raffinose-grown cells than in galactose-grown cells. No α-galactosidase activity was detected in glucose-grown cells. The expression of the aga-galKT operon was modulated by a regulator encoded by the upstream gene galR. The product of galR belongs to the LacI/GalR family of transcriptional regulators. In L. lactis, L. raffinolactis GalR acted as a repressor of aga and lowered the enzyme activity by more than 20-fold. We suggest that the expression of the aga operon in lactococci is negatively controlled by GalR and induced by a metabolite derived from the metabolism of galactosides.
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Boafo, Jonelle, Keith Anderson, Abraham Brody und Tina Sadarangani. „Documenting the Need for Patient-Centered Relevant Outcomes in Adult Day Services“. Innovation in Aging 5, Supplement_1 (01.12.2021): 84. http://dx.doi.org/10.1093/geroni/igab046.322.
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Abstract ADCs are not uniformly regulated at the federal or state level, resulting in the absence of uniform data collection. The lack of large-scale data has resulted in a dearth of evidence on the role ADC services play in the health and well-being of their clients, particularly persons living with dementia (PLWD). The purpose of this study was to compare data being collected across states and evaluate the degree to which patient centered relevant outcomes (PCROs) are being collected. A review of ADC regulations in 50 states found that <10 states, required standardized reporting on ADC participants. Regulatory forms relied on clinical judgment as opposed to validated tools, and focused on eligibility for services as opposed to independence, engagement, or clinical interventions in the ADC. Emphasizing collection of PCROs in ADCs, beginning at the state level, is an essential step in documenting the value and effectiveness of ADCs, particularly for PLWD.
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Moulin, Pauline, Kévin Patron, Camille Cano, Mohamed Amine Zorgani, Emilie Camiade, Elise Borezée-Durant, Agnès Rosenau, Laurent Mereghetti und Aurélia Hiron. „The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival“. Journal of Bacteriology 198, Nr. 24 (26.09.2016): 3265–77. http://dx.doi.org/10.1128/jb.00614-16.
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ABSTRACT The Lmb protein of Streptococcus agalactiae is described as an adhesin that binds laminin, a component of the human extracellular matrix. In this study, we revealed a new role for this protein in zinc uptake. We also identified two Lmb homologs, AdcA and AdcAII, redundant binding proteins that combine with the AdcCB translocon to form a zinc-ABC transporter. Expression of this transporter is controlled by the zinc concentration in the medium through the zinc-dependent regulator AdcR. Triple deletion of lmb , adcA , and adcAII , or that of the adcCB genes, impaired growth and cell separation in a zinc-restricted environment. Moreover, we found that this Adc zinc-ABC transporter promotes S. agalactiae growth and survival in some human biological fluids, suggesting that it contributes to the infection process. These results indicated that zinc has biologically vital functions in S. agalactiae and that, under the conditions tested, the Adc/Lmb transporter constitutes the main zinc acquisition system of the bacterium. IMPORTANCE A zinc transporter, composed of three redundant binding proteins (Lmb, AdcA, and AdcAII), was characterized in Streptococcus agalactiae . This system was shown to be essential for bacterial growth and morphology in zinc-restricted environments, including human biological fluids.
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Yamazaki, Akihiro, Jin Li, Quan Zeng, Devanshi Khokhani, William C. Hutchins, Angela C. Yost, Eulandria Biddle, Eric J. Toone, Xin Chen und Ching-Hong Yang. „Derivatives of Plant Phenolic Compound Affect the Type III Secretion System of Pseudomonas aeruginosa via a GacS-GacA Two-Component Signal Transduction System“. Antimicrobial Agents and Chemotherapy 56, Nr. 1 (03.10.2011): 36–43. http://dx.doi.org/10.1128/aac.00732-11.
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ABSTRACTAntibiotic therapy is the most commonly used strategy to control pathogenic infections; however, it has contributed to the generation of antibiotic-resistant bacteria. To circumvent this emerging problem, we are searching for compounds that target bacterial virulence factors rather than their viability.Pseudomonas aeruginosa, an opportunistic human pathogen, possesses a type III secretion system (T3SS) as one of the major virulence factors by which it secretes and translocates T3 effector proteins into human host cells. The fact that this human pathogen also is able to infect several plant species led us to screen a library of phenolic compounds involved in plant defense signaling and their derivatives for novel T3 inhibitors. Promoter activity screening ofexoS, which encodes a T3-secreted toxin, identified two T3 inhibitors and two T3 inducers ofP. aeruginosaPAO1. These compounds alterexoStranscription by affecting the expression levels of the regulatory small RNAs RsmY and RsmZ. These two small RNAs are known to control the activity of carbon storage regulator RsmA, which is responsible for the regulation of the key T3SS regulator ExsA. As RsmY and RsmZ are the only targets directly regulated by GacA, our results suggest that these phenolic compounds affect the expression ofexoSthrough the GacSA-RsmYZ-RsmA-ExsA regulatory pathway.
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Hartono, Darminto, und Soekotjo Hardiwinoto. „LEGAL PERSPECTIVE ON ASEAN ECONOMIC COMMUNITY“. Diponegoro Law Review 3, Nr. 2 (30.10.2018): 199. http://dx.doi.org/10.14710/dilrev.3.2.2018.199-222.
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Since 2015, the ASEAN Economic Community (AEC) applied in its member countries, Including Indonesia. The preparation effort is regulatory legislation related to the AEC as a guide to achieve country's goals. The research aims to focus on how to inventory of the AEC regulations and how to find out in passing the AEC. The method uses the normative juridical approach and qualitative descriptive data analysis method. These research results that have a global market share, exporting country, investment destination country, a liberalization of ASEAN goods trade, large demographic bonuses, open services sector, aand smoother capital flows constantly. While the challenge is the elevation of the rate of export-import and the inflation rate, the negative impact of broader capital flows, the similarity of export products Which is still diverse must be solved. The Indonesian Government has an authority to regulate the role and function through it policies optimally, because of the opportunities and the existence of Indonesia. It is a matter of course that each member country to face AEC still not enough of expectations.
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Kotani, Daisuke, Yosuke Togashi, Akihito Kawazoe, Toshihiko Doi, Hiroyoshi Nishikawa und Kohei Shitara. „Regulatory-T cells (Tregs) in tumor infiltrating lymphocytes (TILs) from patients with advanced gastric cancer (AGC) after chemotherapy containing ramucirumab.“ Journal of Clinical Oncology 35, Nr. 15_suppl (20.05.2017): e15570-e15570. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15570.
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e15570 Background: Vascular endothelial growth factor-A (VEGF-A) and VEGF recepter-2 (VEGFR-2) axis is known to induce Tregs in tumor bearing mice. Ramucirumab (RAM), a monoclonal antibody for VEGFR-2, was recently approved for patients with AGC. However, little is known about the influence of RAM on Tregs in TILs from AGC patients. Methods: Patients with AGC who had been planned to receive chemotherapy containing RAM were prospectively enrolled for this study from January 2016 to August 2016. Paired samples were obtained from primary tumor at pre- and post-RAM therapy to analyze immune profiles of TILs using flow cytometry assay. Results: A total of 17 patients were analyzed. Median age was 68 years old (range, 46-79). All patients received one or more previous chemotherapy. RAM containing regimens included RAM+paclitaxel (n = 13), RAM monotherapy (n = 3) and RAM+irinotecan (n = 2). FOXP3highCD45RA-CD4+ T cells (effector Tregs: eTregs) in CD4+ T cells was significantly decreased after RAM therapy compared with that in baseline (mean, 19.5% vs.13.6%, P = 0.036). In contrast, no significant change of CD8+ T cells was observed (mean, 36.7% vs. 36.0%, P = 0.86). Expression of programmed cell death-1 (PD-1) on CD8+ T cells was tended to be decreased after RAM therapy. Conclusions: eTregs in TILs was suggested to be decreased after RAM-containing therapy which warrants further evaluation in a larger cohorts. This observation might be a rationale to use RAM as an immunomodulator in combination of immune checkpoint inhibitors for AGC.
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Pataki, Emese, Luba Simhaev, Hamutal Engel, Adiel Cohen, Martin Kupiec und Ronit Weisman. „TOR Complex 2- independent mutations in the regulatory PIF pocket of Gad8AKT1/SGK1 define separate branches of the stress response mechanisms in fission yeast“. PLOS Genetics 16, Nr. 11 (02.11.2020): e1009196. http://dx.doi.org/10.1371/journal.pgen.1009196.
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The Target of rapamycin (TOR) protein kinase forms part of TOR complex 1 (TORC1) and TOR complex 2 (TORC2), two multi-subunit protein complexes that regulate growth, proliferation, survival and developmental processes by phosphorylation and activation of AGC-family kinases. In the fission yeast, Schizosaccharomyces pombe, TORC2 and its target, the AGC kinase Gad8 (an orthologue of human AKT or SGK1) are required for viability under stress conditions and for developmental processes in response to starvation cues. In this study, we describe the isolation of gad8 mutant alleles that bypass the requirement for TORC2 and reveal a separation of function of TORC2 and Gad8 under stress conditions. In particular, osmotic and nutritional stress responses appear to form a separate branch from genotoxic stress responses downstream of TORC2-Gad8. Interestingly, TORC2-independent mutations map into the regulatory PIF pocket of Gad8, a highly conserved motif in AGC kinases that regulates substrate binding in PDK1 (phosphoinositide dependent kinase-1) and kinase activity in several AGC kinases. Gad8 activation is thought to require a two-step mechanism, in which phosphorylation by TORC2 allows further phosphorylation and activation by Ksg1 (an orthologue of PDK1). We focus on the Gad8-K263C mutation and demonstrate that it renders the Gad8 kinase activity independent of TORC2 in vitro and independent of the phosphorylation sites of TORC2 in vivo. Molecular dynamics simulations of Gad8-K263C revealed abnormal high flexibility at T387, the phosphorylation site for Ksg1, suggesting a mechanism for the TORC2-independent Gad8 activity. Significantly, the K263 residue is highly conserved in the family of AGC-kinases, which may suggest a general way of keeping their activity in check when acting downstream of TOR complexes.
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Koide, Akiko, Marta Perego und James A. Hoch. „ScoC Regulates Peptide Transport and Sporulation Initiation in Bacillus subtilis“. Journal of Bacteriology 181, Nr. 13 (01.07.1999): 4114–17. http://dx.doi.org/10.1128/jb.181.13.4114-4117.1999.
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ABSTRACT Oligopeptides are transported into Bacillus subtilis by two ABC transport systems, App and Opp. Transcription of the operon encoding the Opp system was found to occur during exponential growth, whereas the app operon was induced at the onset of stationary phase. Transcription of both operons was completely curtailed by overproduction of the ScoC regulator from a multicopy plasmid and was enhanced in strains with the scoC locus deleted. ScoC, a member of the MarR family of transcription regulators, is known from previous studies to be a negative regulator of sporulation and of protease production that acts by binding directly to the promoters of the genes it regulates. Since peptide transport is essential for inactivation of the negative regulation of sporulation by Rap phosphatases, the control of ScoC transcription repression activity plays a crucial role in the initiation of sporulation.
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Hansen, Sonja, Kim Lewis und Marin Vulić. „Role of Global Regulators and Nucleotide Metabolism in Antibiotic Tolerance in Escherichia coli“. Antimicrobial Agents and Chemotherapy 52, Nr. 8 (02.06.2008): 2718–26. http://dx.doi.org/10.1128/aac.00144-08.
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ABSTRACT Bacterial populations produce a small number of persister cells that exhibit multidrug tolerance. Persister cells are largely responsible for the antibiotic recalcitrance of biofilm infections. The mechanism of persister cell formation largely remains unknown due to the challenges in identifying persister genes. We screened an ordered comprehensive library of 3,985 Escherichia coli knockout strains to identify mutants with altered antibiotic tolerance. Stationary-state cultures in 96-well plates were exposed to ofloxacin at a concentration which allows only tolerant persister cells to survive. The persister cell level of each culture was determined. A total of 150 mutants with decreased persistence were identified in the initial screen, and subsequent validation confirmed that neither the growth rate nor the ofloxacin MIC was affected for 10 of them. The genes affected in these strains were dnaJ and dnaK (chaperones), apaH (diadenosine tetraphosphatase), surA (peptidyl-prolyl cis-trans isomerase), fis and hns (global regulators), hnr (response regulator of RpoS), dksA (transcriptional regulator of rRNA transcription), ygfA (5-formyl-tetrahydrofolate cyclo-ligase), and yigB (flavin mononucleotide [FMN] phosphatase). The prominent presence of global regulators among these strains pointed to the likely redundancy of persister cell formation mechanisms: the elimination of a regulator controlling several redundant persister genes would be expected to produce a phenotype. This observation is consistent with previous findings for a possible role of redundant genes such as toxin/antitoxin modules in persister cell formation. ygfA and yigB were of special interest. The mammalian homolog of YgfA (methenyltetrahydrofolate synthetase) catalyzes the conversion of 5-formyl-tetrahydrofolate (THF) into the rapidly degraded 5,10-methenyl-THF, depleting the folate pool. The YigB protein is a phosphatase of FMN which would deplete the pool of this cofactor. Stochastic overexpression of these genes could lead to dormancy and, hence, tolerance by depleting the folate and FMN pools, respectively. Consistent with this scenario, the overexpression of both genes produced increased tolerance to ofloxacin.
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Ibraheem, Author, IbraheemNaimul Hasan und Omveer Singh. „GASA Tuned Optimal Fuzzy Regulator for AGC of an Interconnected Power System“. International Journal of Computer Applications 20, Nr. 8 (30.04.2011): 43–48. http://dx.doi.org/10.5120/2451-2633.
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Ishibashi, Naoki, Kohei Himeno, Yoshimitsu Masuda, Rodney Honrada Perez, Shun Iwatani, Takeshi Zendo, Pongtep Wilaipun, Vichien Leelawatcharamas, Jiro Nakayama und Kenji Sonomoto. „Gene Cluster Responsible for Secretion of and Immunity to Multiple Bacteriocins, the NKR-5-3 Enterocins“. Applied and Environmental Microbiology 80, Nr. 21 (22.08.2014): 6647–55. http://dx.doi.org/10.1128/aem.02312-14.
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ABSTRACTEnterococcus faeciumNKR-5-3, isolated from Thai fermented fish, is characterized by the unique ability to produce five bacteriocins, namely, enterocins NKR-5-3A, -B, -C, -D, and -Z (Ent53A, Ent53B, Ent53C, Ent53D, and Ent53Z). Genetic analysis with a genome library revealed that the bacteriocin structural genes (enkA[ent53A],enkC[ent53C],enkD[ent53D], andenkZ[ent53Z]) that encode these peptides (except for Ent53B) are located in close proximity to each other. This NKR-5-3ACDZ (Ent53ACDZ) enterocin gene cluster (approximately 13 kb long) includes certain bacteriocin biosynthetic genes such as an ABC transporter gene (enkT), two immunity genes (enkIazandenkIc), a response regulator (enkR), and a histidine protein kinase (enkK). Heterologous-expression studies ofenkTand ΔenkTmutant strains showed thatenkTis responsible for the secretion of Ent53A, Ent53C, Ent53D, and Ent53Z, suggesting that EnkT is a wide-range ABC transporter that contributes to the effective production of these bacteriocins. In addition, EnkIaz and EnkIc were found to confer self-immunity to the respective bacteriocins. Furthermore, bacteriocin induction assays performed with the ΔenkRKmutant strain showed that EnkR and EnkK are regulatory proteins responsible for bacteriocin production and that, together with Ent53D, they constitute a three-component regulatory system. Thus, the Ent53ACDZ gene cluster is essential for the biosynthesis and regulation of NKR-5-3 enterocins, and this is, to our knowledge, the first report that demonstrates the secretion of multiple bacteriocins by an ABC transporter.
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Ostash, Bohdan, Yuriy Rebets, Maksym Myronovskyy, Olga Tsypik, Iryna Ostash, Oleksandr Kulachkovskyy, Yuriy Datsyuk, Tatsunosuke Nakamura, Suzanne Walker und Victor Fedorenko. „Identification and characterization of the Streptomyces globisporus 1912 regulatory gene lndYR that affects sporulation and antibiotic production“. Microbiology 157, Nr. 4 (01.04.2011): 1240–49. http://dx.doi.org/10.1099/mic.0.045088-0.
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Here, we report the identification and functional characterization of the Streptomyces globisporus 1912 gene lndYR, which encodes a GntR-like regulator of the YtrA subfamily. Disruption of lndYR arrested sporulation and antibiotic production in S. globisporus. The results of in vivo and in vitro studies revealed that the ABC transporter genes lndW–lndW2 are targets of LndYR repressive action. In Streptomyces coelicolor M145, lndYR overexpression caused a significant increase in the amount of extracellular actinorhodin. We suggest that lndYR controls the transcription of transport system genes in response to an as-yet-unidentified signal. Features that distinguish lndYR-based regulation from other known regulators are discussed.
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Plotz, Guido, Laura A. Lopez-Garcia, Angela Brieger, Stefan Zeuzem und Ricardo M. Biondi. „Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region“. PLOS ONE 15, Nr. 11 (30.11.2020): e0242819. http://dx.doi.org/10.1371/journal.pone.0242819.
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Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated downstream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphorylation sites but has reduced specific activity. Analysis of the human transcriptome corresponding to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
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WIDMER, Jane, Katherine S. FASSIHI, Susannah C. SCHLICHTER, Kate S. WHEELER, Barbara E. CRUTE, Nicole KING, Nancy NUTILE-McMENEMY et al. „Identification of a second human acetyl-CoA carboxylase gene“. Biochemical Journal 316, Nr. 3 (15.06.1996): 915–22. http://dx.doi.org/10.1042/bj3160915.
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Acetyl-CoA carboxylase (ACC), an important enzyme in fatty acid biosynthesis and a regulator of fatty acid oxidation, is present in at least two isoenzymic forms in rat and human tissues. Previous work has established the existence of a 265000 Da enzyme in both the rat and human (RACC265; HACC265) and a higher-molecular-mass species (275000–280000 Da) in the same species (RACC280; HACC275). An HACC265 gene has previously been localized to chromosome 17. In the present study, we report cloning of a partial-length human cDNA sequence which appears to correspond to HACC275 and its rat homologue, RACC280, as judged by mRNA tissue distribution and cell-specific regulation of mRNA/protein expression. The gene encoding this isoenzymic form of ACC has been localized to the long arm of human chromosome 12. Thus, ACC is represented in a multigene family in both rodents and humans. The newly discovered human gene and its rat homologue appear to be under different regulatory control to the HACC265 gene, as judged by tissue-specific expression in vivo and by independent modulation in cultured cells in vitro.
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Shafeeq, Sulman, Tomas G. Kloosterman und Oscar P. Kuipers. „CelR-mediated activation of the cellobiose-utilization gene cluster in Streptococcus pneumoniae“. Microbiology 157, Nr. 10 (01.10.2011): 2854–61. http://dx.doi.org/10.1099/mic.0.051359-0.
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The human pathogen Streptococcus pneumoniae harbours many genes encoding phosphotransferase systems and sugar ABC (ATP-binding cassette) transporters, including systems for the utilization of the β-glucoside sugar cellobiose. In this study, we show that the transcriptional regulator CelR, which has previously been found to be important for pneumococcal virulence, activates the expression of the cellobiose-utilization gene cluster (cel locus) of S. pneumoniae. Expression directed by the two promoters present in the cel locus was increased in the presence of cellobiose as sole carbon source in the medium, while expression decreased in the presence of glucose in the medium. Furthermore, we have predicted a 22 bp putative CelR regulatory site (5′-YTTTCCWTAWCAWTWAGGAAAA-3′) in the promoters of celA and celB, and in silico analysis showed that it is highly conserved in other pathogenic streptococci as well. Promoter truncations of celA and celB, where the half or full CelR regulatory site was deleted, confirmed that the CelR-binding site in PcelA and PcelB is functional. Transcriptome studies with the celR mutant and in silico prediction of the CelR regulatory site in the entire D39 genome sequence show that the cel locus is the only cluster of genes under the direct control of CelR. Therefore, CelR is a regulator dedicated to the cellobiose-dependent transcriptional activation of the cel locus.
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Mei, Zaoxian, Zhaogang Sun, Dapeng Bai, Yuhui Xu, Zhiling Li, Hairong Huang, Chuanyou Li, Shaofa Xu und Li Li. „Discrepancies in Drug Susceptibility Test for Tuberculosis Patients Resulted from the Mixed Infection and the Testing System“. BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/651980.
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To find the potential reasons for the discrepancies in the drug susceptibility test (DST) ofM. tuberculosisisolates, twenty paired isolates with disputed drug susceptibilities to isoniazid (INH) were selected according to the MGIT960 testing and Löwenstein-Jensen (L-J) proportion methods. Their MICs were confirmed again by broth microdilution method and by L-J proportion method. The spoligotyping results showed that, of all the 20 paired strains, 11 paired isolates belonged to the Beijing genotype and 6 paired isolates belonged to SIT1634, and that each of the remaining 3 paired isolates had two genotypes, namely, SIT1 and SIT1634. Those 3 paired isolates with different intrapair spoligotypes were further confirmed as mixed infection by the results that those three pairs of isolates with different 12 locus MIRU intrapair types and one pair carried different base pair at codon 315 (AGC versus AAC). Totally mutations in thekatGgene were identified in 13 paired isolates. No mutations were found in the regulatory sequences and open reading frames (ORF) of theinhAandahpCgenes in any of the tested isolates. Those results showed that the different test systems and the mixed infection with particular genotypes ofM. tuberculosisstrains contributed to the drug susceptibility discrepancies.
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Clifford, P. E., B. S. Pentland und A. D. Baylis. „Effects of growth regulators on reproductive abscission in faba bean (Vicia faba cv. Troy)“. Journal of Agricultural Science 119, Nr. 1 (August 1992): 71–78. http://dx.doi.org/10.1017/s0021859600071550.
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SummaryGrowth regulators were applied to faba bean (field bean) plants in order to study hormonal control of premature reproductive abscission. Combined data from pairs of racemes sited in a consistently yielding region of the main stem indicated effects of growth regulator treatments. Decapitation increased pod numbers, but the inhibitory influence of the upper shoot could not be replaced completely by indol-3yl-acetic acid (IAA) applied to the cut stem stump. Blockage of auxin transport through the stem with the auxin-transport inhibitors 2, 3, 5-triiodobenzoic acid (TIBA) or methyl-2-chloro-9-hydroxyfluorene-9-carboxylate (CF, chlorflurenol) reduced pod numbers above the application point. The latter effects might have been indirect and due to elevated ethylene levels, since pod retention in this shoot region was decreased when sprayed with the ethylene-releasing compound 1-aminocyclopropane carboxylic acid (ACC) and increased when sprayed with ethylene-biosynthesis inhibitors 2-aminoethoxyvinyl glycine (AVG) or l-amino-2-cyclopropylcyclopropane carboxylic acid (cyclopropyl-ACC). Pod numbers were increased when the reproductive structures themselves were sprayed with IAA, gibberellic acid (GA3) or 6-benzylaminopurine (BAP), although a corresponding increase in total seed weight occurred only with the latter growth regulator. Application of BAP or abscisic acid (ABA) as root drenches showed that levels of reproductive abscission were raised or lowered with BAP treatment, depending on its concentration, and lowered with ABA treatment. It is suggested that growth regulator treatments leading to decreased ethylene production in the shoot and/or increased cytokinin and abscisic levels in the xylem sap are those most likely to reduce abscission.
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Krejčík, Zdeněk, Klaus Hollemeyer, Theo H. M. Smits und Alasdair M. Cook. „Isethionate formation from taurine in Chromohalobacter salexigens: purification of sulfoacetaldehyde reductase“. Microbiology 156, Nr. 5 (01.05.2010): 1547–55. http://dx.doi.org/10.1099/mic.0.036699-0.
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Bacterial generation of isethionate (2-hydroxyethanesulfonate) from taurine (2-aminoethanesulfonate) by anaerobic gut bacteria was established in 1980. That phenomenon in pure culture was recognized as a pathway of assimilation of taurine-nitrogen. Based on the latter work, we predicted from genome-sequence data that the marine gammaproteobacterium Chromohalobacter salexigens DSM 3043 would exhibit this trait. Quantitative conversion of taurine to isethionate, identified by mass spectrometry, was confirmed, and the taurine-nitrogen was recovered as cell material. An eight-gene cluster was predicted to encode the inducible vectorial, scalar and regulatory enzymes involved, some of which were known from other taurine pathways. The genes (Csal_0153–Csal_0156) encoding a putative ATP-binding-cassette (ABC) transporter for taurine (TauAB1B2C) were shown to be inducibly transcribed by reverse transcription (RT-) PCR. An inducible taurine : 2-oxoglutarate aminotransferase [EC 2.6.1.55] was found (Csal_0158); the reaction yielded glutamate and sulfoacetaldehyde. The sulfoacetaldehyde was reduced to isethionate by NADPH-dependent sulfoacetaldehyde reductase (IsfD), a member of the short-chain alcohol dehydrogenase superfamily. The 27 kDa protein (SDS-PAGE) was identified by peptide-mass fingerprinting as the gene product of Csal_0161. The putative exporter of isethionate (IsfE) is encoded by Csal_0160; isfE was inducibly transcribed (RT-PCR). The presumed transcriptional regulator, TauR (Csal_0157), may autoregulate its own expression, typical of GntR-type regulators. Similar gene clusters were found in several marine and terrestrial gammaproteobacteria, which, in the gut canal, could be the source of not only mammalian, but also arachnid and cephalopod isethionate.