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Journal articles on the topic 'Pathway redirection'

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Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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1

Zhang, Honglei, Qingjie Jiao, Yapeng Ou, and Xueyong Guo. "Pyrolysis pathway redirection of HNIW by nano-aluminum." Journal of Analytical and Applied Pyrolysis 137 (January 2019): 293–98. http://dx.doi.org/10.1016/j.jaap.2018.12.011.

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2

Manzoor, Robina, Maqbool Ahmed, Naveeda Riaz, Bushra Hafeez Kiani, Ullah Kaleem, Yasmeen Rashid, Ali Nawaz, et al. "Self-Redirection of Metabolic Flux toward Squalene and Ethanol Pathways by Engineered Yeast." Metabolites 10, no. 2 (February 1, 2020): 56. http://dx.doi.org/10.3390/metabo10020056.

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We have previously reported that squalene overproducing yeast self-downregulate the expression of the ethanol pathway (non-essential pathway) to divert the metabolic flux to the squalene pathway. In this study, the effect of co-production of squalene and ethanol on other non-essential pathways (fusel alcohol pathway, FA) of Saccharomyces cerevisiae was evaluated. However, before that, 13 constitutive promoters, like IRA1p, PET9p, RHO1p, CMD1p, ATP16p, USA3p, RER2p, COQ1p, RIM1p, GRS1p, MAK5p, and BRN1p, were engineered using transcription factor bindings sites from strong promoters HHF2p (−300 to −669 bp) and TEF1p (−300 to −579 bp), and employed to co-overexpress squalene and ethanol pathways in S. cerevisiae. The FSE strain overexpressing the key genes of the squalene pathway accumulated 56.20 mg/L squalene, a 16.43-fold higher than wild type strain (WS). The biogenesis of lipid droplets was stimulated by overexpressing DGA1 and produced 106 mg/L squalene in the FSE strain. AFT1p and CTR1p repressible promoters were also characterized and employed to downregulate the expression of ERG1, which also enhanced the production of squalene in FSE strain up to 42.85- (148.67 mg/L) and 73.49-fold (255.11 mg/L) respectively. The FSE strain was further engineered by overexpressing the key genes of the ethanol pathway and produced 40.2 mg/mL ethanol in the FSE1 strain, 3.23-fold higher than the WS strain. The FSE1 strain also self-downregulated the expression of the FA pathway up to 73.9%, perhaps by downregulating the expression of GCN4 by 2.24-fold. We demonstrate the successful tuning of the strength of yeast promoters and highest coproduction of squalene and ethanol in yeast, and present GCN4 as a novel metabolic regulator that can be manipulated to divert the metabolic flux from the non-essential pathway to engineered pathways.
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3

van der Heide, Meis, Adriana N. Leão, Ida J. Van der Klei, and Marten Veenhuis. "Redirection of peroxisomal alcohol oxidase ofHansenula polymorphato the secretory pathway." FEMS Yeast Research 7, no. 7 (October 2007): 1093–102. http://dx.doi.org/10.1111/j.1567-1364.2007.00225.x.

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4

Campbell, Caroline J., and Brian W. Booth. "Abstract 2536: Investigating the mechanisms of HER2+ breast cancer cell redirection." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2536. http://dx.doi.org/10.1158/1538-7445.am2022-2536.

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Abstract Introduction: Breast cancer research has advanced understanding of breast cancer development and progression greatly over the past few decades. Despite progress in research, breast cancer is the second leading cause of cancer death in North America and is the most frequent type of cancer for women. Better treatments and diagnostic tools have increased breast cancer survival rates, but there is still a fundamental lack of understanding in tumor progression. Previous studies show the normal mammary microenvironment can influence non-mammary cells and tumor-derived cancer cells to participate in normal mammary gland development. The tumorigenic cells lose their tumor-forming capabilities and are “redirected” into phenotypically normal, non-tumorigenic cells. The purpose of this study is to obtain knowledge of the mechanisms that play a role in cancer cell redirection and therefore be able manipulate those mechanisms for therapeutic treatment in a clinical setting. Our hypothesis is that microenvironmental elements control whether a tumorigenic cell will enter a redirected state. We have developed and validated an in vitro model to mimic the mammary microenvironment to study cancer cell redirection. We found that when cancer cells that overexpress HER2+ are redirected in our cancer redirection model, phospho-HER2+ is silenced. We use HER2+ phosphorylation as a marker for cancer cell redirection though not a mechanism for cancer cell redirection. Materials and Methods: HER2+ breast cancer cells and normal breast epithelial cells (BECs) were co-cultured in ratios of 1:1 or 1:50. Monocultures of breast cancer cells and BECs were used as controls. Western analysis and immunostaining was used to assess attenuation of HER2+ and phospho-HER2+ receptors and RNAseq was used for pathway analyses. Images were taken using a Leica confocal microscope. For comparison of 2 or more groups, a one-way analysis of variance was performed. A p-value of less than 0.05 was considered significant. Results and Discussion: We found that the redirected cells underwent a phenotype shift in which the redirected cells adopted a normal mammary epithelial phenotype based on gene expression profiles. Furthermore, when HER2+ breast cancer cells were redirected in vitro they lost their tumor-forming potential in vivo. Signal pathway analyses revealed that redirected cancer cells are adopting a normal phenotype compared to breast cancer cells. Conclusions: These results indicate that epithelial cells provide signals that influence HER2+ breast cancer cells to undergo a shift in phenotype. The phenotypic shift in cancer cell redirection includes multiple intracellular signaling pathways that may be the key towards effective cancer treatment. Acknowledgements: This research was supported by South Carolina Idea Networks of Biomedical Research Excellence (SC INBRE). Citation Format: Caroline J. Campbell, Brian W. Booth. Investigating the mechanisms of HER2+ breast cancer cell redirection [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 2536.
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5

Dokland, Terje. "Molecular Piracy: Redirection of Bacteriophage Capsid Assembly by Mobile Genetic Elements." Viruses 11, no. 11 (October 31, 2019): 1003. http://dx.doi.org/10.3390/v11111003.

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Horizontal transfer of mobile genetic elements (MGEs) is a key aspect of the evolution of bacterial pathogens. Transduction by bacteriophages is especially important in this process. Bacteriophages—which assemble a machinery for efficient encapsidation and transfer of genetic material—often transfer MGEs and other chromosomal DNA in a more-or-less nonspecific low-frequency process known as generalized transduction. However, some MGEs have evolved highly specific mechanisms to take advantage of bacteriophages for their own propagation and high-frequency transfer while strongly interfering with phage production—“molecular piracy”. These mechanisms include the ability to sense the presence of a phage entering lytic growth, specific recognition and packaging of MGE genomes into phage capsids, and the redirection of the phage assembly pathway to form capsids with a size more appropriate for the size of the MGE. This review focuses on the process of assembly redirection, which has evolved convergently in many different MGEs from across the bacterial universe. The diverse mechanisms that exist suggest that size redirection is an evolutionarily advantageous strategy for many MGEs.
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6

Akyol, Ismail, Kalbiye Serdaroglu, Yekta Gezginc, K. Sinan Dayisoylu, M. Sait Ekinci, and Emin Ozkose. "Redirection of Pyruvate Pathway of Lactic Acid Bacteria to Improve Cheese Quality." Food Biotechnology 23, no. 3 (August 11, 2009): 200–213. http://dx.doi.org/10.1080/08905430903102562.

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7

Soma, Yuki, Keigo Tsuruno, Masaru Wada, Atsushi Yokota, and Taizo Hanai. "Metabolic flux redirection from a central metabolic pathway toward a synthetic pathway using a metabolic toggle switch." Metabolic Engineering 23 (May 2014): 175–84. http://dx.doi.org/10.1016/j.ymben.2014.02.008.

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8

Lanot, Alexandra, Denise Hodge, Eng-Kiat Lim, Fabián E. Vaistij, and Dianna J. Bowles. "Redirection of flux through the phenylpropanoid pathway by increased glucosylation of soluble intermediates." Planta 228, no. 4 (June 18, 2008): 609–16. http://dx.doi.org/10.1007/s00425-008-0763-8.

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9

Johnson, Martha B., Juxing Chen, Nicholas Murchison, Frank A. Green, and Caroline A. Enns. "Transferrin Receptor 2: Evidence for Ligand-induced Stabilization and Redirection to a Recycling Pathway." Molecular Biology of the Cell 18, no. 3 (March 2007): 743–54. http://dx.doi.org/10.1091/mbc.e06-09-0798.

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Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe2Tf). TfR2 also binds Fe2Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe2Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe2Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe2Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe2Tf, increases the rate of receptor turnover and prevents stabilization by Fe2Tf, indicating a direct role of Fe2Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif.
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10

Komissarov, Andrey A., Peter A. Andreasen, Paul J. Declerck, Yuichi Kamikubo, Aiwu Zhou, and András Gruber. "Redirection of the reaction between activated protein C and a serpin to the substrate pathway." Thrombosis Research 122, no. 3 (January 2008): 397–404. http://dx.doi.org/10.1016/j.thromres.2007.10.012.

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11

Liu, Liming, Yin Li, Guocheng Du, and Jian Chen. "Redirection of the NADH oxidation pathway in Torulopsis glabrata leads to an enhanced pyruvate production." Applied Microbiology and Biotechnology 72, no. 2 (January 11, 2006): 377–85. http://dx.doi.org/10.1007/s00253-005-0284-3.

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12

Roy, Jennie C. L., Antonia Vitalo, Marissa A. Andrew, Eduarda Mota-Silva, Marina Kovalenko, Zoe Burch, Anh M. Nhu, et al. "Somatic CAG expansion in Huntington's disease is dependent on the MLH3 endonuclease domain, which can be excluded via splice redirection." Nucleic Acids Research 49, no. 7 (March 22, 2021): 3907–18. http://dx.doi.org/10.1093/nar/gkab152.

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Abstract Somatic expansion of the CAG repeat tract that causes Huntington's disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.
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13

Her, Nam-Hu, Seong-In Jeong, Kyucheol Cho, Tae-Kyu Ha, Jykhyon Han, Kyung-Phil Ko, Soon-Ki Park, et al. "PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway." Cell Cycle 12, no. 10 (May 15, 2013): 1521–35. http://dx.doi.org/10.4161/cc.24636.

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14

Shah, Mihir V., Sneh S. Badle, and K. B. Ramachandran. "Hyaluronic acid production and molecular weight improvement by redirection of carbon flux towards its biosynthesis pathway." Biochemical Engineering Journal 80 (November 2013): 53–60. http://dx.doi.org/10.1016/j.bej.2013.09.013.

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15

Becker, Judith, Corinna Klopprogge, Oskar Zelder, Elmar Heinzle, and Christoph Wittmann. "Amplified Expression of Fructose 1,6-Bisphosphatase in Corynebacterium glutamicum Increases In Vivo Flux through the Pentose Phosphate Pathway and Lysine Production on Different Carbon Sources." Applied and Environmental Microbiology 71, no. 12 (December 2005): 8587–96. http://dx.doi.org/10.1128/aem.71.12.8587-8596.2005.

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ABSTRACT The overexpression of fructose 1,6-bisphosphatase (FBPase) in Corynebacterium glutamicum leads to significant improvement of lysine production on different sugars. Amplified expression of FBPase via the promoter of the gene encoding elongation factor TU (EFTU) increased the lysine yield in the feedback-deregulated lysine-producing strain C. glutamicum lysCfbr by 40% on glucose and 30% on fructose or sucrose. Additionally formation of the by-products glycerol and dihydroxyacetone was significantly reduced in the PEFTUfbp mutant. As revealed by 13C metabolic flux analysis on glucose the overexpression of FBPase causes a redirection of carbon flux from glycolysis toward the pentose phosphate pathway (PPP) and thus leads to increased NADPH supply. Normalized to an uptake flux of glucose of 100%, the relative flux into the PPP was 56% for C. glutamicum lysCfbr PEFTUfbp and 46% for C. glutamicum lysCfb r . The flux for NADPH supply was 180% in the PEFTUfbp strain and only 146% in the parent strain. Amplification of FBPase increases the production of lysine via an increased supply of NADPH. Comparative studies with another mutant containing the sod promoter upstream of the fbp gene indicate that the expression level of FBPase relates to the extent of the metabolic effects. The overexpression of FBPase seems useful for starch- and molasses-based industrial lysine production with C. glutamicum. The redirection of flux toward the PPP should also be interesting for the production of other NADPH-demanding compounds as well as for products directly stemming from the PPP.
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16

Mir Derikvand, Mohammad, Jimmy Berrio Sierra, Katia Ruel, Brigitte Pollet, Cao-Trung Do, Johanne Thévenin, Dominique Buffard, Lise Jouanin, and Catherine Lapierre. "Redirection of the phenylpropanoid pathway to feruloyl malate in Arabidopsis mutants deficient for cinnamoyl-CoA reductase 1." Planta 227, no. 5 (November 29, 2007): 943–56. http://dx.doi.org/10.1007/s00425-007-0669-x.

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17

Muthukumaran, Kavitha, and Vani Haridasan. "Proliferation of Digital Payments in India: A Pathway to Cashless Economy." ECS Transactions 107, no. 1 (April 24, 2022): 8777–84. http://dx.doi.org/10.1149/10701.8777ecst.

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The goal of this article is to learn about the demographic characteristics that influence the rise of digital payments in India, compare the various means of digital payments, and examine the challenges that consumers experience. The popularity of digital payments has skyrocketed in recent years, especially since demonetization. This article can be taken into consideration, as it focuses on SDG 1 – Poverty. The rise of digital transactions will aid in the creation of a cashless economy, which will help to reduce black money, corruption, and tax evasion while also increasing transparency in all transactions. This study is based on primary data acquired from 189 respondents via a questionnaire survey utilizing a suitable sampling approach. Fear of security threats was discovered to be one of the causes for non-use of digital payments, according to this study. People with a higher level of education were more aware of digital payments, and the majority of people began utilizing them after the demonetization. Transaction failure was the most common issue users encountered, and security risks included fake calls, redirection to another website, etc. It was also established that the majority of users are likely to suggest digital.
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18

Simon-Molas, Helga, Xavier Vallvé-Martínez, Irene Caldera-Quevedo, Pere Fontova, Claudia Arnedo-Pac, Anna Vidal-Alabró, Esther Castaño, et al. "TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Is Upregulated in Lymphocytes Stimulated with Concanavalin A." International Journal of Molecular Sciences 22, no. 14 (July 11, 2021): 7436. http://dx.doi.org/10.3390/ijms22147436.

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The glycolytic modulator TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) is overexpressed in several types of cancer and has a role in metabolic rewiring during tumor development. However, little is known about the role of this enzyme in proliferative tissues under physiological conditions. In the current work, we analysed the role of TIGAR in primary human lymphocytes stimulated with the mitotic agent Concanavalin A (ConA). We found that TIGAR expression was induced in stimulated lymphocytes through the PI3K/AKT pathway, since Akti-1/2 and LY294002 inhibitors prevented the upregulation of TIGAR in response to ConA. In addition, suppression of TIGAR expression by siRNA decreased the levels of the proliferative marker PCNA and increased cellular ROS levels. In this model, TIGAR was found to support the activity of glucose 6-phosphate dehydrogenase (G6PDH), the first enzyme of the pentose phosphate pathway (PPP), since the inhibition of TIGAR reduced G6PDH activity and increased autophagy. In conclusion, we demonstrate here that TIGAR is upregulated in stimulated human lymphocytes through the PI3K/AKT signaling pathway, which contributes to the redirection of the carbon flux to the PPP.
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19

Okano, Kenji, Shogo Yoshida, Tsutomu Tanaka, Chiaki Ogino, Hideki Fukuda, and Akihiko Kondo. "Homo-d-Lactic Acid Fermentation from Arabinose by Redirection of the Phosphoketolase Pathway to the Pentose Phosphate Pathway in l-Lactate Dehydrogenase Gene-Deficient Lactobacillus plantarum." Applied and Environmental Microbiology 75, no. 15 (June 5, 2009): 5175–78. http://dx.doi.org/10.1128/aem.00573-09.

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ABSTRACT Optically pure d-lactic acid fermentation from arabinose was achieved by using the Lactobacillus plantarum NCIMB 8826 strain whose l-lactate dehydrogenase gene was deficient and whose phosphoketolase gene was substituted with a heterologous transketolase gene. After 27 h of fermentation, 38.6 g/liter of d-lactic acid was produced from 50 g/liter of arabinose.
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20

Bröker, Jan Niklas, Boje Müller, Dirk Prüfer, and Christian Schulze Gronover. "Combinatorial Metabolic Engineering in Saccharomyces cerevisiae for the Enhanced Production of the FPP-Derived Sesquiterpene Germacrene." Bioengineering 7, no. 4 (October 24, 2020): 135. http://dx.doi.org/10.3390/bioengineering7040135.

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Farnesyl diphosphate (FPP)-derived isoprenoids represent a diverse group of plant secondary metabolites with great economic potential. To enable their efficient production in the heterologous host Saccharomyces cerevisiae, we refined a metabolic engineering strategy using the CRISPR/Cas9 system with the aim of increasing the availability of FPP for downstream reactions. The strategy included the overexpression of mevalonate pathway (MVA) genes, the redirection of metabolic flux towards desired product formation and the knockout of genes responsible for competitive reactions. Following the optimisation of culture conditions, the availability of the improved FPP biosynthesis for downstream reactions was demonstrated by the expression of a germacrene synthase from dandelion. Subsequently, biosynthesis of significant amounts of germacrene-A was observed in the most productive strain compared to the wild type. Thus, the presented strategy is an excellent tool to increase FPP-derived isoprenoid biosynthesis in yeast.
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21

Kobayashi, Shunsuke, Hideo Kawaguchi, Tomokazu Shirai, Kazuaki Ninomiya, Kenji Takahashi, Akihiko Kondo, and Yota Tsuge. "Automatic Redirection of Carbon Flux between Glycolysis and Pentose Phosphate Pathway Using an Oxygen-Responsive Metabolic Switch in Corynebacterium glutamicum." ACS Synthetic Biology 9, no. 4 (March 23, 2020): 814–26. http://dx.doi.org/10.1021/acssynbio.9b00493.

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22

Pham, Van Dung, Sivachandiran Somasundaram, Seung Hwan Lee, Si Jae Park, and Soon Ho Hong. "Redirection of Metabolic Flux into Novel Gamma-Aminobutyric Acid Production Pathway by Introduction of Synthetic Scaffolds Strategy in Escherichia Coli." Applied Biochemistry and Biotechnology 178, no. 7 (December 14, 2015): 1315–24. http://dx.doi.org/10.1007/s12010-015-1948-9.

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23

Li, Congjun, Robert W. Li, Theodore H. Elsasser, and Stanislaw Kahl. "Global Genetic Profiles of Gene Network Disruption in Bovine Peripheral Blood Mononuclear Cells Induced by Bovine Leukemia Virus (BLV) Infection." Genetics & Epigenetics 2 (January 2009): GEG.S2853. http://dx.doi.org/10.4137/geg.s2853.

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Efficient nutrient assimilation into useful animal-derived products is the ultimate requirement for successful animal production. Infection in young growing animals can decrease energy and nutrient use required for growth rate by redirection of nutrients to support immune defense processes. Bovine leukemia virus (BLV) infection is prevalent in several regions of the world including the U.S. Most BLV infections are characterized by viral latency in the majority of infected cells. Few, if any, definitive studies in cattle have addressed the potential perturbations of gene expression induced in host cells by BLV infection. This study uses integrated global gene expression information and knowledge of the regulatory events in cells to identify transcription regulation networks that control peripheral blood mononuclear cell (PBMC) responses to BLV infection. The aim is to identify the molecular and cellular pathway responses that are functioning during the viral latency stage of BLV infection. The data and regulatory network analysis indicate that CDC25A and transcription factors such as STAT1 and STAT3 may serve as important signaling pathways for the BLV-induced cellular responses. These findings provide vital information for the functional role of genes that participate in PBMC responses to BLV infection and pinpoint these newly characterized genes as potential molecular targets and biomarkers for animal infectious diseases.
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24

Szabo, Susanne J., Anand S. Dighe, Ueli Gubler, and Kenneth M. Murphy. "Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells." Journal of Experimental Medicine 185, no. 5 (March 3, 1997): 817–24. http://dx.doi.org/10.1084/jem.185.5.817.

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The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) β2 subunit expression. To determine the basis for this selective loss, we examined IL-12R β2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R β2 is not expressed by naive resting CD4+ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-γ were found to significantly modify IL-12 receptor β2 expression after T cell activation. IL-4 inhibited IL-12R β2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN-γ treatment of early developing Th2 cells maintained IL-12R β2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-γ production. Thus, IFN-γ may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R β2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.
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Taylor, G. S., T. A. Haigh, N. H. Gudgeon, R. J. Phelps, S. P. Lee, N. M. Steven, and A. B. Rickinson. "Dual Stimulation of Epstein-Barr Virus (EBV)-Specific CD4+- and CD8+-T-Cell Responses by a Chimeric Antigen Construct: Potential Therapeutic Vaccine for EBV-Positive Nasopharyngeal Carcinoma." Journal of Virology 78, no. 2 (January 15, 2004): 768–78. http://dx.doi.org/10.1128/jvi.78.2.768-778.2004.

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ABSTRACT Virus-associated malignancies are potential targets for immunotherapeutic vaccines aiming to stimulate T-cell responses against viral antigens expressed in tumor cells. Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma, a high-incidence tumor in southern China, expresses a limited set of EBV proteins, including the nuclear antigen EBNA1, an abundant source of HLA class II-restricted CD4+ T-cell epitopes, and the latent membrane protein LMP2, a source of subdominant CD8+ T-cell epitopes presented by HLA class I alleles common in the Chinese population. We used appropriately modified gene sequences from a Chinese EBV strain to generate a modified vaccinia virus Ankara recombinant, MVA-EL, expressing the CD4 epitope-rich C-terminal domain of EBNA1 fused to full-length LMP2. The endogenously expressed fusion protein EL is efficiently processed via the HLA class I pathway, and MVA-EL-infected dendritic cells selectively reactivate LMP2-specific CD8+ memory T-cell responses from immune donors in vitro. Surprisingly, endogenously expressed EL also directly accesses the HLA class II presentation pathway and, unlike endogenously expressed EBNA1 itself, efficiently reactivates CD4+ memory T-cell responses in vitro. This unscheduled access to the HLA class II pathway is coincident with EL-mediated redirection of the EBNA1 domain from its native nuclear location to dense cytoplasmic patches. Given its immunogenicity to both CD4+ and CD8+ T cells, MVA-EL has potential as a therapeutic vaccine in the context of nasopharyngeal carcinoma.
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Rossi, Ernesto, Michela Croce, Francesco Reggiani, Giovanni Schinzari, Marianna Ambrosio, Rosaria Gangemi, Giampaolo Tortora, Ulrich Pfeffer, and Adriana Amaro. "Uveal Melanoma Metastasis." Cancers 13, no. 22 (November 13, 2021): 5684. http://dx.doi.org/10.3390/cancers13225684.

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Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovative therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of mitogen activated kinase kinase inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM), show only limited effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T-cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers, and YAP/TAZ specific drugs give new hope to repeating the success of innovative therapy obtained for CM.
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27

Nakano, Tetsuo, Koichiro Miyake, Masato Ikeda, Toru Mizukami, and Ryoichi Katsumata. "Mechanism of the Incidental Production of a Melanin-Like Pigment during 6-Demethylchlortetracycline Production inStreptomyces aureofaciens." Applied and Environmental Microbiology 66, no. 4 (April 1, 2000): 1400–1404. http://dx.doi.org/10.1128/aem.66.4.1400-1404.2000.

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ABSTRACT The secondary metabolite 6-demethylchlortetracycline (6-DCT), which is produced by Streptomyces aureofaciens, is used as a precursor of semisynthetic tetracyclines. Strains that produce 6-DCT also produce a melanin-like pigment (MP). The correlation between MP production and 6-DCT production was investigated by using S. aureofaciens NRRL 3203. Production of both MP and 6-DCT was repressed by phosphate or ammonium ions, suggesting that syntheses of these compounds are controlled by the same regulators. Ten chlortetracycline-producing recombinants were derived from 6-DCT-producing mutant NRRL 3203 by gene replacement. All of the recombinants produced chlortetracycline but not MP, indicating that MP production is the results of a defect in the 6-methylation step and suggesting that the polyketide nonaketideamide is a common intermediate leading to MP as well as 6-DCT. To further examine the possibility that MP might be synthesized via the 6-DCT-biosynthetic pathway, mutants defective in 6-DCT biosynthesis were derived from a 6-DCT producer. Some of these mutants were able to produce MP, while others, including mutants with mutations in the gene encoding anhydrotetracycline oxygenase, an enzyme catalyzing the penultimate step in the pathway, produced neither 6-DCT nor MP. Production of 6-DCT and production of MP were restored simultaneously by integrative transformation with the corresponding 6-DCT-biosynthetic genes, indicating that some of 6-DCT-biosynthetic enzymes are indispensable for MP production. These findings suggest that a defect in the 6-methylation step results in redirection of carbon flux from a certain intermediate in the 6-DCT-biosynthetic pathway to a shunt pathway and results in MP production.
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Pudlik, Agata M., and Juke S. Lolkema. "Rerouting Citrate Metabolism in Lactococcus lactis to Citrate-Driven Transamination." Applied and Environmental Microbiology 78, no. 18 (July 13, 2012): 6665–73. http://dx.doi.org/10.1128/aem.01811-12.

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ABSTRACTOxaloacetate is an intermediate of the citrate fermentation pathway that accumulates in the cytoplasm ofLactococcus lactisILCitM(pFL3) at a high concentration due to the inactivation of oxaloacetate decarboxylase. An excess of toxic oxaloacetate is excreted into the medium in exchange for citrate by the citrate transporter CitP (A. M. Pudlik and J. S. Lolkema, J. Bacteriol. 193:4049–4056, 2011). In this study, transamination of amino acids with oxaloacetate as the keto donor is described as an additional mechanism to relieve toxic stress. Redirection of the citrate metabolic pathway into the transamination route in the presence of the branched-chain amino acids Ile, Leu, and Val; the aromatic amino acids Phe, Trp, and Tyr; and Met resulted in the formation of aspartate and the corresponding α-keto acids. Cells grown in the presence of citrate showed 3.5 to 7 times higher transaminase activity in the cytoplasm than cells grown in the absence of citrate. The study demonstrates that transaminases ofL. lactisaccept oxaloacetate as a keto donor. A significant fraction of 2-keto-4-methylthiobutyrate formed from methionine by citrate-driven transaminationin vivowas further metabolized, yielding the cheese aroma compounds 2-hydroxy-4-methylthiobutyrate and methyl-3-methylthiopropionate. Reducing equivalents required for the former compound were produced in the citrate fermentation pathway as NADH. Similarly, phenylpyruvate, the transamination product of phenylalanine, was reduced to phenyllactate, while the dehydrogenase activity was not observed for the branched-chain keto acids. Both α-keto acids and α-hydroxy acids are known substrates of CitP and may be excreted from the cell in exchange for citrate or oxaloacetate.
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Pan, Yuan, Xiao Zhao, Xiao-li Wu, Yu Wang, Jun Tan, and Da-xia Chen. "Transcriptomic and metabolomic analyses provide insights into the biosynthesis of chlorogenic acids in Lonicera macranthoides Hand.-Mazz." PLOS ONE 16, no. 5 (May 26, 2021): e0251390. http://dx.doi.org/10.1371/journal.pone.0251390.

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Lonicera macranthoides Hand.-Mazz (L. macranthoides) is a medicinal herb that is widely distributed in South China. The developmental stage and corolla dehiscence of the flower are the important factors affecting the quality of medicinal ingredients. However, neither the regulatory mechanism controlling chlorogenic acids biosynthesis in L. macranthoides nor the molecular basis of effect of corolla dehiscence on the quality of medicinal materials is fully understood. In this study, metabolomics and transcriptomics were used to analyze the metabolic and transcriptional differences of two different cultivars closed bud type (Bt), and flowering type (Ft), as well as the effect of jasmonic acid methyl ester (MeJA) on chlorogenic acids (CGAs) biosynthesis. In total, large number of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were filtered among three lines of samples. Gene metabolite correlation analyses revealed a ‘core set’ of 30 genes and 54 genes that were strongly correlated with CGAs biosynthesis and regulating the flowering, respectively. Quantitative real-time polymerase chain reaction results proved the alterations in the expression levels of genes encoding the pathways involved in CGAs biosynthesis. The ion abundances of CGAs were most significantly increased, while some of the CGAs derived and Caffeoyl-CoA-derived substances showed the most largely reduced abundances in the closed bud type (Bt) compared to the flowering type (Ft). MeJA may leads to the activation of downstream genes in CGAs biosynthesis pathway. Overall, there were significant differences in the transcriptional and metabolic levels of CGAs biosynthesis pathway in flower buds of different flowering cultivars. The redirection of metabolic flux may contribute to increased accumulation of CGAs. However, whether MeJA and flowering have direct effects on the accumulation of CGAs needs further studied. These researches effectively expanded the functional genomic library and provide new insights into CGAs biosynthesis in L. macranthoides.
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Czechowski, Tomasz, Tony R. Larson, Theresa M. Catania, David Harvey, Geoffrey D. Brown, and Ian A. Graham. "Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism." Proceedings of the National Academy of Sciences 113, no. 52 (December 7, 2016): 15150–55. http://dx.doi.org/10.1073/pnas.1611567113.

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Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in the most effective treatment for malaria currently available. We identified a mutation that disrupts the amorpha-4,11-diene C-12 oxidase (CYP71AV1) enzyme, responsible for a series of oxidation reactions in the artemisinin biosynthetic pathway. Detailed metabolic studies of cyp71av1-1 revealed that the consequence of blocking the artemisinin biosynthetic pathway is the redirection of sesquiterpene metabolism to a sesquiterpene epoxide, which we designate arteannuin X. This sesquiterpene approaches half the concentration observed for artemisinin in wild-type plants, demonstrating high-flux plasticity in A. annua glandular trichomes and their potential as factories for the production of novel alternate sesquiterpenes at commercially viable levels. Detailed metabolite profiling of leaf maturation time-series and precursor-feeding experiments revealed that nonenzymatic conversion steps are central to both artemisinin and arteannuin X biosynthesis. In particular, feeding studies using 13C-labeled dihydroartemisinic acid (DHAA) provided strong evidence that the final steps in the synthesis of artemisinin are nonenzymatic in vivo. Our findings also suggest that the specialized subapical cavity of glandular secretory trichomes functions as a location for both the chemical conversion and the storage of phytotoxic compounds, including artemisinin. We conclude that metabolic engineering to produce high yields of novel secondary compounds such as sesquiterpenes is feasible in complex glandular trichomes. Such systems offer advantages over single-cell microbial hosts for production of toxic natural products.
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Meisig, Johannes, Nadine Dreser, Marion Kapitza, Margit Henry, Tamara Rotshteyn, Jörg Rahnenführer, Jan G. Hengstler, et al. "Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation." Nucleic Acids Research 48, no. 22 (November 27, 2020): 12577–92. http://dx.doi.org/10.1093/nar/gkaa1089.

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Abstract Thousands of transcriptome data sets are available, but approaches for their use in dynamic cell response modelling are few, especially for processes affected simultaneously by two orthogonal influencing variables. We approached this problem for neuroepithelial development of human pluripotent stem cells (differentiation variable), in the presence or absence of valproic acid (signaling variable). Using few basic assumptions (sequential differentiation states of cells; discrete on/off states for individual genes in these states), and time-resolved transcriptome data, a comprehensive model of spontaneous and perturbed gene expression dynamics was developed. The model made reliable predictions (average correlation of 0.85 between predicted and subsequently tested expression values). Even regulations predicted to be non-monotonic were successfully validated by PCR in new sets of experiments. Transient patterns of gene regulation were identified from model predictions. They pointed towards activation of Wnt signaling as a candidate pathway leading to a redirection of differentiation away from neuroepithelial cells towards neural crest. Intervention experiments, using a Wnt/beta-catenin antagonist, led to a phenotypic rescue of this disturbed differentiation. Thus, our broadly applicable model allows the analysis of transcriptome changes in complex time/perturbation matrices.
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32

Sadykov, Marat R., Michael E. Olson, Steven Halouska, Yefei Zhu, Paul D. Fey, Robert Powers, and Greg A. Somerville. "Tricarboxylic Acid Cycle-Dependent Regulation of Staphylococcus epidermidis Polysaccharide Intercellular Adhesin Synthesis." Journal of Bacteriology 190, no. 23 (September 26, 2008): 7621–32. http://dx.doi.org/10.1128/jb.00806-08.

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ABSTRACT Staphylococcus epidermidis is a major nosocomial pathogen primarily infecting immunocompromised individuals or those with implanted biomaterials (e.g., catheters). Biomaterial-associated infections often involve the formation of a biofilm on the surface of the medical device. In S. epidermidis, polysaccharide intercellular adhesin (PIA) is an important mediator of biofilm formation and pathogenesis. Synthesis of PIA is regulated by at least three DNA binding proteins (IcaR, SarA, and σB) and several environmental and nutritional conditions. Previously, we observed the environmental conditions that increased PIA synthesis decreased tricarboxylic acid (TCA) cycle activity. In this study, S. epidermidis TCA cycle mutants were constructed, and the function of central metabolism in PIA biosynthesis was examined. TCA cycle inactivation altered the metabolic status of S. epidermidis, resulting in a massive derepression of PIA biosynthetic genes and a redirection of carbon from growth into PIA biosynthesis. These data demonstrate that the bacterial metabolic status is a critical regulatory determinant of PIA synthesis. In addition, these data lead us to propose that the TCA cycle acts as a signal transduction pathway to translate external environmental cues into intracellular metabolic signals that modulate the activity of transcriptional regulators.
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33

Schumacher-Klinger, Adi, Joseph Fanous, Shira Merzbach, Michael Weinmüller, Florian Reichart, Andreas F. B. Räder, Agata Gitlin-Domagalska, Chaim Gilon, Horst Kessler, and Amnon Hoffman. "Enhancing Oral Bioavailability of Cyclic RGD Hexa-peptides by the Lipophilic Prodrug Charge Masking Approach: Redirection of Peptide Intestinal Permeability from a Paracellular to Transcellular Pathway." Molecular Pharmaceutics 15, no. 8 (July 5, 2018): 3468–77. http://dx.doi.org/10.1021/acs.molpharmaceut.8b00466.

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34

Okano, Kenji, Shogo Yoshida, Ryosuke Yamada, Tsutomu Tanaka, Chiaki Ogino, Hideki Fukuda, and Akihiko Kondo. "Improved Production of Homo-d-Lactic Acid via Xylose Fermentation by Introduction of Xylose Assimilation Genes and Redirection of the Phosphoketolase Pathway to the Pentose Phosphate Pathway in l-Lactate Dehydrogenase Gene-Deficient Lactobacillus plantarum." Applied and Environmental Microbiology 75, no. 24 (October 9, 2009): 7858–61. http://dx.doi.org/10.1128/aem.01692-09.

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ABSTRACT The production of optically pure d-lactic acid via xylose fermentation was achieved by using a Lactobacillus plantarum NCIMB 8826 strain whose l-lactate dehydrogenase gene was deficient and whose phosphoketolase genes were replaced with a heterologous transketolase gene. After 60 h of fermentation, 41.2 g/liter of d-lactic acid was produced from 50 g/liter of xylose.
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Peralta, Eigen, Emily Carron, Hui-Yi Chu, Lorraine Loter, Natalie Navarrete, Arvin Tam, Amit Mehta, et al. "138 Synthetic re-direction of TGFβ receptors as a novel strategy to enhance the anti-tumor activity of CAR-T cells in solid tumors." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A147. http://dx.doi.org/10.1136/jitc-2021-sitc2021.138.

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BackgroundTransforming growth factor beta (TGFβ) is an immuno-suppressive cytokine present in the tumor microenvironment (TME) that creates considerable challenges for the treatment of solid tumors. Small molecule inhibitors targeting TGFβ exist, but the pleiotropic nature of TGFβ signaling suggests that a more targeted approach is preferential, especially in the context of cellular therapy. We hypothesized that primary T cells and iPSC-derived chimeric antigen receptor-T cells (CAR-iT cells) would benefit not only from blockade of TGFβ signaling, but also from re-direction of the signaling event toward specific cytokine pathways that activate cell function. Here we discuss novel synthetic TGFβ redirector constructs that overcome TME limitations and enhance CAR-iT cell function for improved efficacy in treating solid tumors.MethodsTo identify activation pathways for redirection of TGFβ signaling, we screened a panel of cytokines for their effect on the anti-tumor activity of CAR-iT cells. We then developed synthetic redirector receptors where a TGFBR2 ectodomain was fused to the top selected cytokine receptor endodomains. Redirection of TGFβ signaling was confirmed by phospho-flow of key signaling proteins. Anti-tumor activity of CAR-iT cells expressing these synthetic redirector constructs was tested in serial restimulation assays in the absence of cytokine support and in the presence of recombinant TGFβ (rTGFβ).ResultsA dose-dependent decrease in CAR-iT cell cytolytic capacity in the presence of rTGFβ was observed, with the activity of CAR-iT cells rescued in the presence of unique cytokines. We designed and tested synthetic TGFβ redirector constructs and demonstrated a rTGFβ-dependent increase in pSTAT5 positive cells (2.8-fold over control). The serial stimulation assay was then used to test CAR-iT cells engineered with synthetic TGFβ redirector receptors. After three rounds of restimulation, an increase in tumor cell numbers for non-engineered and dominant negative TGFBR2 CAR-iT cell controls was observed (41-fold and 32-fold increase over base input, respectively). In contrast, the synthetic TGFβ redirector receptor improved the ability of CAR-iT cells to control tumor cell growth with remarkable efficiency, limiting tumor growth to only 1.5-fold over three rounds of restimulation.ConclusionsThese studies demonstrate that a novel synthetic construct comprised of fusion of cytokine endodomains to a TGFBR2 ectodomain can be deployed to hijack the immuno-suppressive signal of TGFβ often found in the TME and activate CAR-iT cells for enhanced anti-tumor activity in solid tumors. Additional studies are underway to assess the temporal expression and activity of these synthetic redirector receptors in various preclinical models which will be further discussed.
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Pan, Yuan, Xiao Zhao, Yu Wang, Jun Tan, and Da-xia Chen. "Metabolomics integrated with transcriptomics reveals the distribution of iridoid and crocin metabolic flux in Gardenia jasminoides Ellis." PLOS ONE 16, no. 9 (September 10, 2021): e0256802. http://dx.doi.org/10.1371/journal.pone.0256802.

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Gardenia jasminoides Ellis (G. jasminoides) fruits are used as a resource for obtaining natural colorants and in traditional Chinese herbal medicine. However, G. jasminoides presents a relatively long flowering period and different ripening periods, so there are significant differences in the accumulation of metabolites in fruits of different colors. In addition, the complete metabolic pathways of iridoidsand crocins, which are used as medicinal composition of G. jasminoides, are poorly understood at present. In this research, we comprehensively compared the transcriptome and metabolites profiles of the developmental stages and locations of iridoid and crocin biosynthesis. A large number of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were detected in four groups of samples, and clear variation in the pattern of metabolite abundance and gene expression were observed among different fruit colors and parts. Geniposide and gardenoside mainly accumulated in the sarcocarp of green fruit (GFS) and the sarcocarp of red fruit (FS), respectively. Crocin mainly accumulated in the peel and sarcocarp of red fruits. In the iridoid pathway, we hypothesized that there was a transport mechanism from the sarcocarp to the peel of G. jasminoides because of the inconsistent expression of G8O, 10-HGO and IS associated with differences in fruit ripening. UGTs play an important role in the biosynthesis of the active components of G. jasminoides. Combined transcriptome and metabonomics analysis showed a negative correlation between the biosynthesis of geniposide and crocin. The redirection of the metabolic flux and the regulation of key enzymes may be the main reasons for the changes in the biosynthesis of iridoid and crocin in G. jasminoides fruit. Our study expended valuable information for functional genomic library and provided new insights for metabolic engineering of secondary metabolite in G. Jasminoides.
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Lindner, Steffen N., Dimitar P. Petrov, Christian T. Hagmann, Alexander Henrich, Reinhard Krämer, Bernhard J. Eikmanns, Volker F. Wendisch, and Gerd M. Seibold. "Phosphotransferase System-Mediated Glucose Uptake Is Repressed in Phosphoglucoisomerase-Deficient Corynebacterium glutamicum Strains." Applied and Environmental Microbiology 79, no. 8 (February 8, 2013): 2588–95. http://dx.doi.org/10.1128/aem.03231-12.

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ABSTRACTCorynebacterium glutamicumis particularly known for its industrial application in the production of amino acids. Amino acid overproduction comes along with a high NADPH demand, which is covered mainly by the oxidative part of the pentose phosphate pathway (PPP). In previous studies, the complete redirection of the carbon flux toward the PPP by chromosomal inactivation of thepgigene, encoding the phosphoglucoisomerase, has been applied for the improvement ofC. glutamicumamino acid production strains, but this was accompanied by severe negative effects on the growth characteristics. To investigate these effects in a genetically defined background, we deleted thepgigene in the type strainC. glutamicumATCC 13032. The resulting strain,C. glutamicumΔpgi, lacked detectable phosphoglucoisomerase activity and grew poorly with glucose as the sole substrate. Apart from the already reported inhibition of the PPP by NADPH accumulation, we detected a drastic reduction of the phosphotransferase system (PTS)-mediated glucose uptake inC. glutamicumΔpgi. Furthermore, Northern blot analyses revealed that expression ofptsG, which encodes the glucose-specific EII permease of the PTS, was abolished in this mutant. Applying our findings, we optimizedl-lysine production in the model strainC. glutamicumDM1729 by deletion ofpgiand overexpression of plasmid-encodedptsG.l-Lysine yields and productivity withC. glutamicumΔpgi(pBB1-ptsG) were significantly higher than those withC. glutamicumΔpgi(pBB1). These results show thatptsGoverexpression is required to overcome the repressed activity of PTS-mediated glucose uptake inpgi-deficientC. glutamicumstrains, thus enabling efficient as well as fastl-lysine production.
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Choi and Back. "Suppression of Melatonin 2-Hydroxylase Increases Melatonin Production Leading to the Enhanced Abiotic Stress Tolerance against Cadmium, Senescence, Salt, and Tunicamycin in Rice Plants." Biomolecules 9, no. 10 (October 8, 2019): 589. http://dx.doi.org/10.3390/biom9100589.

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Melatonin 2-hydroxylase (M2H) catalyzes the conversion of melatonin into 2hydroxymelatonin (2OHM), which is present in plants at a higher concentration than melatonin. Although M2H has been cloned, the in vivo function of its product is unknown. Here, we generated stable T2 homozygous transgenic rice plants in which expression of endogenous M2H was suppressed (RNAi lines). However, we failed to generate M2H overexpression transgenic rice due to failure of somatic embryogenesis. The M2H transcript level showed a diurnal rhythm with a peak at night concomitantly with the peak concentration of 2OHM. RNAi rice showed a reduced M2H mRNA level and 2OHM and melatonin concentrations. The unexpected decrease in the melatonin concentration was caused by redirection of melatonin into cyclic 3hydroxymelatonin via a detour catabolic pathway. Thus, the decrease in the melatonin concentration in M2H RNAi rice led to slowed seedling growth and delayed germination. By contrast, the transient increase in the melatonin concentration was of greater magnitude in the M2H RNAi than the wild-type rice upon cadmium treatment due to possible suppression of melatonin degradation. Due to its higher concentration of melatonin, the M2H RNAi rice displayed tolerance to senescence, salt, and tunicamycin stresses. Therefore, the increase in the melatonin concentration caused by suppression of melatonin degradation or by overexpression of melatonin biosynthetic genes enhances stress tolerance in rice.
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39

Santiesteban, Gretel Maria Torres, Rajan Bhandari, Heetaek Yang, Paul Spezza, Tamer Basel Shabaneh, Karen Liby, Mary Jo Turk, and Patricia A. Pioli. "Reprograming of Tumor-Associated Macrophages in Human BrafV600EMutant Melanoma." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.27. http://dx.doi.org/10.4049/jimmunol.204.supp.242.27.

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Abstract Melanoma tumors are highly immunogenic, making them an attractive target for immunotherapy. However, many patients do not mount robust clinical responses to targeted therapies, which is attributable, at least in part, to suppression of immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Using a human in vitro culture system, we have shown that the synthetic triterpenoid CDDO-Me enhances immune activation by reprogramming macrophages from immuno-suppressive to immuno-stimulatory. CDDO-Me significantly reduced CCL2, VEGF and IL-6 secretion by macrophages and inhibited surface expression of CD163, a marker associated with poor clinical outcomes. Furthermore, CDDO-Me mediated both contact-dependent and independent effects on macrophage activation in tri-cultures of macrophages with activated autologous T cells and BRAFV600E mutant melanoma cells. Signaling pathway activation was interrogated to identify the potential mechanism by which CDDO-Me attenuates the pro-tumorigenic macrophage activation profile. Our results demonstrated that CDDO-Me inhibited STAT3 phosphorylation, which is a known regulator of TAM activation. Given these results, we hypothesize that, in addition to mediating direct anti-tumorigenic effects, CDDO-Me may also enhance the efficacy of additional immunotherapies, including BRAF inhibition. Collectively, our studies suggest that the redirection of immuno-suppressive myeloid cell activation may provide both a direct means of inhibiting melanoma growth and may enhance the efficacy of additional targeted immunotherapies through relief of immune suppression in the TME.
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40

Krömer, Jens Olaf, Oliver Sorgenfrei, Kai Klopprogge, Elmar Heinzle, and Christoph Wittmann. "In-Depth Profiling of Lysine-Producing Corynebacterium glutamicum by Combined Analysis of the Transcriptome, Metabolome, and Fluxome." Journal of Bacteriology 186, no. 6 (March 15, 2004): 1769–84. http://dx.doi.org/10.1128/jb.186.6.1769-1784.2004.

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ABSTRACT An in-depth analysis of the intracellular metabolite concentrations, metabolic fluxes, and gene expression (metabolome, fluxome, and transcriptome, respectively) of lysine-producing Corynebacterium glutamicum ATCC 13287 was performed at different stages of batch culture and revealed distinct phases of growth and lysine production. For this purpose, 13C flux analysis with gas chromatography-mass spectrometry-labeling measurement of free intracellular amino acids, metabolite balancing, and isotopomer modeling were combined with expression profiling via DNA microarrays and with intracellular metabolite quantification. The phase shift from growth to lysine production was accompanied by a decrease in glucose uptake flux, the redirection of flux from the tricarboxylic acid (TCA) cycle towards anaplerotic carboxylation and lysine biosynthesis, transient dynamics of intracellular metabolite pools, such as an increase of lysine up to 40 mM prior to its excretion, and complex changes in the expression of genes for central metabolism. The integrated approach was valuable for the identification of correlations between gene expression and in vivo activity for numerous enzymes. The glucose uptake flux closely corresponded to the expression of glucose phosphotransferase genes. A correlation between flux and expression was also observed for glucose-6-phosphate dehydrogenase, transaldolase, and transketolase and for most TCA cycle genes. In contrast, cytoplasmic malate dehydrogenase expression increased despite a reduction of the TCA cycle flux, probably related to its contribution to NADH regeneration under conditions of reduced growth. Most genes for lysine biosynthesis showed a constant expression level, despite a marked change of the metabolic flux, indicating that they are strongly regulated at the metabolic level. Glyoxylate cycle genes were continuously expressed, but the pathway exhibited in vivo activity only in the later stage. The most pronounced changes in gene expression during cultivation were found for enzymes at entry points into glycolysis, the pentose phosphate pathway, the TCA cycle, and lysine biosynthesis, indicating that these might be of special importance for transcriptional control in C. glutamicum.
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41

Damen, Merel P. M., Trang H. Phan, Roy Ummels, Alba Rubio-Canalejas, Wilbert Bitter, and Edith N. G. Houben. "Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system." Journal of Biological Chemistry 295, no. 18 (March 17, 2020): 5960–69. http://dx.doi.org/10.1074/jbc.ra119.011682.

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Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1.
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42

Krauss, Oliver, Ruth Hollinshead, Michael Hollinshead, and Geoffrey L. Smith. "An investigation of incorporation of cellular antigens into vaccinia virus particles." Journal of General Virology 83, no. 10 (October 1, 2002): 2347–59. http://dx.doi.org/10.1099/0022-1317-83-10-2347.

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Vaccinia virus (VV) infection produces several types of virus particle called intracellular mature virus (IMV), intracellular enveloped virus (IEV), cell-associated enveloped virus (CEV) and extracellular enveloped virus (EEV). Some cellular antigens are associated with EEV and these vary with the cell type used to grow the virus. To investigate if specific cell antigens are associated with VV particles, and to address the origin of membranes used to envelope IMV and IEV/CEV/EEV, we have studied whether cell antigens and foreign antigens expressed by recombinant VVs are incorporated into VV particles. Membrane proteins that are incorporated into the endoplasmic reticulum (ER), intermediate compartment (IC), cis/medial-Golgi, trans-Golgi network (TGN) or plasma membrane were not detected in purified IMV particles. In contrast, proteins present in the TGN or membrane compartments further downstream in the exocytic pathway co-purify with EEV particles when analysed by immunoblotting. Immunoelectron microscopy found only low levels of these proteins in IEV, CEV/EEV. The incorporation of foreign antigens into VV particles was not affected by loss of individual IEV or EEV-specific proteins or by redirection of B5R to the ER. These data suggest that (i) host cell antigens are excluded from the lipid envelope surrounding the IMV particle and (ii) membranes of the ER, IC and cis/medial-Golgi are not used to wrap IMV particles to form IEV. Lastly, the VV haemagglutinin was absent from one-third of IEV and CEV/EEV particles, whereas other EEV antigens were present in all these virions.
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43

Erland, Lauren A. E., Ryland T. Giebelhaus, Jerrin M. R. Victor, Susan J. Murch, and Praveen K. Saxena. "The Morphoregulatory Role of Thidiazuron: Metabolomics-Guided Hypothesis Generation for Mechanisms of Activity." Biomolecules 10, no. 9 (August 28, 2020): 1253. http://dx.doi.org/10.3390/biom10091253.

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Thidiazuron (TDZ) is a diphenylurea synthetic herbicide and plant growth regulator used to defoliate cotton crops and to induce regeneration of recalcitrant species in plant tissue culture. In vitro cultures of African violet thin petiole sections are an ideal model system for studies of TDZ-induced morphogenesis. TDZ induces de novo shoot organogenesis at low concentrations and somatic embryogenesis at higher concentrations of exposure. We used an untargeted metabolomics approach to identify metabolites in control and TDZ-treated tissues. Statistical analysis including metabolite clustering, pattern and pathway tools, logical algorithms, synthetic biotransformations and hormonomics identified TDZ-induced changes in metabolism. A total of 18,602 putative metabolites with extracted masses and predicted formulae were identified with 1412 features that were found only in TDZ-treated tissues and 312 that increased in response to TDZ. The monomer of TDZ was not detected intact in the tissues but putative oligomers were found in the database and we hypothesize that these may form by a Diels–Alder reaction. Accumulation oligomers in the tissue may act as a reservoir, slowly releasing the active TDZ monomer over time. Cleavage of the amide bridge released TDZ-metabolites into the tissues including organic nitrogen and sulfur containing compounds. Metabolomics data analysis generated six novel hypotheses that can be summarized as an overall increase in uptake of sugars from the culture media, increase in primary metabolism, redirection of terpene metabolism and mediation of stress metabolism via indoleamine and phenylpropanoid metabolism. Further research into the specific mechanisms hypothesized is likely to unravel the mode of action of TDZ and to provide new insights into the control of plant morphogenesis.
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Falabella, Patrizia, Paola Varricchio, Bertille Provost, Eric Espagne, Roberto Ferrarese, Annalisa Grimaldi, Magda de Eguileor, et al. "Characterization of the IκB-like gene family in polydnaviruses associated with wasps belonging to different Braconid subfamilies." Journal of General Virology 88, no. 1 (January 1, 2007): 92–104. http://dx.doi.org/10.1099/vir.0.82306-0.

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Polydnaviruses (PDVs) are obligate symbionts of hymenopteran parasitoids of lepidopteran larvae that induce host immunosuppression and physiological redirection. PDVs include bracoviruses (BVs) and ichnoviruses (IVs), which are associated with braconid and ichneumonid wasps, respectively. In this study, the gene family encoding IκB-like proteins in the BVs associated with Cotesia congregata (CcBV) and Toxoneuron nigriceps (TnBV) was analysed. PDV-encoded IκB-like proteins (ANK) are similar to insect and mammalian IκB, an inhibitor of the transcription factor nuclear factor κB (NF-κB), but display shorter ankyrin domains and lack the regulatory domains for signal-mediated degradation and turnover. Phylogenetic analysis of ANK proteins indicates that those of IVs and BVs are closely related, even though these two taxa are believed to lack a common ancestor. Starting from a few hours after parasitization, the transcripts of BV ank genes were detected, at different levels, in several host tissues. The structure of the predicted proteins suggests that they may stably bind NF-κB/Rel transcription factors of the tumour necrosis factor (TNF)/Toll immune pathway. Accordingly, after bacterial challenge of Heliothis virescens host larvae parasitized by T. nigriceps, NF-κB immunoreactive material failed to enter the nucleus of host haemocytes and fat body cells. Moreover, transfection experiments in human HeLa cells demonstrated that a TnBV ank1 gene product reduced the efficiency of the TNF-α-induced expression of a reporter gene under NF-κB transcriptional control. Altogether, these results suggest strongly that TnBV ANK proteins cause retention of NF-κB/Rel factors in the cytoplasm and may thus contribute to suppression of the immune response in parasitized host larvae.
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45

Tanaka, Yoshikazu, and Filippa Brugliera. "Flower colour and cytochromes P450." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1612 (February 19, 2013): 20120432. http://dx.doi.org/10.1098/rstb.2012.0432.

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Cytochromes P450 play important roles in biosynthesis of flavonoids and their coloured class of compounds, anthocyanins, both of which are major floral pigments. The number of hydroxyl groups on the B-ring of anthocyanidins (the chromophores and precursors of anthocyanins) impact the anthocyanin colour, the more the bluer. The hydroxylation pattern is determined by two cytochromes P450, flavonoid 3′-hydroxylase (F3′H) and flavonoid 3′,5′-hydroxylase (F3′5′H) and thus they play a crucial role in the determination of flower colour. F3′H and F3′5′H mostly belong to CYP75B and CYP75A, respectively, except for the F3′5′Hs in Compositae that were derived from gene duplication of CYP75B and neofunctionalization. Roses and carnations lack blue/violet flower colours owing to the deficiency of F3′5′H and therefore lack the B-ring-trihydroxylated anthocyanins based upon delphinidin. Successful redirection of the anthocyanin biosynthesis pathway to delphinidin was achieved by expressing F3′5′H coding regions resulting in carnations and roses with novel blue hues that have been commercialized. Suppression of F3′5′H and F3′H in delphinidin-producing plants reduced the number of hydroxyl groups on the anthocyanidin B-ring resulting in the production of monohydroxylated anthocyanins based on pelargonidin with a shift in flower colour to orange/red. Pelargonidin biosynthesis is enhanced by additional expression of a dihydroflavonol 4-reductase that can use the monohydroxylated dihydrokaempferol (the pelargonidin precursor). Flavone synthase II (FNSII)-catalysing flavone biosynthesis from flavanones is also a P450 (CYP93B) and contributes to flower colour, because flavones act as co-pigments to anthocyanins and can cause blueing and darkening of colour. However, transgenic plants expression of a FNSII gene yielded paler flowers owing to a reduction of anthocyanins because flavanones are precursors of anthocyanins and flavones.
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46

Pencavel, Tim D., Dirk C. Strauss, Greg P. Thomas, J. Meirion Thomas, and Andrew J. Hayes. "Does the two-week rule pathway improve the diagnosis of soft tissue sarcoma? A retrospective review of referral patterns and outcomes over five years in a regional sarcoma centre." Annals of The Royal College of Surgeons of England 92, no. 5 (July 2010): 417–21. http://dx.doi.org/10.1308/003588410x12664192075972.

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INTRODUCTION The NHS Cancer Plan was introduced in 2000 and included guidelines for the rapid assessment and referral of cases of suspected malignancy. We wished to assess the efficiency and appropriateness of patients referred under the Department of Health's general practitioner referral guidelines implemented for sarcomas in December 2000. PATIENTS AND METHODS A retrospective case-note review was performed of all patients referred to our regional soft tissue sarcoma unit between 1 January 2004 and 31 December 2008. Patients referred under the two-week guidelines and all patients referred routinely were analysed. The main outcome measures were the total number of patients referred on the basis of the two-week guidelines and the proportion they constitute of all referrals. The referring criteria were noted and compared to the observed criteria recorded. The final histo-logical diagnosis of patients referred on the basis of the two-week guidelines are documented. RESULTS A total of 2746 referrals for suspected sarcoma were made from January 2004 to December 2008. Of these, 154 referrals were made under the two-week rule of which 102 were referred purely on the clinical criteria for suspected soft tissue sarcoma. The remaining patients were referred after non-urgent special investigations indicated the possibility of sarcoma. Twelve patients referred under the two-week rule were proved to have sarcoma, nine after specific investigations including imaging or histological diagnosis. Of the 102 patients referred on clinical suspicion of a sarcoma, two patients had proven soft tissue sarcomas and one patient a cutaneous sarcoma. Between 2004 and 2008, the number of 2-week referrals rose 25-fold but accounted for an increase of less than 1% of the sarcomas treated in this unit. CONCLUSIONS The numbers of all referrals for suspected sarcoma are increasing; however, the rate of increase of 2-week referrals is increasing faster than routine referrals and will exceed it in 2012 if current trends continue. There has not been a commensurate rise in the detection of sarcoma or, more specifically, diagnosis of the deep sarcomas associated with worse prognosis. Current clinical guidelines have essentially had no impact on the early diagnosis and treatment of soft tissue sarcoma, and may negatively impact on the treatment of patients with proven sarcoma by delaying treatment within a regional centre because of redirection of a large number of patients with benign abnormalities to such centres.
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47

Yang, Fan, Yan Yan, Zeyu Xiong, Irene H. Chen, Hong Wang, and Xiao-Feng Yang. "Novel Model of Stimulation-Responsive Splicing for Generation of Immunogenic Isoforms of Tumor Antigens and Autoantigens." Blood 108, no. 11 (November 16, 2006): 5188. http://dx.doi.org/10.1182/blood.v108.11.5188.5188.

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Abstract Alternative splicing is a process that removes introns and alters exons to generate multiple isoforms from a single pre-mRNA transcript. Alternative splicing is the major mechanism by which a small number of human genes (6 × 104) can encode the larger complexity of the human proteome (1 × 106 proteins). Previously we demonstrated that alternative splicing of apoptosis-regulatory protein transcripts regulates immune responses by modulating lymphocyte survival (Immunity, 1997; Mol. Immunol. 2002; J Exp Med, 2002; Oncogene 2005; Biochem J, 2005). To examine the hypothesis that alternative splicing plays a role in selection of nonmutated self-protein isoforms for tumor antigens and autoantigens, recently, we showed that alternative splicing is a major mechanism in regulation of the immunogenicity of tumor antigen CML66 (J. Immunol. 2004). In addition, we found that alternative splicing occurs in 100% of the autoantigen transcripts. This is significantly higher than the approximately 42% rate of alternative splicing observed in the 10,000 randomly selected human gene transcripts (p<0.001) [J. Allergy Clin. Immunol., 2004 (cover article)]. Here, we report that essential alternative splicing factor ASF/SF2 expression in samples from patients with chronic inflammation is lower than that of the healthy controls (p<0.05). In addition, TNF-a significantly downregulates ASF/SF2 expression (7 folds) in cultured cells in comparison to the expression variations of b-actin control. These findings demonstrate that ASF/SF2, presumably affecting splicing of self-antigen transcripts, is downregulated in autoimmune inflammatory disease potentially via a TNF-a-mediated pathway. Collectively, we propose for the first time a novel model of “stimulation-responsive splicing”, which emphasizes that stimulation-responsive splicing plays a critical role in selection of nonmutated self-protein isoforms to become tumor antigens and autoantigens (Clin. Immunol. Invited Review, in press, 2006). The new model for the definition of immunogenic isoforms of tumor antigens and autoantigens is significant in facilitating the development of: immunogenic antigen isoform microarrays for disease diagnosis and prognosis; autoantigen-tolerizing therapy and splicing-redirection therapy for autoimmune diseases; and immunogenic antigen isoforms-based immunotherapy for tumors.
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48

Hackstadt, Ted. "Redirection of Host Vesicle Trafficking Pathways by Intracellular Parasites." Traffic 1, no. 2 (February 2000): 93–99. http://dx.doi.org/10.1034/j.1600-0854.2000.010201.x.

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49

Chupin, Andey V., Andrey E. Zotikov, Aleksandra S. Kutovaya, Aleksandr L. Golovyuk, Aleksandr F. Kharazov, Vladimir A. Kul’bak, Anzhelika V. Kozhanova, Aleksey B. Varava, and Irina E. Tiimina. "Coronary-Vertebral Collaterals in Takayasu Arteritis: Case Report." I.P. Pavlov Russian Medical Biological Herald 30, no. 3 (October 7, 2022): 387–96. http://dx.doi.org/10.17816/pavlovj104656.

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INTRODUCTION: PNonspecific aortoarteritis is a rare autoimmune disease with the involvement and narrowing of the aorta and its branches leading to ischemia of the respective arterial region. In the territory of the Russian Federation, the most common manifestation of Takayasu nonspecific aortoarteritis is lesion of the branches of the aortic arch, which in rare cases leads to development of the so called bald arch syndrome. In response to hypoxia, intersystemic collaterals are formed through the neoangiogenesis or redirection of the blood flow from the occluded vessels to small-diameter vessels. In patients with bald arch syndrome, the key role in blood supply to the brain is played by the vertebral arteries. Here, collateral blood supply is realized through the intersystemic anastomoses, most often through the anastomotic leaks between the intercostal and internal thoracic arteries. In the literature, single cases of formation of collaterals between coronary and bronchial arteries are reported. The article presents a clinical case of coronary-vertebral anastomoses in a patient with extremely severe course of Takayasu arteritis with occlusion of the brachiocephalic trunk, right common carotid artery (CA), left common CA, right internal CA, left internal CA (bald arch syndrome). The probable cause of such course of the disease was late referral for medical help by the patient and lack of adequate basic therapy. CONCLUSION: The demonstrated case is the fourth case in the world literature describing the existence of collaterals between the coronary arteries and cerebral arteries, and the first case in the world describing the existence of collaterals from the right and left coronary arteries to the vertebral artery. Such unusual pathway of collateral blood supply in the patient is explained by the absence of the possibility for collateral compensation from the systems of subclavian and intercostal arteries, severe chronic cerebral ischemia. Usually, the causes of angina pectoris in patients with nonspecific aortoarteritis are spread of arteritis to the coronary arteries, insufficiency of the aortic valve, hypertrophy of the left ventricle. In the described case, none of these conditions was present, and angina can only be attributed to the existence of unusual collaterals and the development of a transient steal syndrome.
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50

IJzendoorn, Sven C. D. van, Mirjam M. P. Zegers, Jan Willem Kok, and Dick Hoekstra. "Segregation of Glucosylceramide and Sphingomyelin Occurs in the Apical to Basolateral Transcytotic Route in HepG2 Cells." Journal of Cell Biology 137, no. 2 (April 21, 1997): 347–57. http://dx.doi.org/10.1083/jcb.137.2.347.

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HepG2 cells are highly differentiated hepatoma cells that have retained an apical, bile canalicular (BC) plasma membrane polarity. We investigated the dynamics of two BC-associated sphingolipids, glucosylceramide (GlcCer) and sphingomyelin (SM). For this, the cells were labeled with fluorescent acyl chainlabeled 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)- amino]hexanoic acid (C6-NBD) derivatives of either GlcCer (C6-NBD-GlcCer) or SM (C6-NBD-SM). The pool of the fluorescent lipid analogues present in the basolateral plasma membrane domain was subsequently depleted and the apically located C6-NBD-lipid was chased at 37°C. By using fluorescence microscopical analysis and a new assay that allows an accurate estimation of the fluorescent lipid pool in the apical membrane, qualitative and quantitative insight was obtained concerning kinetics, extent and (intra)cellular sites of the redistribution of apically located C6-NBD-GlcCer and C6-NBD-SM. It is demonstrated that both lipids display a preferential localization, C6-NBD-GlcCer in the apical and C6-NBD-SM in the basolateral area. Such a preference is expressed during transcytosis of both sphingolipids from the apical to the basolateral plasma membrane domain, a novel lipid trafficking route in HepG2 cells. Whereas the vast majority of the apically derived C6-NBD-SM was rapidly transcytosed to the basolateral surface, most of the apically internalized C6-NBD-GlcCer was efficiently redirected to the BC. The redirection of C6-NBD-GlcCer did not involve trafficking via the Golgi apparatus. Evidence is provided which suggests the involvement of vesicular compartments, located subjacent to the apical plasma membrane. Interestingly, the observed difference in preferential localization of C6-NBD-GlcCer and C6NBD-SM was perturbed by treatment of the cells with dibutyryl cAMP, a stable cAMP analogue. While the preferential apical localization of C6-NBD-GlcCer was amplified, dibutyryl cAMP-treatment caused apically retrieved C6-NBD-SM to be processed via a similar pathway as that of C6-NBD-GlcCer. The data unambiguously demonstrate that segregation of GlcCer and SM occurs in the reverse transcytotic route, i.e., during apical to basolateral transport, which results in the preferential localization of GlcCer and SM in the apical and basolateral region of the cells, respectively. A role for non-Golgi–related, sub-apical vesicular compartments in the sorting of GlcCer and SM is proposed.
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