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RECHSTEINER, Martin, Claudio REALINI, and Vicença USTRELL. "The proteasome activator 11 S REG (PA28) and Class I antigen presentation." Biochemical Journal 345, no. 1 (1999): 1–15. http://dx.doi.org/10.1042/bj3450001.
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There are two immune responses in vertebrates: humoral immunity is mediated by circulating antibodies, whereas cytotoxic T lymphocytes (CTL) confer cellular immunity. CTL lyse infected cells upon recognition of cell-surface MHC Class I molecules complexed with foreign peptides. The displayed peptides are produced in the cytosol by degradation of host proteins or proteins from intracellular pathogens that might be present. Proteasomes are cylindrical multisubunit proteases that generate many of the peptides eventually transferred to the cell surface for immune surveillance. In mammalian proteasomes, six active sites face a central chamber. As this chamber is sealed off from the enzyme's surface, there must be mechanisms to promote entry of substrates. Two protein complexes have been found to bind the ends of the proteasome and activate it. One of the activators is the 19 S regulatory complex of the 26 S proteasome; the other activator is ‘11 S REG’ [Dubiel, Pratt, Ferrell and Rechsteiner (1992) J. Biol. Chem. 267, 22369-22377] or ‘PA28’ [Ma, Slaughter and DeMartino (1992) J. Biol. Chem. 267, 10515-10523]. During the past 7 years, our understanding of the structure of REG molecules has increased significantly, but much less is known about their biological functions. There are three REG subunits, namely α, β and γ. Recombinant REGα forms a ring-shaped heptamer of known crystal structure. 11 S REG is a heteroheptamer of α and β subunits. REGγ is also presumably a heptameric ring, and it is found in the nuclei of the nematode work Caenorhabditis elegans and higher organisms, where it may couple proteasomes to other nuclear components. REGα and REGβ, which are abundant in vertebrate immune tissues, are located mostly in the cytoplasm. Synthesis of REG α and β subunits is induced by interferon-γ, and this has led to the prevalent hypothesis that REG α/β hetero-oligomers play an important role in Class I antigen presentation. In the present review we focus on the structural properties of REG molecules and on the evidence that REGα/β functions in the Class I immune response.
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Elsen, Sylvie, Lee R. Swem, Danielle L. Swem, and Carl E. Bauer. "RegB/RegA, a Highly Conserved Redox-Responding Global Two-Component Regulatory System." Microbiology and Molecular Biology Reviews 68, no. 2 (2004): 263–79. http://dx.doi.org/10.1128/mmbr.68.2.263-279.2004.
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SUMMARY The Reg regulon from Rhodobacter capsulatus and Rhodobacter sphaeroides encodes proteins involved in numerous energy-generating and energy-utilizing processes such as photosynthesis, carbon fixation, nitrogen fixation, hydrogen utilization, aerobic and anaerobic respiration, denitrification, electron transport, and aerotaxis. The redox signal that is detected by the membrane-bound sensor kinase, RegB, appears to originate from the aerobic respiratory chain, given that mutations in cytochrome c oxidase result in constitutive RegB autophosphorylation. Regulation of RegB autophosphorylation also involves a redox-active cysteine that is present in the cytosolic region of RegB. Both phosphorylated and unphosphorylated forms of the cognate response regulator RegA are capable of activating or repressing a variety of genes in the regulon. Highly conserved homologues of RegB and RegA have been found in a wide number of photosynthetic and nonphotosynthetic bacteria, with evidence suggesting that RegB/RegA plays a fundamental role in the transcription of redox-regulated genes in many bacterial species.
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Masuda, Shinji, Yumi Matsumoto, Kenji V. P. Nagashima, et al. "Structural and Functional Analyses of Photosynthetic Regulatory Genes regA and regBfrom Rhodovulum sulfidophilum, Roseobacter denitrificans, and Rhodobacter capsulatus." Journal of Bacteriology 181, no. 14 (1999): 4205–15. http://dx.doi.org/10.1128/jb.181.14.4205-4215.1999.
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ABSTRACT Genes coding for putative RegA, RegB, and SenC homologues were identified and characterized in the purple nonsulfur photosynthetic bacteria Rhodovulum sulfidophilum and Roseobacter denitrificans, species that demonstrate weak or no oxygen repression of photosystem synthesis. This additional sequence information was then used to perform a comparative analysis with previously sequenced RegA, RegB, and SenC homologues obtained fromRhodobacter capsulatus and Rhodobacter sphaeroides. These are photosynthetic bacteria that exhibit a high level of oxygen repression of photosystem synthesis controlled by the RegA-RegB two-component regulatory system. The response regulator, RegA, exhibits a remarkable 78.7 to 84.2% overall sequence identity, with total conservation within a putative helix-turn-helix DNA-binding motif. The RegB sensor kinase homologues also exhibit a high level of sequence conservation (55.9 to 61.5%) although these additional species give significantly different responses to oxygen. ARhodovulum sulfidophilum mutant lacking regA orregB was constructed. These mutants produced smaller amounts of photopigments under aerobic and anaerobic conditions, indicating that the RegA-RegB regulon controls photosynthetic gene expression in this bacterium as it does as in Rhodobacterspecies. Rhodobacter capsulatus regA- orregB-deficient mutants recovered the synthesis of a photosynthetic apparatus that still retained regulation by oxygen tension when complemented with reg genes fromRhodovulum sulfidophilum and Roseobacter denitrificans. These results suggest that differential expression of photosynthetic genes in response to aerobic and anaerobic growth conditions is not the result of altered redox sensing by the sensor kinase protein, RegB.
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Realini, Claudio, Christopher C. Jensen, Zhi-guo Zhang та ін. "Characterization of Recombinant REGα, REGβ, and REGγ Proteasome Activators". Journal of Biological Chemistry 272, № 41 (1997): 25483–92. http://dx.doi.org/10.1074/jbc.272.41.25483.
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Elsen, Sylvie, Wanda Dischert, Annette Colbeau, and Carl E. Bauer. "Expression of Uptake Hydrogenase and Molybdenum Nitrogenase in Rhodobacter capsulatus Is Coregulated by the RegB-RegA Two-Component Regulatory System." Journal of Bacteriology 182, no. 10 (2000): 2831–37. http://dx.doi.org/10.1128/jb.182.10.2831-2837.2000.
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ABSTRACT Purple photosynthetic bacteria are capable of generating cellular energy from several sources, including photosynthesis, respiration, and H2 oxidation. Under nutrient-limiting conditions, cellular energy can be used to assimilate carbon and nitrogen. This study provides the first evidence of a molecular link for the coregulation of nitrogenase and hydrogenase biosynthesis in an anoxygenic photosynthetic bacterium. We demonstrated that molybdenum nitrogenase biosynthesis is under the control of the RegB-RegA two-component regulatory system in Rhodobacter capsulatus. Footprint analyses and in vivo transcription studies showed that RegA indirectly activates nitrogenase synthesis by binding to and activating the expression of nifA2, which encodes one of the two functional copies of the nif-specific transcriptional activator, NifA. Expression of nifA2 but notnifA1 is reduced in the reg mutants up to eightfold under derepressing conditions and is also reduced under repressing conditions. Thus, although NtrC is absolutely required fornifA2 expression, RegA acts as a coactivator ofnifA2. We also demonstrated that in regmutants, [NiFe]hydrogenase synthesis and activity are increased up to sixfold. RegA binds to the promoter of the hydrogenase gene operon and therefore directly represses its expression. Thus, the RegB-RegA system controls such diverse processes as energy-generating photosynthesis and H2 oxidation, as well as the energy-demanding processes of N2 fixation and CO2 assimilation.
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Wang, Hong, Marko Vatamaniuk, Zeping Zhao, and Xin Gen Lei. "Altering Two Major Redox Enzymes Affected Expression and Function of Murine REG Family Proteins." Current Developments in Nutrition 4, Supplement_2 (2020): 1850. http://dx.doi.org/10.1093/cdn/nzaa067_077.
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Abstract Objectives We previously revealed a substantially-suppressed expression of regenerating islets-derived protein 2 (Reg2) in murine pancreatic islets by overexpression of glutathione peroxidase-1 (Gpx1-OE). Two experiments were conducted to determine: 1) how knockouts of Gpx1 and superoxide dismutase-1 (Sod1) alone and together (dKO) affected the expression profiles of the full Reg family genes in three tissues; and 2) how GPX1 and SOD1 activities regulated effects of REG2 on islet proliferation. Methods In Expt. 1, six groups of mice (Gpx1−/−, Gpx1-OE, and their wild-type, WT1; Sod1−/−, dKO, and their WT2) (male, 2–4 months old (n = 6 – 8) were fed an Se-adequate diet and killed to collect islets, liver, and intestine samples. In Expt. 2, islets isolated from the 6 groups of mice were cultured in RPMI 1640 medium and treated with recombinant REG2 and REG2 mutant proteins (1 μg/mL), GPX mimic (ebselen, 50 μM) and SOD mimic (CuDIP, 10 μM) for 48 h. The proliferation of islets was estimated using the bromodeoxyuridine (Sigma) assay. Results Compared with the WT1 mice, the Gpx1−/− mice had greater (P < 0.05) and the Gpx1-OE mice had lower (P < 0.05) mRNA levels of all 7 assayed Reg genes with a few exceptions of Reg3ẞ,Reg3δ, or Reg4 in the three tissues. Similar inductions of the 7 Reg mRNA levels were also seen in the islets of Sod1−/− and dKO mice over their controls. However, responses of these 7 genes in the liver and intestine of these two genotypes in comparison with the controls were less consistent. The incubation of islets with REG2, but not the REG2 mutant, inhibited islet proliferation in the Gpx1−/−, Sod1−/−, dKO, and Gpx1-OE groups, where no such effect was seen in the two WT groups. Co-incubations of islets with CuDIP and ebselen partially blocked the REG2 inhibitory effect on the islet proliferation. Conclusions Altering GPX1 and SOD1 expression and activity affected the Reg family gene expression in the islets, liver, and intestine of mice as well as the function of REG2 protein in the islets. Our results reveal a novel dependence of the REG family protein expression and function on cellular redox status. Funding Sources This research was supported in an NIH grant DK 53,018.
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Li, Bing, Xiao Wang, and Jun-Li Liu. "Pancreatic acinar-specific overexpression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 2 (2010): G413—G421. http://dx.doi.org/10.1152/ajpgi.00500.2009.
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Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3δ] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet β-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3α increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased β-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 promoter (Ela-Reg2) to develop an acinar cell-specific overexpression of the Reg2 gene. Western blot analysis, real-time PCR, and immunohistochemistry revealed barely detectable levels of endogenous Reg2 in the pancreas of normal wild-type mice and increased Reg2 levels in the pancreas of Ela-Reg2 mice that were similar to or higher than Reg2 levels induced in experimental diabetes or pancreatitis. Compared with wild-type littermates, growth, blood glucose and insulin levels, and glucose tolerance were normal in Ela-Reg2 mice; pancreatic histology revealed no change in endocrine or exocrine tissues. Acinar-specific overexpression of the Reg2 gene offered no protection against streptozotocin-induced β-cell damage and diabetes, in hyperglycemia and weight loss, and no advantage in restoring glucose homeostasis and islet function within 3 mo. Furthermore, serum amylase level and pancreatic histochemistry showed that Reg2 overexpression did not protect acinar cells against caerulein-induced acute pancreatitis. In contrast to INGAP or Reg3β, exocrine overexpression of Reg2 offered no protection to the endocrine or exocrine pancreas, indicating clear subtype specificities of the Reg family of proteins.
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Du, Shouying, Jean-Louis K. Kouadio, and Carl E. Bauer. "Regulated Expression of a Highly Conserved Regulatory Gene Cluster Is Necessary for Controlling Photosynthesis Gene Expression in Response to Anaerobiosis in Rhodobacter capsulatus." Journal of Bacteriology 181, no. 14 (1999): 4334–41. http://dx.doi.org/10.1128/jb.181.14.4334-4341.1999.
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ABSTRACT We utilized primer extension analysis to demonstrate that the divergently transcribed regB and senC-regA-hvrAtranscripts contain stable 5′ ends 43 nucleotides apart within theregB-senC intergenic region. DNA sequence analysis indicates that this region contains two divergent promoters with overlapping ς70 type −35 and −10 promoter recognition sequences. In vivo analysis of expression patterns ofregB::lacZ andsenC-regA-hvrA::lacZ reporter gene fusions demonstrates that the regB andsenC-regA-hvrA transcripts are both negatively regulated by the phosphorylated form of the global response regulator RegA. DNase I protection assays with a constitutively active variant of RegA indicate that RegA binds between regB and senCoverlapping −10 and −35 promoter recognition sequences. Two mutations were also isolated in a regB-deficient background that increased expression of the senC-regA-hvrA operon 10- and 5-fold, respectively. As a consequence of increased RegA expression, these mutants exhibited elevated aerobic and anaerobic photosynthesis (puf) gene expression, even in the absence of the sensor kinase RegB. These results indicate that autoregulation by RegA is a factor contributing to the maintenance of an optimal low level of RegA expression that allows responsiveness to activation by phosphorylation.
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Frederick, D. L., and K. Tatchell. "The REG2 gene of Saccharomyces cerevisiae encodes a type 1 protein phosphatase-binding protein that functions with Reg1p and the Snf1 protein kinase to regulate growth." Molecular and Cellular Biology 16, no. 6 (1996): 2922–31. http://dx.doi.org/10.1128/mcb.16.6.2922.
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The GLC7 gene of Saccharomyces cerevisiae encodes the catalytic subunit of type 1 protein phosphatase (PP1) and is essential for cell growth. We have isolated a previously uncharacterized gene, REG2, on the basis of its ability to interact with Glc7p in the two-hybrid system. Reg2p interacts with Glc7p in vivo, and epitope-tagged derivatives of Reg2p and Glc7p coimmunoprecipitate from cell extracts. The predicted protein product of the REG2 gene is similar to Reg1p, a protein believed to direct PP1 activity in the glucose repression pathway. Mutants with a deletion of reg1 display a mild slow-growth defect, while reg2 mutants exhibit a wild-type phenotype. However, mutants with deletions of both reg1 and reg2 exhibit a severe growth defect. Overexpression of REG2 complements the slow-growth defect of a reg1 mutant but does not complement defects in glycogen accumulation or glucose repression, two traits also associated with a reg1 deletion. These results indicate that REG1 has a unique role in the glucose repression pathway but acts together with REG2 to regulate some as yet uncharacterized function important for growth. The growth defect of a reg1 reg2 double mutant is alleviated by a loss-of-function mutation in the SNF1-encoded protein kinase. The snf1 mutation also suppresses the glucose repression defects of reg1. Together, our data are consistent with a model in which Reg1p and Reg2p control the activity of PP1 toward substrates that are phosphorylated by the Snf1p kinase.
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Singh, Bhagirath, Thomas Hill, Olga Krougly, et al. "Role of IL-22 in tissue regeneration in autoimmunity (P5164)." Journal of Immunology 190, no. 1_Supplement (2013): 195.11. http://dx.doi.org/10.4049/jimmunol.190.supp.195.11.
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Abstract The various cell types in our bodies are constantly regenerating but at a different rate. In autoimmune diseases cells once destroyed can regenerate. However, immune system once activated continues to target and destroy these cells. Thus, tissue regeneration remains a challenge in these diseases. Cytokines play a major role in immune regulation, inflammation, tissue injury and autoimmunity. We have shown that immunostimulation by mycobacterial adjuvants such as BCG vaccine as well as complete Freund’s adjuvant (CFA) can prevent the autoimmune process and can stimulate tissue regeneration. These adjuvants induce regulatory Th17 (Treg17) cells and stimulate expression of Regenerative (Reg) genes such as Reg1 and Reg2 in pancreatic islets. Th17 cells also produce Interleukin-22 (IL-22) that has been shown to stimulate This is probably mediated through STAT3/ERK signaling. Reg gene expression. Blocking of IL-22 prevented the expression of Reg genes in vivo. In this study we explored the cell types that express Reg genes following IL-22 treatment by using RT-PCR analysis and by histological staining. Our hypothesis is that the Reg gene expression drives the islet regeneration following tissue injury by autoimmunity in type 1 diabetes. These approaches offer alternatives to tissue transplantation in autoimmunity.
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Zhang, Zhiguo, Andrew Krutchinsky, Scott Endicott, Claudio Realini, Martin Rechsteiner та Kenneth G. Standing. "Proteasome Activator 11S REG or PA28: Recombinant REGα/REGβ Hetero-oligomers Are Heptamers1". Biochemistry 38, № 17 (1999): 5651–58. http://dx.doi.org/10.1021/bi990056+.
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Downing, Shawna, Fan Zhang, Zijing Chen, and Emmanuel S. Tzanakakis. "MicroRNA-7 directly targets Reg1 in pancreatic cells." American Journal of Physiology-Cell Physiology 317, no. 2 (2019): C366—C374. http://dx.doi.org/10.1152/ajpcell.00013.2019.
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Regenerating islet-derived (Reg) proteins, which were first discovered in the pancreas, are associated with increased proliferation, prevention of apoptosis, and enhanced differentiation in normal and disease states, but very little is known about the regulation of their expression. We hypothesized that Reg expression is influenced by microRNAs. Bioinformatic analysis predicted Reg1 to be a target of microRNA-7 (miR-7), which influences pancreatic β-cell function. To this end, we investigated the effects of miR-7 on Reg1 expression in pancreatic acinar and islet β-cells. High levels of Reg1 were noted by immunostaining and Western blotting in acinar cells in contrast to islet cells. A reciprocal expression pattern was observed for miR-7. Overexpression of miR-7 resulted in Reg1 mRNA suppression and reduction of secreted Reg1 protein. Conversely, miR-7 knockdown led to increases in Reg1. Targeting of Reg1 by miR-7 was confirmed via luciferase activity assays. In contrast, miR-7 did not directly repress the human ortholog of Reg1 REG1A as well as REG1B indicating species differences in the regulation of Reg expression. This is the first account of microRNA modulation of any Reg member warranting studies to fill gaps in our knowledge of Reg protein biology, particularly in disease contexts.
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Lu, Yarong, André Ponton, Hiroshi Okamoto, Shin Takasawa, Pedro L. Herrera, and Jun-Li Liu. "Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas." American Journal of Physiology-Endocrinology and Metabolism 291, no. 1 (2006): E50—E58. http://dx.doi.org/10.1152/ajpendo.00596.2005.
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We have recently reported that Pdx1-Cre-mediated whole pancreas inactivation of IGF-I gene [in pancreatic-specific IGF-I gene-deficient (PID) mice] results in increased β-cell mass and significant protection against both type 1 and type 2 diabetes. Because the phenotype is unlikely a direct consequence of IGF-I deficiency, the present study was designed to explore possible activation of proislet factors in PID mice by using a whole genome DNA microarray. As a result, multiple members of the Reg family genes (Reg2, -3α, and -3β, previously not known to promote islet cell growth) were significantly upregulated in the pancreas. This finding was subsequently confirmed by Northern blot and/or real-time PCR, which exhibited 2- to 8-fold increases in the levels of these mRNAs. Interestingly, these Reg family genes were also activated after streptozotocin-induced β-cell damage and diabetes (wild-type T1D mice) when islet cells were undergoing regeneration. Immunohistochemistry revealed increased Reg proteins in exocrine as well as endocrine pancreas and suggested their potential role in β-cell neogenesis in PID or T1D mice. Previously, other Reg proteins (Reg1 and islet neogenesis-associated protein) have been shown to promote islet cell replication and neogenesis. These uncharacterized Reg proteins may play a similar but more potent role, not only in normal islet cell growth in PID mice, but also in islet cell regeneration after T1D.
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Johnson, S. L., and J. A. Weston. "Temperature-sensitive mutations that cause stage-specific defects in Zebrafish fin regeneration." Genetics 141, no. 4 (1995): 1583–95. http://dx.doi.org/10.1093/genetics/141.4.1583.
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Abstract When amputated, the fins of adult zebrafish rapidly regenerate the missing tissue. Fin regeneration proceeds through several stages, including wound healing, establishment of the wound epithelium, recruitment of the blastema from mesenchymal cells underlying the wound epithelium, and differentiation and outgrowth of the regenerate. We screened for temperature-sensitive mutations that affect the regeneration of the fin. Seven mutations were identified, including five that fail to regenerate their fins, one that causes slow growth during regeneration, and one that causes dysmorphic bumps or tumors to develop in the regenerating fin. reg5 mutants fail to regenerate their caudal fins, whereas reg6 mutants develop dysmorphic bumps in their regenerates at the restrictive temperature. Temperature-shift experiments indicate that reg5 and reg6 affect different stages of regeneration. The critical period for reg5 occurs during the early stages of regeneration before or during establishment of the blastema, resulting in defects in subsequent growth of the blastema and failure to differentiate bone-forming cells. The critical period for reg6 occurs after the onset of bone differentiation and during early stages of regenerative outgrowth. Both reg5 and reg6 also show temperature-sensitive defects in embryonic development or in ontogenetic outgrowth of the juvenile fin.
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Wang, Hong, Marko Z. Vatamaniuk, Zeping Zhao, and Xin Gen Lei. "Interdependencies of Gene Expression and Function between Two Redox Enzymes and REG Family Proteins in Murine Pancreatic Islets and Human Pancreatic Cells." Antioxidants 12, no. 4 (2023): 849. http://dx.doi.org/10.3390/antiox12040849.
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Our laboratory previously revealed that regenerating islets-derived protein 2 (REG2) was diminished in pancreatic islets of glutathione peroxidase-1-overexpressing mice (Gpx1-OE). It remained unknown if there is an inverse relationship between the expression and function of all Reg family genes and antioxidant enzymes in the pancreatic islets or human pancreatic cells. This research was to determine how altering the Gpx1 and superoxide dismutase-1 (Sod1) genes alone or together (dKO) affected the expression of all seven murine Reg genes in murine pancreatic islets. In Experiment 1, Gpx1-/-, Gpx1-OE, their wild-type (WT), Sod1-/-, dKO, and their WT (male, 8-wk old, n = 4–6) were fed a Se-adequate diet and their islets were collected to assay the mRNA levels of Reg family genes. In Experiment 2, islets from the six groups of mice were treated with phosphate-buffered saline (PBS), REG2, or REG2 mutant protein (1 µg/mL), and/or GPX mimic (ebselen, 50 µM) and SOD mimic (copper [II] diisopropyl salicylate, CuDIPS, 10 µM) for 48 h before the proliferation assay using bromodeoxyuridine (BrdU). In Experiment 3, human pancreatic cells (PANC1) were treated with REG2 (1 µg/mL) and assayed for REG gene expression, GPX1 and SOD1 activities, viability, and responses to Ca2+. Compared with the WT, knockouts of Gpx1 and/or Sod1 up-regulated (p < 0.05) the mRNA levels of most of the murine Reg genes in islets whereas the Gpx1 overexpression down-regulated (p < 0.05) Reg mRNA levels. REG2, but not the REG2 mutant, inhibited islet proliferation in Gpx1 or Sod1-altered mice. Such inhibition was abolished by co-incubation the Gpx1-/- islets with ebselen and the Sod1-/- islets with CuDIPS. Treating PANC1 cells with murine REG2 protein induced expression of its human orthologue REG1B and three other REG genes, but decreased SOD1 and GPX1 activities and cell viability. In conclusion, our results revealed an interdependence of REG family gene expression and/or function on intracellular GPX1 and SOD1 activities in murine islets and human pancreatic cells.
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Swem, Danielle L., and Carl E. Bauer. "Coordination of Ubiquinol Oxidase and Cytochrome cbb3 Oxidase Expression by Multiple Regulators in Rhodobacter capsulatus." Journal of Bacteriology 184, no. 10 (2002): 2815–20. http://dx.doi.org/10.1128/jb.184.10.2815-2820.2002.
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ABSTRACT Rhodobacter capsulatus utilizes two terminal oxidases for aerobic respiration, cytochrome cbb 3 and ubiquinol oxidase. To determine the transcription factors involved in terminal oxidase expression, ccoN-lacZ and cydA-lacZ protein fusions were assayed in a variety of regulatory mutants. The results of this and previous studies indicate that cytochrome cbb 3 expression is controlled by regB-regA, fnrL, and hvrA and that ubiquinol oxidase expression is controlled by regB-regA, fnrL, hvrA, crtJ, and aerR.
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Phung, Yen, Zhaohui Wang, Inga Aksamit, Sarah G. Green, Karen Todoroff, and Kimberly A. Bergstrom. "Guideline-based treatment utilization, treatment time, and cost of chemotherapy for metastatic colon cancer patients treated in U.S. community oncology practices from 2005 to 2009." Journal of Clinical Oncology 30, no. 15_suppl (2012): e14118-e14118. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14118.
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e14118 Background: Adherence (Ad) to national treatment guidelines (TG) is important in improving the quality, outcomes, and cost of cancer treatment (TX) in the U.S. We examined regimens (Reg) utilized, TG-Ad, time on metastatic TX, and cost of chemotherapy prescribed by U.S. community oncology practices to treat patients (Pts) with metastatic colon cancer (MCC) in 2005 and 2009. Methods: Adult colon cancer Pts beginning first line metastatic treatment (LOT-1) in each full calendar year for 2005 and 2009 were reviewed from a large U.S. medical oncology clinical database derived from web-based drug dispensing technology. Reg utilized and 2-yr time on metastatic TX were analyzed and compared to TG recommendations. Reg costs based on Medicare reimbursement were compared. Results: The average number of LOT and number of unique drugs Pts were exposed to were similar between 2005 and 2009. About 70% of Pts received only one LOT. In LOT-1 and 2, TG regs were prescribed more often than Non-TG regs for both groups. TG-Ad was significantly higher in 2009 than in 2005 for LOT-1 (p < 0.0001). Pts receiving TG-Ad Reg for LOT-1 had a significantly longer total metastatic treatment time in both 2005 and 2009. In both 2005 and 2009, FOLFOX+Bev was the most frequent LOT-1 Reg given (37% of Pts), while FOLFIRI+Bev was the most frequent LOT-2 Reg given. 69% of Pts received Bev with LOT-1 in both 2005 and 2009; of those, 28-30% continued to receive Bev with LOT-2. Costs for the top 5 LOT-1 Regs were $17,031 to $34,400 and $5,512 to $39,835 for 2005 and 2009, respectively. Conclusions: U.S. community oncology practices significantly improved guideline Ad in the TX of MCC from 2005 to 2009. In LOT-1, TG Regs were prescribed more than non-TG Regs for both groups. TG Ad for LOT-1 significantly improved time on metastatic TX in both groups. FOLFOX+Bev and FOLFIRI+Bev were most frequently prescribed for LOT-1 and LOT-2, respectively. Costs for the five most utilized Regs vary considerably. [Table: see text]
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Szabo, Sandor, Zsolt Totka, Jozsef Nagy-Bozsoky, Istvan Pinter, Mihaly Bagany, and Michael Bodo. "Rheoencephalography: A non-invasive method for neuromonitoring." Journal of Electrical Bioimpedance 15, no. 1 (2024): 10–25. http://dx.doi.org/10.2478/joeb-2024-0003.
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Abstract In neurocritical care, the gold standard method is intracranial pressure (ICP) monitoring for the patient's lifesaving. Since it is an invasive method, it is desirable to use an alternative, noninvasive technique. The computerized real-time invasive cerebral blood flow (CBF) autoregulation (AR) monitoring calculates the status of CBF AR, called the pressure reactivity index (PRx). Studies documented that the electrical impedance of the head (Rheoencephalography – REG) can detect the status of CBF AR (REGx) and ICP noninvasively. We aimed to test REG to reflect ICP and CBF AR. For nineteen healthy subjects we recorded bipolar bifrontal and bitemporal REG derivations and arm bioimpedance pulses with a 200 Hz sampling rate. The challenges were a 30-second breath-holding and head-down-tilt (HDT – Trendelenburg) position. Data were stored and processed offline. REG pulse wave morphology and REGx were calculated. The most relevant finding was the significant morphological change of the REG pulse waveform (2nd peak increase) during the HDT position. Breath-holding caused REG amplitude increase, but it was not significant. REGx in male and female group averages have similar trends during HDT by indicating the active status of CBF AR. The morphological change of REG pulse wave during HDT position was identical to ICP waveform change during increased ICP, reflecting decreased intracranial compliance. A correlation study between ICP and REG was initiated in neurocritical care patients. The noninvasive REG monitoring would also be useful in space research as well as in military medicine during the transport of wounded service members as well as for fighter pilots to indicate the loss of CBF and consciousness.
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Abdou, Elias, Amélie Deredjian, María Pilar Jiménez de Bagüés, Stephan Köhler, and Véronique Jubier-Maurin. "RegA, the Regulator of the Two-Component System RegB/RegA of Brucella suis, Is a Controller of Both Oxidative Respiration and Denitrification Required for Chronic Infection in Mice." Infection and Immunity 81, no. 6 (2013): 2053–61. http://dx.doi.org/10.1128/iai.00063-13.
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ABSTRACTAdaptation to oxygen deficiency is essential for virulence and persistence ofBrucellainside the host. The flexibility of this bacterium with respect to oxygen depletion is remarkable, sinceBrucella suiscan use an oxygen-dependent transcriptional regulator of the FnrN family, two high-oxygen-affinity terminal oxidases, and a complete denitrification pathway to resist various conditions of oxygen deficiency. Moreover, our previous results suggested that oxidative respiration and denitrification can be simultaneously used byB. suisunder microaerobiosis. The requirement of a functional cytochromebdubiquinol oxidase for nitrite reductase expression evidenced the linkage of these two pathways, and the central role of the two-component system RegB/RegA in the coordinated control of both respiratory systems was demonstrated. We propose a scheme for global regulation ofB. suisrespiratory pathways by the transcriptional regulator RegA, which postulates a role for the cytochromebdubiquinol oxidase in redox signal transmission to the histidine sensor kinase RegB. More importantly, RegA was found to be essential forB. suispersistencein vivowithin oxygen-limited target organs. It is conceivable that RegA acts as a controller of numerous systems involved in the establishment of the persistent state, characteristic of chronic infections byBrucella.
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Sigurdardottir, D., J. Sohn, J. Kass, and E. Selsing. "Regulatory regions 3' of the immunoglobulin heavy chain intronic enhancer differentially affect expression of a heavy chain transgene in resting and activated B cells." Journal of Immunology 154, no. 5 (1995): 2217–25. http://dx.doi.org/10.4049/jimmunol.154.5.2217.
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Abstract We have compared the expression patterns of three Ig heavy chain transgenes. The three constructs differ only by deletion of J-C intron sequences located downstream of the Emu enhancer region. When stably transfected into a myeloma cell line, all three constructs are expressed at comparable levels. However, transgenic mice carrying each construct show dramatic differences in transgene expression. Our results indicate that, in addition to the Emu enhancer, at least two regions, RegA and RegS, within the J-C intron influence transgene expression. RegA, located directly downstream of the core Emu enhancer, is involved in up-regulation of transgene expression after LPS activation of splenocytes. RegS, located within or downstream of the Smu switch region, is important for normal levels of transgene expression in splenocytes of heavy chain transgenic mice.
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Chung, Davi d. J., Marco Rossi, Emanuela Romano, et al. "Regulatory T Cells Expanded by Autologous Mature Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase Are Potent Suppressors of T Cell Proliferation." Blood 112, no. 11 (2008): 1553. http://dx.doi.org/10.1182/blood.v112.11.1553.1553.
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Abstract Best characterized as initiators of immunity, dendritic cells (DCs) also play an integral role in immune modulation. Immature DCs, for example, process self-antigens to induce and maintain tolerance. The immunoregulatory effects of DCs, however, are not limited to immature subtypes. Immunogenic mature DCs can also induce T regs to curb immune responses. We have found that human monocyte-derived DCs (moDCs) upregulate the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) with maturation and expand functionally active, naturally occurring as well as inducible regulatory T cells (T regs) in an IDO-dependent manner. Priming of resting bulk T cells with autologous, IDO-expressing, mature moDCs in the absence of exogenous cytokines results in up to 10-fold expansion of CD4+CD25hiFoxp3+CD127neg T cells that mediate significant dose-dependent suppression of both allogeneic and autologous T cells stimulated de novo by DCs. The expansion of T regs by IDO-expressing moDCs involves cell-to-cell contact, CD80/CD86 ligation, and IL-2. Autologous priming in the presence of a competitive inhibitor of IDO, 1-methyl-tryptophan, diminishes T reg expansion. Candidate T regs were further characterized after cytofluorographic sorting primed bulk T cells into CD4+CD25hi, CD4+CD25int, and CD4+CD25neg subpopulations. Post-sort analysis showed that &gt;60% of the CD4+CD25hi cells coexpressed Foxp3, which was not present in the CD4+CD25neg cells. CD4+CD25hi T regs exerted dose-dependent inhibition of DC-stimulated allogeneic T cell proliferation, with &gt;90% inhibition at a suppressor to responder T cell ratio of 1:1 and ~50% inhibition at a ratio of 1:25. CD4+CD25int cells produced intermediate suppression depending on dose, and CD4+CD25neg cells were not inhibitory. CD4+CD25hi T regs mediated similar suppression of autologous T cell responses to stimulation de novo by DCs. CD4+CD25hi T regs also inhibited the generation of cytotoxic T lymphocytes (CTLs) specific for the Wilms’ tumor gene product (WT-1). The addition of CD4+CD25hi T regs to CTL-priming cultures resulted in a &gt;80% decrease in specific target cell lysis of a WT-1-expressing cell line. Separate studies showed that T reg-mediated suppression is contact dependent and also requires TGF-beta, suggesting inhibition by naturally occurring and inducible T regs, respectively. Depletion of CD4+CD25hi T cells from bulk T cells by negative immunoselection with anti-CD25 magnetic beads at the outset of autologous priming significantly blunts T reg expansion, indicating a requirement for pre-existing T regs in the bulk T cell population. T reg expansion also occurs in priming cultures using cytofluorographically-sorted CD4+CD25neg T cells, indicating de novo generation of T regs from CD4+CD25neg precursors. In summary, our results demonstrate a mechanism by which mature, IDO-expressing, human moDCs expand autologous, naturally occurring as well as inducible T regs that functionally suppress the proliferation of both autologous and allogeneic T cells. Inhibition of this counter-regulatory pathway should result in more sustained benefit from active DC-based immunotherapy.
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Zangrando, Mariana Schutzer Ragghianti, Giovanna Fernanda Favero Silva, Maria Laura Bignotto Bigotto, et al. "Blocking tubules technologies for dentin hypersensitivity in periodontal patients – pilot study." Research, Society and Development 10, no. 13 (2021): e35101320398. http://dx.doi.org/10.33448/rsd-v10i13.20398.
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Periodontal patients often report dentin hypersensitivity (DH) caused by root surface exposure or periodontal treatment. Tubular blocking technologies in toothpastes are effective for pain relief, but no specific chemical/physical agent has been reported for periodontal patients. This double-blind randomized clinical trial compared the effects of three technologies in reducing DH in periodontal patients. Eighteen (18) participants were randomly assigned into three groups: SEN (NOVAMIN technology); REG (REFIX technology); REGK (REFIX technology + potassium citrate). Periodontal patients presenting with DH were evaluated at 6 moments: T1 and T2 - immediately before and after scaling and root planing procedures (SRP); T3 - after polishing sensitive areas with their assigned dentifrice and T4, T5, T6 - after 2, 4 and 8 weeks of SRP respectively. Sensitivity was assessed by air blast (Schiff scale) and patients’ perceptions using the visual analogue scale (VAS). Data were analyzed by two-way repeated measures ANOVA complemented by the Tukey test with significance set at 5% (p <0.05). Preliminary outcomes revealed SEN, REG and REGP reduced DH in periodontal patients (n=18). All patients initially presented moderate to severe pain (64.3) and after treatment they reported mild pain (21.3). Similarly, the dentist evaluation showed significant reduction in DH with the use of the three technologies (2.26 to 0.56). No statistically significant differences were found between the three study groups for patients (p=0.751) and dentist evaluations (p=0.632). According to these preliminary outcomes, all three technologies equally reduced DH in periodontal patients. Clinical trials #NCT04422184
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Ke, Nijia, and Carl E. Bauer. "The Response Regulator RegA Is a Copper Binding Protein That Covalently Dimerizes When Exposed to Oxygen." Microorganisms 10, no. 5 (2022): 934. http://dx.doi.org/10.3390/microorganisms10050934.
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In Rhodobacter capsulatus, the histidine kinase RegB is believed to phosphorylate its cognate transcriptional factor RegA only under anaerobic conditions. However, transcriptome evidence indicates that RegA regulates 47 genes involved in energy storage, energy production, signaling and transcription, under aerobic conditions. In this study, we provide evidence that RegA is a copper binding protein and that copper promotes the dimerization of RegA under aerobic conditions. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicates that RegA binds Cu1+ and Cu2+ in a 1:1 and 2:1 ratio, respectively. Through LC-MS/MS, ESI-MS and non-reducing SDS-PAGE gels, we show that Cu2+ stimulates disulfide bond formation in RegA at Cys156 in the presence of oxygen. Finally, we used DNase I footprint analysis to demonstrate that Cu2+-mediated covalent dimerized RegA is capable of binding to the ccoN promoter, which drives the expression of cytochrome cbb3 oxidase subunits. This study provides a new model of aerobic regulation of gene expression by RegA involving the formation of an intermolecular disulfide bond.
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Masson, Patrick, Daniel Lundin, Fredrik Söderbom та Patrick Young. "Characterization of a REG/PA28 Proteasome Activator Homolog in Dictyostelium discoideum Indicates that the Ubiquitin- and ATP-Independent REGγ Proteasome Is an Ancient Nuclear Protease". Eukaryotic Cell 8, № 6 (2009): 844–51. http://dx.doi.org/10.1128/ec.00165-08.
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ABSTRACT The nuclear proteasome activator REGγ/PA28γ is an ATP- and ubiquitin-independent activator of the 20S proteasome and has been proposed to degrade and thereby regulate both a key human oncogene, encoding the coactivator SRC-3/AIB1, and the cyclin-dependent kinase inhibitor p21 (Waf/Cip1). We report the identification and characterization of a PA28/REG homolog in Dictyostelium. Association of a recombinant Dictyostelium REG with the purified Dictyostelium 20S proteasome led to the preferential stimulation of the trypsin-like proteasome peptidase activity. Immunolocalization studies demonstrated that the proteasome activator is localized to the nucleus and is present in growing as well as starving Dictyostelium cells. Our results indicate that the Dictyostelium PA28/REG activator can stimulate both the trypsin-like and chymotrypsin-like activities of the 20S proteasome and supports the idea that the REGγ-20S proteasome represents an early unique nuclear degradation pathway for eukaryotic cells.
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Leal, Alexis Diane, Fang-Shu Ou, Aimery De Gramont, et al. "Outcomes in the second line treatment of metastatic colorectal cancer (mCRC): Findings from 6,462 patients (pts) in the ARCAD database." Journal of Clinical Oncology 35, no. 4_suppl (2017): 757. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.757.
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757 Background: Progression free survival (PFS) and overall survival (OS) appear to differ across trials, even when pts receive the same regimen (REG). This analysis aimed to benchmark the clinical outcomes in the 2nd line treatment of metastatic colorectal cancer (mCRC). Methods: Individual patient (pt) data was available on 6,462 pts with mCRC enrolled in 7 2ndline clinical trials (8 REGs) in the ARCAD database. Regimens used in at least two trials included FOLFIRI +/- an EGFR inhibitor (EGFRi), FOLFOX +/- a VEGF inhibitor (VEGFi), and irinotecan (IRI). Descriptive statistics were used to describe pt demographics. Multivariable Cox models were used to assess differences (DIFFs) in PFS and OS, while p-value <0.05 were considered statistically significant (SS). Results: 500-1400 pts received each REG (see Table). Median OS and PFS differed by 0.2 to 4.6 months (mo) and 0.8 to 2.5 mo across trials within the same REG. These DIFFs were SS except for PFS in REGs containing FOLFIRI +/- EGFRi. After multivariable adjustment, all DIFFs in OS were attenuated and non-significant. DIFFs in PFS attenuated for most REGs but remained SS for FOLFOX and IRI. Conclusions: After multivariable adjustment, there were no SS DIFFs in outcomes across trials within the same REG, with the exception of PFS in FOLFOX and IRI. The initial observed DIFFs in outcomes could be due to confounding factors and the remaining SS DIFFs in PFS in FOLFOX and IRI may be due to variation in definition of progression across trials. Therefore, caution is warranted when using historical data to design future trials.[Table: see text]
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Daubner, Barbara, Monika Groux-Keller, Thomas Kawabata, et al. "Multiple drug hypersensitivity: role of T regulatory cells (55.15)." Journal of Immunology 186, no. 1_Supplement (2011): 55.15. http://dx.doi.org/10.4049/jimmunol.186.supp.55.15.
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Abstract Introduction: Up to 10% of patients with severe immune-mediated drug hypersensitivity tend to develop multiple drug hypersensitivities (MDH), and react clinically and immunologically to various drugs. Objective: Evaluating the role of T regulatory (T reg) cells in drug reactions and developing an improved clinical and immunological definition of MDH. Methods: T cell reactivity to various drugs was assessed by expression analysis of activation markers and cross-reactivity of drug specific T cell clones to various drugs was analyzed. The role of T regs (Foxp3+/CD25high) was analyzed functionally in T reg depletion assays. The phenotype of reacting T cells was characterized by analysis of activation and cell exhaustion markers. Results: T regs from MDH patients are functionally highly active and suppress T cell proliferation similar to T regs from monoallergic patients and healthy controls. Removal of T regs enhances the reactivity to involved drugs, but does not facilitate an immune response to not exposed drugs in vitro. Drug reactive T cells from monoallergic patients reside in the resting CD4+CD25neg T cell fraction while in MDH patients they reside in an in vivo activated cell fraction (CD4+/CD25dim/CD38+/HLA-DR+/PD-1+). Conclusion: T regs are able to regulate drug specific immune responses. In MDH patients, the drug reactive T cells are contained in a pre-activated cell fraction. This may enhance their responsiveness to drugs and thus explain MDH.
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De Luna, Xavier, I.-Ni Hsieh, Mitchell White, and Kevan L. Hartshorn. "Exploring anti-viral and immunomodulatory activities of Regenerating Islet-Derived proteins." Journal of Immunology 200, no. 1_Supplement (2018): 168.3. http://dx.doi.org/10.4049/jimmunol.200.supp.168.3.
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Abstract The Regenerating Islet Derived Protein 3 (REG3) family are classified as antimicrobial peptides typically expressed in the gut epithelia of mammals, and help maintain host-bacteria homeostasis in our gastrointestinal tract. However, recent data has shown that the peptides are expressed in respiratory epithelia as well and play an important role in host defense in the lung against gram positive bacteria. The expression of one of the REG peptides in the lung is suppressed by IAV infection in mice and this contributes to bacterial superinfections which complicate influenza. REG3 peptides are classified as C-type lectins and our lab focuses on anti-microbial peptides as well as C-type lectins (mannose-binding lectin and surfactant protein D) and their function against Influenza A virus. Here I will be describing the previously unknown effects REG3 family of peptides on IAV infection. Preliminary data I have generated indicate that REG3 peptides inhibit the infectivity of IAV. I have compared the activity two different REG3 peptides and gained preliminary evidence that they not only inhibit viral infectivity but disrupt viral membranes (using electron microscopy) and alter viral interactions with epithelial cells using confocal microscopy. Of interest, the peptides also increase uptake of IAV by neutrophils and also increase neutrophil respiratory burst responses to the virus. These data suggest that REG proteins have significant and previously unknown effects to inhibit viral infectivity but also can modulate responsiveness of phagocyte to viruses
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Funderburk, Keaton E., Jungseog Kang та Henry J. Li. "Regulation of Life & Death by REGγ". Cells 11, № 15 (2022): 2281. http://dx.doi.org/10.3390/cells11152281.
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REGγ, a proteasome activator belonging to the 11S (otherwise known as REG, PA28, or PSME) proteasome activator family, is widely present in many eukaryotes. By binding to the 20S catalytic core particle, REGγ acts as a molecular sieve to selectively target proteins for degradation in an ATP- and ubiquitin-independent manner. This non-canonical proteasome pathway directly regulates seemingly unrelated cellular processes including cell growth and proliferation, apoptosis, DNA damage response, immune response, and metabolism. By affecting different pathways, REGγ plays a vital role in the regulation of cellular life and death through the maintenance of protein homeostasis. As a promoter of cellular growth and a key regulator of several tumor suppressors, many recent studies have linked REGγ overexpression with tumor formation and suggested the REGγ-proteasome as a potential target of new cancer-drug development. This review will present an overview of the major functions of REGγ as it relates to the regulation of cellular life and death, along with new mechanistic insights into the regulation of REGγ.
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Srikhanta, Yogitha N., Dianna M. Hocking, Judyta Praszkier, et al. "RegR Virulence Regulon of Rabbit-Specific Enteropathogenic Escherichia coli Strain E22." Infection and Immunity 81, no. 4 (2013): 1078–89. http://dx.doi.org/10.1128/iai.01325-12.
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ABSTRACTAraC-like regulators play a key role in the expression of virulence factors in enteric pathogens, such as enteropathogenicEscherichia coli(EPEC), enterotoxigenicE. coli, enteroaggregativeE. coli, andCitrobacter rodentium. Bioinformatic analysis of the genome of rabbit-specific EPEC (REPEC) strain E22 (O103:H2) revealed the presence of a gene encoding an AraC-like regulatory protein, RegR, which shares 71% identity to the global virulence regulator, RegA, ofC. rodentium. Microarray analysis demonstrated that RegR exerts 25- to 400-fold activation on transcription of several genes encoding putative virulence-associated factors, including a fimbrial operon (SEF14), a serine protease, and an autotransporter adhesin. These observations were confirmed by proteomic analysis of secreted and heat-extracted surface-associated proteins. The mechanism of RegR-mediated activation was investigated by using its most highly upregulated gene target,sefA. Transcriptional analyses and electrophoretic mobility shift assays showed that RegR activates the expression ofsefAby binding to a region upstream of thesefApromoter, thereby relieving gene silencing by the global regulatory protein H-NS. Moreover, RegR was found to contribute significantly to virulence in a rabbit infection experiment. Taken together, our findings indicate that RegR controls the expression of a series of accessory adhesins that significantly enhance the virulence of REPEC strain E22.
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Li, Bing, Yarong Lu, Coimbatore B. Srikant, Zu-Hua Gao, and Jun-Li Liu. "Intestinal adaptation and Reg gene expression induced by antidiabetic duodenal-jejunal bypass surgery in Zucker fatty rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 304, no. 7 (2013): G635—G645. http://dx.doi.org/10.1152/ajpgi.00275.2012.
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The antidiabetic mechanism of bariatric surgery includes specific changes in the secretion of incretins. To identify additional players originating from the gut, we evaluated the effects of duodenal-jejunal bypass (DJB) in morbidly obese Zucker fatty rats. A fast relief of hyperglycemia and hyperinsulinemia was achieved even before a significant weight loss occurred. Fourteen days after DJB, we characterized the changes in intestinal histochemistry in the bypassed duodenum and shortcut jejunum that was reanastomosed directly to the starting point of the duodenum and compared with the corresponding regions of sham-operated rats. The bypassed duodenum exhibited mucosal atrophy and apoptosis and decreased proliferative renewal. In shortcut jejunum, DJB resulted in 40% significantly enlarged intestinal circumference and increased epithelial proliferation, especially in putative transit-amplifying (TA) cells and the crypt. Because Reg family proteins promote cell growth and survival, we explored their expression in the intestine. With the use of immunohistochemistry, Reg1, -3α, and -3β were normally expressed in intestinal mucosa. After DJB, the level of Reg1 protein was reduced, whereas Reg3α and -3β were not changed in bypassed duodenum. Downstream in shortcut jejunum, the levels of Reg1 and -3β were greatly induced and especially concentrated in the putative TA cells. Our results revealed significant changes in the integrity and proliferation of the intestinal mucosa as a consequence of DJB, and in cell- and isoform-specific expression of Reg proteins within the replicating mucosal epithelium, and provide evidence indicating that the activation of Reg proteins may contribute to intestinal compensation against increased load and/or to improving insulin sensitivity.
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Samy, Eileen T., Lucy A. Parker, Colin P. Sharp, and Kenneth S. K. Tung. "Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node." Journal of Experimental Medicine 202, no. 6 (2005): 771–81. http://dx.doi.org/10.1084/jem.20041033.
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This study investigated the unresolved issue of antigen-dependency and antigen-specificity of autoimmune disease suppression by CD4+CD25+ T cells (T regs). Based on autoimmune ovarian disease (AOD) in day 3 thymectomized (d3tx) mice and polyclonal T regs expressing the Thy1.1 marker, we determined: (a) the location of recipient T cell suppression, (b) the distribution of AOD-suppressing T regs, and (c) the relative efficacy of male versus female T regs. Expansion of recipient CD4+ T cells, activation/memory marker expression, and IFN-γ production were inhibited persistently in the ovary-draining LNs but not elsewhere. The cellular changes were reversed upon Thy1.1+ T reg depletion, with emergence of potent pathogenic T cells and severe AOD. Similar changes were detected in the regional LNs during autoimmune dacryoadenitis and autoimmune prostatitis suppression. Although the infused Thy1.1+ T regs proliferated and were disseminated in peripheral lymphoid organs, only those retrieved from ovary-draining LNs adoptively suppressed AOD at a suboptimal cell dose. By depriving d3tx recipients of ovarian antigens, we unmasked the supremacy of ovarian antigen-exposed female over male T regs in AOD suppression. Thus, disease suppression by polyclonal T regs depends on endogenous antigen stimulation; this occurs in a location where potent antigen-specific T regs accumulate and continuously negate pathogenic T cell response.
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Xing, Shaojun, Kexin Gai, Xiang Li, et al. "Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells." Journal of Experimental Medicine 216, no. 4 (2019): 847–66. http://dx.doi.org/10.1084/jem.20182010.
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Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg–overrepresented signature genes such as Ikzf4 and Izumo1r. Unexpectedly, Tcf1 and Lef1 were necessary for restraining expression of cytotoxic CD8+ effector T cell–associated genes in T reg cells, including Prdm1 and Ifng. Tcf1 ChIP-seq revealed substantial overlap between Tcf1 and Foxp3 binding peaks in the T reg cell genome, with Tcf1-Foxp3 cooccupancy observed at key T reg signature and cytotoxic effector genes. Our data collectively indicate that Tcf1 and Lef1 are critical for sustaining T reg suppressive functions and preventing loss of self-tolerance.
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Wolf, Dennis, Teresa Gerhardt, Holger Winkels, et al. "Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B 100 –Reactive CD4 + T-Regulatory Cells." Circulation 142, no. 13 (2020): 1279–93. http://dx.doi.org/10.1161/circulationaha.119.042863.
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Background: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 + T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B 100 (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T H 1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 + T cells with an atheroprotective, regulatory T cell (T reg ) phenotype in healthy individuals. Yet, the function of apoB-reactive T regs and their relationship with pathogenic T H 1 cells remain unknown. Methods: To interrogate the function of autoreactive CD4 + T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B 978-993 (apoB + ) at the single-cell level. Results: We found that apoB + T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T reg -like transcriptome, although only 21% of all apoB + T cells expressed the T reg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB + T cells formed several clusters with mixed T H signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T H 1, T helper cell type 2 (T H 2), and T helper cell type 17 (T H 17), and of follicular-helper T cells. ApoB + T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T H 1/T H 17-like cells with proinflammatory properties and only a residual T reg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T H 1/T H 17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB + T regs in lineage tracing of hyperlipidemic Apoe –/– mice. In adoptive transfer experiments, converting apoB + T regs failed to protect from atherosclerosis. Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T regs as a novel cellular target in atherosclerosis.
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Volodarsky, Igor, Sara Shimoni, Dan Haberman, et al. "Circulating Regulatory B-Lymphocytes in Patients with Acute Myocardial Infarction: A Pilot Study." Journal of Cardiovascular Development and Disease 10, no. 1 (2022): 2. http://dx.doi.org/10.3390/jcdd10010002.
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Background: Inflammation plays on important role in plaque instability and acute coronary syndromes. The anti-inflammatory effects of B-regulatory lymphocytes (B-regs) in atherosclerosis was tested mainly in animal models with inconclusive results. Herein, we studied for the first time, levels of circulating B-regs in patients with acute myocardial infarction (MI). Methods: We examined circulating levels of B-regs by flow cytometry in 29 patients with recent ST-segment elevation MI and 18 patients with stable angina pectoris (SAP) and coronary artery disease. We re-assessed B-reg levels on average 4 months later. Results: The mean level of CD20+ cells was similar in patients with MI and patients with SAP (p = 0.60). The levels of CD24hiCD38hi cells among CD20+ cells were 5.7 ± 4% and 11.6 ± 6% in patients with MI and SAP, respectively, (p < 0.001). The level of CD24hiCD38hi B-regs remained related to acute MI after correcting for age, gender, and risk factors. Circulating levels of CD24hiCD38hi B-regs in patients with MI did not change significantly at follow-up in a small patient groups (p = 0.408). Conclusions: Circulating B-regs are reduced in patients with MI compared to patients with SAP. This finding may shed further light on the inflammatory pathophysiologic factors related to plaque rupture.
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Elsaghir, Alaa, Ehsan M. W. El-Sabaa, Asmaa M. Zahran, et al. "Elevated CD39+T-Regulatory Cells and Reduced Levels of Adenosine Indicate a Role for Tolerogenic Signals in the Progression from Moderate to Severe COVID-19." International Journal of Molecular Sciences 24, no. 24 (2023): 17614. http://dx.doi.org/10.3390/ijms242417614.
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Viral infections trigger inflammation by controlling ATP release. CD39 ectoenzymes hydrolyze ATP/ADP to AMP, which is converted by CD73 into anti-inflammatory adenosine (ADO). ADO is an anti-inflammatory and immunosuppressant molecule which can enhance viral persistence and severity. The CD39-CD73-adenosine axis contributes to the immunosuppressive T-reg microenvironment and may affect COVID-19 disease progression. Here, we investigated the link between CD39 expression, mostly on T-regs, and levels of CD73, adenosine, and adenosine receptors with COVID-19 severity and progression. Our study included 73 hospitalized COVID-19 patients, of which 33 were moderately affected and 40 suffered from severe infection. A flow cytometric analysis was used to analyze the frequency of T-regulatory cells (T-regs), CD39+ T-regs, and CD39+CD4+ T-cells. Plasma concentrations of adenosine, IL-10, and TGF-β were quantified via an ELISA. An RT-qPCR was used to analyze the gene expression of CD73 and adenosine receptors (A1, A2A, A2B, and A3). T-reg cells were higher in COVID-19 patients compared to healthy controls (7.4 ± 0.79 vs. 2.4 ± 0.28; p < 0.0001). Patients also had a higher frequency of the CD39+ T-reg subset. In addition, patients who suffered from a severe form of the disease had higher CD39+ T-regs compared with moderately infected patients. CD39+CD4+ T cells were increased in patients compared to the control group. An analysis of serum adenosine levels showed a marked decrease in their levels in patients, particularly those suffering from severe illness. However, this was paralleled with a marked decline in the expression levels of CD73. IL-10 and TGF-β levels were higher in COVID-19; in addition, their values were also higher in the severe group. In conclusion, there are distinct immunological alterations in CD39+ lymphocyte subsets and a dysregulation in the adenosine signaling pathway in COVID-19 patients which may contribute to immune dysfunction and disease progression. Understanding these immunological alterations in the different immune cell subsets and adenosine signaling provides valuable insights into the pathogenesis of the disease and may contribute to the development of novel therapeutic approaches targeting specific immune mechanisms.
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Camacho, Virginia, Sam Wolock, Danielle Tenen, and Robert Welner. "Distinct tissue specific functions for bone marrow regulatory T cells." Journal of Immunology 200, no. 1_Supplement (2018): 103.5. http://dx.doi.org/10.4049/jimmunol.200.supp.103.5.
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Abstract While the influence of T-regs has been explored in numerous contexts, their role within the bone marrow (BM) has not been elucidated. In this study, we establish that BM derived T-regs represent a specialized population with a tissue-specific role. Functional homing assays demonstrate that BM T-regs preferentially traffic back to this site, revealing that specific signaling cues recruit T-regs to this microenvironment. This is supported by RNA-seq data showing that the chemokine and cytokine receptor profiles of BM T-regs differ from T-regs in secondary lymphoid tissues. BM Tregs are also characterized by a higher expression of CD127/IL7Ra conventionally not expressed on peripheral T-regs. Depletion of Tregs via anti-CD25 treatment has widespread effects across several BM populations, especially the stem cell compartment. Loss of T-regs results in increased HSC cycling and proliferation, while fostering myeloid skewed differentiation. Key stem cell features including repopulation capacity and dormancy are also disrupted. Moreover, supportive niche populations are also altered by Treg depletion, as evidenced by increased cycling and proliferation of stromal cells. Non-genotoxic conditioning and transplantation, reveals that the T-reg depleted microenvironment is less supportive of HSCs, thus establishing a novel role for Tregs in maintaining niche function. Remarkably, the effects of Treg depletion are found to be longlasting. In the absence of continued treatment, cohorts sustain a myeloid bias, as well as increased numbers of HSCs and stromal cells. These observations support the conclusion that BM T-regs represent a unique subset that maintains numerous populations and have a specialized function within this tissue.
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Maziarz, Marcin, Aishwarya Shevade, LaKisha Barrett, and Sergei Kuchin. "Springing into Action: Reg2 Negatively Regulates Snf1 Protein Kinase and Facilitates Recovery from Prolonged Glucose Starvation in Saccharomyces cerevisiae." Applied and Environmental Microbiology 82, no. 13 (2016): 3875–85. http://dx.doi.org/10.1128/aem.00154-16.
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ABSTRACTGlucose is the preferred carbon source for the yeastSaccharomyces cerevisiae. Glucose limitation activates Snf1 protein kinase, a key regulator of energy homeostasis that promotes utilization of alternative carbon sources and enforces energy conservation. Snf1 activation requires phosphorylation of its T-loop threonine (Thr210) by upstream kinases. When glucose is abundant, Snf1 is inhibited by Thr210 dephosphorylation. This involves the function of the type 1 protein phosphatase Glc7, which is targeted to Snf1 by a regulatory subunit, Reg1. Thereg1mutation causes increased Snf1 activity and mimics various aspects of glucose limitation, including slower growth. Reg2 is another Glc7 regulatory subunit encoded by a paralogous gene,REG2. Previous evidence indicated that thereg2mutation exacerbates the Snf1-dependent slow-growth phenotype caused byreg1, suggesting a link between Reg2 and Snf1. Here, we explore this link in more detail and present evidence that Reg2 contributes to Snf1 Thr210 dephosphorylation. Consistent with this role, Reg2 interacts with wild-type Snf1 but not with nonphosphorylatable Snf1-T210A. Reg2 accumulation increases in a Snf1-dependent manner during prolonged glucose deprivation, and glucose-starved cells lacking Reg2 exhibit delayed Snf1 Thr210 dephosphorylation and slower growth recovery upon glucose replenishment. Accordingly, cells lacking Reg2 are outcompeted by wild-type cells in the course of several glucose starvation/replenishment cycles. Collectively, our results support a model in which Reg2-Glc7 contributes to the negative control of Snf1 in response to glucose refeeding after prolonged starvation. The competitive growth advantage provided by Reg2 underscores the evolutionary significance of this paralog forS. cerevisiae.IMPORTANCEThe ability of microorganisms to respond to stress is essential for their survival. However, rapid recovery from stress could be equally crucial in competitive environments. Therefore, a wise stress response program should prepare cells for quick recovery upon reexposure to favorable conditions. Glucose is the preferred carbon source for the yeastS. cerevisiae. Glucose depletion activates the stress response protein kinase Snf1, which functions to limit energy-consuming processes, such as growth. We show that prolonged glucose deprivation also leads to Snf1-dependent accumulation of Reg2 and that this protein helps to inhibit Snf1 and to accelerate growth recovery upon glucose replenishment. Cells lacking Reg2 are readily outcompeted by wild-type cells during glucose depletion/replenishment cycles. Thus, while prolonged glucose deprivation might seem to put yeast cells “on their knees,” concomitant accumulation of Reg2 helps configure the cells into a “sprinter's crouch start position” to spring into action once glucose becomes available.
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Bauer, Carl, Sylvie Elsen, Lee R. Swem, Danielle L. Swem, and Shinji Masuda. "Redox and light regulation of gene expression in photosynthetic prokaryotes." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 358, no. 1429 (2003): 147–54. http://dx.doi.org/10.1098/rstb.2002.1189.
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All photosynthetic organisms control expression of photosynthesis genes in response to alterations in light intensity as well as to changes in cellular redox potential. Light regulation in plants involves a well–defined set of red– and blue–light absorbing photoreceptors called phytochrome and cryptochrome. Less understood are the factors that control synthesis of the plant photosystem in response to changes in cellular redox. Among a diverse set of photosynthetic bacteria the best understood regulatory systems are those synthesized by the photosynthetic bacterium Rhodobacter capsulatus . This species uses the global two–component signal transduction cascade, RegB and RegA, to anaerobically de–repress anaerobic gene expression. Under reducing conditions, the phosphate on RegB is transferred to RegA, which then activates genes involved in photosynthesis, nitrogen fixation, carbon fixation, respiration and electron transport. In the presence of oxygen, there is a second regulator known as CrtJ, which is responsible for repressing photosynthesis gene expression. CrtJ responds to redox by forming an intramolecular disulphide bond under oxidizing, but not reducing, growth conditions. The presence of the disulphide bond stimulates DNA binding activity of the repressor. There is also a flavoprotein that functions as a blue–light absorbing anti–repressor of CrtJ in the related bacterial species Rhodobacter sphaeroides called AppA. AppA exhibits a novel long–lived photocycle that is initiated by blue–light absorption by the flavin. Once excited, AppA binds to CrtJ thereby inhibiting the repressor activity of CrtJ. Various mechanistic aspects of this photocycle will be discussed.
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Baessato, Francesca, Laura Fusini, Manuela Muratori, et al. "Echocardiography vs. CMR in the Quantification of Chronic Mitral Regurgitation: A Happy Marriage or Stormy Divorce?" Journal of Cardiovascular Development and Disease 10, no. 4 (2023): 150. http://dx.doi.org/10.3390/jcdd10040150.
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Quantification of chronic mitral regurgitation (MR) is essential to guide patients’ clinical management and define the need and appropriate timing for mitral valve surgery. Echocardiography represents the first-line imaging modality to assess MR and requires an integrative approach based on qualitative, semiquantitative, and quantitative parameters. Of note, quantitative parameters, such as the echocardiographic effective regurgitant orifice area, regurgitant volume (RegV), and regurgitant fraction (RegF), are considered the most reliable indicators of MR severity. In contrast, cardiac magnetic resonance (CMR) has demonstrated high accuracy and good reproducibility in quantifying MR, especially in cases with secondary MR; nonholosystolic, eccentric, and multiple jets; or noncircular regurgitant orifices, where quantification with echocardiography is an issue. No gold standard for MR quantification by noninvasive cardiac imaging has been defined so far. Only a moderate agreement has been shown between echocardiography, either with transthoracic or transesophageal approaches, and CMR in MR quantification, as supported by numerous comparative studies. A higher agreement is evidenced when echocardiographic 3D techniques are used. CMR is superior to echocardiography in the calculation of the RegV, RegF, and ventricular volumes and can provide myocardial tissue characterization. However, echocardiography remains fundamental in the pre-operative anatomical evaluation of the mitral valve and of the subvalvular apparatus. The aim of this review is to explore the accuracy of MR quantification provided by echocardiography and CMR in a head-to-head comparison between the two techniques, with insight into the technical aspects of each imaging modality.
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Drokov, Mikhail Yu, Elena N. Parovichnikova, Julia Davydova, et al. "Granzyme B Expression in T-Regulatory Cells Is a Strong Predictor of Acute Graft-Versus-Host Disease after Day +30 in Patients with "Classic" Immunosuppression after Allo-HSCT." Blood 128, no. 22 (2016): 2238. http://dx.doi.org/10.1182/blood.v128.22.2238.2238.
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Abstract Introduction. Granzyme B is a serine protease commonly found in the granules of cytotoxic lymphocytes and natural killer cells. It is secreted with the pore forming protein perforin and mediates apoptosis in target cells. Granzyme B mediated cytolysis is one of the regulatory mechanisms (together with IL-2 receptors (CD25)) by which T-regulatory cells (T-regs) influence on T-effectors cells. Despite the well-known fact that T-regs participate in pathogenesis of aGVHD and their amount after allo-HSCT inversely correlates with the probability of aGVHD incidence, data about functional status of T-regs and aGVHD is still limited. Patients and methods. Peripheral blood samples were collected in EDTA-tubes at day +30 after allo-HSCT. We use PBMC from 29 patients with hematological malignancies obtained by density gradient media. This method was used due to lymphopenia in this group of patients. Group with no aGVHD consist of 22 patients (AML=12, ALL n=5, LPD=1, CML=2, AA=1, MDS=1) after allo-HSCT n=17 from MUD, n=5 from mismatch unrelated donor. MAC conditioning regimen was used in 17 cases, 5 patients receive RIC. The group of aGVHD after day +30 include 7 patients. (AML=4, ALL n=3) after allo-HSCT from MUD (n=5), mismatch unrelated donor (n=1) and n=1 from sibling HLA-identical donor. Two patients receive MAC and 5 patients receive RIC conditioning regimen. All patients in both groups receive standard immunosuppression (MMF+CSA+ATG). All patients developed II-IV grade aGVHD (II (n=1); III (n=4); IV (n=2)) with a median time onset on day +50 (34-150). The anti-CD4-APC-Cy7, anti-CD25-APC, anti-CD127-FITC and anti-Granzyme B-PE (Becton Dickinson, USA) antibodies were used to determine T-regulatory cells population. A Bland-Altman plot (difference plot) was used in analyzing the agreement between the two different methods of T-regs assay (CD4+CD25high and CD4+CD25highCD127low) - differences were not found (p=0,942). Due to this fact in our experiments CD4+CD25high cells were identified as T-reg cells (Gregg et al., 2005). 30000 of CD4+ cells were analyzed on a BD FACSCanto II to achieve sufficient statistical power (Becton Dickinson, USA). Results. As we can see on chart 1 level of Granzyme B was higher in patients who never developed aGVHD. In accordance with chart 2 percentage of Granzyme B positive T-regs in group of patients who never developed aGVHD was 7,26±1,89% in comparison with 2,04±0,93% in group who developed aGVHD after day +30 (p=0,02*). We should note that according to our previous experiments bacterial or viral infection (e.g CMV) and HLA-disparity does not affect the level of granzyme B expression in T-regs. Using ROC- curve analysis (see Chart 3) we obtained area under curve (AUC) 0,74. Conclusion. Our data shows that Granzyme B in T-reg cells after allo-HSCT in patients with standard IST may predict aGVHD onset after day +30 with satisfactory test results (AUC=0,74, «cut-off» - 4,15%; sensitivity - 85,71%; specificity - 45,45%).). According to data of our transplant center (for 2006-2016), "granzyme B-based strategy" can help us to predict up to 47,3% of all aGVHD. Disclosures: No relevant conflicts of interest to declare. Chart 1: Example of Granzyme B expression (right; shown on horizontal axis) in T-regs (left; upper right quadrant) on day +30 after allo-HSCT in group with standard immunosuppression Chart 2: Percentage of Granzyme B positive T-reg cells in patient without aGVHD and patients who develop aGVHD after day +30. Chart 3: ROC curve analysis of Granzyme B in T-regs as predictor of aGVHD. Figure Figure. Figure Figure. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Kaushik, Ekata, Vivek Prakash, Om Prakash Mahela, et al. "Optimal Placement of Renewable Energy Generators Using Grid-Oriented Genetic Algorithm for Loss Reduction and Flexibility Improvement." Energies 15, no. 5 (2022): 1863. http://dx.doi.org/10.3390/en15051863.
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Optimal planning of renewable energy generator (REG) units helps to meet future power demand with improved flexibility. Hence, this paper proposes a grid-oriented genetic algorithm (GOGA) based on a hybrid combination of a genetic algorithm (GA) and a solution using analytical power flow equations for optimal sizing and placement of REG units in a power system network. The objective of the GOGA is system loss minimization and flexibility improvement. The objective function expresses the system losses as a function of the power generated by different generators, using the Kron equation. A flexibility index (FI) is proposed to evaluate the improvement in the flexibility, based on the voltage deviations and system losses. A power flow run is performed after placement of REGs at various buses of the test system, and system losses are computed, which are considered as chromosome fitness values. The GOGA searches for the lowest value of the fitness function by changing the location of REG units. Crossover, mutation, and replacement operators are used by the GOGA to generate new chromosomes until the optimal solution is obtained in terms of size and location of REGs. A study is performed on a part of the practical transmission network of Rajasthan Rajya Vidyut Prasaran Nigam Ltd. (RVPN), India for the base year 2021 and the projected year 2031. Load forecasting for the 10-year time horizon is computed using a linear fit mathematical model. A cost–benefit analysis is performed, and it is established that the proposed GOGA provides a financially viable solution with improved flexibility. It is established that GOGA ensures high convergence speed and good solution accuracy. Further, the performance of the GOGA is superior compared to a conventional GA.
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Sawaki, A., R. Takayama, N. Mizuno, et al. "Serum REG4 protein in pancreatic cancer as a tumor marker: A prospective study." Journal of Clinical Oncology 25, no. 18_suppl (2007): 15063. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15063.
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15063 Background: Pancreatic cancer (PC) shows the worst mortality rate in common malignancies, with 5-year survival rate of 4%. The only way to cure the disease is surgical resection of early stage PC. Establishment of a screening strategy to detect early stage PC is eagerly expected. REG4, a member of the regenerating islet-derived (REG) family, are secreted proteins that play a role in tissue regeneration and inflammation in digestive organs. We reported overexpression of REG4 in PC cells and serum, and preliminary data of the serum REG4 level of pancreatic disease patients including PC patients. We conducted a prospective study to evaluate the role of serum REG4 in PC. Methods: The series included 57 patients diagnosed pathologically as PC between November 2004 and December 2005. Serum REG4 was quantified by standard sandwich ELISA (Enzyme Linked Immunosorbent Assay) using original kit (MBL116: provided by Medical and Biological Laboratories Co., LTD, Japan) before treatment. The upper limit of the test was set at 3.52ng/ml and was based on studies of serum from 48 healthy control subjects. Results: With a specificity of 100%, the diagnostic sensitivity and accuracy were 63.2% and 80.0%, respectively. The ROC (receiver operating characteristic) analysis showed that area under the curve was 0.91. REG4 levels were a significant differences between PC and control (p<0.001), between each T stage and control (T1,T2, T3 or T4 v control), and between each TMN stage and control (stage 1, stage 2, stage 3 or stage 4 v control), but were not a statistical significance with T stage (T1 v T2 v T3 v T4), M stage (M0 v M1) or TNM stage (stage 1 v stage 2 v stage 3 v stage 4) in PC patients. The diagnostic sensitivity of carcinoembryonic antigen (CEA>5.0ng/ml) and carbohydrate antigen19–9 (CA19–9>50U/ml) was 56.5% and 68.4%, respectively. No significant correlation was demonstrated between REG4 and CA19–9 (coefficient of correlation [rs]=0.45). Conclusions: This study shows the potential of serum REG4 as a screening test for PC, especially for early PC. REG4 is considered to be a more useful marker in combination with CA19- 9. No significant financial relationships to disclose.
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Liao, Hsien-Tzung, and Chang-Youh Tsai. "Cytokines and regulatory T cells in ankylosing spondylitis." Bone & Joint Research 12, no. 2 (2023): 133–37. http://dx.doi.org/10.1302/2046-3758.122.bjr-2022-0195.r1.
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AimsTo investigate the correlations among cytokines and regulatory T cells (T-regs) in ankylosing spondylitis (AS) patients, and their changes after anti-tumour necrosis factor-α (TNF-α) treatment.MethodsWe included 72 AS patients with detailed medical records, disease activity score (Bath Ankylosing Spondylitis Disease Activity Index), functional index (Bath Ankylosing Spondylitis Functional Index), and laboratory data (interleukin (IL)-2, IL-4, IL-10, TNF-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, ESR, and CRP). Their peripheral blood mononuclear cells (PBMCs) were marked with anti-CD4, anti-CD25, and anti-FoxP3 antibodies, and triple positive T cells were gated by flow cytometry as T-regs. Their correlations were calculated and the changes after anti-TNF-α therapy were compared.ResultsThe frequency of T-regs in PBMCs was positively correlated to ESR and CRP in AS (r = 0.35 and 0.43; p = 0.032 and 0.027, respectively), and there was also a significant correlation between serum level of TNF-α and CRP (p = 0.041). The frequency of T-regs in PBMCs positively correlated to serum levels of TNF-α, IL-10, and TGF-β, while IL-2, IL-4, and IFN-γ showed opposite results. After anti-TNF-α treatment, there were significantly lower serum levels of TNF-α, IL-10, TGF-β, and frequency of T-regs in PBMCs among these AS patients (p = 0.026, 0.032, 0.029, and 0.037, respectively).ConclusionIn AS patients, proinflammatory cytokine may give positive feedback to induce more T-reg production and anti-inflammatory cytokine secretion to suppress this inflammatory status, and they can be reversed by anti-TNF-α therapy. However, the detailed interactions among T-regs and complex cytokine networks in autoinflammatory diseases still need more studies and further functional assay.Cite this article: Bone Joint Res 2023;12(2):133–137.
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Tadmor, Tamar, Yu Zhang, Robert Dunn, Seung-uon Shin, Hyung-Mee Cho, and Joseph Rosenblatt. "B Cell Depletion Reduces the Number and Function of T- Regulatory Cells and Enhances the Anti Tumor response." Blood 114, no. 22 (2009): 3668. http://dx.doi.org/10.1182/blood.v114.22.3668.3668.
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Abstract Abstract 3668 Poster Board III-604 Increasing evidence suggests that B lymphocytes play a central role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are still poorly understood. In this study, we investigated how the presence or absence of B cells affects expansion and function of T- regulatory cells (‘Tregs’) in a murine tumor model (EMT-6). We compared tumor growth, and the number and function of T- regs cells in wild type immune competent mice ( ICM), B cell deficient mice ( BCDM) and /or in BALB-C mice following B- cell depletion induced by injection of anti murine CD20 antibodies (mCD20 Ab, 18B12, mouse IgG1,k, Biogen-IDEC) Mice were either tumor-naïve or implanted with EMT6 mammary adenocarcinoma cells. Absence of B cells as in BCDM completely inhibited tumor growth in the majority of mice, while B cell depletion in normal mice substantially slowed the growth of EMT-6 tumors compared to wild type mice (ICM). Substantial T regs expansion, as defined by CD4+/CD25+/FOXP3+ cells, was evident on day 26 post tumor inoculation in EMT-6 tumor bearing ICM in comparison to the non- tumor bearing mice ( 15.2 +/− 1.2. % and 11.9 +/− 1.1% respectively), isolated from spleen as compared to naïve or tumor bearing BCDM (10.1+/− 0.2% and 10.8+/− 1.2%) The percentage and absolute number of T-regs in the spleen, tumor draining lymph nodes and tumor bed were significantly reduced in the BCDM and/or B cell depleted ICM compared to tumor bearing ICM (10%+/−0.8, 13.9+/− 1.23% and 17+/− 1.3% respectively p<0.01. data from single cell suspensions isolated from spleens on day 20 post tumor inoculation). Similar effects of B cell depletion on the numbers of T-regs were observed in the setting of pre-established EMT6 mammary tumors. In contrast to tumor bearing mice, differences in T-reg number and function were minimal in tumor free B cell deficient or in B cell depleted naïve mice compared to ICM. T-reg function, measured by suppression assay and proliferation assays, was also markedly reduced in tumor bearing BCDM compared to ICM. Combining B cell and T-reg depletion using i.p. injection of anti CD 25 antibody (PC61 or PBS) resulted in similar rates of tumor regression in B cell depleted mice as were seen in BCDM suggesting that the combination of B cells depletion and further depletion of Tregs augmented anti-tumor response. In conclusion, our studies indicate that B cell depletion may play a useful role in augmenting the T cell anti-tumor response, in part due to their effects on T-regulatory cell biology. Disclosures: Dunn: Biogen IDEC: Employment.
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Semple, John W., Daoxin Ma, Rukhsana Aslam, Ming Hou, Heyu Ni, and Yu Hu. "Human and Murine Immune Thrombocytopenia (ITP) Is Associated with a Peripheral Deficiency of CD4- T Regulatory Cells (Tc-regs)." Blood 120, no. 21 (2012): 3333. http://dx.doi.org/10.1182/blood.v120.21.3333.3333.
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Abstract Abstract 3333 CD8+ T suppressor cells were originally described by Gershon on Kondo more than 40 years ago, however, because of difficulties in their characterization, they fell out of favor for decades. T suppression was resurrected by the discovery of CD4+ CD25+ FoxP3+ T regulatory cells as being the critical cell in the maintenance of self tolerance. Recently, a non-conventional CD4-CD25+FoxP3+ T cell subset termed Tc regulatory cells (Tc-regs) has been described that are also important in inducing tolerance against self. A peripheral CD4+ Treg deficiency has been suggested to be the potential cause of ITP, however, the role of this newly described CD4- T cell population has not been determined. To address the role of these cells, we studied lymphocyte responses in 36 patients with ITP (18 newly-diagnosed and 18 in remission) and a murine model of ITP. Peripheral blood mononuclear cells from patients or spleens and thymi from mice were isolated and FoxP3 expressing Tc-regs were evaluated by flow cytometry. Results show that compared with healthy control subjects, the percentages of peripheral Tc-regs in newly diagnosed patients with ITP were significantly decreased. The Tc-reg deficiency was rescued in those patients in remission due to therapy. Similar results were observed in an active model of murine ITP. Additionally, the murine model of ITP revealed that the CD4- deficient population expressed CD8. These results suggest that, like CD4+ T regs, there is a significant reduction in peripheral Tc-regs in both human and murine ITP and disease remission correlates with rescuing the deficiency. Disclosures: No relevant conflicts of interest to declare.
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Esser, Karyn. "AGE-ASSOCIATED DECLINE IN TISSUE CIRCADIAN CLOCK FUNCTION." Innovation in Aging 7, Supplement_1 (2023): 511. http://dx.doi.org/10.1093/geroni/igad104.1679.
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Abstract Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes but these changes exhibit tissue specific patterns. In general, aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. These REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. We determined there were tissue specific changes in the phase distribution of REGs with the hypothalamus and skeletal muscle tissues of the old mice showing a large reduction with REG peak expression at only one phase of the day. Analyzing all expressed genes within a tissue for differences at four distinct times of day identified unique clusters of differentially expressed genes (DEGs). These outcomes identify non-circadian but temporally distinct age associated changes in gene expression. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.
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Sharma, Rajni, Manju Kumari, Suman Mishra, et al. "Exosomes Secreted by Umbilical Cord Blood-Derived Mesenchymal Stem Cell Attenuate Diabetes in Mice." Journal of Diabetes Research 2021 (December 10, 2021): 1–15. http://dx.doi.org/10.1155/2021/9534574.
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Mesenchymal stem cell (MSC) therapy is an innovative approach in diabetes due to its capacity to modulate tissue microenvironment and regeneration of glucose-responsive insulin-producing cells. In this study, we investigated the role of MSC-derived exosomes in pancreatic regeneration and insulin secretion in mice with streptozotocin-induced diabetes. Mesenchymal stem cells (MSCs) were isolated and characterized from umbilical cord blood (UCB). Exosomes were isolated and characterized from these MSCs. Diabetes was induced in male C57Bl/6 mice by streptozotocin (STZ; 40 mg/kg body weight, i.p.) for five consecutive days. The diabetic mice were administered (i.v.) with MSC ( 1 × 10 5 umbilical cord blood MSC cells/mice/day), their derived exosomes (the MSC-Exo group that received exosomes derived from 1 × 10 5 MSC cells/mice/day), or the same volume of PBS. Before administration, the potency of MSCs and their exosomes was evaluated in vitro by T cell activation experiments. After day 7 of the treatments, blood samples and pancreatic tissues were collected. Histochemistry was performed to check cellular architecture and β cell regeneration. In body weight, blood glucose level, and insulin level, cell proliferation assay was done to confirm regeneration of cells after MSC and MSC-Exo treatments. Hyperglycemia was also attenuated in these mice with a concomitant increase in insulin production and an improved histological structure compared to mice in the PBS-treated group. We found increased expression of genes associated with tissue regeneration pathways, including Reg2, Reg3, and Amy2b in the pancreatic tissue of mice treated with MSC or MSC-Exo relative to PBS-treated mice. MicroRNA profiling of MSC-derived exosomes showed the presence of miRs that may facilitate pancreatic regeneration by regulating the Extl3-Reg-cyclinD1 pathway. These results demonstrate a potential therapeutic role of umbilical cord blood MSC-derived exosomes in attenuating insulin deficiency by activating pancreatic islets’ regenerative abilities.
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Bauer, Evelyne, Thomas Kaspar, Hans-Martin Fischer, and Hauke Hennecke. "Expression of the fixR-nifA Operon inBradyrhizobium japonicum Depends on a New Response Regulator, RegR." Journal of Bacteriology 180, no. 15 (1998): 3853–63. http://dx.doi.org/10.1128/jb.180.15.3853-3863.1998.
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ABSTRACT Many nitrogen fixation-associated genes in the soybean symbiontBradyrhizobium japonicum are regulated by the transcriptional activator NifA, whose activity is inhibited by aerobiosis. NifA is encoded in the fixR-nifAoperon, which is expressed at a low level under aerobic conditions and induced approximately fivefold under low-oxygen tension. This induction depends on a −24/−12-type promoter (fixRp 1) that is recognized by the ς54 RNA polymerase and activated by NifA. Low-level aerobic expression and part of the anaerobic expression originates from a second promoter (fixRp 2) that overlaps withfixRp 1 and depends on an upstream DNA region (UAS) located around position −68 (H. Barrios, H. M. Fischer, H. Hennecke, and E. Morett, J. Bacteriol. 177:1760–1765, 1995). A protein binding to the UAS was previously postulated to act as an activator. This protein has now been purified, and the corresponding gene (regR) has been cloned. On the basis of the predicted amino acid sequence, RegR belongs to the family of response regulators of two-component regulatory systems. We identified upstream of the regR gene an additional gene (regS) encoding a putative sensor kinase. AregR mutant was constructed in which neither a specific UAS-binding activity nor fixRp 2-dependent transcript formation and fixR′-′lacZ expression was detected in aerobically grown cells. Anaerobic fixR′-′lacZexpression was also decreased in regR mutants to about 10% of the level observed in the wild type. Similarly, regRmutants showed only about 2% residual nitrogen fixation activity, but unlike nodules induced by nifA mutants, the morphology of those nodules was normal, displaying no signs of necrosis. WhileregR mutants grew only slightly slower in free-living, aerobic conditions, they displayed a strong growth defect under anaerobic conditions. The phenotypic properties of regSmutants differed only marginally, if at all, from those of the wild type, suggesting the existence of a compensating sensor activity in these strains. The newly identified RegR protein may be regarded as a master regulator in the NifA-dependent network controllingnif and fix gene expression in B. japonicum.
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Ragni, Margaret V., Lynn M. Malec, Craig D. Seaman, and Lisa Butterfield. "Regulatory T Cell Response to Factor VIII in Mothers of Children with Hemophilia Inhibitors." Blood 126, no. 23 (2015): 3512. http://dx.doi.org/10.1182/blood.v126.23.3512.3512.
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Abstract Background: Inhibitor formation is among the most serious complications of hemophilia A. These alloantibodies are directed against foreign infused factor VIII (FVIII) and occur in up to 25-30% of children with severe hemophilia A, after the first 9-10 exposures to FVIII. The inhibitor neutralizes infused FVIII, requiring alternative "bypass" therapy to treat bleeds, e.g. factor VIIa or FEIBA, to "bypass" the missing factor, and immune tolerance to suppress the inhibitor. Despite these approaches, bleeding is poorly controlled, resulting in 2-fold as many hospitalizations, 10-fold the cost, and 1.7-fold higher mortality. As the burden of disease is high, efforts have been directed at preventing inhibitors. There is increasing evidence that a specialized subset of T cells known as T-regs or CD4+/CD25+/FoxP3+ regulatory T cells, may play a role in mediating immune response to FVIII. Differentiation and function of T-regs are controlled by the X-chromosome-encoded transcription factor, FoxP3, and are generated centrally in the thymus and peripherally in extrathymic tissues. In the inhibitor-prone hemophilia A mouse (FVIII exon 16 knockout) T-regs reduce or prevent immune response to factor VIII: this is presumed to occur through T-reg-mediated hyporesponsiveness of T helper cells to factor VIII. T-regs also mediate maternal tolerance to the fetus in normal pregnancy. In early pregnancy there is an increase in immunosuppressive T-regs, peaking during the second trimester, and declining postpartum. T-regs are hypothesized to modify maternal immune response to the fetal "allograft" to promote tolerance to foreign paternal-derived antigens in the developing fetus. We hypothesized that defects in maternal T regulatory response to factor VIII might be associated with lack of normal FVIII tolerance in their offspring, leading to an alloantibody response, i.e. inhibitor formation. We therefore sought to quantitate and functionally characterize T-regs in mothers of children with congenital hemophilia A with inhibitors, in order to determine if maternal lack of tolerance to FVIII is associated with inhibitor formation in their affected sons. Methods: Following informed consent, heparinized tubes were drawn from four mothers of hemophilic children, two with and two without inhibitors, cared for at the Hemophilia Center of Western PA (HCWP). T-reg responses to factor VIII were quantitated by flow cytometry, and phenotyping was performed by staining with anti-CD4/Foxp3/CD3/CD25/CD39 monoclonal antibody markers. Functional characteristics of the T-regs were determined in a T-reg proliferation assay using autologous antigen presenting cells (DCs) in the presence or absence of FVIII. Results: CD4+ T cell proliferative responses to factor VIII (FVIII) were decreased in all four mothers (Figure 1). Mothers of hemophilic sons with inhibitors demonstrated a 1.36-fold decrease (Pt 001) and a 1.1-fold decrease (Pt 002), as compared with mothers of hemophilic sons without inhibitors, who demonstrated a 1.47-fold decrease (Pt 003) and a 1.45-fold decrease (Pt 005) in CD4+ proliferative responses, unlike the two healthy donors who showed minimal (or no) factor VIII response. Patients showed slightly less proliferation with Factor VIII vs. no antigen; healthy donors showed minimal (or no) Factor VIII response (Figure 1). Discussion: These preliminary results demonstrate lower T cell proliferative responses to FVIII in mothers of children with inhibitor patients than in mother of children without inhibitors. This suggests there is lack of tolerance to FVIII in mothers of children with hemophilia, with or without inhibitors. These responses would also imply these mothers have no tolerance to paternal FVIII, but further studies will be needed to confirm these findings and to characterize maternal T regulatory response to factor VIII, and, in particular, paternal FVIII. Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Figure 1. Percent CD4+ T Helper Cell Proliferation +/- Factor VIII (FVIII) Disclosures Ragni: Alnylam: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Biogen: Research Funding; SPARK: Research Funding; Pfizer: Research Funding; Ferring Pharmceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Medscape, Web MD: Honoraria; Genentech Roche: Research Funding; Vascular Medicine Institute: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; CSL Behring: Research Funding; Dimension Therapeutics: Research Funding; Biomarin: Research Funding. Malec:Biogen: Research Funding; Baxalta: Research Funding. Seaman:Vascular Medicine Institute: Research Funding.
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Kaptein, Steven J., Koen J. van de Wal, Leon P. J. Kamp, Vincenzo Armenio, Herman J. H. Clercx, and Matias Duran-Matute. "Analysis of one-dimensional models for exchange flows under strong stratification." Ocean Dynamics 70, no. 1 (2019): 41–56. http://dx.doi.org/10.1007/s10236-019-01320-z.
Full textAbstract:
AbstractOne-dimensional models of exchange flows driven by horizontal density gradients are well known for performing poorly in situations with weak turbulent mixing. The main issue with these models is that the horizontal density gradient is usually imposed as a constant, leading to non-physically high stratification known as runaway stratification. Here, we propose two new parametrizations of the horizontal density gradient leading to one-dimensional models able to tackle strongly stratified exchange flows at high and low Schmidt number values. The models are extensively tested against results from laminar two-dimensional simulations and are shown to outperform the models using the classical constant parametrization for the horizontal density gradients. Four different flow regimes are found by exploring the parameter space defined by the gravitational Reynolds number Reg, the Schmidt number Sc, and the aspect ratio of the channel Γ. For small values of RegΓ, when diffusion dominates, all models perform well. However, as RegΓ increases, two clearly distinct regimes emerge depending on the Sc value, with an equally clear distinction of the performance of the one-dimensional models.