Sample records for factor hnf 4-gamma
-
Phenotypic screening of hepatocyte nuclear factor (HNF) 4-{gamma} receptor knockout mice
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gerdin, Anna Karin; Surve, Vikas V.; Joensson, Marie
2006-10-20
Using the mouse as a model organism in pharmaceutical research presents unique advantages as its physiology in many ways resembles the human physiology, it also has a relatively short generation time, low breeding and maintenance costs, and is available in a wide variety of inbred strains. The ability to genetically modify mouse embryonic stem cells to generate mouse models that better mimic human disease is another advantage. In the present study, a comprehensive phenotypic screening protocol is applied to elucidate the phenotype of a novel mouse knockout model of hepatocyte nuclear factor (HNF) 4-{gamma}. HNF4-{gamma} is expressed in the kidneys,more » gut, pancreas, and testis. First level of the screen is aimed at general health, morphologic appearance, normal cage behaviour, and gross neurological functions. The second level of the screen looks at metabolic characteristics and lung function. The third level of the screen investigates behaviour more in-depth and the fourth level consists of a thorough pathological characterisation, blood chemistry, haematology, and bone marrow analysis. When compared with littermate wild-type mice (HNF4-{gamma}{sup +/+}), the HNF4-{gamma} knockout (HNF4-{gamma}{sup -/-}) mice had lowered energy expenditure and locomotor activity during night time that resulted in a higher body weight despite having reduced intake of food and water. HNF4-{gamma}{sup -/-} mice were less inclined to build nest and were found to spend more time in a passive state during the forced swim test.« less
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ferre, Silvia; Veenstra, Gert Jan C.; Bouwmeester, Rianne
2011-01-07
Research highlights: {yields} Defects in HNF-1B transcription factor affect Mg{sup 2+} handling in the distal kidney. {yields} {gamma}a- and {gamma}b- subunits of the Na{sup +}/K{sup +}-ATPase colocalize in the distal convoluted tubule of the nephron. {yields} HNF-1B specifically activates {gamma}a expression. {yields} HNF-1B mutants have a dominant negative effect on wild type HNF-1B activity. {yields} Defective transcription of {gamma}a may promote renal Mg{sup 2+} wasting. -- Abstract: Hepatocyte nuclear factor-1B (HNF-1B) is a transcription factor involved in embryonic development and tissue-specific gene expression in several organs, including the kidney. Recently heterozygous mutations in the HNF1B gene have been identified inmore » patients with hypomagnesemia due to renal Mg{sup 2+} wasting. Interestingly, ChIP-chip data revealed HNF-1B binding sites in the FXYD2 gene, encoding the {gamma}-subunit of the Na{sup +}/K{sup +}-ATPase. The {gamma}-subunit has been described as one of the molecular players in the renal Mg{sup 2+} reabsorption in the distal convoluted tubule (DCT). Of note, the FXYD2 gene can be alternatively transcribed into two main variants, namely {gamma}a and {gamma}b. In the present study, we demonstrated via two different reporter gene assays that HNF-1B specifically acts as an activator of the {gamma}a-subunit, whereas the {gamma}b-subunit expression was not affected. Moreover, the HNF-1B mutations H69fsdelAC, H324S325fsdelCA, Y352finsA and K156E, previously identified in patients with hypomagnesemia, prevented transcription activation of {gamma}a-subunit via a dominant negative effect on wild type HNF1-B. By immunohistochemistry, it was shown that the {gamma}a- and {gamma}b-subunits colocalize at the basolateral membrane of the DCT segment of mouse kidney. On the basis of these data, we suggest that abnormalities involving the HNF-1B gene may impair the relative abundance of {gamma}a and {gamma}b, thus affecting the transcellular Mg
-
Ceelie, H; Spaargaren-Van Riel, C C; De Jong, M; Bertina, R M; Vos, H L
2003-08-01
Prothrombin is a key component in blood coagulation. Overexpression of prothrombin leads to an increased risk of venous thrombosis. Therefore, the study of the transcriptional regulation of the prothrombin gene may help to identify mechanisms of overexpression. The aim of our study was to localize the regions within the prothrombin enhancer responsible for its activity, to identify the proteins binding to these regions, and to establish their functional importance. We constructed a set of prothrombin promoter 5' deletion constructs containing the firefly luciferase reporter gene, which were transiently transfected in HepG2, HuH7 and HeLa cells. Putative transcription factor (TF) binding sites were evaluated by electrophoretic mobility shift assays. The functional importance of each TF binding site was evaluated by site directed mutagenesis and transient transfection of the mutant constructs. We confirmed the major contribution of the enhancer region to the transcriptional activity of the prothrombin promoter. Analysis of this region revealed putative binding sites for hepatocyte nuclear factor HNF4, HNF3-beta and specificity protein(Sp)1. We identified six different TFs binding to three evolutionary conserved sites in the enhancer: HNF4-alpha (site 1), HNF1-alpha, HNF3-beta and an as yet unidentified TF (site 2) and the ubiquitously expressed TFs Sp1 and Sp3 (site 3). Mutagenesis studies showed that loss of binding of HNF3-beta resulted in a considerable decrease of enhancer activity, whereas loss of HNF4-alpha or Sp1/Sp3 resulted in milder reductions. The prothrombin enhancer plays a major role in regulation of prothrombin expression. Six different TFs are able to bind to this region. At least three of these TFs, HNF4-alpha, HNF3-beta and Sp1/Sp3, are important in regulation of prothrombin expression.
-
Boj, Sylvia F.; Servitja, Joan Marc; Martin, David; Rios, Martin; Talianidis, Iannis; Guigo, Roderic; Ferrer, Jorge
2009-01-01
OBJECTIVE The evolutionary conservation of transcriptional mechanisms has been widely exploited to understand human biology and disease. Recent findings, however, unexpectedly showed that the transcriptional regulators hepatocyte nuclear factor (HNF)-1α and -4α rarely bind to the same genes in mice and humans, leading to the proposal that tissue-specific transcriptional regulation has undergone extensive divergence in the two species. Such observations have major implications for the use of mouse models to understand HNF-1α– and HNF-4α–deficient diabetes. However, the significance of studies that assess binding without considering regulatory function is poorly understood. RESEARCH DESIGN AND METHODS We compared previously reported mouse and human HNF-1α and HNF-4α binding studies with independent binding experiments. We also integrated binding studies with mouse and human loss-of-function gene expression datasets. RESULTS First, we confirmed the existence of species-specific HNF-1α and -4α binding, yet observed incomplete detection of binding in the different datasets, causing an underestimation of binding conservation. Second, only a minor fraction of HNF-1α– and HNF-4α–bound genes were downregulated in the absence of these regulators. This subset of functional targets did not show evidence for evolutionary divergence of binding or binding sequence motifs. Finally, we observed differences between conserved and species-specific binding properties. For example, conserved binding was more frequently located near transcriptional start sites and was more likely to involve multiple binding events in the same gene. CONCLUSIONS Despite evolutionary changes in binding, essential direct transcriptional functions of HNF-1α and -4α are largely conserved between mice and humans. PMID:19188435
-
Tan, Yongjun; Adami, Guy; Costa, Robert H
2002-04-01
The hepatocyte nuclear factor 3 (HNF-3) proteins are members of the Forkhead Box (Fox) family of transcription factors that play important roles in regulating expression of genes involved in cellular proliferation, differentiation, and metabolic homeostasis. In previous studies we increased liver expression of HNF-3beta by using either transgenic mice (transthyretin HNF-3beta) or recombinant adenovirus infection (AdHNF3beta), and observed diminished hepatic levels of glycogen, and glucose transporter 2 (Glut-2), as well as the HNF-6, HNF-3, HNF-1alpha, HNF-4alpha, and C/EBPalpha transcription factors. We conducted the present study to determine whether maintaining HNF-6 protein expression during AdHNF3beta infection prevents reduction of hepatic levels of glycogen and the earlier-mentioned genes. Here, we show that AdHNF3beta- and AdHNF6-infected mouse liver displayed increased hepatic levels of glycogen, Glut-2, HNF-3gamma, HNF-1alpha, and HNF-4alpha at 2 and 3 days postinfection (PI). Furthermore, restoration of hepatic glycogen levels after AdHNF3beta and AdHNF6 coinfection was associated with increased Glut-2 expression. AdHNF6 infection alone caused a 2-fold increase in hepatic Glut-2 levels, suggesting that HNF 6 stimulates in vivo transcription of the Glut-2 gene. DNA binding assays showed that only recombinant HNF-6 protein, but not the HNF-3 proteins, binds to the mouse -185 to -144 bp Glut-2 promoter sequences. Cotransfection assays in human hepatoma (HepG2) cells with either HNF-3 or HNF-6 expression vectors show that only HNF-6 provided significant transcriptional activation of the Glut-2 promoter. In conclusion, these studies show that the hepatic Glut-2 promoter is a direct target for HNF-6 transcriptional activation.
-
Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY).
Yamagata, Kazuya
2014-01-01
Mutations in the genes encoding hepatocyte nuclear factor (HNF)1α and HNF4α cause a monogenic form of diabetes mellitus known as maturity-onset diabetes of the young (MODY). The primary cause of MODY is an impairment of glucose-stimulated insulin secretion by pancreatic β-cells, indicating the important roles of HNF1α and HNF4α in β-cells. Large-scale genetic studies have clarified that the common variants of HNF1α and HNF4α genes are also associated with type 2 diabetes, suggesting that they are involved in the pathogenesis of both diseases. Recent experimental studies revealed that HNF1α controls both β-cell function and growth by regulating target genes such as glucose transporter 2, pyruvate kinase, collectrin, hepatocyte growth factor activator, and HNF4α. In contrast, HNF4α mainly regulates the function of β-cells. Although direct target genes of HNF4α in β-cells are largely unknown, we recently identified Anks4b as a novel target of HNF4α that regulates β-cell susceptibility to endoplasmic reticulum stress. Studies of MODY have led to a better understanding of the molecular mechanism of glucose-stimulated insulin secretion by pancreatic β-cells. © 2014 Elsevier Inc. All rights reserved.
-
Kyithar, M P; Bacon, S; Pannu, K K; Rizvi, S R; Colclough, K; Ellard, S; Byrne, M M
2011-12-01
The prevalence of hepatocyte nuclear factor (HNF)-1A and HNF4A mutations, and the clinical implications following the genetic diagnosis of maturity-onset diabetes of the young (MODY) in the Irish population, remain unknown. The aim of this study was to establish the occurrence of HNF1A and HNF4A mutations in subjects classified clinically as MODY to identify novel mutations, and to determine the phenotypic features and response to therapy. A total of 36 unrelated index cases with a clinical diagnosis of MODY were analyzed for HNF1A/HNF4A mutations. OGTT was performed to determine the degree of glucose tolerance and insulin secretory response. Also, 38 relatives underwent OGTT and were tested for the relevant known mutations. HNF1A-/HNF4A-MODY subjects were compared with nine HNF1A mutation-negative relatives and 20 type 2 diabetic (T2DM) patients. Seven different HNF1A mutations were identified in 11/36 (30.5%) index cases, two of which were novel (S352fsdelG and F426X), as well as two novel HNF4A mutations (M1? and R290C; 6%). Family screening revealed 20 subjects with HNF1A and seven with HNF4A mutations. Only 51.6% of HNF1A mutation carriers were diagnosed with diabetes by age 25 years; 11 of the mutation carriers were overweight and four were obese. Insulin secretory response to glucose was significantly lower in HNF1A-MODY subjects than in T2DM patients and HNF1A mutation-negative relatives (P=0.01). Therapeutic changes occurred in 48% of mutation carriers following genetic diagnosis. There was an HNF1A-MODY pick-up rate of 30.5% and an HNF4A-MODY pick-up rate of 6% in Irish MODY families. Genetically confirmed MODY has significant therapeutic implications. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
-
Dong, Yewei; Wang, Shuqi; Chen, Junliang; Zhang, Qinghao; Liu, Yang; You, Cuihong; Monroig, Óscar; Tocher, Douglas R.; Li, Yuanyou
2016-01-01
Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the capability of biosynthesizing long-chain polyunsaturated fatty acids (LC-PUFA) from C18 precursors, and to possess a Δ4 fatty acyl desaturase (Δ4 Fad) which was the first report in vertebrates, and is a good model for studying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. In order to understand regulatory mechanisms of transcription of Δ4 Fad, the gene promoter was cloned and characterized in the present study. An upstream sequence of 1859 bp from the initiation codon ATG was cloned as the promoter candidate. On the basis of bioinformatic analysis, several binding sites of transcription factors (TF) including GATA binding protein 2 (GATA-2), CCAAT enhancer binding protein (C/EBP), nuclear factor 1 (NF-1), nuclear factor Y (NF-Y), hepatocyte nuclear factor 4α (HNF4α) and sterol regulatory element (SRE), were identified in the promoter by site-directed mutation and functional assays. HNF4α and NF-1 were confirmed to interact with the core promoter of Δ4 Fad by gel shift assay and mass spectrometry. Moreover, over-expression of HNF4α increased promoter activity in HEK 293T cells and mRNA level of Δ4 Fad in rabbitfish primary hepatocytes, respectively. The results indicated that HNF4α is a TF of rabbitfish Δ4 Fad. To our knowledge, this is the first report on promoter structure of a Δ4 Fad, and also the first demonstration of HNF4α as a TF of vertebrate Fad gene involved in transcription regulation of LC-PUFA biosynthesis. PMID:27472219
-
Moore, Benjamin D; Jin, Ramon U; Lo, Heiyong; Jung, Min; Wang, Haiyan; Battle, Michele A; Wollheim, Claes B; Urano, Fumihiko; Mills, Jason C
2016-03-18
The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4α (HNF4α) directly induces XBP1 expression. Mutations in HNF4α cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human- disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca(2+) homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4α-deficient β-cells. Our findings uncover a transcriptional relationship between HNF4α and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
-
Chen, M; Hieng, S; Qian, X; Costa, R; Ou, J H
1994-11-15
Hepatitis B virus (HBV) ENI enhancer can activate the expression of HBV and non-HBV genes in a liver-specific manner. By performing the electrophoretic mobility-shift assays, we demonstrated that the three related, liver-enriched, transcription factors, HNF3 alpha, HNF3 beta, and HNF3 gamma could all bind to the 2c site of HBV ENI enhancer. Mutations introduced in the 2c site to abolish the binding by HNF3 reduced the enhancer activity approximately 15-fold. Moreover, expression of HNF3 antisense sequences to suppress the expression of HNF3 in Huh-7 hepatoma cells led to reduction of the ENI enhancer activity. These results indicate that HNF3 positively regulates the ENI enhancer activity and this regulation is most likely mediated through the 2c site. The requirement of HNF3 for the ENI enhancer activity could explain the liver specificity of this enhancer element.
-
Trichloroethylene perturbs HNF4a expression and activity in the developing chick heart.
Harris, Alondra P; Ismail, Kareem A; Nunez, Martha; Martopullo, Ira; Lencinas, Alejandro; Selmin, Ornella I; Runyan, Raymond B
2018-03-15
Exposure to trichloroethylene (TCE) is linked to formation of congenital heart defects in humans and animals. Prior interactome analysis identified the transcription factor, Hepatocyte Nuclear Factor 4 alpha (HNF4a), as a potential target of TCE exposure. As a role for HNF4a is unknown in the heart, we examined developing avian hearts for HNF4a expression and for sensitivity to TCE and the HNF4a agonist, Benfluorex. In vitro analysis using a HNF4a reporter construct showed both TCE and HFN4a to be antagonists of HNF4a-mediated transcription at the concentrations tested. HNF4a mRNA is expressed transiently in the embryonic heart during valve formation and cardiac development. Embryos were examined for altered gene expression in the presence of TCE or Benfluorex. TCE altered expression of selected mRNAs including HNF4a, TRAF6 and CYP2C45. There was a transition between inhibition and induction of marker gene expression in embryos as TCE concentration increased. Benfluorex was largely inhibitory to selected markers. Echocardiography of exposed embryos showed reduced cardiac function with both TCE and Benfluorex. Cardiac contraction was reduced by 29% and 23%, respectively at 10 ppb. The effects of TCE and Benfluorex on autocrine regulation of HNF4a, selected markers and cardiac function argue for a functional interaction of TCE and HNF4a. Further, the dose-sensitive shift between inhibition and induction of marker expression may explain the nonmonotonic-like dose response observed with TCE exposure in the heart. Copyright © 2018 Elsevier B.V. All rights reserved.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Rha, Geun Bae; Wu, Guangteng; Shoelson, Steven E.
2010-04-15
Hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) is a novel nuclear receptor that participates in a hierarchical network of transcription factors regulating the development and physiology of such vital organs as the liver, pancreas, and kidney. Among the various transcriptional coregulators with which HNF4{alpha} interacts, peroxisome proliferation-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}) represents a novel coactivator whose activation is unusually robust and whose binding mode appears to be distinct from that of canonical coactivators such as NCoA/SRC/p160 family members. To elucidate the potentially unique molecular mechanism of PGC-1{alpha} recruitment, we have determined the crystal structure of HNF4{alpha} in complex with amore » fragment of PGC-1{alpha} containing all three of its LXXLL motifs. Despite the presence of all three LXXLL motifs available for interactions, only one is bound at the canonical binding site, with no additional contacts observed between the two proteins. However, a close inspection of the electron density map indicates that the bound LXXLL motif is not a selected one but an averaged structure of more than one LXXLL motif. Further biochemical and functional studies show that the individual LXXLL motifs can bind but drive only minimal transactivation. Only when more than one LXXLL motif is involved can significant transcriptional activity be measured, and full activation requires all three LXXLL motifs. These findings led us to propose a model wherein each LXXLL motif has an additive effect, and the multiple binding modes by HNF4{alpha} toward the LXXLL motifs of PGC-1{alpha} could account for the apparent robust activation by providing a flexible mechanism for combinatorial recruitment of additional coactivators and mediators.« less
-
HNF4alpha dysfunction as a molecular rational for cyclosporine induced hypertension.
Niehof, Monika; Borlak, Jürgen
2011-01-27
Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear
-
Barrett, Timothy; Stals, Karen; Shield, Julian P; Ellard, Sian; Ferrer, Jorge; Hattersley, Andrew T
2007-01-01
Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4α) and HNF1A/TCF1 (encoding HNF-1α), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. Methods and Findings We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic β-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. Conclusions HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and
-
Ekholm, E; Shaat, N; Holst, J J
2012-10-01
The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703.8, T2D: 556.4 ± 698.2, HNF4A MODY: 1,257.0 ± 999.3, HNF1A MODY: 697.1 ± 818.4) but with a different secretion pattern. The AUC insulin during the test meal was strongly correlated with the GIP secretion (Correlation coefficient 1.0, P < 0.001). No such correlation was seen for insulin and GLP-1. Patients with HNF4A and HNF1A MODY showed an attenuated early phase of insulin secretion similar to T2Ds. AUC insulin during the test meal was strongly correlated with GIP secretion, whereas no such correlation was seen for insulin and GLP-1. Thus, GIP may be a more important factor for insulin secretion than GLP-1 in MODY patients.
-
Urbanova, Jana; Andel, Michal; Potockova, Jana; Klima, Josef; Macek, Jan; Ptacek, Pavel; Mat'oska, Vaclav; Kumstyrova, Tereza; Heneberg, Petr
2015-01-01
Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1α or HNF-4α despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a(-/-) mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects. Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration. We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied. We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a(-/-) mouse model.
-
De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed.
Stanik, Juraj; Dusatkova, Petra; Cinek, Ondrej; Valentinova, Lucia; Huckova, Miroslava; Skopkova, Martina; Dusatkova, Lenka; Stanikova, Daniela; Pura, Mikulas; Klimes, Iwar; Lebl, Jan; Gasperikova, Daniela; Pruhova, Stepanka
2014-03-01
MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Furumiya, Mai; Department of Biopharmaceutics, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521; Inoue, Katsuhisa
2013-02-08
Highlights: ► We examined transcription factors that may regulate PCFT expression in the intestine. ► PCFT promoter activity is basically induced by KLF4. ► KLF4-induced PCFT promoter activity is enhanced by HNF4α synergistically. ► CDX2 and C/EBPα suppress PCFT promoter activity induced by KLF4 and HNF4α. -- Abstract: Proton-coupled folate transporter (PCFT), which is responsible for the intestinal uptake of folates and analogs, is expressed only in the proximal region in the small intestine. The present study was to examine its transcriptional regulation, which may be involved in such a unique expression profile and potentially in its alteration, using dual-luciferasemore » reporter assays in human embryonic kidney (HEK) 293 cells. The luciferase activity derived from the reporter construct containing the 5′-flanking sequence of −1695/+96 of the human PCFT gene was enhanced most extensively by the introduction of Krüppel-like factor 4 (KLF4). The KLF4-induced luciferase activity was further enhanced by hepatocyte nuclear factor 4α (HNF4α) synergistically. To the contrary, caudal-type homeobox transcription factor 2 (CDX2) and CCAAT/enhancer-binding protein α (C/EBPα) extensively suppressed the luciferase activity induced by KLF4 alone and also that induced by KLF4 and HNF4α. Western blot analysis using the rat small intestine indicated uniform expression of KLF4 along the intestinal tract, proximal-oriented expression of HNF4α, distal-oriented expression of CDX2 and C/EBPα. These results suggest that the activity of PCFT promoter is basically induced by KLF4 and the gradiented expression profile of PCFT may be at least in part accounted for by those of HNF4α, CDX2 and C/EBPα.« less
-
Forced expression of Hnf4a induces hepatic gene activation through directed differentiation.
Yahoo, Neda; Pournasr, Behshad; Rostamzadeh, Jalal; Fathi, Fardin
2016-08-05
Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Wang, Shuqi; Chen, Junliang; Jiang, Danli; Zhang, Qinghao; You, Cuihong; Tocher, Douglas R; Monroig, Óscar; Dong, Yewei; Li, Yuanyou
2018-06-01
Long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis is an important metabolic pathway in vertebrates, especially fish, considering they are the major source of n-3 LC-PUFA in the human diet. However, most fish have only limited capability for biosynthesis of LC-PUFA. The rabbitfish (Siganus canaliculatus) is able to synthesize LC-PUFA as it has all the key enzyme activities required including Δ6Δ5 Fads2, Δ4 Fads2, Elovl5, and Elovl4. We previously reported a direct interaction between the transcription factor Hnf4α and the promoter regions of Δ4 and Δ6Δ5 Fads2, which suggested that Hnf4α was involved in the transcriptional regulation of fads2 in rabbitfish. For functionally investigating it further, a full-length cDNA of 1736-bp-encoding rabbitfish Hnf4α with 454 amino acids was cloned, which was highly expressed in intestine, followed by liver and eyes. Similar to the expression characteristics of its target genes Δ4 and Δ6Δ5 fads2, levels of hnf4α mRNA in liver and eyes were higher in fish reared at low salinity than those reared in high salinity. After the rabbitfish primary hepatocytes were, respectively, incubated with alverine, benfluorex or BI6015, which were anticipated agonists or antagonist for Hnf4α, the mRNA level of Δ6Δ5 and Δ4 fads2 displayed a similar change tendency with that of hnf4α mRNA. Furthermore, when the mRNA level of hhf4α was knocked down using siRNA, the expression of Δ6Δ5 and Δ4 fads2 also decreased. Together, these data suggest that Hnf4α is involved in the transcriptional regulation of LC-PUFA biosynthesis, specifically, by targeting Δ4 and Δ6Δ5 fads2 in rabbitfish.
-
HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl; Kim, Kyung-Tae; Liu, Xiuping; Yao, Hui; Jung, Hae Rim; Lemos, Robert; Seo, Hye Hyun; Park, Hee Seo; Gim, Youme; Hong, Dongwan; Huh, Iksoo; Kim, Young-Woo; Tan, Dongfeng; Liu, Chang-Gong; Powis, Garth; Park, Taesung; Liang, Han; Kim, Yon Hui
2016-01-01
Background Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. Methods We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Results Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development. PMID:25410163
-
Liu, Tao; Zhang, Shichang; Xiang, Dedong; Wang, Yingjie
2013-11-01
Hepatocytes can be generated from embryonic stem cells (ESCs) using inducers such as chemical compounds and cytokines, but issues related to low differentiation efficiencies remain to be resolved. Recent work has shown that overexpression of lineage-specific transcription factors can directly cause cells phenotypic changes, including differentiation, trans-differentiation, and de-differentiation. We hypothesized that lentivirus-mediated constitutive expression of forkhead box A2 (Foxa2) and hepatocyte nuclear factor 4 alpha (Hnf4a) could promote inducing mouse ESCs to hepatocyte-likes cells. First, ESC lines that stably expressed Foxa2, Hnf4a, or Foxa2/Hnf4a were constructed via lentiviral expression vectors. Second, observations of cell morphology changes were made during the cell culture process, followed by experiments examining teratoma formation. Then, the effects of constitutive expression of Foxa2 and Hnf4a on hepatic differentiation and maturation were determined by measuring the marker gene expression levels of Albumin, α-fetoprotein, Cytokeratin18, and α1-antitrypsin. The results indicate that constitutive expression of Foxa2 and Hnf4a does not affect ESCs culture, teratoma formation, or the expression levels of the specific hepatocyte genes under autonomous differentiation. However, with some assistance from inducing factors, Foxa2 significantly increased the hepatic differentiation of ESCs, whereas the expression of Hnf4a alone or Foxa2/Hnf4a could not. Differentiated CCE-Foxa2 cells were more superior in expressing several liver-specific markers and protein, storing glycogen than differentiated CCE cells. Therefore, our method employing the transduction of Foxa2 would be a valuable tool for the efficient generation of functional hepatocytes derived from ESCs. © 2013 Wiley Periodicals, Inc.
-
FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol.
Ganjam, Goutham Kumar; Dimova, Elitsa Y; Unterman, Terry G; Kietzmann, Thomas
2009-11-06
Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol.
-
Wiedmann, Mareike M; Aibara, Shintaro; Spring, David R; Stewart, Murray; Brenton, James D
2016-09-01
The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in ovarian clear cell carcinoma (CCC) and is a potential therapeutic target. To explore potential approaches that block HNF1β transcription we have identified and characterised extensively the nuclear localisation signal (NLS) for HNF1β and its interactions with the nuclear protein import receptor, Importin-α. Pull-down assays demonstrated that the DNA binding domain of HNF1β interacted with a spectrum of Importin-α isoforms and deletion constructs tagged with eGFP confirmed that the HNF1β (229)KKMRRNR(235) sequence was essential for nuclear localisation. We further characterised the interaction between the NLS and Importin-α using complementary biophysical techniques and have determined the 2.4Å resolution crystal structure of the HNF1β NLS peptide bound to Importin-α. The functional, biochemical, and structural characterisation of the nuclear localisation signal present on HNF1β and its interaction with the nuclear import protein Importin-α provide the basis for the development of compounds targeting transcription factor HNF1β via its nuclear import pathway. Copyright © 2016. Published by Elsevier Inc.
-
FoxO1 and HNF-4 Are Involved in Regulation of Hepatic Glucokinase Gene Expression by Resveratrol*
Ganjam, Goutham Kumar; Dimova, Elitsa Y.; Unterman, Terry G.; Kietzmann, Thomas
2009-01-01
Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol. PMID:19740748
-
Opposing roles of nuclear receptor HNF4α isoforms in colitis and colitis-associated colon cancer
Chellappa, Karthikeyani; Deol, Poonamjot; Evans, Jane R; Vuong, Linh M; Chen, Gang; Briançon, Nadege; Bolotin, Eugene; Lytle, Christian; Nair, Meera G; Sladek, Frances M
2016-01-01
HNF4α has been implicated in colitis and colon cancer in humans but the role of the different HNF4α isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4α is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4α in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4α have different colonic gene expression profiles, interacting proteins, cellular migration, ion transport and epithelial barrier function. The mice also exhibit altered susceptibilities to experimental colitis (DSS) and colitis-associated colon cancer (AOM+DSS). When P2-HNF4α-only mice (which have elevated levels of the cytokine resistin-like β, RELMβ, and are extremely sensitive to DSS) are crossed with Retnlb-/- mice, they are rescued from mortality. Furthermore, P2-HNF4α binds and preferentially activates the RELMβ promoter. In summary, HNF4α isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer. DOI: http://dx.doi.org/10.7554/eLife.10903.001 PMID:27166517
-
Control of ACAT2 liver expression by HNF4{alpha}: lesson from MODY1 patients.
Pramfalk, C; Karlsson, E; Groop, L; Rudel, L L; Angelin, B; Eriksson, M; Parini, P
2009-08-01
ACAT2 is thought to be responsible for cholesteryl ester production in chylomicron and VLDL assembly. Recently, we identified HNF1alpha as an important regulator of the human ACAT2 promoter. Thus, we hypothesized that MODY3 (HNF1alpha gene mutations) and possibly MODY1 (HNF4alpha, upstream regulator of HNF1alpha, gene mutations) subjects may have lower VLDL esterified cholesterol. Serum analysis and lipoprotein separation using size-exclusion chromatography were performed in controls and MODY1 and MODY3 subjects. In vitro analyses included mutagenesis and cotransfections in HuH7 cells. Finally, the relevance in vivo of these findings was tested by ChIP assays in human liver. Whereas patients with MODY3 had normal lipoprotein composition, those with MODY1 had lower levels of VLDL and LDL esterified cholesterol, as well as of VLDL triglyceride. Mutagenesis revealed one important HNF4 binding site in the human ACAT2 promoter. ChIP assays and protein-to-protein interaction studies showed that HNF4alpha, directly or indirectly (via HNF1alpha), can bind to the ACAT2 promoter. We identified HNF4alpha as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter. Our results suggest that the lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may-at least in part-be attributable to lower ACAT2 activity in these patients.
-
Bacon, S; Kyithar, M P; Condron, E M; Vizzard, N; Burke, M; Byrne, M M
2016-12-01
HNF4A is an established cause of maturity onset diabetes of the young (MODY). Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene. A dual phenotype is observed in HNF4A-MODY with hyperinsulinaemic hypoglycaemia in the neonatal period progressing to diabetes in adulthood. The nature and timing of the transition remain poorly defined. We performed an observational study to establish changes in glycaemia and insulin secretion over a 6-year period. We investigated glycaemic variability and hypoglycaemia in HNF4A-MODY using a continuous glucose monitoring system (CGMS). An OGTT with measurement of glucose, insulin and C-peptide was performed in HNF4A participants with diabetes mellitus (DM) (n = 14), HNF4A-IGT (n = 7) and age- and BMI-matched MODY negative family members (n = 10). Serial assessment was performed in the HNF4A-IGT cohort. In a subset of HNF4A-MODY mutation carriers (n = 10), CGMS was applied over a 72-h period. There was no deterioration in glycaemic control in the HNF4A-IGT cohort. The fasting glucose-to-insulin ratio was significantly lower in the HNF4A-IGT cohort when compared to the normal control group (0.13 vs. 0.24, p = 0.03). CGMS profiling demonstrated prolonged periods of hypoglycaemia in the HNF4A-IGT group when compared to the HNF4A-DM group (432 vs. 138 min p = 0.04). In a young adult HNF4A-IGT cohort, we demonstrate preserved glucose, insulin and C-peptide secretory responses to oral glucose. Utilising CGMS, prolonged periods of hypoglycaemia are evident despite a median age of 21 years. We propose a prolonged hyperinsulinaemic phase into adulthood is responsible for the notable hypoglycaemic episodes.
-
Kaledin, V I; Pakharukova, M Yu; Pivovarova, E N; Kropachev, K Yu; Baginskaya, N V; Vasilieva, E D; Ilnitskaya, S I; Nikitenko, E V; Kobzev, V F; Merkulova, T I
2009-04-01
It is known that the carcinogenic effect of estragole, a component of essential oils of many spicy plants, is characterized by species, tissue, and sex specificity. It causes mainly liver tumors in female mice but is not carcinogenic for male mice and for rats. In this work, the estragole hepatocarcinogenicity was shown for female mice of previously not studied ICR line. The strict correlation between estragole hepatocarcinogenicity and its ability to decrease the level of glucocorticoid induction of liver-specific enzymes tyrosine aminotransferase (TAT) and tryptophan oxygenase (TO) was found. Inhibition of TAT and TO inducibility by estragole takes place only in female mice but not in male mice and in rats. Studying the estragole effect on DNA-binding activity of transcription factors, present mainly in liver and regulating expression of genes encoding liver-specific proteins, has shown that estragole decreases FOXA and HNF4 activities but not activities of C/EBP and HNF1, and this happens only in female mice, for which this substance is hepatocarcinogen, but not in male mice and in rats. Pentachlorophenol, preventing hepatocarcinogenic effect of estragole, abolishes inhibitory influence of the latter on the TAT and TO glucocorticoid induction and restores DNA-binding activity of FOXA and HNF4. Thus, a correlation was revealed between the estragole hepatocarcinogenic effect and decrease in DNA-binding activity of transcription factors FOXA and HNF4, which might be indicative of the role of these factors in tumor suppression mechanisms in liver.
-
Jucá, Patrícia Chaves de Freitas Campos; Corrêa, Stephany; Vignal, Giselle Maria; Accioly, Maria Theresa de Souza; Lustosa, Suzana Angélica Silva; Abdelhay, Eliana; Matos, Delcio
2017-06-05
Among the many challenges in cancer diagnosis is the early distinction between metastatic cancer and a secondary tumor. This difficulty stems from the lack of markers that offer high sensitivity and specificity and can be easily applied in routine laboratory work. An example of this challenge is distinguishing gastric metastases originating from breast cancer from a gastric primary tumor. Hepatocyte nuclear factor 4 alpha (HNF4A) has been suggested as a potential marker in these cases. The aim of this study was to analyze the expression of HNF4A, estrogen receptor (ER), progesterone receptor (PR) and gross cystic disease fluid protein 15 (GCDFP-15) in a Brazilian cohort. We performed immunohistochemistry analysis of HNF4A, ER, PR and GCDFP-15 in 126 patients divided into three cohorts: primary breast cancer, primary gastric cancer and both types of tumors. Our data confirmed the sensitivity and specificity of the HNF4A marker compared to other currently used clinical markers. HNF4A alone could be a gold standard marker for distinguishing primary gastric cancer from breast metastasis, thus validating its potential clinical use, especially in populations with high genetic diversity.
-
Granados-Silvestre, M A; Ortiz-López, M G; Granados, J; Canizales-Quinteros, S; Peñaloza-Espinosa, Rosenda I; Lechuga, C; Acuña-Alonzo, V; Sánchez-Pozos, K; Menjivar, M
2017-12-01
The genetic risk of developing type 2 diabetes (T2D) increases in parallel with the proportion of Native American ancestry. Mestizo Mexicans have a 70% Native Amerindian genetic background. The T130I polymorphism in the HNF4A gene has been associated with early-onset T2D in mestizo Mexicans. Thus, the aim of the present study was to evaluate the frequency and relationship of the T130I variant in the HNF4A gene with risk factors for developing T2D in eleven indigenous groups from Mexico. In two groups, all exons of the HNF4A gene were directly sequenced; in the remaining the T130I polymorphism was analyzed by restriction fragment length polymorphism. Ancestry informative markers were assessed to confirm the Amerindian component. An additional analysis of EHH was carried out. Interestingly, HNF4A gene screening revealed only the presence of the T130I polymorphism. The range frequency of the risk allele (T) in the indigenous groups was from 2.7 to 16%. Genotypic frequencies (T130I/I130I) were higher and significantly different from those of all of the populations included in the HapMap Project (P < 0.005). EHH scores suggest a positive selection for T130I polymorphism. Metabolic traits indicate a relationship between the T130I/I130I genotypes with high triglyceride concentrations in the indigenous groups (P < 0.005). These results strongly suggest that the high frequency of the T130I polymorphism and its biological relationship with dysfunction in lipid metabolism in Mexican indigenous groups is a risk factor for the developing of T2D in Mexicans.
-
Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile
Thanabalasingham, Gaya; Huffman, Jennifer E.; Kattla, Jayesh J.; Novokmet, Mislav; Rudan, Igor; Gloyn, Anna L.; Hayward, Caroline; Adamczyk, Barbara; Reynolds, Rebecca M.; Muzinic, Ana; Hassanali, Neelam; Pucic, Maja; Bennett, Amanda J.; Essafi, Abdelkader; Polasek, Ozren; Mughal, Saima A.; Redzic, Irma; Primorac, Dragan; Zgaga, Lina; Kolcic, Ivana; Hansen, Torben; Gasperikova, Daniela; Tjora, Erling; Strachan, Mark W.J.; Nielsen, Trine; Stanik, Juraj; Klimes, Iwar; Pedersen, Oluf B.; Njølstad, Pål R.; Wild, Sarah H.; Gyllensten, Ulf; Gornik, Olga; Wilson, James F.; Hastie, Nicholas D.; Campbell, Harry; McCarthy, Mark I.; Rudd, Pauline M.; Owen, Katharine R.; Lauc, Gordan; Wright, Alan F.
2013-01-01
A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction. PMID:23274891
-
Yang, Ying; Zhou, Tai-Cheng; Liu, Yong-Ying; Li, Xiao; Wang, Wen-Xue; Irwin, David M; Zhang, Ya-Ping
2016-01-01
Maturity-onset diabetes of the young (MODY) is characterized by the onset of diabetes before the age of 25 years, positive family history, high genetic predisposition, monogenic mutations, and an autosomal dominant mode of inheritance. Here, we aimed to investigate the mutations and to characterize the phenotypes of a Han Chinese family with early-onset maternally inherited type 2 diabetes. Detailed clinical assessments and genetic screening for mutations in the HNF4α, GCK, HNF-1α, IPF-1, HNF1β, and NEUROD1 genes were carried out in this family. One HNF4A mutation (p.T130I) and two HNF1A polymorphisms (p.I27L and p.S487N) were identified. Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes. We demonstrated that mutation p.T130I in HNF4A was pathogenic as were the predicted polymorphisms p.I27L and p.S487N in HNF1A by genetic and functional analysis. Our results show that mutations in HNF4A and HNF1A genes might account for this early-onset inherited type 2 diabetes.
-
HNF1β Is Essential for Nephron Segmentation during Nephrogenesis
Naylor, Richard W.; Przepiorski, Aneta; Ren, Qun; Yu, Jing
2012-01-01
Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1β paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms’ tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1β factors are essential for normal segmentation of nephrons during kidney organogenesis. PMID:23160512
-
HNF1β is essential for nephron segmentation during nephrogenesis.
Naylor, Richard W; Przepiorski, Aneta; Ren, Qun; Yu, Jing; Davidson, Alan J
2013-01-01
Nephrons comprise a blood filter and an epithelial tubule that is subdivided into proximal and distal segments, but what directs this patterning during kidney organogenesis is not well understood. Using zebrafish, we found that the HNF1β paralogues hnf1ba and hnf1bb, which encode homeodomain transcription factors, are essential for normal segmentation of nephrons. Embryos deficient in hnf1ba and hnf1bb did not express proximal and distal segment markers, yet still developed an epithelial tubule. Initiating hnf1ba/b expression required Pax2a and Pax8, but hnf1ba/b-deficient embryos did not exhibit the expected downregulation of pax2a and pax8 at later stages of development, suggesting complex regulatory loops involving these molecules. Embryos deficient in hnf1ba/b also did not express the irx3b transcription factor, which is responsible for differentiation of the first distal tubule segment. Reciprocally, embryos deficient in irx3b exhibited downregulation of hnf1ba/b transcripts in the distal early segment, suggesting a segment-specific regulatory circuit. Deficiency of hnf1ba/b also led to ectopic expansion of podocytes into the proximal tubule domain. Epistasis experiments showed that the formation of podocytes required wt1a, which encodes the Wilms' tumor suppressor-1 transcription factor, and rbpj, which encodes a mediator of canonical Notch signaling, downstream or parallel to hnf1ba/b. Taken together, these results suggest that Hnf1β factors are essential for normal segmentation of nephrons during kidney organogenesis.
-
High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.
McDonald, Tim J; Shields, Beverley M; Lawry, Jane; Owen, Katharine R; Gloyn, Anna L; Ellard, Sian; Hattersley, Andrew T
2011-08-01
Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P < 0.001) and type 1 diabetes (1.10 [0.50-1.85] mg/L; P < 0.001), HNF4A-MODY (1.45 [0.46-2.88] mg/L; P < 0.001), GCK-MODY (0.60 [0.30-1.80] mg/L; P < 0.001), and HNF1B-MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP <0.75 mg/L showing 79% sensitivity and 70% specificity (receiver operating characteristic area under the curve = 0.84). hs-CRP levels are lower in HNF1A-MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.
-
Dietrich, Christoph G; Martin, Ina V; Porn, Anne C; Voigt, Sebastian; Gartung, Carsten; Trautwein, Christian; Geier, Andreas
2007-09-01
Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4alpha/PGC-1alpha-pathway. Because HNF4alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1alpha in electrophoretic mobility shift assays remained unchanged, HNF4alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4alpha and PGC-1alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4alpha, PGC-1alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4alpha/PGC-1alpha pathway.
-
Barry, William E; Thummel, Carl S
2016-01-01
Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal. DOI: http://dx.doi.org/10.7554/eLife.11183.001 PMID:27185732
-
Najmi, Laeya Abdoli; Aukrust, Ingvild; Flannick, Jason; Molnes, Janne; Burtt, Noel; Molven, Anders; Groop, Leif; Altshuler, David; Johansson, Stefan; Njølstad, Pål Rasmus
2017-01-01
Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73–5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to <60% of normal (wild-type) activity was strongly associated with diabetes in the general population (combined MAF 0.22%; OR 5.04; 95% CI 1.99–12.80; P = 0.0007). Our functional investigations indicate that 0.44% of the population carry HNF1A variants that result in a substantially increased risk for developing diabetes. These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population. PMID:27899486
-
Hepatocyte nuclear factor-4 alpha in noise-induced cochlear neuropathy.
Groth, Jane Bjerg; Kao, Shyan-Yuan; Briët, Martijn C; Stankovic, Konstantina M
2016-12-01
Noise-induced hearing loss (NIHL) is a problem of profound clinical significance and growing magnitude. Alarmingly, even moderate noise levels, previously assumed to cause only temporary shifts in auditory thresholds ("temporary" NIHL), are now known to cause cochlear synaptopathy and subsequent neuropathy. To uncover molecular mechanisms of this neuropathy, a network analysis of genes reported to have significantly altered expression after temporary threshold shift-inducing noise exposure was performed. The transcription factor Hepatocyte Nuclear Factor-4 alpha (HNF4α), which had not previously been studied in the context of cochlear response to noise, was identified as a hub of a top-ranking network. Hnf4α expression and localization using quantitative RT-PCR and in situ hybridization, respectively, were described in adolescent and adult mice exposed to neuropathic noise levels in adolescence. Isoforms α3 and α12 in the cochlea were also identified. At every age examined, Hnf4α mRNA expression in the cochlear apex was similar to expression in the base. Hnf4α expression was evident in select cochlear cells, including spiral ganglion neurons (SGNs) and hair cells, and was significantly upregulated from 6 to 70 weeks of age, especially in SGNs. This age-related Hnf4α upregulation was inhibited by neuropathic noise exposure in adolescence. Hnf4α silencing with shRNA transfection into auditory neuroblast cells (VOT-33) reduced cell viability, as measured with the MTT assay, suggesting that Hnf4α may be involved in SGN survival. Our results motivate future studies of HNF4α in cochlear pathophysiology, especially because HNF4α mutations and polymorphisms are associated with human diseases that may include hearing loss. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1374-1386, 2016. © 2016 Wiley Periodicals, Inc.
-
Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease.
Zhao, Juanjuan; Lupino, Katherine; Wilkins, Benjamin J; Qiu, Chengxiang; Liu, Jian; Omura, Yasuhiro; Allred, Amanda L; McDonald, Caitlin; Susztak, Katalin; Barish, Grant D; Pei, Liming
2018-05-22
Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.
-
Wei, Shengnan; Zhang, Ming; Yu, Yang; Xue, Huan; Lan, Xiaoxin; Liu, Shuping; Hatch, Grant; Chen, Li
2016-11-15
Hepatocyte Nuclear Factor-4α (HNF-4α) is a key nuclear receptor protein required for liver development. miR-122 is a predominant microRNA expressed in liver and is involved in the regulation of cholesterol and fatty acid metabolism. HNF-4α is know to regulate expression of miR-122 in liver. We examined how HNF-4α regulated gluconeogenesis and lipid metabolism through miR-122 in vivo and in vitro. Expression of miR-122, HNF-4α, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), sterol response elementary binding protein-1 (SREBP-1), fatty acid synthase-1 (FAS-1), carnitine palmitoyltransferase-1 (CPT-1) and acetyl Coenzyme A carboxylase alpha (ACCα) were determined in livers of Type 2 diabetic mice and in insulin resistant palmitate-treated HepG2 cells. CPT-1 and phosphorylated ACCα expression were significantly decreased in livers of Type 2 diabetic mice and in palmitate-treated HepG2 cells compared to controls. In contrast, expression of miR-122, HNF-4α, PEPCK, G6Pase, SREBP-1, FAS-1 and ACCα were significantly elevated in liver of Type 2 diabetic mice and in palmitate-treated HepG2 cells compared to controls. Expression of HNF-4α increased whereas siRNA knockdown of HNF-4α decreased miR-122 levels in HepG2 cells compared to controls. In addition, expression of HNF-4α in HepG2 cells increased PEPCK, G6Pase, SREBP-1, FAS-1, ACCα mRNA and protein expression and decreased CPT-1 and p-ACCα mRNA and protein expression compared to controls. Addition of miR-122 inhibitors attenuated the HNF-4α mediated effect on expression of these gluconeogenic and lipid metabolism proteins. The results indicate that HNF-4α regulated miR-122 contributes to development of the gluconeogenic and lipid metabolism alterations observed in Type 2 diabetic mice and in palmitate-treated HepG2 cells. Copyright © 2016 Elsevier B.V. All rights reserved.
-
Black, Mary Helen; Fingerlin, Tasha E.; Allayee, Hooman; Zhang, Weiming; Xiang, Anny H.; Trigo, Enrique; Hartiala, Jaana; Lehtinen, Allison B.; Haffner, Steven M.; Bergman, Richard N.; McEachin, Richard C.; Kjos, Siri L.; Lawrence, Jean M.; Buchanan, Thomas A.; Watanabe, Richard M.
2015-01-01
OBJECTIVE We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes. RESEARCH DESIGN AND METHODS The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests. RESULTS Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401). CONCLUSIONS Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes. PMID:18162503
-
Ohguchi, Hiroto; Tanaka, Toshiya; Uchida, Aoi; Magoori, Kenta; Kudo, Hiromi; Kim, Insook; Daigo, Kenji; Sakakibara, Iori; Okamura, Masashi; Harigae, Hideo; Sasaki, Takeshi; Osborne, Timothy F; Gonzalez, Frank J; Hamakubo, Takao; Kodama, Tatsuhiko; Sakai, Juro
2008-06-01
Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4alpha (HNF4alpha)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T4 and rT3 concentrations are elevated in these mice compared with those in HNF4alpha-floxed control littermates; however, serum T3 levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4alpha plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4alpha site (direct repeat 1 [TGGACAAAGGTGC]; HNF4alpha-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4alpha. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4alpha-RE. Furthermore, KLF9 functions together with HNF4alpha and GATA4 to synergistically activate the mouse Dio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4alpha and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4alpha regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gu Ning; Laboratory of Neurochemistry, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto; Adachi, Tetsuya
2006-08-04
Dipeptidylpeptidase IV (DPP-IV) is a well-documented drug target for the treatment of type 2 diabetes. Hepatocyte nuclear factors (HNF)-1{alpha} and HNF-1{beta}, known as the causal genes of MODY3 and MODY5, respectively, have been reported to be involved in regulation of DPP-IV gene expression. But, it is not completely clear (i) that they play roles in regulation of DPP-IV gene expression, and (ii) whether DPP-IV gene activity is changed by mutant HNF-1{alpha} and mutant HNF-1{beta} in MODY3 and MODY5. To explore these questions, we investigated transactivation effects of wild HNF-1{alpha} and 13 mutant HNF-1{alpha}, as well as wild HNF-1{beta} and 2more » mutant HNF-1{beta}, on DPP-IV promoter luciferase gene in Caco-2 cells by means of a transient experiment. Both wild HNF-1{alpha} and wild HNF-1{beta} significantly transactivated DPP-IV promoter, but mutant HNF-1{alpha} and mutant HNF-1{beta} exhibited low transactivation activity. Moreover, to study whether mutant HNF-1{alpha} and mutant HNF-1{beta} change endogenous DPP-IV enzyme activity, we produced four stable cell lines from Caco-2 cells, in which wild HNF-1{alpha} or wild HNF-1{beta}, or else respective dominant-negative mutant HNF-1{alpha}T539fsdelC or dominant-negative mutant HNF-1{beta}R177X, was stably expressed. We found that DPP-IV gene expression and enzyme activity were significantly increased in wild HNF-1{alpha} cells and wild HNF-1{beta} cells, whereas they decreased in HNF-1{alpha}T539fsdelC cells and HNF-1{beta}R177X cells, compared with DPP-IV gene expression and enzyme activity in Caco-2 cells. These results suggest that both wild HNF-1{alpha} and wild HNF-1{beta} have a stimulatory effect on DPP-IV gene expression, but that mutant HNF-1{alpha} and mutant HNF-1{beta} attenuate the stimulatory effect.« less
-
Yu, Xianming; Mertz, Janet E.
2003-01-01
To study the effects of the nuclear receptors (NRs) HNF4α and COUP-TF1 on the life cycle of hepatitis B virus (HBV), the human hepatoma cell line Huh7 was transiently cotransfected with plasmids containing the HBV genome and encoding these two NRs. Overexpression of HNF4α and COUP-TF1 led to a 9-fold increase and a 7- to 10-fold decrease, respectively, in viral DNA synthesis. These two NRs also exhibited distinct modes of regulation of viral transcription. Overexpression of HNF4α led to a more-than-10-fold increase in synthesis of the pregenomic RNA but to only a 2- to 3-fold increase in synthesis of the pre-C and S RNAs. Moreover, the NR response element within the pre-C promoter, NRREpreC, played the major role in activation of pregenomic RNA synthesis by HNF4α. On the other hand, overexpression of COUP-TF1 led to an over-10-fold repression of synthesis of both pre-C and pregenomic RNAs mediated through either NRREpreC or NRREenhI. HNF4α and COUP-TF1 antagonized each other's effects on synthesis of pregenomic RNA and viral DNA when they were co-overexpressed. A naturally occurring HBV variant which allows for binding by HNF4α but not COUP-TF1 in its NRREpreC exhibited significantly higher levels of synthesis of pregenomic RNA and viral DNA than wild-type HBV in coexpression experiments. Last, deletion analysis revealed that non-NRRE sequences located within both the C and pre-S1 regions are also essential for maximum activation of the pregenomic promoter by HNF4α but not for repression by COUP-TF1. Thus, HNF4α and COUP-TF1 function through different mechanisms to regulate expression of the HBV genes. PMID:12551987
-
Yu, Xianming; Mertz, Janet E
2003-02-01
To study the effects of the nuclear receptors (NRs) HNF4alpha and COUP-TF1 on the life cycle of hepatitis B virus (HBV), the human hepatoma cell line Huh7 was transiently cotransfected with plasmids containing the HBV genome and encoding these two NRs. Overexpression of HNF4alpha and COUP-TF1 led to a 9-fold increase and a 7- to 10-fold decrease, respectively, in viral DNA synthesis. These two NRs also exhibited distinct modes of regulation of viral transcription. Overexpression of HNF4alpha led to a more-than-10-fold increase in synthesis of the pregenomic RNA but to only a 2- to 3-fold increase in synthesis of the pre-C and S RNAs. Moreover, the NR response element within the pre-C promoter, NRRE(preC,) played the major role in activation of pregenomic RNA synthesis by HNF4alpha. On the other hand, overexpression of COUP-TF1 led to an over-10-fold repression of synthesis of both pre-C and pregenomic RNAs mediated through either NRRE(preC) or NRRE(enhI). HNF4alpha and COUP-TF1 antagonized each other's effects on synthesis of pregenomic RNA and viral DNA when they were co-overexpressed. A naturally occurring HBV variant which allows for binding by HNF4alpha but not COUP-TF1 in its NRRE(preC) exhibited significantly higher levels of synthesis of pregenomic RNA and viral DNA than wild-type HBV in coexpression experiments. Last, deletion analysis revealed that non-NRRE sequences located within both the C and pre-S1 regions are also essential for maximum activation of the pregenomic promoter by HNF4alpha but not for repression by COUP-TF1. Thus, HNF4alpha and COUP-TF1 function through different mechanisms to regulate expression of the HBV genes.
-
Takayama, Kazuo; Inamura, Mitsuru; Kawabata, Kenji; Katayama, Kazufumi; Higuchi, Maiko; Tashiro, Katsuhisa; Nonaka, Aki; Sakurai, Fuminori; Hayakawa, Takao; Kusuda Furue, Miho; Mizuguchi, Hiroyuki
2012-01-01
Hepatocyte-like cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are expected to be a useful source of cells drug discovery. Although we recently reported that hepatic commitment is promoted by transduction of SOX17 and HEX into human ESC- and iPSC-derived cells, these hepatocyte-like cells were not sufficiently mature for drug screening. To promote hepatic maturation, we utilized transduction of the hepatocyte nuclear factor 4α (HNF4α) gene, which is known as a master regulator of liver-specific gene expression. Adenovirus vector-mediated overexpression of HNF4α in hepatoblasts induced by SOX17 and HEX transduction led to upregulation of epithelial and mature hepatic markers such as cytochrome P450 (CYP) enzymes, and promoted hepatic maturation by activating the mesenchymal-to-epithelial transition (MET). Thus HNF4α might play an important role in the hepatic differentiation from human ESC-derived hepatoblasts by activating the MET. Furthermore, the hepatocyte like-cells could catalyze the toxication of several compounds. Our method would be a valuable tool for the efficient generation of functional hepatocytes derived from human ESCs and iPSCs, and the hepatocyte-like cells could be used for predicting drug toxicity. PMID:22068426
-
Hepatocyte nuclear factor-4alpha is a central transactivator of the mouse Ntcp gene.
Geier, Andreas; Martin, Ina V; Dietrich, Christoph G; Balasubramaniyan, Natarajan; Strauch, Sonja; Suchy, Frederick J; Gartung, Carsten; Trautwein, Christian; Ananthanarayanan, Meenakshisundaram
2008-08-01
Sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake system for conjugated bile acids. Deletions of hepatocyte nuclear factor (HNF)-1alpha and retinoid X receptor-alpha:retinoic acid receptor-alpha binding sites in the mouse 5'-flanking region corresponding to putatively central regulatory elements of rat Ntcp do not significantly reduce promoter activity. We hypothesized that HNF-4alpha, which is increasingly recognized as a central regulator of hepatocyte function, may directly transactivate mouse (mNtcp). A 1.1-kb 5'-upstream region including the mouse Ntcp promoter was cloned and compared with the rat promoter. In contrast to a moderate 3.5-fold activation of mNtcp by HNF-1alpha, HNF-4alpha cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4alpha consensus site at -345/-326 and -335/-316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1alpha but shows a 50-fold enhanced activity upon cotransfection with HNF-4alpha. Gel mobility shift assays demonstrated a complex of the HNF-4alpha-element formed with liver nuclear extracts that was blocked by an HNF-4alpha specific antibody. HNF-4alpha binding was confirmed by chromatin immunoprecipitation. Using Hepa 1-6 cells, HNF-4alpha-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4alpha via a conserved distal cis-element independently of HNF-1alpha.
-
Real Hernandez, Luis M.; Fan, Junfeng; Johnson, Michelle H.; Gonzalez de Mejia, Elvira
2015-01-01
Hepatocyte nuclear factor-1α (HNF-1α) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1α. By studying the interactions of compounds from berries and citrus fruits have with HNF-1α, pre-transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF-1α were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1α. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1α was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1α expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1
-
Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients.
Szopa, Magdalena; Osmenda, Grzegorz; Wilk, Grzegorz; Matejko, Bartłomiej; Skupien, Jan; Zapala, Barbara; Młynarski, Wojciech; Guzik, Tomasz; Malecki, Maciej T
2015-03-01
Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY. A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0±1.4 mm, whereas it reached 6.3±1.4 mm in GCK mutation carriers and 6.3±1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9±4.6%) and GCK-MODY (11.1±4.6%) patients in comparison with controls (13.9±4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls. Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype. © 2015 European Society of Endocrinology.
-
Wang, Zi-nian; Li, Mi-jie; Lan, Xian-yong; Li, Ming-xun; Lei, Chu-zhao; Chen, Hong
2014-08-10
Hepatocyte nuclear factor-4α (HNF-4α), a member of the hepatocyte nuclear factor family, plays an important role in regulating the expression of genes involved in the development, differentiation and normal function of liver and pancreatic β cells, as well as the maintenance of glucose homeostasis. Tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) is a new method offering fast detection and extreme simplicity at a negligible cost for SNP genotyping. In this paper, we characterize the polymorphisms of the bovine HNF-4α gene in three Chinese indigenous cattle breeds (n=660). Six novel SNPs were identified including 1 mutation in the coding region and others in introns. The statistical analyses indicated that 4 SNPs (g.T53729C, g.A53861G, g.A65188C and g.T65444C) affected growth traits markedly (P<0.05) in Qinchuan cattle (2 years after birth). Besides, haplotypes involving these 4 SNP sites in the bovine HNF-4α gene were identified and their effects on growth traits were also analyzed. The results showed that haplotypes 2, 7, 9 and 11 were predominant and accounted for 73.2%, 59.6%, and 67.1% in Qinchuan, Nanyang and Jiaxian cattle breeds, respectively. Hap9 (TAAT) was extremely predominant in all test populations, which suggested that individuals with Hap9 were more adapted to the environment. Furthermore, 4 combined haplotypes were constructed to guarantee the reliability of analysis results in Qinchuan cattle. There were also significant differences in body length (P<0.05). These findings will benefit for the application of DNA marker related to the growth traits on marker-assisted selection (MAS), and improve the performance of beef cattle. Copyright © 2014 Elsevier B.V. All rights reserved.
-
Ohguchi, Hiroto; Tanaka, Toshiya; Uchida, Aoi; Magoori, Kenta; Kudo, Hiromi; Kim, Insook; Daigo, Kenji; Sakakibara, Iori; Okamura, Masashi; Harigae, Hideo; Sasaki, Takeshi; Osborne, Timothy F.; Gonzalez, Frank J.; Hamakubo, Takao; Kodama, Tatsuhiko; Sakai, Juro
2008-01-01
Type 1 iodothyronine deiodinase (Dio1), a selenoenzyme catalyzing the bioactivation of thyroid hormone, is highly expressed in the liver. Dio1 mRNA and enzyme activity levels are markedly reduced in the livers of hepatocyte nuclear factor 4α (HNF4α)-null mice, thus accounting for its liver-specific expression. Consistent with this deficiency, serum T4 and rT3 concentrations are elevated in these mice compared with those in HNF4α-floxed control littermates; however, serum T3 levels are unchanged. Promoter analysis of the mouse Dio1 gene demonstrated that HNF4α plays a key role in the transactivation of the mouse Dio1 gene. Deletion and substitution mutation analyses demonstrated that a proximal HNF4α site (direct repeat 1 [TGGACAAAGGTGC]; HNF4α-RE) is crucial for transactivation of the mouse Dio1 gene by HNF4α. Mouse Dio1 is also stimulated by thyroid hormone signaling, but a direct role for thyroid hormone receptor action has not been reported. We also showed that thyroid hormone-inducible Krüppel-like factor 9 (KLF9) stimulates the mouse Dio1 promoter very efficiently through two CACCC sequences that are located on either side of HNF4α-RE. Furthermore, KLF9 functions together with HNF4α and GATA4 to synergistically activate the mouse Dio1 promoter, suggesting that Dio1 is regulated by thyroid hormone in the mouse through an indirect mechanism requiring prior KLF9 induction. In addition, we showed that physical interactions between the C-terminal zinc finger domain (Cf) of GATA4 and activation function 2 of HNF4α and between the basic domain adjacent to Cf of GATA4 and a C-terminal domain of KLF9 are both required for this synergistic response. Taken together, these results suggest that HNF4α regulates thyroid hormone homeostasis through transcriptional regulation of the mouse Dio1 gene with GATA4 and KLF9. PMID:18426912
-
Forced expression of Hnf1b/Foxa3 promotes hepatic fate of embryonic stem cells.
Yahoo, Neda; Pournasr, Behshad; Rostamzadeh, Jalal; Hakhamaneshi, Mohammad Saeed; Ebadifar, Asghar; Fathi, Fardin; Baharvand, Hossein
2016-05-20
Embryonic stem (ES) cell-derived hepatocytes have the potential to be used for basic research, regenerative medicine, and drug discovery. Recent reports demonstrated that in addition to conventional differentiation inducers such as chemical compounds and cytokines, overexpression of lineage-specific transcription factors could induce ES cells to differentiate to a hepatic fate. Here, we hypothesized that lentivirus-mediated inducible expression of hepatic lineage transcription factors could enhance mouse ES cells to hepatocyte-like cells. We screened the effects of candidate transcription factors Hnf1b, Hnf1a, Hnf4a, Foxa1, Foxa3 and Hex, and determined that the combination of Hnf1b/Foxa3 promoted expression of several hepatic lineage-specific markers and proteins, in addition to glycogen storage, ICG uptake, and secretion of albumin and urea. The differentiated cells were engraftable and expressed albumin when transplanted into a carbon tetrachloride-injured mouse model. These results demonstrated the crucial role of Hnf1b and Foxa3 in hepatogenesis in vitro and provided a valuable tool for the efficient differentiation of HLCs from ES cells. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Sousa, Josane F.; Nam, Ki Taek; Petersen, Christine P.; Lee, Hyuk-Joon; Yang, Han-Kwang; Kim, Woo Ho; Goldenring, James R.
2016-01-01
Objective Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both marked by gene expression alterations in comparison to normal stomach. Since miRNAs are important regulators of gene expression, we sought to investigate the role of miRNAs on the development of stomach metaplasias. Design We performed miRNA profiling using a qRT-PCR approach on laser capture microdissected human intestinal metaplasia and SPEM. Data integration of the miRNA profile with a previous mRNA profile from the same samples was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with selected miRNA mimics and inhibitors was used to evaluate their effects on the expression of putative targets and additional metaplasia markers. Results We identified several genes as potential targets of miRNAs altered during metaplasia progression. We showed evidence that HNF4γ (upregulated in intestinal metaplasia) is targeted by miR-30 and that miR-194 targets a known co-regulator of HNF4 activity, NR2F2 (downregulated in intestinal metaplasia). Intestinal metaplasia markers such as VIL1, TFF2 and TFF3 were down-regulated after overexpression of miR-30a in a HNF4γ-dependent manner. In addition, overexpression of HNF4γ was sufficient to induce the expression of VIL1 and this effect was potentiated by down-regulation of NR2F2. Conclusion The interplay of the two transcription factors HNF4γ and NR2F2 and their coordinate regulation by miR-30 and miR-194, respectively, represent a miRNA to transcription factor network responsible for the expression of intestinal transcripts in stomach cell lineages during the development of intestinal metaplasia. PMID:25800782
-
Repression of HNF1α-mediated transcription by amino-terminal enhancer of split (AES)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Han, Eun Hee; Gorman, Amanda A.; Singh, Puja
2015-12-04
HNF1α (Hepatocyte Nuclear Factor 1α) is one of the master regulators in pancreatic beta-cell development and function, and the mutations in Hnf1α are the most common monogenic causes of diabetes mellitus. As a member of the POU transcription factor family, HNF1α exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge in their functional complex formation. In this study, we identified the Groucho protein AES (Amino-terminal Enhancer of Split) as a HNF1α-specific physical binding partner and functional repressor of HNF1α-mediated transcription, which has a direct link to glucose-stimulated insulin secretion in beta-cells that ismore » impaired in the HNF1α mutation-driven diabetes. - Highlights: • We identified AES as a transcriptional repressor for HNF1α in pancreatic beta-cell. • AES's repressive activity was HNF1α-specific and was not observed with HNF1β. • AES interacts with the transactivation domain of HNF1α. • Small molecules can be designed or discovered to disrupt this interaction and improve insulin secretion and glucose homeostasis.« less
-
Ahn, Ji-Eun; Guarino, Linda A; Zhu-Salzman, Keyan
2010-02-26
CmCatB, a cathepsin B-type cysteine protease, is insensitive to inhibition by the soybean cysteine protease inhibitor (scN). Cowpea bruchids dramatically induce CmCatB expression when major digestive proteases are inactivated by dietary scN, which is presumably an adaptive strategy that insects use to minimize effects of nutrient deficiency. In this study, we cloned the cowpea bruchid hepatocyte nuclear factor 4 (CmHNF-4) and demonstrated its involvement in transcriptional activation of CmCatB in the digestive tract of scN-adapted bruchids. Electrophoretic mobility shift assays demonstrated that CmHNF-4 binds to a CmCatB promoter region containing two tandem chicken ovalbumin upstream promoter (COUP) sites, which is also the cis-element for Seven-up (CmSvp), a previously identified transcriptional repressor of CmCatB. Although CmSvp is predominantly expressed in unadapted insect midgut, CmHNF-4 is more abundant in adapted bruchids. When transiently expressed in Drosophila S2 cells, CmHNF-4 substantially increased CmCatB expression through COUP binding. CmSvp inhibited CmHNF-4-mediated transcriptional activation even in the absence of its DNA-binding domain. Thus antagonism resulted, at least in part, from protein-protein interactions between CmSvp and CmHNF-4. Association of the two transcription factors was subsequently confirmed by glutathione S-transferase pulldown assays. Interestingly, anti-CmHNF-4 serum caused a supershift not only with nuclear extracts of scN-adapted insect midgut but with that of unadapted control insects as well. The presence of CmHNF-4 in unadapted insects further supported the idea that interplay between CmSvp and CmHNF-4 controls CmCatB transcription activation. Together, these results suggest that coordination between CmHNF-4 and CmSvp is important in counter-defense gene regulation in insects.
-
Walesky, Chad; Gunewardena, Sumedha; Terwilliger, Ernest F; Edwards, Genea; Borude, Prachi; Apte, Udayan
2013-01-01
Hepatocyte nuclear factor-4α (HNF4α) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4α may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4α knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4α in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4α resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4α target genes involved in hepatic differentiation. Interestingly, ≥500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4α, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4α at three of these genes. Furthermore, overexpression of HNF4α in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4α actively inhibits hepatocyte proliferation by repression of specific promitogenic genes.
-
Huang, Qike; Pu, Meng; Zhao, Ge; Dai, Bin; Bian, Zhenyuan; Tang, Haili; Chen, Chong; Liu, Wei; Qu, Xuan; Shen, Liangliang; Tao, Kaishan
2017-08-28
Determining the origin of liver cancer stem cells is important for treating hepatocellular carcinoma. Tg737 deficiency plays an important role in the malignant transformation of liver stem cells, but the underlying mechanism remains unclear. Here we established a chemical-induced mouse hepatoma model and found that Tg737 and hepatocyte nuclear factor 4-alpha (HNF4α) expression decreased and epithelial-mesenchymal transition (EMT)-related marker expression increased during liver cancer development. To investigate the underlying mechanism, we knocked down Tg737 in WB-F344 (WB) rat hepatic oval cells. Loss of Tg737 resulted in nuclear β-catenin accumulation and activation of the Wnt/β-catenin pathway, which further promoted EMT and the malignant phenotype. XAV939, a β-catenin inhibitor, attenuated WB cell malignant transformation due to Tg737 knockdown. To clarify the relationships of Tg737, the β-catenin pathway, and HNF4α, we inhibited Snail and overexpressed HNF4α after Tg737 knockdown in WB cells and found that Snail and HNF4α comprise a negative feedback circuit. Taken together, the results showed that Tg737 regulates a Wnt/β-catenin/Snail-HNF4α negative feedback circuit, thereby blocking EMT and the malignant transformation of liver stem cells to liver cancer stem cells. Copyright © 2017 Elsevier B.V. All rights reserved.
-
Repression of HNF1α-mediated transcription by amino-terminal enhancer of split (AES).
Han, Eun Hee; Gorman, Amanda A; Singh, Puja; Chi, Young-In
HNF1α (Hepatocyte Nuclear Factor 1α) is one of the master regulators in pancreatic beta-cell development and function, and the mutations in Hnf1α are the most common monogenic causes of diabetes mellitus. As a member of the POU transcription factor family, HNF1α exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge in their functional complex formation. In this study, we identified the Groucho protein AES (Amino-terminal Enhancer of Split) as a HNF1α-specific physical binding partner and functional repressor of HNF1α-mediated transcription, which has a direct link to glucose-stimulated insulin secretion in beta-cells that is impaired in the HNF1α mutation-driven diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.
-
Circulating CD36 is reduced in HNF1A-MODY carriers.
Bacon, Siobhan; Kyithar, Ma P; Schmid, Jasmin; Costa Pozza, Andre; Handberg, Aase; Byrne, Maria M
2013-01-01
Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY) accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A) accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36) are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus. We recruited 37 participants with HNF1A-MODY diabetes and compared levels of sCD36 with BMI-matched participants with type 2 diabetes mellitus and normoglycaemic HNF1A-MODY negative family controls. Levels of sCD36 were correlated with phenotypic and biochemical parameters. HNF1A-MODY participants were lean, normotensive, with higher HDL and lower triglyceride levels when compared to controls and participants with type 2 diabetes mellitus. sCD36 was also significantly lower in HNF1A-MODY participants when compared to both the normoglycaemic family controls and to lean participants with type 2 diabetes mellitus. In conclusion, sCD36 is significantly lower in lean participants with HNF1A-MODY diabetes when compared to weight-matched normoglycaemic familial HNF1A-MODY negative controls and to lean participants with type 2 diabetes mellitus. Lower levels of this pro-atherogenic marker may result from the higher HDL component in the lipid profile of
-
Lobo, Daniel; Morokuma, Junji; Levin, Michael
2016-09-01
Automated computational methods can infer dynamic regulatory network models directly from temporal and spatial experimental data, such as genetic perturbations and their resultant morphologies. Recently, a computational method was able to reverse-engineer the first mechanistic model of planarian regeneration that can recapitulate the main anterior-posterior patterning experiments published in the literature. Validating this comprehensive regulatory model via novel experiments that had not yet been performed would add in our understanding of the remarkable regeneration capacity of planarian worms and demonstrate the power of this automated methodology. Using the Michigan Molecular Interactions and STRING databases and the MoCha software tool, we characterized as hnf4 an unknown regulatory gene predicted to exist by the reverse-engineered dynamic model of planarian regeneration. Then, we used the dynamic model to predict the morphological outcomes under different single and multiple knock-downs (RNA interference) of hnf4 and its predicted gene pathway interactors β-catenin and hh Interestingly, the model predicted that RNAi of hnf4 would rescue the abnormal regenerated phenotype (tailless) of RNAi of hh in amputated trunk fragments. Finally, we validated these predictions in vivo by performing the same surgical and genetic experiments with planarian worms, obtaining the same phenotypic outcomes predicted by the reverse-engineered model. These results suggest that hnf4 is a regulatory gene in planarian regeneration, validate the computational predictions of the reverse-engineered dynamic model, and demonstrate the automated methodology for the discovery of novel genes, pathways and experimental phenotypes. michael.levin@tufts.edu. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
-
Khurana, Satish; Jaiswal, Amit K; Mukhopadhyay, Asok
2010-02-12
Hematopoietic stem cells can directly transdifferentiate into hepatocytes because of cellular plasticity, but the molecular basis of transdifferentiation is not known. Here, we show the molecular basis using lineage-depleted oncostatin M receptor beta-expressing (Lin(-)OSMRbeta(+)) mouse bone marrow cells in a hepatic differentiation culture system. Differentiation of the cells was marked by the expression of albumin. Hepatocyte nuclear factor (HNF)-4alpha was expressed and translocated into the nuclei of the differentiating cells. Suppression of its activation in OSM-neutralized culture medium inhibited cellular differentiation. Ectopic expression of full-length HNF4alpha in 32D myeloid cells resulted in decreased myeloid colony-forming potential and increased expression of hepatocyte-specific genes and proteins. Nevertheless, the neohepatocytes produced in culture expressed active P450 enzyme. The obligatory role of HNF4alpha in hepatic differentiation was confirmed by transfecting Lin(-)OSMRbeta(+) cells with dominant negative HNF4alpha in the differentiation culture because its expression inhibited the transcription of the albumin and tyrosine aminotransferase genes. The loss and gain of functional activities strongly suggested that HNF4alpha plays a central role in the transdifferentiation process. For the first time, this report demonstrates the mechanism of transdifferentiation of hematopoietic cells into hepatocytes, in which HNF4alpha serves as a molecular switch.
-
Cai, Shao-hang; Lu, Shi-xun; Liu, Li-li; Zhang, Chris Zhiyi; Yun, Jing-ping
2017-01-01
Background: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. Methods: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan–Meier analysis was conducted to assess the prognostic value of P2-HNF4α. Results: The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression (p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC (p = 0.002) and vascular invasion (p = 0.017). Kaplan–Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group (p = 0.01), validation group (p = 0.034), and overall group of patients with HCC (p < 0.001). Conclusions: Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC. PMID:29051787
-
Cai, Shao-Hang; Lu, Shi-Xun; Liu, Li-Li; Zhang, Chris Zhiyi; Yun, Jing-Ping
2017-10-01
Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry. The relationship between P2-HNF4α and clinical features of HCC patients were analysed. Kaplan-Meier analysis was conducted to assess the prognostic value of P2-HNF4α. The results showed that the expression of P2-HNF4α in HCC was noticeably increased in HCC tissues compared with the nontumourous tissues. In addition, P1-HNF4α expression was negatively correlated with P2-HNF4α expression ( p = 0.023). High P2-HNF4α expression was significantly associated with poor differentiation of HCC ( p = 0.002) and vascular invasion ( p = 0.017). Kaplan-Meier analysis showed that P2-HNF4α expression was closely correlated with overall survival in the training group ( p = 0.01), validation group ( p = 0.034), and overall group of patients with HCC ( p < 0.001). Our data show that the role of HNF4α in cancer development needs to be further refined. P2-HNF4α, different from P1-HNF4α, is markedly upregulated and serves as an oncogene-associated protein in HCC. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC.
-
Zheng, Xing-Wu; Kudaravalli, Rama; Russell, Theresa T; DiMichele, Donna M; Gibb, Constance; Russell, J Eric; Margaritis, Paris; Pollak, Eleanor S
2011-10-01
Severe coagulant factor VII (FVII) deficiency in postpubertal dizygotic twin males results from two point mutations in the FVII gene, a promoter region T→C transition at -60 and a His-to-Arg substitution at amino acid 348; both mutations prevent persistence of plasma functional FVII. This report documents longitudinal laboratory measurements from infancy to adulthood of FVII coagulant activity (FVII:C) in the twin FVII-deficient patients; it also details specific biochemical analyses of the -60 T→C mutation. The results revealed FVII:C levels of less than 1% in infancy that remain severely decreased through puberty and into adulthood. In-vitro analyses utilizing hepatocyte nuclear factor 4α (HNF4α) co-transfection and a chromatin immunoprecipitation assay indicate that the -60 T→C mutation severely diminishes functional interaction between the FVII promoter and transcription factor HNF4α. The importance of interaction between the FVII gene and HNF4α in normal FVII expression provides an in-vivo illustration of the regulated expression of an autosomal gene encoding a coagulation protein. The constancy of FVII:C and peripubertal patient symptomatology reported here illustrates androgen-independent expression in contrast to expression with an analogous mutation in the promoter region of the gene encoding coagulation FIX.
-
Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M.
2016-01-01
Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122
-
Wei, Shengnan; Zhang, Ming; Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M
2016-01-01
Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122
-
Transcriptional regulation of the human Liver X Receptor α gene by Hepatocyte Nuclear Factor 4α
DOE Office of Scientific and Technical Information (OSTI.GOV)
Theofilatos, Dimitris; Anestis, Aristomenis; Hashimoto, Koshi
Liver X Receptors (LXRs) are sterol-activated transcription factors that play major roles in cellular cholesterol homeostasis, HDL biogenesis and reverse cholesterol transport. The aim of the present study was to investigate the mechanisms that control the expression of the human LXRα gene in hepatic cells. A series of reporter plasmids containing consecutive 5′ deletions of the hLXRα promoter upstream of the luciferase gene were constructed and the activity of each construct was measured in HepG2 cells. This analysis showed that the activity of the human LXRα promoter was significantly reduced by deleting the −111 to −42 region suggesting the presence of positivemore » regulatory elements in this short proximal fragment. Bioinformatics data including motif search and ChIP-Seq revealed the presence of a potential binding motif for Hepatocyte Nuclear Factor 4 α (HNF-4α) in this area. Overexpression of HNF-4α in HEK 293T cells increased the expression of all LXRα promoter constructs except −42/+384. In line, silencing the expression of endogenous HNF-4α in HepG2 cells was associated with reduced LXRα protein levels and reduced activity of the −111/+384 LXRα promoter but not of the −42/+384 promoter. Using ChiP assays in HepG2 cells combined with DNAP assays we mapped the novel HNF-4α specific binding motif (H4-SBM) in the −50 to −40 region of the human LXRα promoter. A triple mutation in this H4-SBM abolished HNF-4α binding and reduced the activity of the promoter to 65% relative to the wild type. Furthermore, the mutant promoter could not be transactivated by HNF-4α. In conclusion, our data indicate that HNF-4α may have a wider role in cell and plasma cholesterol homeostasis by controlling the expression of LXRα in hepatic cells. - Highlights: • The human LXRα promoter contains a HNF-4α specific binding motif in the proximal −50/−40 region. • Mutations in this motif abolished HNF4α binding and transactivation of
-
Hang, Hua-Lian; Liu, Xin-Yu; Wang, Hai-Tian; Xu, Ning; Bian, Jian-Min; Zhang, Jian-Jun; Xia, Lei; Xia, Qiang
2017-11-15
Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of β-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote β-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. Copyright © 2017 Elsevier Inc. All rights reserved.
-
Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.
McDonald, Tim J; McEneny, Jane; Pearson, Ewan R; Thanabalasingham, Gaya; Szopa, Magdalena; Shields, Beverley M; Ellard, Sian; Owen, Katharine R; Malecki, Maciej T; Hattersley, Andrew T; Young, Ian S
2012-05-18
The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.
-
Yu, Dongsheng; Chen, Gang; Pan, Minglin; Zhang, Jia; He, Wenping; Liu, Yang; Nian, Xue; Sheng, Liang; Xu, Bin
2018-06-01
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over-accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4α (HNF4α), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4α in NAFLD remains to be elucidated. In the present study, we found that high fat diet (HFD) induced cytoplasmic retention of HNF4α in hepatocytes, which led to down-regulation of hepatic ApoB expression and its protein level in serum, as well as reduced secretion of VLDL. We further revealed that oxidative stress, elevated in fatty liver, was the key factor inducing the cytoplasmic retention of HNF4α in hepatocytes by activating protein kinase C (PKC)-mediated phosphorylation in HNF4α. Thus, our findings reveal a novel mechanism underlying HFD-induced fatty liver that oxidative stress impairs function of HNF4α on ApoB expression and VLDL secretion via PKC activation, eventually promoting fat accumulation in the liver. Therefore, oxidative stress/PKC/HNF4α pathway may be a novel target to treat diet-induced fatty liver. © 2017 Wiley Periodicals, Inc.
-
Painter, Jodie N.; O'Mara, Tracy A.; Batra, Jyotsna; Cheng, Timothy; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Kaufmann, Susanne; Hillman, Kristine M.; Walpole, Carina; Moya, Leire; Pollock, Pamela; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Hodgson, Shirley; De Polanco, Ma. Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Santos, Erika; Teixeira, Manuel R.; Carvajal-Carmona, Luis; Shu, Xiao-Ou; Long, Jirong; Zheng, Wei; Xiang, Yong-Bing; Montgomery, Grant W.; Webb, Penelope M.; Scott, Rodney J.; McEvoy, Mark; Attia, John; Holliday, Elizabeth; Martin, Nicholas G.; Nyholt, Dale R.; Henders, Anjali K.; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Renner, Stefan P.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo; Lambrechts, Diether; Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic; Winterhoff, Boris; Dowdy, Sean C.; Goode, Ellen L.; Teoman, Attila; Salvesen, Helga B.; Trovik, Jone; Njolstad, Tormund S.; Werner, Henrica M.J.; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Tzortzatos, Gerasimos; Mints, Miriam; Tham, Emma; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Hopper, John L.; Southey, Melissa C.; Ekici, Arif B.; Ruebner, Matthias; Johnson, Nicola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K.; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Depreeuw, Jeroen; Moisse, Matthieu; Chang-Claude, Jenny; Rudolph, Anja; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; Bruinsma, Fiona; Cunningham, Julie M.; Fridley, Brooke L.; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Cox, Angela; Swerdlow, Anthony J.; Orr, Nicholas; Bolla, Manjeet K.; Wang, Qin; Weber, Rachel Palmieri; Chen, Zhihua; Shah, Mitul; French, Juliet D.; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Easton, Douglas F.; Edwards, Stacey L.; Thompson, Deborah J.; Spurdle, Amanda B.
2015-01-01
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. PMID:25378557
-
Howell, Meredith; Li, Rui; Zhang, Rui; Li, Yang; Chen, Wei; Chen, Guoxun
2014-02-01
Vitamin A status regulates obesity development, hyperlipidemia, and hepatic lipogenic gene expression in Zucker fatty (ZF) rats. The development of hyperlipidemia in acne patients treated with retinoic acid (RA) has been attributed to the induction of apolipoprotein C-III expression. To understand the role of retinoids in the development of hyperlipidemia in ZF rats, the expression levels of several selected RA-responsive genes in the liver and isolated hepatocytes from Zucker lean (ZL) and ZF rats were compared using real-time PCR. The Rarb and Srebp-1c mRNA levels are higher in the liver and isolated hepatocytes from ZF than ZL rats. The Apoc3 mRNA level is only higher in the isolated hepatocytes from ZF than ZL rats. To determine whether dynamic RA production acutely regulates Apoc3 expression, its mRNA levels in response to retinoid treatments or adenovirus-mediated overexpression of hepatocyte nuclear factor 4 alpha (HNF4α) and chicken ovalbumin upstream-transcription factor II (COUP-TFII) were analyzed. Retinoid treatments for 2-6 h did not induce the expression of Apoc3 mRNA. The overexpression of HNF4α or COUP-TFII induced or inhibited Apoc3 expression, respectively. We conclude that short-term retinoid treatments could not induce Apoc3 mRNA expression, which is regulated by HNF4α and COUP-TFII in hepatocytes.
-
Cystatin C is not a good candidate biomarker for HNF1A-MODY.
Nowak, Natalia; Szopa, Magdalena; Thanabalasingham, Gaya; McDonald, Tim J; Colclough, Kevin; Skupien, Jan; James, Timothy J; Kiec-Wilk, Beata; Kozek, Elzbieta; Mlynarski, Wojciech; Hattersley, Andrew T; Owen, Katharine R; Malecki, Maciej T
2013-10-01
Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
-
Painter, Jodie N; O'Mara, Tracy A; Batra, Jyotsna; Cheng, Timothy; Lose, Felicity A; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S; Kaufmann, Susanne; Hillman, Kristine M; Walpole, Carina; Moya, Leire; Pollock, Pamela; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Hodgson, Shirley; De Polanco, Ma Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Santos, Erika; Teixeira, Manuel R; Carvajal-Carmona, Luis; Shu, Xiao-Ou; Long, Jirong; Zheng, Wei; Xiang, Yong-Bing; Montgomery, Grant W; Webb, Penelope M; Scott, Rodney J; McEvoy, Mark; Attia, John; Holliday, Elizabeth; Martin, Nicholas G; Nyholt, Dale R; Henders, Anjali K; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo; Lambrechts, Diether; Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic; Winterhoff, Boris; Dowdy, Sean C; Goode, Ellen L; Teoman, Attila; Salvesen, Helga B; Trovik, Jone; Njolstad, Tormund S; Werner, Henrica M J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Tzortzatos, Gerasimos; Mints, Miriam; Tham, Emma; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Hopper, John L; Southey, Melissa C; Ekici, Arif B; Ruebner, Matthias; Johnson, Nicola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Depreeuw, Jeroen; Moisse, Matthieu; Chang-Claude, Jenny; Rudolph, Anja; Couch, Fergus J; Olson, Janet E; Giles, Graham G; Bruinsma, Fiona; Cunningham, Julie M; Fridley, Brooke L; Børresen-Dale, Anne-Lise; Kristensen, Vessela N; Cox, Angela; Swerdlow, Anthony J; Orr, Nicholas; Bolla, Manjeet K; Wang, Qin; Weber, Rachel Palmieri; Chen, Zhihua; Shah, Mitul; French, Juliet D; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Edwards, Stacey L; Thompson, Deborah J; Spurdle, Amanda B
2015-03-01
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
-
Sang, Yanmei; Xu, Zidi; Liu, Min; Yan, Jie; Wu, Yujun; Zhu, Cheng; Ni, Guichen
2014-01-01
We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 α (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.
-
Galán, Maria; García-Herrero, Carmen-Maria; Azriel, Sharona; Gargallo, Manuel; Durán, Maria; Gorgojo, Juan-Jose; Andía, Victor-Manuel; Navas, Maria-Angeles
2011-01-01
Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The variability of the MODY3 clinical phenotype can be due to environmental and genetic factors as well as to the type and position of mutations. Thus, functional characterization of HNF1A mutations might provide insight into the molecular defects explaining the variability of the MODY3 phenotype. We have functionally characterized six HNF1A mutations identified in diabetic patients: two novel ones, p.Glu235Gly and c-57-64delCACGCGGT;c-55G>C; and four previously described, p.Val133Met, p.Thr196Ala, p.Arg271Trp and p.Pro379Arg. The effects of mutations on transcriptional activity have been measured by reporter assays on a subset of HNF-1α target promoters in Cos7 and Min6 cells. Target DNA binding affinities have been quantified by electrophoretic mobility shift assay using bacterially expressed glutathione-S-transferase (GST)-HNF-1α fusion proteins and nuclear extracts of transfected Cos7 cells. Our functional studies revealed that mutation c-57-64delCACGCGGT;c-55G>C reduces HNF1A promoter activity in Min6 cells and that missense mutations have variable effects. Mutation p.Arg271Trp impairs HNF-1α activity in all conditions tested, whereas mutations p.Val133Met, p.Glu235Gly and p.Pro379Arg exert differential effects depending on the target promoter. In contrast, substitution p.Thr196Ala does not appear to alter HNF-1α function. Our results suggest that HNF1A mutations may have differential effects on the regulation of specific target genes, which could contribute to the variability of the MODY3 clinical phenotype. PMID:21170474
-
Babeu, Jean-Philippe; Jones, Christine; Geha, Sameh; Carrier, Julie C; Boudreau, François
2018-06-13
HNF4α is a key nuclear receptor for regulating gene expression in the gut. While both P1 and P2 isoform classes of HNF4α are expressed in colonic epithelium, specific inhibition of P1 isoforms is commonly found in colorectal cancer. Previous studies have suggested that P1 and P2 isoforms may regulate different cellular functions. Despite these advances, it remains unclear whether these isoform classes are functionally divergent in the context of human biology. Here, the consequences of specific inhibition of P1 or P2 isoform expression was measured in a human colorectal cancer cell transcriptome. Results indicate that P1 isoforms were specifically associated with the control of cell metabolism while P2 isoforms globally supported aberrant oncogenic signalization, promoting cancer cell survival and progression. P1 promoter-driven isoform expression was found to be repressed by β-catenin, one of the earliest oncogenic pathways to be activated during colon tumorigenesis. These findings identify a novel cascade by which the expression of P1 isoforms are rapidly shut down in the early stages of colon tumorigenesis, allowing a change in HNF4α-dependent transcriptome thereby promoting colorectal cancer progression. © 2018. Published by The Company of Biologists Ltd.
-
Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb
Lancman, Joseph J.; Zvenigorodsky, Natasha; Gates, Keith P.; Zhang, Danhua; Solomon, Keely; Humphrey, Rohan K.; Kuo, Taiyi; Setiawan, Linda; Verkade, Heather; Chi, Young-In; Jhala, Ulupi S.; Wright, Christopher V. E.; Stainier, Didier Y. R.; Dong, P. Duc Si
2013-01-01
Although the liver and ventral pancreas are thought to arise from a common multipotent progenitor pool, it is unclear whether these progenitors of the hepatopancreas system are specified by a common genetic mechanism. Efforts to determine the role of Hnf1b and Wnt signaling in this crucial process have been confounded by a combination of factors, including a narrow time frame for hepatopancreas specification, functional redundancy among Wnt ligands, and pleiotropic defects caused by either severe loss of Wnt signaling or Hnf1b function. Using a novel hypomorphic hnf1ba zebrafish mutant that exhibits pancreas hypoplasia, as observed in HNF1B monogenic diabetes, we show that hnf1ba plays essential roles in regulating β-cell number and pancreas specification, distinct from its function in regulating pancreas size and liver specification, respectively. By combining Hnf1ba partial loss of function with conditional loss of Wnt signaling, we uncover a crucial developmental window when these pathways synergize to specify the entire ventrally derived hepatopancreas progenitor population. Furthermore, our in vivo genetic studies demonstrate that hnf1ba generates a permissive domain for Wnt signaling activity in the foregut endoderm. Collectively, our findings provide a new model for HNF1B function, yield insight into pancreas and β-cell development, and suggest a new mechanism for hepatopancreatic specification. PMID:23720049
-
MODY3, renal cysts, and Dandy-Walker variants with a microdeletion spanning the HNF1A gene.
Matsukura, Hiro; Nagamori, Mariko; Miya, Kazushi; Yorifuji, Tohru
2017-09-01
Heterozygous hepatocyte nuclear factor-1-α gene (
HNF1A ) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused byHNF1B mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported.HNF1A mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, theHNF1B gene had no mutations. Array comparative genomic hybridization analysis identified a de-novo interstitial 12q24.22-q24.31 deletion of 5.6 Mb encompassing theHNF1A gene, which is compatible with a diagnosis of MODY3. The variety of phenotypes suggests a novel microdeletion syndrome spanning theHNF1A gene. BecauseHNF1B functions as anHNF1A/HNF1B heterodimer, haploinsufficientHNF1A interacts with a certainHNF1B haplotype. The resulting truncated heterodimer might engender renal cysts. More patients with well-defined deletion within 12q.24.31 must be evaluated to produce a detailed genotype-phenotype correlation and to elucidate this emerging microdeletion syndrome. . -
Goh, Grace Y S; Winter, Johnathan J; Bhanshali, Forum; Doering, Kelsie R S; Lai, Regina; Lee, Kayoung; Veal, Elizabeth A; Taubert, Stefan
2018-06-01
Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, hepatocyte nuclear factor 4 (HNF4) and peroxisome proliferator-activated receptor α (PPARα), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monooxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, with two of them making critical contributions to the oxidative stress resistance of wild-type and long-lived glp-1 mutants worms. Similar to its role in lipid metabolism, NHR-49 requires the mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. We show that activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is also important for peroxide-induced expression of a subset of NHR-49-dependent genes that includes fmo-2. However, organic peroxide increases NHR-49 protein levels, by a posttranscriptional mechanism that does not require PMK-1 activation. Together, these findings establish a new role for the HNF4/PPARα-related NHR-49 as a stress-activated regulator of cytoprotective gene expression. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
-
The Common HNF1A Variant I27L is a Modifier of Age at Diabetes Diagnosis in HNF1A-MODY Individuals.
Locke, Jonathan M; Saint-Martin, Cécile; Laver, Thomas W; Patel, Kashyap A; Wood, Andrew R; Sharp, Seth A; Ellard, Sian; Bellanné-Chantelot, Christine; Hattersley, Andrew T; Harries, Lorna W; Weedon, Michael N
2018-06-12
There is wide variation in the age at diagnosis of diabetes in individuals with Maturity-Onset Diabetes of the Young (MODY) due to a mutation in the HNF1A gene. We hypothesised that common variants at the HNF1A locus (rs1169288, I27L; rs1800574, A98V), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in HNF1A-MODY individuals. Meta-analysis of two independent cohorts, comprising 781 HNF1A-MODY individuals, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant (PTV) or missense), we found each 27L allele to be associated with a 1.6 year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n=444) of HNF1A-MODY individuals with a PTV. The effect size was similar and significant across the two independent cohorts of HNF1A-MODY individuals. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype. © 2018 by the American Diabetes Association.
-
Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.
Mughal, S A; Park, R; Nowak, N; Gloyn, A L; Karpe, F; Matile, H; Malecki, M T; McCarthy, M I; Stoffel, M; Owen, K R
2013-02-01
Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.
-
Ross-Adams, Helen; Ball, Stephen; Lawrenson, Kate; Halim, Silvia; Russell, Roslin; Wells, Claire; Strand, Siri H.; Ørntoft, Torben F.; Larson, Melissa; Armasu, Sebastian; Massie, Charles E.; Asim, Mohammad; Mortensen, Martin M.; Borre, Michael; Woodfine, Kathryn; Warren, Anne Y.; Lamb, Alastair D.; Kay, Jonathan; Whitaker, Hayley; Ramos-Montoya, Antonio; Murrell, Adele; Sørensen, Karina D.; Fridley, Brooke L.; Goode, Ellen L.; Gayther, Simon A.; Masters, John
2016-01-01
Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor. PMID:27732966
-
Aboulnasr, Fatma; Hazari, Sidhartha; Nayak, Satyam; Chandra, Partha K.; Panigrahi, Rajesh; Ferraris, Pauline; Chava, Srinivas; Kurt, Ramazan; Song, Kyongsub; Dash, Asha; Balart, Luis A.; Garry, Robert F.; Wu, Tong; Dash, Srikanta
2015-01-01
Background HCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined. Aim To investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model. Methods IFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-α or IFN-λ. The relative antiviral effects of IFN-α and IFN-λ1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined. Results We have shown that IFN-λ1 induces HCV clearance in IFN-α resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-λ1 induced antiviral activity in HCV cell culture. IFN-λ1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4α) through miR-24 in R4-GFP cells. Reduced expression of HNF4α is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-λ1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-λ1 activates the Stat 3-HNF4α feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture. Conclusions In addition to the classical Jak–Stat antiviral signaling pathway, IFN-λ1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3–HNF4α feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non
-
MiR-495 and miR-218 regulate the expression of the Onecut transcription factors HNF-6 and OC-2
DOE Office of Scientific and Technical Information (OSTI.GOV)
Simion, Alexandru; Laudadio, Ilaria; Prevot, Pierre-Paul
2010-01-01
MicroRNAs are small, non-coding RNAs that posttranscriptionally regulate gene expression mainly by binding to the 3'UTR of their target mRNAs. Recent data revealed that microRNAs have an important role in pancreas and liver development and physiology. Using cloning and microarray profiling approaches, we show that a unique repertoire of microRNAs is expressed at the onset of liver and pancreas organogenesis, and in pancreas and liver at key stages of cell fate determination. Among the microRNAs that are expressed at these stages, miR-495 and miR-218 were predicted to, respectively, target the Onecut (OC) transcription factors Hepatocyte Nuclear Factor-6 (HNF-6/OC-1) and OC-2,more » two important regulators of liver and pancreas development. MiR-495 and miR-218 are dynamically expressed in developing liver and pancreas, and by transient transfection, we show that they target HNF-6 and OC-2 3'UTRs. Moreover, when overexpressed in cultured cells, miR-495 and miR-218 decrease the endogenous levels of HNF-6 and OC-2 mRNA. These results indicate that the expression of regulators of liver and pancreas development is modulated by microRNAs. They also suggest a developmental role for miR-495 and miR-218.« less
-
Laron Dwarfism and Non-Insulin-Dependent Diabetes Mellitus in the Hnf-1α Knockout Mouse
Lee, Ying-Hue; Sauer, Brian; Gonzalez, Frank J.
1998-01-01
Mice deficient in hepatocyte nuclear factor 1 alpha (HNF-1α) were produced by use of the Cre-loxP recombination system. HNF-1α-null mice are viable but sterile and exhibit a phenotype reminiscent of both Laron-type dwarfism and non-insulin-dependent diabetes mellitus (NIDDM). In contrast to an earlier HNF-1α-null mouse line that had been produced by use of standard gene disruption methodology (M. Pontoglio, J. Barra, M. Hadchouel, A. Doyen, C. Kress, J. P. Bach, C. Babinet, and M. Yaniv, Cell 84:575–585, 1996), these mice exhibited no increased mortality and only minimal renal dysfunction during the first 6 months of development. Both dwarfism and NIDDM are most likely due to the loss of expression of insulin-like growth factor I (IGF-I) and lower levels of insulin, resulting in stunted growth and elevated serum glucose levels, respectively. These results confirm the functional significance of the HNF-1α regulatory elements that had previously been shown to reside in the promoter regions of both the IGF-I and the insulin genes. PMID:9566924
-
Identification of circulating microRNAs in HNF1A-MODY carriers.
Bonner, C; Nyhan, K C; Bacon, S; Kyithar, M P; Schmid, J; Concannon, C G; Bray, I M; Stallings, R L; Prehn, J H M; Byrne, M M
2013-08-01
HNF1A-MODY is a monogenic form of diabetes caused by mutations in the HNF1A gene. Here we identify, for the first time, HNF1A-MODY-associated microRNAs (miRNAs) that can be detected in the serum of HNF1A-MODY carriers. An miRNA array was carried out in rat INS-1 insulinoma cells inducibly expressing the common human Pro291fsinsC-HNF1A frame shift mutation. Differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of miRNAs in the serum of HNF1A-MODY carriers (n = 31), MODY-negative family members (n = 10) and individuals with type 2 diabetes mellitus (n = 17) was quantified by absolute real-time PCR analysis. Inducible expression of Pro291fsinsC-HNF1A in INS-1 cells caused a significant upregulation of three miRNAs (miR-103, miR-224, miR-292-3p). The differential expression of two miRNAs (miR-103 and miR-224) was validated in vitro. Strongly elevated levels of miR-103 and miR-224 could be detected in the serum of HNF1A-MODY carriers compared with MODY-negative family controls. Serum levels of miR-103 distinguished HNF1A-MODY carriers from HbA1c-matched individuals with type 2 diabetes mellitus. Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers.
-
Xie, Peiyi; Hu, Xiaojun; Li, Dan; Xie, Sidong; Zhou, Zhiyang; Meng, Xiaochun; Shan, Hong
2018-05-14
The purposes of this study were to construct immortalized human bone marrow mesenchymal stem cells (UE7T-13) with overexpression of the hepatocyte nuclear factor4α (hHNF4α) and luciferase2-mKate2 dual-fusion reporter gene, further investigate their impact on treating acute liver injury (ALI) in rats, and track their biodistribution and survival by bioluminescence imaging (BLI). The hHNF4α and luciferase2-mKate2 genes were transduced by a lentiviral vector into UE7T-13 cells (named E7-hHNF4α-R cells), and expression was verified by immunofluorescence, RT-PCR, and flow cytometry. E7-hGFP-R cells expressing the luciferase2-mKate2/hGFP gene served as a negative group. A correlation between the bioluminescence signal and cell number was detected by BLI. The ALI rats were established and divided into three groups: PBS, E7-hGFP-R, and E7-hHNF4α-R. After transplantation of 2.0 × 10 6 cells, BLI was used to dynamically track their biodistribution and survival. The restoration of biological functions was assessed by serum biochemical and histological analyses. Stable high-level expression of hHNF4α and mKate2 protein was established in the E7-hHNF4α-R cells in vitro. The E7-hHNF4α-R cells strongly expressed hGFP, hHNF4α, and mKate2 proteins, and the hHNF4α gene. hGFP-mKate2 dual-positive cell expression reached approximately 93 %. BLI verified that a linear relationship existed between the cell number and bioluminescence signal (R 2 = 0.9991). The cells improved liver function in vivo after transplantation into the ALI rat liver, as evidenced by the fact that AST and ALT temporarily returned to normal levels in the recipient ALI rats. The presence of the transplanted E7-hGFP-R and E7-hHNF4α-R cells in recipient rat livers was confirmed by BLI and immunohistochemistry. However, the cells were cleared by the immune system a short time after transplantation into ALI rats with a normal immune system. Our data revealed that the E7-hHNF4α-R cells can
-
An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides.
Armour, Sean M; Remsberg, Jarrett R; Damle, Manashree; Sidoli, Simone; Ho, Wesley Y; Li, Zhenghui; Garcia, Benjamin A; Lazar, Mitchell A
2017-09-15
The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis.
-
Chaya, D; Fougère-Deschatrette, C; Weiss, M C
1997-01-01
Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver. PMID:9343392
-
Chaya, D; Fougère-Deschatrette, C; Weiss, M C
1997-11-01
Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.
-
Verzi, Michael P.; Shin, Hyunjin; San Roman, Adrianna K.
2013-01-01
Tissue-specific gene expression requires modulation of nucleosomes, allowing transcription factors to occupy cis elements that are accessible only in selected tissues. Master transcription factors control cell-specific genes and define cellular identities, but it is unclear if they possess special abilities to regulate cell-specific chromatin and if such abilities might underlie lineage determination and maintenance. One prevailing view is that several transcription factors enable chromatin access in combination. The homeodomain protein CDX2 specifies the embryonic intestinal epithelium, through unknown mechanisms, and partners with transcription factors such as HNF4A in the adult intestine. We examined enhancer chromatin and gene expression following Cdx2 or Hnf4a excision in mouse intestines. HNF4A loss did not affect CDX2 binding or chromatin, whereas CDX2 depletion modified chromatin significantly at CDX2-bound enhancers, disrupted HNF4A occupancy, and abrogated expression of neighboring genes. Thus, CDX2 maintains transcription-permissive chromatin, illustrating a powerful and dominant effect on enhancer configuration in an adult tissue. Similar, hierarchical control of cell-specific chromatin states is probably a general property of master transcription factors. PMID:23129810
-
Hoang, Lien N; Han, Guangming; McConechy, Melissa; Lau, Sherman; Chow, Christine; Gilks, C Blake; Huntsman, David G; Köbel, Martin; Lee, Cheng-Han
2014-03-01
The great majority of ovarian clear cell carcinomas have a hepatocyte nuclear factor 1 homeobox B (HNF-1β)-positive and oestrogen receptor (ER)-negative immunoprofile. However, the pattern of HNF-1β and ER immunostaining in clear cell carcinomas of the endometrium and the usefulness of this panel in distinguishing clear cell carcinoma from other histological types of endometrial carcinoma have yet to be well defined. We examined the immunostaining patterns of HNF-1β, ER and p53 in 15 morphologically classic pure endometrial clear cell carcinomas, and compared these patterns with 15 endometrioid and 15 serous carcinomas of the endometrium. We observed the presence of diffuse (>70%) moderate to strong nuclear HNF-1β staining and negative ER staining in 14 of 15 clear cell carcinomas, with the remaining case showing both diffuse strong nuclear HNF-1β staining and focal ER staining. In comparison, only one of 15 serous carcinomas and none of 15 endometrioid carcinomas showed a combination of diffuse moderate to strong HNF-1β nuclear staining and negative ER staining. Aberrant p53 immunostaining was observed in five of 15 (33%) clear cell carcinomas. Overall, our findings demonstrate that, similarly to the situation for the ovary, a diagnostic panel of HNF-1β and ER may be considered for separating clear cell carcinoma from endometrioid and serous carcinoma of the endometrium. © 2013 John Wiley & Sons Ltd.
-
Prevalence of Retinopathy in Adult Patients with GCK-MODY and HNF1A-MODY.
Szopa, M; Wolkow, J; Matejko, B; Skupien, J; Klupa, T; Wybrańska, I; Trznadel-Morawska, I; Kiec-Wilk, B; Borowiec, M; Malecki, M T
2015-10-01
We aimed to assess the prevalence of diabetic retinopathy (DR) in adult patients with GCK-MODY and HNF1A-MODY in Poland and to identify biochemical and clinical risk factors associated with its occurrence.We examined 74 GCK mutation carriers, 51 with diabetes and 23 with prediabetes, respectively, and 63 patients with HNF1A-MODY. Retinal photographs, 12 for each patient, were done by a fundus camera. Signs of DR were graded according to the DR disease severity scale. Statistical tests were performed to assess differences between the groups and logistic regression was done for the association with DR.The mean age at examination was 34.5±14.8 and 39.9±15.2 in the GCK-MODY and HNF1A-MODY groups, respectively. Mild nonproliferative DR (NPDR) was found in one patient with the GCK mutation and likely concomitant type 1 diabetes, whereas DR was diagnosed in 15 HNF1A-MODY patients: 9 with proliferative, 3 with moderate NPDR and 2 with mild NPDR. In univariate logistic regression analysis in the HNF1A-MODY group, significant results were found for diabetes duration, fasting glycemia, HbA1c, arterial hypertension, age at the examination, and eGFR. The strongest independent predictors of DR in HNF1A-MODY were markers of glucose control: HbA1c (OR: 2.05, CL%95: 1.2-3.83, p=0.01) and glucose (p=0.006, OR: 1.40, CL%95: 1.12-1.83) analyzed in 2 separated models. Additionally, arterial hypertension independently predicted DR (OR: 9.06, CL%95: 1.19-98.99, p=0.04) in the model with HbA1c as glycaemic control marker.In conclusion, DR of any degree was not present in our GCK-MODY group, while in spite of young age almost every fourth subject with HNF1A-MODY showed signs of this complication. © Georg Thieme Verlag KG Stuttgart · New York.
-
Takahashi, Shigeru; Matsuura, Naomi; Kurokawa, Takako; Takahashi, Yuji; Miura, Takashi
2002-01-01
We reported previously that the 5'-flanking region (nucleotides -1976 to -1655) of the human haem oxygenase-1 ( hHO-1 ) gene enhances hHO-1 promoter activity in human hepatoma HepG2 cells, but not in HeLa cells [Takahashi, Takahashi, Ito, Nagano, Shibahara and Miura (1999) Biochim. Biophys. Acta 1447, 231-235]. To define more precisely the regulatory elements involved, in the present study we have functionally dissected this region and localized the enhancer to a 50 bp fragment (-1793 to -1744). Site-direct mutagenesis analysis revealed that two regions were responsible for this enhancer activity, i.e. a hepatocyte nuclear factor-4 (HNF-4) homologous region and a GC box motif homologous region. Mutation in either region alone moderately decreased enhancer activity. However, mutations in both regions reduced promoter activity to the basal level. Electrophoretic mobility-shift assays demonstrated that the P5-2 fragment (-1793 to -1744) interacted with at least two nuclear factors, i.e. HNF-4 and Sp1/Sp3. Co-transfection experiments using Drosophila SL2 cells revealed that HNF-4 and Sp1/Sp3 synergistically stimulated the enhancer activity of the P5-2 fragment. These results indicate that co-operation of HNF-4 with Sp1 or Sp3 leads to the activation of hHO-1 gene expression in hepatoma cells. PMID:12133007
-
Takahashi, Shigeru; Matsuura, Naomi; Kurokawa, Takako; Takahashi, Yuji; Miura, Takashi
2002-11-01
We reported previously that the 5'-flanking region (nucleotides -1976 to -1655) of the human haem oxygenase-1 ( hHO-1 ) gene enhances hHO-1 promoter activity in human hepatoma HepG2 cells, but not in HeLa cells [Takahashi, Takahashi, Ito, Nagano, Shibahara and Miura (1999) Biochim. Biophys. Acta 1447, 231-235]. To define more precisely the regulatory elements involved, in the present study we have functionally dissected this region and localized the enhancer to a 50 bp fragment (-1793 to -1744). Site-direct mutagenesis analysis revealed that two regions were responsible for this enhancer activity, i.e. a hepatocyte nuclear factor-4 (HNF-4) homologous region and a GC box motif homologous region. Mutation in either region alone moderately decreased enhancer activity. However, mutations in both regions reduced promoter activity to the basal level. Electrophoretic mobility-shift assays demonstrated that the P5-2 fragment (-1793 to -1744) interacted with at least two nuclear factors, i.e. HNF-4 and Sp1/Sp3. Co-transfection experiments using Drosophila SL2 cells revealed that HNF-4 and Sp1/Sp3 synergistically stimulated the enhancer activity of the P5-2 fragment. These results indicate that co-operation of HNF-4 with Sp1 or Sp3 leads to the activation of hHO-1 gene expression in hepatoma cells.
-
HNF1α defect influences post-prandial lipid regulation
St-Jean, Matthieu; Boudreau, François; Carpentier, André C.
2017-01-01
Purpose Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). Methods We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). Results We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. Conclusion In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels. PMID:28493909
-
Galson, D L; Tsuchiya, T; Tendler, D S; Huang, L E; Ren, Y; Ogura, T; Bunn, H F
1995-04-01
The erythropoietin (Epo) gene is regulated by hypoxia-inducible cis-acting elements in the promoter and in a 3' enhancer, both of which contain consensus hexanucleotide hormone receptor response elements which are important for function. A group of 11 orphan nuclear receptors, transcribed and translated in vitro, were screened by the electrophoretic mobility shift assay. Of these, hepatic nuclear factor 4 (HNF-4), TR2-11, ROR alpha 1, and EAR3/COUP-TF1 bound specifically to the response elements in the Epo promoter and enhancer and, except for ROR alpha 1, formed DNA-protein complexes that had mobilities similar to those observed in nuclear extracts of the Epo-producing cell line Hep3B. Moreover, both anti-HNF-4 and anti-COUP antibodies were able to supershift complexes in Hep3B nuclear extracts. Like Epo, HNF-4 is expressed in kidney, liver, and Hep3B cells but not in HeLa cells. Transfection of a plasmid expressing HNF-4 into HeLa cells enabled an eightfold increase in the hypoxic induction of a luciferase reporter construct which contains the minimal Epo enhancer and Epo promoter, provided that the nuclear hormone receptor consensus DNA elements in both the promoter and the enhancer were intact. The augmentation by HNF-4 in HeLa cells could be abrogated by cotransfection with HNF-4 delta C, which retains the DNA binding domain of HNF-4 but lacks the C-terminal activation domain. Moreover, the hypoxia-induced expression of the endogenous Epo gene was significantly inhibited in Hep3B cells stably transfected with HNF-4 delta C. On the other hand, cotransfection of EAR3/COUP-TF1 and the Epo reporter either with HNF-4 into HeLa cells or alone into Hep3B cells suppressed the hypoxia induction of the Epo reporter. These electrophoretic mobility shift assay and functional experiments indicate that HNF-4 plays a critical positive role in the tissue-specific and hypoxia-inducible expression of the Epo gene, whereas the COUP family has a negative modulatory role.
-
Maturity Onset Diabetes of the Young (MODY) in Tunisia: Low frequencies of GCK and HNF1A mutations.
Ben Khelifa, S; Martinez, R; Dandana, A; Khochtali, I; Ferchichi, S; Castaño, L
2018-04-20
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in β-cell function. Mutations in the GCK and HNF1A genes are the most common cause of MODY among Caucasians. The etiology of MODY in Tunisia stills a challenge for researchers. The aim of this study was to screen for mutations in GCK, HNF1A, HNF4A and INS genes in North African Tunisians subjects, in whom the clinical profile was very suggestive of MODY. A total of 23 unrelated patients, with clinical presentation of MODY were tested for mutations in GCK, HNF1A, HNF4A and INS genes, using Denaturing High Performance Liquid Chromatography (DHPLC), Multiplex Ligation-depend Probe Amplification (MLPA) and sequencing analysis. We identified the previously reported mutation c-169C > T in one patient as well as a new mutation c-457C > T in two unrelated patients. No mutations were detected in the HNF1A and INS genes. Despite restrictive clinical criteria used for selecting patients in this study, the most common genes known for MODY do not explain the majority of cases in Tunisians. This suggests that there are others candidate or unidentified genes contributing to the etiology of MODY in Tunisians families. Copyright © 2018 Elsevier B.V. All rights reserved.
-
Nowak, Natalia; Hohendorff, Jerzy; Solecka, Iwona; Szopa, Magdalena; Skupien, Jan; Kiec-Wilk, Beata; Mlynarski, Wojciech; Malecki, Maciej T
2015-12-01
Ghrelin is a hormone that regulates appetite. It is likely to be involved in the pathophysiology of varying forms of diabetes. In animal studies, the ghrelin expression was regulated by the hepatocyte nuclear factor 1 alpha (HNF1A). Mutations of the HNF1A gene cause maturity onset diabetes of the young (MODY). We aimed to assess the circulating ghrelin levels in HNF1A-MODY and in other types of diabetes and to evaluate its association with HNF1A mutation status. Our cohort included 46 diabetic HNF1A gene mutation carriers, 55 type 2 diabetes (T2DM) subjects, 42 type 1 diabetes (T1DM) patients, and 31 glucokinase (GCK) gene mutation carriers with diabetes as well as 51 healthy controls. Plasma ghrelin concentration was measured using the immunoenzymatic assay with polyclonal antibody against the C-terminal fragment of its acylated and desacylated forms. Ghrelin concentrations were 0.75 ± 0.32, 0.70 ± 0.21, 0.50 ± 0.20, and 0.40 ± 0.16 ng/ml in patients with HNF1A-MODY, GCK-MODY, T1DM, and T2DM, respectively. The ghrelin levels were higher in HNF1A-MODY and GCK-MODY than in T1DM and T2DM (p < 0.001 for all comparisons) but lower than in non-diabetic controls (1.02 ± 0.29 ng/ml, p < 0.001 for both comparisons). In the multivariate linear model, the differences between both MODY groups and common diabetes types remained significant. Analysis by a HNF1A mutation type indicated that ghrelin concentration is similar in patients with different types of sequence differences. Plasma ghrelin level is higher in HNF1A-MODY and GCK-MODY than in the common polygenic forms of diabetes.
-
Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao
2016-04-14
The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.
-
Hor, S Y; Lee, S C; Wong, C I; Lim, Y W; Lim, R C; Wang, L Z; Fan, L; Guo, J Y; Lee, H S; Goh, B C; Tan, T
2008-04-01
Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for
-
Shen, Chunhong; Zhang, Bijun; Liu, Zhirong; Tang, Yelei; Zhang, Yinxi; Wang, Shan; Guo, Yi; Ding, Yao; Wang, Shuang; Ding, Meiping
2017-10-01
The aim of the study is to investigate the effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on plasma oxcarbazepine (OXC) concentrations and therapeutic efficacy in Han Chinese patients with epilepsy. We recruited 116 Han Chinese patients with epilepsy who were receiving OXC monotherapy. Blood samples were taken and OXC levels were measured. The polymorphisms of ABCB1 rs1045642, ABCC2 rs2273697, UGT2B7 rs7439366, and HNF4α rs2071197 were determined. The therapeutic efficacy of OXC at the 1-year time-point was assessed. Data analysis was performed using IBM SPSS Statistics 22.0. The genetic polymorphism of ABCB1 rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05). As for UGT2B7 rs7439366, the allele polymorphism exhibited a correlation with treatment outcome, but not OXC concentration. The polymorphisms of ABCC2 rs2273697 and HNF4α rs2071197 was not associated with OXC concentrations and therapeutic efficacy. These results suggested that ABCB1 rs1045642 and UGT2B7 rs7439366 may affect OXC pharmacokinetics and therapeutic efficacy in Han Chinese patients with epilepsy. However, further studies in larger populations and other ethnic groups are required. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
-
Desai, Seema S.; Tung, Jason C.; Zhou, Vivian X.; Grenert, James P.; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M.; Chang, Tammy T.
2016-01-01
Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of hepatic-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150Pa and increased to 1–6kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α) whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase (FAK). In addition, blockade of the Rho/Rho-associated protein kinase (ROCK) pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Conclusion Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/ROCK pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. PMID:26755329
-
Wu, Ying; McDade, Thomas W; Kuzawa, Christopher W; Borja, Judith; Li, Yun; Adair, Linda S; Mohlke, Karen L; Lange, Leslie A
2012-04-01
Recent genome-wide association studies have related several genetic loci, including C-reactive protein (CRP), hepatocyte nuclear factor 1 homeobox (HNF1A), and genetic variations in the leptin receptor (LEPR), to circulating CRP levels in populations of European ancestry. The genetic effects in other populations and across varying levels of exposure to a pathogenic environment, an important environmental factor associated with CRP, remain to be determined. We tested 2,073,674 single-nucleotide polymorphisms (SNPs) for association with plasma CRP (limited to ≤10 mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey. The strongest evidence of association was observed with variants at CRP (rs876537, P = 1.4 × 10(-9)) and HNF1A (rs7305618, P = 1.0 × 10(-8)). Among other previously reported CRP-associated loci, the apolipoprotein E ε4 haplotype was associated with decreased CRP level (P = 7.1 × 10(-4)), and modest association was observed with LEPR (rs1892534, P = 0.076), with direction of effects consistent with previous studies. The strongest signal at a locus not previously reported mapped to a gene desert region on chromosome 6q16.1 (rs1408282, P = 2.9 × 10(-6)). Finally, we observed nominal evidence of interaction with exposure to a pathogenic environment for top main effect SNPs at HNF1A (rs7305618, P = 0.031), LEPR (rs1892535, P = 0.030) and 6q16.1 (rs1408282, P = 0.046). Our findings demonstrate convincing evidence that genetic variants in CRP and HNF1A contribute to plasma CRP in Filipino women and provide the first evidence that exposure to a pathogenic environment may modify the genetic influence at the HNF1A, LEPR, and 6q16.1 loci on plasma CRP level.
-
P., Sneha; D., Thirumal Kumar; C., George Priya Doss; R., Siva; Zayed, Hatem
2017-01-01
Maturity-onset diabetes of the young type 3 (MODY3) is a non-ketotic form of diabetes associated with poor insulin secretion. Over the past years, several studies have reported the association of missense mutations in the Hepatocyte Nuclear Factor 1 Alpha (HNF1A) with MODY3. Missense mutations in the POU homeodomain (POUH) of HNF1A hinder binding to the DNA, thereby leading to a dysfunctional protein. Missense mutations of the HNF1A were retrieved from public databases and subjected to a three-step computational mutational analysis to identify the underlying mechanism. First, the pathogenicity and stability of the mutations were analyzed to determine whether they alter protein structure and function. Second, the sequence conservation and DNA-binding sites of the mutant positions were assessed; as HNF1A protein is a transcription factor. Finally, the biochemical properties of the biological system were validated using molecular dynamic simulations in Gromacs 4.6.3 package. Two arginine residues (131 and 203) in the HNF1A protein are highly conserved residues and contribute to the function of the protein. Furthermore, the R131W, R131Q, and R203C mutations were predicted to be highly deleterious by in silico tools and showed lower binding affinity with DNA when compared to the native protein using the molecular docking analysis. Triplicate runs of molecular dynamic (MD) simulations (50ns) revealed smaller changes in patterns of deviation, fluctuation, and compactness, in complexes containing the R131Q and R131W mutations, compared to complexes containing the R203C mutant complex. We observed reduction in the number of intermolecular hydrogen bonds, compactness, and electrostatic potential, as well as the loss of salt bridges, in the R203C mutant complex. Substitution of arginine with cysteine at position 203 decreases the affinity of the protein for DNA, thereby destabilizing the protein. Based on our current findings, the MD approach is an important tool for
-
Desai, Seema S; Tung, Jason C; Zhou, Vivian X; Grenert, James P; Malato, Yann; Rezvani, Milad; Español-Suñer, Regina; Willenbring, Holger; Weaver, Valerie M; Chang, Tammy T
2016-07-01
Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4α), whereas fibrotic matrix stiffness inhibited the HNF4α transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4α expression from hepatocytes cultured on stiff matrix. Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4α transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). © 2016 by the American Association for the Study of Liver Diseases.
-
Heterogeneity of SOX9 and HNF1β in Pancreatic Ducts Is Dynamic.
Rezanejad, Habib; Ouziel-Yahalom, Limor; Keyzer, Charlotte A; Sullivan, Brooke A; Hollister-Lock, Jennifer; Li, Wan-Chun; Guo, Lili; Deng, Shaopeng; Lei, Ji; Markmann, James; Bonner-Weir, Susan
2018-03-13
Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic growth and regeneration. However, genetic lineage-tracing experiments with pancreatic duct-specific Cre expression have given conflicting results. Using immunofluorescence and flow cytometry, we show heterogeneous expression of both HNF1β and SOX9 in adult human and murine ductal epithelium. Their expression was dynamic and diminished significantly after induced replication. Purified pancreatic duct cells formed organoid structures in 3D culture, and heterogeneity of expression of Hnf1β and Sox9 was maintained even after passaging. Using antibodies against a second cell surface molecule CD51 (human) or CD24 (mouse), we could isolate living subpopulations of duct cells enriched for high or low expression of HNF1β and SOX9. Only the CD24 high (Hnfβ high /Sox9 high ) subpopulation was able to form organoids. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
-
Bellanné-Chantelot, C; Coste, J; Ciangura, C; Fonfrède, M; Saint-Martin, C; Bouché, C; Sonnet, E; Valéro, R; Lévy, D-J; Dubois-Laforgue, D; Timsit, J
2016-02-01
Low plasma levels of high-sensitivity C-reactive protein (hs-CRP) have been suggested to differentiate hepatocyte nuclear factor 1 alpha-maturity-onset diabetes of the young (HNF1A-MODY) from type 2 diabetes (T2D). Yet, differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes (F-YT2D) remains a difficult challenge. Thus, this study assessed the added value of hs-CRP to distinguish between the two conditions. This prospective multicentre study included 143 HNF1A-MODY patients, 310 patients with a clinical history suggestive of HNF1A-MODY, but not confirmed genetically (F-YT2D), and 215 patients with T2D. The ability of models, including clinical characteristics and hs-CRP to predict HNF1A-MODY was analyzed, using the area of the receiver operating characteristic (AUROC) curve, and a grey zone approach was used to evaluate these models in clinical practice. Median hs-CRP values were lower in HNF1A-MODY (0.25mg/L) than in F-YT2D (1.14mg/L) and T2D (1.70mg/L) patients. Clinical parameters were sufficient to differentiate HNF1A-MODY from classical T2D (AUROC: 0.99). AUROC analyses to distinguish HNF1A-MODY from F-YT2D were 0.82 for clinical features and 0.87 after including hs-CRP. For the grey zone analysis, the lower boundary was set to miss<1.5% of true positives in non-tested subjects, while the upper boundary was set to perform 50% of genetic tests in individuals with no HNF1A mutation. On comparing HNF1A-MODY with F-YT2D, 65% of patients were classified in between these categories - in the zone of diagnostic uncertainty - even after adding hs-CRP to clinical parameters. hs-CRP does not improve the differential diagnosis of HNF1A-MODY and F-YT2D. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
-
Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta.
Coffinier, Catherine; Gresh, Lionel; Fiette, Laurence; Tronche, François; Schütz, Günther; Babinet, Charles; Pontoglio, Marco; Yaniv, Moshe; Barra, Jacqueline
2002-04-01
The inactivation of the Hnf1beta gene identified an essential role in epithelial differentiation of the visceral endoderm and resulted in early embryonic death. In the present study, we have specifically inactivated this gene in hepatocytes and bile duct cells using the Cre/loxP system. Mutant animals exhibited severe jaundice caused by abnormalities of the gallbladder and intrahepatic bile ducts (IHBD). The paucity of small IHBD was linked to a failure in the organization of duct structures during liver organogenesis, suggesting an essential function of Hnf1b in bile duct morphogenesis. Mutant mice also lacked interlobular arteries. As HNF1beta is not expressed in these cells, it further emphasizes the link between arterial and biliary formation. Hepatocyte metabolism was also affected and we identified hepatocyte-specific HNF1beta target genes involved in bile acids sensing and in fatty acid oxidation.
-
[Monogenic form of diabetes mellitus due to HNF4α mutation (MODY-1) - the first case in Hungary].
Jermendy, György; Balogh, István; Gaál, Zsolt
2016-03-20
The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4α mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4α gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members.
-
Shirpoor, Alireza; Heshmati, Elaheh; Kheradmand, Fatemeh; Gharalari, Farzaneh Hosseini; Chodari, Leila; Naderi, Roya; Majd, Farideh Nezami; Samadi, Mahrokh
2018-05-28
The association between chronic alcohol consumption and the development of alcpholic liver disease is a very well known phenomenon, but the precise underlying molecular mediators involved in ethanol-induced liver disease remain elusive. This study aimed to characterize the lipid metabolism alterations and the molecular mediators which are related to lipid metabolism in liver under the heavy ethanol exposure alone or combined with ginger extract. Twenty-four male wistar rats were assigned into three groups, namely control, ethanol, and ginger extract treated ethanol (GETE) groups. Six weeks after the treatment, the ethanol group showed a significant increase in fatty acid translocase (FAT)/CD36, protein tyrosine phosphatase 1B (PTP1B) and decrease hepatocyte nuclear factor 4 Alpha (HNF4A) genes expressions compared to the control group. The ethanol administration also significantly increased plasma LDL, cholesterol, triglyceride, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared to the control group. Moreover, compared to the control group, the ethanol group showed liver histhological changes, such as fibrosis, focal microvesicular steatosis, some apoptotic hepatocytes, spotty necrosis, portal lymphocytic inflammation, mallory-denk bodies, giant mitochondria, piecemeal necrosis. Consumption of ginger extract along with ethanol, partially ameliorated gene expression alteration and histological changes, improved undesirable lipid profile and liver enzymes changes compare to those in the ethanol group. These findings indicate that ethanol-induced liver abnormalities may in part be associated with lipid homeostasis changes mediated by overexpression of FAT/CD36, PTP1B and downexpressionof HNF4A genes. It also show that these effects can be reduced by using ginger extract as an antioxidant and anti-inflammatory agent. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
-
Pfeiffer, S; Halang, L; Düssmann, H; Byrne, M M; Prehn, Jhm
2015-01-01
Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo.
-
Pfeiffer, S; Halang, L; Düssmann, H; Byrne, MM; Prehn, JHM
2015-01-01
Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo. PMID:27551471
-
Lin, K; Dorman, J B; Rodan, A; Kenyon, C
1997-11-14
The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks. In contrast, mutants with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, age more slowly than normal and live more than twice as long. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators. In humans, insulin down-regulates the expression of certain genes by antagonizing the activity of HNF-3, raising the possibility that aspects of this regulatory system have been conserved.
-
Bacon, S; Kyithar, M P; Rizvi, S R; Donnelly, E; McCarthy, A; Burke, M; Colclough, K; Ellard, S; Byrne, M M
2016-07-01
HNF1A gene mutations are the most common cause of maturity-onset diabetes of the young (MODY) in the UK. Persons with HNF1A-MODY display sensitivity to sulphonylurea therapy; however, the long-term efficacy is not established. There is limited literature as to the prevalence of micro- and macrovascular complications in this unique cohort. The aim of this study was to determine the natural progression and clinical management of HNF1A-MODY diabetes in a dedicated MODY clinic. Sixty patients with HNF1A-MODY and a cohort of 60 BMI-, age-, ethnicity- and diabetes duration-matched patients with Type 1 diabetes mellitus participated in the study. All patients were phenotyped in detail. Clinical follow-up of the HNF1A-MODY cohort occurred on a bi-annual basis. Following a genetic diagnosis of MODY, the majority of the cohort treated with sulphonylurea therapy remained insulin independent at 84-month follow-up (80%). The HbA1c in the HNF1A-MODY group treated with sulphonylurea therapy alone improved significantly over the study period [from 49 (44-63) mmol/mol, 6.6 (6.2-7.9)% to 41 (31-50) mmol/mol, 5.9 (5-6.7)%; P = 0.003]. The rate of retinopathy was significantly lower than that noted in the Type 1 diabetes mellitus group (13.6 vs. 50%; P = 0.0001).There was also a lower rate of microalbuminuria and cardiovascular disease in the HNF1A-MODY group compared with the Type 1 diabetes mellitus group. This study demonstrates that the majority of patients with HNF1A-MODY can be maintained successfully on sulphonylurea therapy with good glycaemic control. We note a significantly lower rate of micro- and macrovascular complications than reported previously. The use of appropriate therapy at early stages of the disorder may decrease the incidence of complications. © 2015 Diabetes UK.
-
Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.
Santana, L S; Caetano, L A; Costa-Riquetto, A D; Quedas, E P S; Nery, M; Collett-Solberg, P; Boguszewski, M C S; Vendramini, M F; Crisostomo, L G; Floh, F O; Zarabia, Z I; Kohara, S K; Guastapaglia, L; Passone, C G B; Sewaybricker, L E; Jorge, A A L; Teles, M G
2017-10-01
Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
-
Hani, E H; Suaud, L; Boutin, P; Chèvre, J C; Durand, E; Philippi, A; Demenais, F; Vionnet, N; Furuta, H; Velho, G; Bell, G I; Laine, B; Froguel, P
1998-01-01
Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family. PMID:9449683
-
Choi, Yun-Hee; McNally, Brian T; Igarashi, Peter
2013-07-01
Hepatocyte nuclear factor-1β (HNF-1β) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1β in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1β in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1β. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1β. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1β. Overexpression of zyxin stimulates the transcriptional activity of HNF-1β, whereas small interfering RNA silencing of zyxin inhibits HNF-1β-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1β-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1β, knockdown of zyxin, or inhibition of Akt inhibits EGF-stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation.
-
Shen, Hui; Fridley, Brooke L.; Song, Honglin; Lawrenson, Kate; Cunningham, Julie M.; Ramus, Susan J.; Cicek, Mine S.; Tyrer, Jonathan; Stram, Douglas; Larson, Melissa C.; Köbel, Martin; Ziogas, Argyrios; Zheng, Wei; Yang, Hannah P.; Wu, Anna H.; Wozniak, Eva L.; Woo, Yin Ling; Winterhoff, Boris; Wik, Elisabeth; Whittemore, Alice S.; Wentzensen, Nicolas; Weber, Rachel Palmieri; Vitonis, Allison F.; Vincent, Daniel; Vierkant, Robert A.; Vergote, Ignace; Van Den Berg, David; Van Altena, Anne M.; Tworoger, Shelley S.; Thompson, Pamela J.; Tessier, Daniel C.; Terry, Kathryn L.; Teo, Soo-Hwang; Templeman, Claire; Stram, Daniel O.; Southey, Melissa C.; Sieh, Weiva; Siddiqui, Nadeem; Shvetsov, Yurii B.; Shu, Xiao-Ou; Shridhar, Viji; Wang-Gohrke, Shan; Severi, Gianluca; Schwaab, Ira; Salvesen, Helga B.; Rzepecka, Iwona K.; Runnebaum, Ingo B.; Rossing, Mary Anne; Rodriguez-Rodriguez, Lorna; Risch, Harvey A.; Renner, Stefan P.; Poole, Elizabeth M.; Pike, Malcolm C.; Phelan, Catherine M.; Pelttari, Liisa M.; Pejovic, Tanja; Paul, James; Orlow, Irene; Omar, Siti Zawiah; Olson, Sara H.; Odunsi, Kunle; Nickels, Stefan; Nevanlinna, Heli; Ness, Roberta B.; Narod, Steven A.; Nakanishi, Toru; Moysich, Kirsten B.; Monteiro, Alvaro N.A.; Moes-Sosnowska, Joanna; Modugno, Francesmary; Menon, Usha; McLaughlin, John R.; McGuire, Valerie; Matsuo, Keitaro; Adenan, Noor Azmi Mat; Massuger, Leon F.A. G.; Lurie, Galina; Lundvall, Lene; Lubiński, Jan; Lissowska, Jolanta; Levine, Douglas A.; Leminen, Arto; Lee, Alice W.; Le, Nhu D.; Lambrechts, Sandrina; Lambrechts, Diether; Kupryjanczyk, Jolanta; Krakstad, Camilla; Konecny, Gottfried E.; Kjaer, Susanne Krüger; Kiemeney, Lambertus A.; Kelemen, Linda E.; Keeney, Gary L.; Karlan, Beth Y.; Karevan, Rod; Kalli, Kimberly R.; Kajiyama, Hiroaki; Ji, Bu-Tian; Jensen, Allan; Jakubowska, Anna; Iversen, Edwin; Hosono, Satoyo; Høgdall, Claus K.; Høgdall, Estrid; Hoatlin, Maureen; Hillemanns, Peter; Heitz, Florian; Hein, Rebecca; Harter, Philipp; Halle, Mari K.; Hall, Per; Gronwald, Jacek; Gore, Martin; Goodman, Marc T.; Giles, Graham G.; Gentry-Maharaj, Aleksandra; Garcia-Closas, Montserrat; Flanagan, James M.; Fasching, Peter A.; Ekici, Arif B.; Edwards, Robert; Eccles, Diana; Easton, Douglas F.; Dürst, Matthias; du Bois, Andreas; Dörk, Thilo; Doherty, Jennifer A.; Despierre, Evelyn; Dansonka-Mieszkowska, Agnieszka; Cybulski, Cezary; Cramer, Daniel W.; Cook, Linda S.; Chen, Xiaoqing; Charbonneau, Bridget; Chang-Claude, Jenny; Campbell, Ian; Butzow, Ralf; Bunker, Clareann H.; Brueggmann, Doerthe; Brown, Robert; Brooks-Wilson, Angela; Brinton, Louise A.; Bogdanova, Natalia; Block, Matthew S.; Benjamin, Elizabeth; Beesley, Jonathan; Beckmann, Matthias W.; Bandera, Elisa V.; Baglietto, Laura; Bacot, François; Armasu, Sebastian M.; Antonenkova, Natalia; Anton-Culver, Hoda; Aben, Katja K.; Liang, Dong; Wu, Xifeng; Lu, Karen; Hildebrandt, Michelle A.T.; Schildkraut, Joellen M.; Sellers, Thomas A.; Huntsman, David; Berchuck, Andrew; Chenevix-Trench, Georgia; Gayther, Simon A.; Pharoah, Paul D.P.; Laird, Peter W.; Goode, Ellen L.; Pearce, Celeste Leigh
2013-01-01
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes. PMID:23535649
-
Scassa, María E; Guberman, Alejandra S; Ceruti, Julieta M; Cánepa, Eduardo T
2004-07-02
Although the negative regulation of gene expression by insulin has been widely studied, the transcription factors responsible for the insulin effect are still unknown. The purpose of this work was to explore the molecular mechanisms involved in the insulin repression of the 5-aminolevulinate synthase (ALAS) gene. Deletion analysis of the 5'-regulatory region allowed us to identify an insulin-responsive region located at -459 to -354 bp. This fragment contains a highly homologous insulin-responsive (IRE) sequence. By transient transfection assays, we determined that hepatic nuclear factor 3 (HNF3) and nuclear factor 1 (NF1) are necessary for an appropriate expression of the ALAS gene. Insulin overrides the HNF3beta or HNF3beta plus NF1-mediated stimulation of ALAS transcriptional activity. Electrophoretic mobility shift assay and Southwestern blotting indicate that HNF3 binds to the ALAS promoter. Mutational analysis of this region revealed that IRE disruption abrogates insulin action, whereas mutation of the HNF3 element maintains hormone responsiveness. This dissociation between HNF3 binding and insulin action suggests that HNF3beta is not the sole physiologic mediator of insulin-induced transcriptional repression. Furthermore, Southwestern blotting assay shows that at least two polypeptides other than HNF3beta can bind to ALAS promoter and that this binding is dependent on the integrity of the IRE. We propose a model in which insulin exerts its negative effect through the disturbance of HNF3beta binding or transactivation potential, probably due to specific phosphorylation of this transcription factor by Akt. In this regard, results obtained from transfection experiments using kinase inhibitors support this hypothesis. Due to this event, NF1 would lose accessibility to the promoter. The posttranslational modification of HNF3 would allow the binding of a protein complex that recognizes the core IRE. These results provide a potential mechanism for the insulin
-
Mrozinska, Sandra; Radkowski, Piotr; Gosiewski, Tomasz; Szopa, Magdalena; Bulanda, Malgorzata; Ludwig-Galezowska, Agnieszka H.; Morawska, Iwona; Sroka-Oleksiak, Agnieszka; Matejko, Bartlomiej; Kapusta, Przemyslaw; Salamon, Dominika; Malecki, Maciej T.; Wolkow, Pawel
2016-01-01
Background. Type 2 diabetes mellitus (T2DM) is determined by genetic and environmental factors. There have been many studies on the relationship between the composition of the gastrointestinal bacterial flora, T2DM, and obesity. There are no data, however, on the gut microbiome structure in monogenic forms of the disease including Maturity Onset Diabetes of the Young (MODY). Methods. The aim of the investigation was to compare the qualitative parameters of the colonic flora in patients with HNF1A-MODY and T2DM and healthy individuals. 16S sequencing of bacterial DNA isolated from the collected fecal samples using the MiSeq platform was performed. Results. There were significant between-group differences in the bacterial profile. At the phylum level, the amount of Proteobacteria was higher (p = 0.0006) and the amount of Bacteroidetes was lower (p = 0.0005) in T2DM group in comparison to the control group. In HNF1A-MODY group, the frequency of Bacteroidetes was lower than in the control group (p = 0.0143). At the order level, Turicibacterales was more abundant in HNF1A-MODY group than in T2DM group. Conclusions. It appears that there are differences in the gut microbiome composition between patients with HNF1A-MODY and type 2 diabetes. Further investigation on this matter should be conducted. PMID:27807544
-
Mrozinska, Sandra; Radkowski, Piotr; Gosiewski, Tomasz; Szopa, Magdalena; Bulanda, Malgorzata; Ludwig-Galezowska, Agnieszka H; Morawska, Iwona; Sroka-Oleksiak, Agnieszka; Matejko, Bartlomiej; Kapusta, Przemyslaw; Salamon, Dominika; Malecki, Maciej T; Wolkow, Pawel; Klupa, Tomasz
2016-01-01
Background . Type 2 diabetes mellitus (T2DM) is determined by genetic and environmental factors. There have been many studies on the relationship between the composition of the gastrointestinal bacterial flora, T2DM, and obesity. There are no data, however, on the gut microbiome structure in monogenic forms of the disease including Maturity Onset Diabetes of the Young (MODY). Methods . The aim of the investigation was to compare the qualitative parameters of the colonic flora in patients with HNF1A - MODY and T2DM and healthy individuals. 16S sequencing of bacterial DNA isolated from the collected fecal samples using the MiSeq platform was performed. Results . There were significant between-group differences in the bacterial profile. At the phylum level, the amount of Proteobacteria was higher ( p = 0.0006) and the amount of Bacteroidetes was lower ( p = 0.0005) in T2DM group in comparison to the control group. In HNF1A-MODY group, the frequency of Bacteroidetes was lower than in the control group ( p = 0.0143). At the order level, Turicibacterales was more abundant in HNF1A-MODY group than in T2DM group. Conclusions . It appears that there are differences in the gut microbiome composition between patients with HNF1A-MODY and type 2 diabetes. Further investigation on this matter should be conducted.
-
Effect of gamma irradiation on antinutritional factors in broad bean
NASA Astrophysics Data System (ADS)
Al-Kaisey, Mahdi T.; Alwan, Abdul-Kader H.; Mohammad, Manal H.; Saeed, Amjed H.
2003-06-01
The effect of gamma irradiation on the level of antinutritional factors (trypsin inhibitor (TI), phytic acid and oligosaccharides) of broad bean was investigated. The seeds were subjected to gamma irradiation at 0, 2.5, 5, 7.5 and 10 kGy, respectively using cobalt-60 gamma radiation with a dose rate 2.37 kGy/h. TI activity was reduced by 4.5%, 6.7%, 8.5% and 9.2% at 2.5, 5, 7.5 and 10 kGy, respectively. Meanwhile, irradiation at 10.2, 12.3, 15.4 and 18.2 kGy reduced the phytic acid content. The flatulence causing oligosaccharides were decreased as the radiation dose increased. The chemical composition (protein, oil, ash and total carbohydrates) of the tested seeds was determined. Gamma radiation seems to be a good procedure to improve the quality of broad bean from the nutritional point of view.
-
Morita, Kazunori; Saruwatari, Junji; Tanaka, Takahiro; Oniki, Kentaro; Kajiwara, Ayami; Miyazaki, Hiroko; Yoshida, Akira; Jinnouchi, Hideaki; Nakagawa, Kazuko
2017-02-01
This study investigated the associations between the common hepatocyte nuclear factor-1A (HNF1A) variants and the risk of diabetic retinopathy (DR) in relation to the glycemic control and weight status. A retrospective longitudinal analysis was conducted among 354 Japanese patients with type 2 diabetes mellitus (T2DM) (mean follow-up duration: 5.8±2.5 years). The multivariable-adjusted hazard ratio (HR) for the cumulative incidence of DR was calculated using a Cox proportional hazard model. During the observation period, the longitudinal associations of the HNF1A diplotypes with the risk of DR and the clinical parameters were also analyzed using the generalized estimating equations approach. The combination of risk variants, i.e., rs1169288-C, rs1183910-A and rs2464196-A, was defined as the H1 haplotype. The incidence of DR was higher in the H1/H1 diplotype cases than in the others (HR 2.75 vs. non-H1/non-H1; p=0.02). Only in normal-weight subjects, the risks of DR and poor glycemic control were higher in the H1/H1 diplotype cases than in the others [odds ratio 4.08 vs. non-H1/non-H1, p=0.02; odds ratio 3.03, p=0.01; respectively]. This study demonstrated that the common HNF1A diplotype of three risk variants may be an independent risk factor for the development of DR resulting from poor glycemic control in normal-weight patients with T2DM. These results need to be replicated in larger and more varied study populations. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Huang, Tao; Wang, Tiange; Heianza, Yoriko; Sun, Dianjianyi; Ivey, Kerry; Durst, Ronen; Schwarzfuchs, Dan; Stampfer, Meir J; Bray, George A; Sacks, Frank M; Shai, Iris; Qi, Lu
2018-06-01
To determine whether weight-loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1α (HNF1A) rs7957197 on weight loss and improvement of insulin resistance. We analysed the interaction between HNF1A rs7957197 and weight-loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults. In the POUNDS Lost trial, we found that a high-fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high-fat diet group (P = .04, .03 and .01, respectively). Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high-fat diet. © 2018 John Wiley & Sons Ltd.
-
Pruhova, Stepanka; Dusatkova, Petra; Neumann, David; Hollay, Erik; Cinek, Ondrej; Lebl, Jan; Sumnik, Zdenek
2013-09-01
Hepatocyte nuclear factor-1A maturity-onset diabetes of the young (HNF1A-MODY) is a monogenic form of diabetes caused by heterozygous mutations in HNF1A. Currently, a history of diabetic ketoacidosis (DKA) is an exclusion criterion for genetic testing for MODY. In this article, we describe two unrelated patients aged 17 and 24 years with severe DKA developed several years after the diagnosis of HNF1A-MODY. Both patients were treated with insulin, but their metabolic control was poor (HbA1c 15%, 140 mmol/mol and 13%, 119 mmol/mol, respectively) due to noncompliance and missed insulin injections. In both patients, DKA followed a course of recurrent vomiting with dehydration and prerenal acute kidney injury. Their glycemia, blood pH, and base excess at admission were 97 mmol/L [1,748 mg/dL], 6.80, and -33 mmol/L (patient 1) and 34 mmol/L [613 mg/dL], 7.03, and -14 mmol/L (patient 2). This anecdotal observation supports the notion that a history of DKA does not exclude MODY.
-
Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.
Estrada, Karol; Aukrust, Ingvild; Bjørkhaug, Lise; Burtt, Noël P; Mercader, Josep M; García-Ortiz, Humberto; Huerta-Chagoya, Alicia; Moreno-Macías, Hortensia; Walford, Geoffrey; Flannick, Jason; Williams, Amy L; Gómez-Vázquez, María J; Fernandez-Lopez, Juan C; Martínez-Hernández, Angélica; Jiménez-Morales, Silvia; Centeno-Cruz, Federico; Mendoza-Caamal, Elvia; Revilla-Monsalve, Cristina; Islas-Andrade, Sergio; Córdova, Emilio J; Soberón, Xavier; González-Villalpando, María E; Henderson, E; Wilkens, Lynne R; Le Marchand, Loic; Arellano-Campos, Olimpia; Ordóñez-Sánchez, Maria L; Rodríguez-Torres, Maribel; Rodríguez-Guillén, Rosario; Riba, Laura; Najmi, Laeya A; Jacobs, Suzanne B R; Fennell, Timothy; Gabriel, Stacey; Fontanillas, Pierre; Hanis, Craig L; Lehman, Donna M; Jenkinson, Christopher P; Abboud, Hanna E; Bell, Graeme I; Cortes, Maria L; Boehnke, Michael; González-Villalpando, Clicerio; Orozco, Lorena; Haiman, Christopher A; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Altshuler, David; Njølstad, Pål R; Florez, Jose C; MacArthur, Daniel G
2014-06-11
Latino populations have one of the highest prevalences of type 2 diabetes worldwide. To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). Using whole-exome sequencing
-
Chen, Liming; Bao, Yifan; Piekos, Stephanie C; Zhu, Kexin; Zhang, Lirong; Zhong, Xiao-Bo
2018-07-01
Cytochrome P450 (P450) enzymes are responsible for metabolizing drugs. Expression of P450s can directly affect drug metabolism, resulting in various outcomes in therapeutic efficacy and adverse effects. Several nuclear receptors are transcription factors that can regulate expression of P450s at both basal and drug-induced levels. Some long noncoding RNAs (lncRNAs) near a transcription factor are found to participate in the regulatory functions of the transcription factors. The aim of this study is to determine whether there is a transcriptional regulatory network containing nuclear receptors and lncRNAs controlling both basal and drug-induced expression of P450s in HepaRG cells. Small interfering RNAs or small hairpin RNAs were applied to knock down four nuclear receptors [hepatocyte nuclear factor 1 α (HNF1 α ), hepatocyte nuclear factor 4 α (HNF4 α ), pregnane X receptor (PXR), and constitutive androstane receptor (CAR)] as well as two lncRNAs [HNF1 α antisense RNA 1 (HNF1 α -AS1) and HNF4 α antisense RNA 1 (HNF4 α -AS1)] in HepaRG cells with or without treatment of phenobarbital or rifampicin. Expression of eight P450 enzymes was examined in both basal and drug-induced levels. CAR and PXR mainly regulated expression of specific P450s. HNF1 α and HNF4 α affected expression of a wide range of P450s as well as other transcription factors. HNF1 α and HNF4 α controlled the expression of their neighborhood lncRNAs, HNF1 α -AS1 and HNF4 α -AS1, respectively. HNF1 α -AS1 and HNF4 α -AS1 was also involved in the regulation of P450s and transcription factors in diverse manners. Altogether, our study concludes that a transcription regulatory network containing the nuclear receptors and lncRNAs controls both basal and drug-induced expression of P450s in HepaRG cells. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
-
The molecular functions of hepatocyte nuclear factors - In and beyond the liver.
Lau, Hwee Hui; Ng, Natasha Hui Jin; Loo, Larry Sai Weng; Jasmen, Joanita Binte; Teo, Adrian Kee Keong
2018-05-01
The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
-
Display gamma is an important factor in Web image viewing
NASA Astrophysics Data System (ADS)
Zhang, Xuemei; Lavin, Yingmei; Silverstein, D. Amnon
2001-06-01
We conducted a perceptual image preference experiment over the web to find our (1) if typical computer users have significant variations in their display gamma settings, and (2) if so, do the gamma settings have significant perceptual effect on the appearance of images in their web browsers. The digital image renderings used were found to have preferred tone characteristics from a previous lab- controlled experiment. They were rendered with 4 different gamma settings. The subjects were asked to view the images over the web, with their own computer equipment and web browsers. The subjects werewe asked to view the images over the web, with their own computer equipment and web browsers. The subjects made pair-wise subjective preference judgements on which rendering they liked bets for each image. Each subject's display gamma setting was estimated using a 'gamma estimator' tool, implemented as a Java applet. The results indicated that (1) the user's gamma settings, as estimated in the experiment, span a wide range from about 1.8 to about 3.0; (2) the subjects preferred images that werewe rendered with a 'correct' gamma value matching their display setting. Subjects disliked images rendered with a gamma value not matching their displays'. This indicates that display gamma estimation is a perceptually significant factor in web image optimization.
-
Thyroid epithelial cell hyperplasia in IFN-gamma deficient NOD.H-2h4 mice.
Yu, Shiguang; Sharp, Gordon C; Braley-Mullen, Helen
2006-01-01
The role of inflammatory cells in thyroid epithelial cell (thyrocyte) hyperplasia is unknown. Here, we demonstrate that thyrocyte hyperplasia in IFN-gamma-/- NOD.H-2h4 mice has an autoimmune basis. After chronic exposure to increased dietary iodine, 60% of IFN-gamma-/- mice had severe thyrocyte hyperplasia with minimal or moderate lymphocyte infiltration, and thyroid dysfunction with reduced serum T4. All mice produced anti-thyroglobulin autoantibody. Some wild-type NOD.H-2h4 mice had isolated areas of thyrocyte hyperplasia with predominantly lymphocytic infiltration, whereas IL-4-/- and 50% of wild-type NOD.H-2h4 mice developed lymphocytic thyroiditis but no thyrocyte hyperplasia. Both thyroid infiltrating inflammatory cells and environmental factors (iodine) were required to induce thyrocyte hyperplasia. Splenocytes from IFN-gamma-/- mice with thyrocyte hyperplasia, but not splenocytes from naïve IFN-gamma-/- mice, induced hyperplasia in IFN-gamma-/- NOD.H-2h4.SCID mice. These results may provide clues for understanding the mechanisms underlying development of epithelial cell hyperplasia not only in thyroids but also in other tissues and organs.
-
Technical Note: PRESAGE three-dimensional dosimetry accurately measures Gamma Knife output factors
Klawikowski, Slade J.; Yang, James N.; Adamovics, John; Ibbott, Geoffrey S.
2014-01-01
Small-field output factor measurements are traditionally very difficult because of steep dose gradients, loss of lateral electronic equilibrium, and dose volume averaging in finitely sized detectors. Three-dimensional (3D) dosimetry is ideal for measuring small output factors and avoids many of these potential challenges of point and two-dimensional detectors. PRESAGE 3D polymer dosimeters were used to measure the output factors for the 4 mm and 8 mm collimators of the Leksell Perfexion Gamma Knife radiosurgery treatment system. Discrepancies between the planned and measured distance between shot centers were also investigated. A Gamma Knife head frame was mounted onto an anthropomorphic head phantom. Special inserts were machined to hold 60 mm diameter, 70 mm tall cylindrical PRESAGE dosimeters. The phantom was irradiated with one 16 mm shot and either one 4 mm or one 8 mm shot, to a prescribed dose of either 3 Gy or 4 Gy to the 50% isodose line. The two shots were spaced between 30 mm and 60 mm apart and aligned along the central axis of the cylinder. The Presage dosimeters were measured using the DMOS-RPC optical CT scanning system. Five independent 4 mm output factor measurements fell within 2% of the manufacturer’s Monte Carlo simulation-derived nominal value, as did two independent 8 mm output factor measurements. The measured distances between shot centers varied by ± 0.8 mm with respect to the planned shot displacements. On the basis of these results, we conclude that PRESAGE dosimetry is excellently suited to quantify the difficult-to-measure Gamma Knife output factors. PMID:25368961
-
Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.
Pontoglio, M; Sreenan, S; Roe, M; Pugh, W; Ostrega, D; Doyen, A; Pick, A J; Baldwin, A; Velho, G; Froguel, P; Levisetti, M; Bonner-Weir, S; Bell, G I; Yaniv, M; Polonsky, K S
1998-01-01
Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function. PMID:9593777
-
Hohendorff, J; Szopa, M; Skupien, J; Kapusta, M; Zapala, B; Platek, T; Mrozinska, S; Parpan, T; Glodzik, W; Ludwig-Galezowska, A; Kiec-Wilk, B; Klupa, T; Malecki, M T
2017-08-01
SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes. We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level. There were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was -6.57 ± 7.34 mg/ml (p = 0.04). A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.
-
Grzanka, Malgorzata; Matejko, Bartlomiej; Szopa, Magdalena; Kiec-Wilk, Beata; Malecki, Maciej T; Klupa, Tomasz
2016-01-01
The most common form of maturity-onset diabetes of the young (MODY) is caused by mutations in the hepatocyte nuclear factor 1A (HNF1A) gene. However, most HNF1A mutation-carriers are initially misdiagnosed with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus; hence, they often receive nonoptimal treatment. The aim of our study was to test newly proposed clinical criteria for the identification of HNF1A MODY in patients with a diagnosis of T1DM or T2DM. To achieve this, the following criteria to preselect patients for screening were used: for T1DM: TDIR (total daily insulin requirement) > 0.3 IU of insulin/kg and the percentage of basal insulin > 30% of TDIR; for T2DM: sulphonylurea- (SU-) based oral treatment (monotherapy or combined with Metformin) > 15 years and BMI < 30 kg/m(2). We reviewed the clinical data of 140 patients with T1DM and 524 clinically diagnosed with T2DM. On the basis of these criteria, we found a HNF1A mutation in 1 out of 2 individuals with a diagnosis of T1DM and 1 out of 11 selected individuals with a diagnosis of T2DM. We believe that the simplicity of the proposed criteria might prove useful in clinical practice, as an alternative to more time-consuming classical diagnostic techniques.
-
The pig CYP2E1 promoter is activated by COUP-TF1 and HNF-1 and is inhibited by androstenone.
Tambyrajah, Winston S; Doran, Elena; Wood, Jeffrey D; McGivan, John D
2004-11-15
Functional analysis of the pig cytochrome P4502E1 (CYP2E1) promoter identified two major activating elements. One corresponded to the hepatic nuclear factor 1 (HNF-1) consensus binding sequence at nucleotides -128/-98 and the other was located in the region -292/-266. The binding of proteins in pig liver nuclear extracts to a synthetic double-stranded oligonucleotide corresponding to this more distal activating sequence was studied by electrophoretic mobility shift assay. The minimum protein binding sequence was identified as TGTTCTGACCTCTGGG. Gel super-shift assays identified the protein binding to this site as chick ovalbumin upstream promoter transcription factor 1 (COUP-TF1). Androstenone inhibited promoter activity in transfection experiments only with constructs which included the COUP-TF1 binding site. Androstenone inhibited COUP-TF1 binding to synthetic oligonucleotides but did not affect HNF-1 binding. The results offer an explanation for the inhibition of CYP2E1 protein expression by androstenone in isolated pig hepatocytes and may be relevant to the low expression of hepatic CYP2E1 in those pigs which accumulate high levels of androstenone in vivo.
-
Yamamoto, Hideaki; Tonello, Jane Marie; Sambuichi, Takanori; Kawabe, Yoshinori; Ito, Akira; Kamihira, Masamichi
2018-01-01
New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.
-
Inactivation of RNA Viruses by Gamma Irradiation: A Study on Mitigating Factors
Hume, Adam J.; Ames, Joshua; Rennick, Linda J.; Duprex, W. Paul; Marzi, Andrea; Tonkiss, John; Mühlberger, Elke
2016-01-01
Effective inactivation of biosafety level 4 (BSL-4) pathogens is vital in order to study these agents safely. Gamma irradiation is a commonly used method for the inactivation of BSL-4 viruses, which among other advantages, facilitates the study of inactivated yet morphologically intact virions. The reported values for susceptibility of viruses to inactivation by gamma irradiation are sometimes inconsistent, likely due to differences in experimental protocols. We analyzed the effects of common sample attributes on the inactivation of a recombinant vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein and green fluorescent protein. Using this surrogate virus, we found that sample volume and protein content of the sample modulated viral inactivation by gamma irradiation but that air volume within the sample container and the addition of external disinfectant surrounding the sample did not. These data identify several factors which alter viral susceptibility to inactivation and highlight the usefulness of lower biosafety level surrogate viruses for such studies. Our results underscore the need to validate inactivation protocols of BSL-4 pathogens using “worst-case scenario” procedures to ensure complete sample inactivation. PMID:27455307
-
Morris, L; Troutt, A B; McLeod, K S; Kelso, A; Handman, E; Aebischer, T
1993-01-01
For murine cutaneous leishmaniasis, data to date suggest a correlation between the presence of gamma interferon (IFN-gamma) and resistance in C57BL/6 mice and the presence of interleukin-4 (IL-4) and disease in BALB/c mice. In this study, 13 inbred strains of mice covering the range of susceptibility to disease were infected with Leishmania major to determine whether the subsequent expression of IFN-gamma or IL-4 is a reliable indicator of cure or progressive disease. The presence of IL-4 and IFN-gamma mRNAs in the draining lymph nodes was examined 9 weeks after infection, when differences in disease severity became obvious. There were large differences in the levels of IL-4 mRNA among the different strains, whereas IFN-gamma mRNA was detected at similar levels in all strains. The levels of IL-4 mRNA correlated with lesion score, with susceptible and intermediate strains containing up to 100-fold more than any of the resistant strains. Differences in the levels of IFN-gamma mRNA were within only a fourfold range, with significant overlap among susceptible, intermediate, and resistant strains. Similarly, the levels of IFN-gamma secreted in vitro by lymph node cells from infected mice in response to L. major antigens were within a 10-fold range for most strains, and there was no correlation with lesion score. Analysis of Leishmania-specific antibody levels revealed a correlation between immunoglobulin G1 (IgG1) titers and lesion score, consistent with the role of IL-4 as a switch factor for IgG1. In contrast, there was no correlation between IgG2a titers and lesion score, supporting the notion that IFN-gamma synthesis (which promotes IgG2a production) is not correlated with disease state. These data suggest that along the spectrum of murine cutaneous leishmaniasis, IL-4 is a reliable indicator of disease, but IFN-gamma is not prognostic for resistance. Images PMID:8335376
-
Lopez, Ariel Pablo; Foscaldi, Sabrina Andrea; Perez, Maria Silvia; Rodriguez, Martín; Traversa, Mercedes; Puchulu, Félix Miguel; Bergada, Ignacio; Frechtel, Gustavo Daniel
2011-02-01
There are at least six subtypes of Maturity Onset Diabetes of the Young (MODY) with distinctive genetic causes. MODY 3 is caused by mutations in HNF1A gene, an insulin transcription factor, so mutations in this gene are associated with impaired insulin secretion. MODY 3 prevalence differs according to the population analyzed, but it is one of the most frequent subtypes. Therefore, our aims in this work were to find mutations present in the HNF1A gene and provide information on their prevalence. Mutations screening was done in a group of 80 unrelated patients (average age 17.1 years) selected by clinical characterization of MODY, by SSCP electrophoresis followed by sequenciation. We found eight mutations, of which six were novel and four sequence variants, which were all novel. Therefore the prevalence of MODY 3 in this group was 10%. Compared clinical data between the non-MODY 3 patients and the MODY 3 diagnosed patients did not show any significant difference. Eight patients were diagnosed as MODY 3 and new data about the prevalence of that subtype is provided. Our results contribute to reveal novel mutations, providing new data about the prevalence of that subtype. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
-
Carrillo, Elena; Lomas, Amparo; Pinés, Pedro J; Lamas, Cristina
2017-01-01
Mutations in hepatocyte nuclear factor 1β gene ( HNF1B ) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations. HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome.The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A family history
-
Hršak, Hrvoje; Majer, Marija; Grego, Timor; Bibić, Juraj; Heinrich, Zdravko
2014-12-01
Dosimetry for Gamma-Knife requires detectors with high spatial resolution and minimal angular dependence of response. Angular dependence and end effect time for p-type silicon detectors (PTW Diode P and Diode E) and PTW PinPoint ionization chamber were measured with Gamma-Knife beams. Weighted angular dependence correction factors were calculated for each detector. The Gamma-Knife output factors were corrected for angular dependence and end effect time. For Gamma-Knife beams angle range of 84°-54°. Diode P shows considerable angular dependence of 9% and 8% for the 18 mm and 14, 8, 4 mm collimator, respectively. For Diode E this dependence is about 4% for all collimators. PinPoint ionization chamber shows angular dependence of less than 3% for 18, 14 and 8 mm helmet and 10% for 4 mm collimator due to volumetric averaging effect in a small photon beam. Corrected output factors for 14 mm helmet are in very good agreement (within ±0.3%) with published data and values recommended by vendor (Elekta AB, Stockholm, Sweden). For the 8 mm collimator diodes are still in good agreement with recommended values (within ±0.6%), while PinPoint gives 3% less value. For the 4 mm helmet Diodes P and E show over-response of 2.8% and 1.8%, respectively. For PinPoint chamber output factor of 4 mm collimator is 25% lower than Elekta value which is generally not consequence of angular dependence, but of volumetric averaging effect and lack of lateral electronic equilibrium. Diodes P and E represent good choice for Gamma-Knife dosimetry. Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.
-
Gad, S; Lefèvre, S H; Khoo, S K; Giraud, S; Vieillefond, A; Vasiliu, V; Ferlicot, S; Molinié, V; Denoux, Y; Thiounn, N; Chrétien, Y; Méjean, A; Zerbib, M; Benoît, G; Hervé, J M; Allègre, G; Bressac-de Paillerets, B; Teh, B T; Richard, S
2006-01-01
BHD, TP53, and HNF1β on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1β mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype. PMID:17133269
-
Li, Min; Tang, Yuxiao; Wu, Lusha; Mo, Fengfeng; Wang, Xin; Li, Hongxia; Qi, Ruirui; Zhang, Hongwei; Srivastava, Arun; Ling, Chen
2017-08-24
Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe -/- ) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy. © 2017 by The American Society of Hematology.
-
Bonner, Caroline; Farrelly, Angela M.; Concannon, Caoimhín G.; Dussmann, Heiko; Baquié, Mathurin; Virard, Isabelle; Wobser, Hella; Kögel, Donat; Wollheim, Claes B.; Rupnik, Marjan; Byrne, Maria M.; König, Hans-Georg; Prehn, Jochen H. M.
2011-01-01
Inactivating mutations in the transcription factor hepatocyte nuclear factor (HNF) 1A cause HNF1A–maturity-onset diabetes of the young (HNF1A-MODY), the most common monogenic form of diabetes. To examine HNF1A-MODY-induced defects in gene expression, we performed a microarray analysis of the transcriptome of rat INS-1 cells inducibly expressing the common hot spot HNF1A frameshift mutation, Pro291fsinsC-HNF1A. Real-time quantitative PCR (qPCR), Western blotting, immunohistochemistry, reporter assays, and chromatin immunoprecipitation (ChIP) were used to validate alterations in gene expression and to explore biological activities of target genes. Twenty-four hours after induction of the mutant HNF1A protein, we identified a prominent down-regulation of the bone morphogenetic protein 3 gene (Bmp-3) mRNA expression. Reporter assays, qPCR, and Western blot analysis validated these results. In contrast, inducible expression of wild-type HNF1A led to a time-dependent increase in Bmp-3 mRNA and protein levels. Moreover, reduced protein levels of BMP-3 and insulin were detected in islets of transgenic HNF1A-MODY mice. Interestingly, treatment of naïve INS-1 cells or murine organotypic islet cultures with recombinant human BMP-3 potently increased their insulin levels and restored the decrease in SMAD2 phosphorylation and insulin gene expression induced by the HNF1A frameshift mutation. Our study suggests a critical link between HNF1A-MODY-induced alterations in Bmp-3 expression and insulin gene levels in INS-1 cells and indicates that the reduced expression of growth factors involved in tissue differentiation may play an important role in the pathophysiology of HNF1A-MODY. PMID:21628466
-
Factors influencing in situ gamma-ray measurements
NASA Astrophysics Data System (ADS)
Loonstra, E. H.; van Egmond, F. M.
2009-04-01
Introduction In situ passive gamma-ray sensors are very well suitable for mapping physical soil properties. In order to make a qualitative sound soil map, high quality input parameters for calibration are required. This paper will focus on the factors that affect the output of in situ passive gamma-ray sensors, the primary source, soil, not taken into account. Factors The gamma-ray spectrum contains information of naturally occurring nuclides 40K, 238U and 232Th and man-made nuclides like 137Cs, as well as the total count rate. Factors that influence the concentration of these nuclides and the count rate can be classified in 3 categories. These are sensor design, environmental conditions and operational circumstances. Sensor design The main elements of an in situ gamma-ray sensor that influence the outcome and quality of the output are the crystal and the spectrum analysis method. Material and size of the crystal determine the energy resolution. Though widely used, NaI crystals are not the most efficient capturer of gamma radiation. Alternatives are BGO and CsI. BGO has a low peak resolution, which prohibits use in cases where man-made nuclides are subject of interest. The material is expensive and prone to temperature instability. CsI is robust compared to NaI and BGO. The density of CsI is higher than NaI, yielding better efficiency, especially for smaller crystal sizes. More volume results in higher energy efficiency. The reduction of the measured spectral information into concentration of radionuclides is mostly done using the Windows analysis method. In Windows, the activities of the nuclides are found by summing the intensities of the spectrum found in a certain interval surrounding a peak. A major flaw of the Windows method is the limited amount of spectral information that is incorporated into the analysis. Another weakness is the inherent use of ‘stripping factors' to account for contributions of radiation from nuclide A into the peak of nuclide B. This
-
Precision imaging of 4.4 MeV gamma rays using a 3-D position sensitive Compton camera.
Koide, Ayako; Kataoka, Jun; Masuda, Takamitsu; Mochizuki, Saku; Taya, Takanori; Sueoka, Koki; Tagawa, Leo; Fujieda, Kazuya; Maruhashi, Takuya; Kurihara, Takuya; Inaniwa, Taku
2018-05-25
Imaging of nuclear gamma-ray lines in the 1-10 MeV range is far from being established in both medical and physical applications. In proton therapy, 4.4 MeV gamma rays are emitted from the excited nucleus of either 12 C* or 11 B* and are considered good indicators of dose delivery and/or range verification. Further, in gamma-ray astronomy, 4.4 MeV gamma rays are produced by cosmic ray interactions in the interstellar medium, and can thus be used to probe nucleothynthesis in the universe. In this paper, we present a high-precision image of 4.4 MeV gamma rays taken by newly developed 3-D position sensitive Compton camera (3D-PSCC). To mimic the situation in proton therapy, we first irradiated water, PMMA and Ca(OH)2 with a 70 MeV proton beam, then we identified various nuclear lines with the HPGe detector. The 4.4 MeV gamma rays constitute a broad peak, including single and double escape peaks. Thus, by setting an energy window of 3D-PSCC from 3 to 5 MeV, we show that a gamma ray image sharply concentrates near the Bragg peak, as expected from the minimum energy threshold and sharp peak profile in the cross section of 12 C(p,p) 12 C*.
-
Yamamura, Nobuhisa; Fugo, Kazunori; Kishimoto, Takashi
2017-09-01
Alpha-fetoprotein (AFP)-producing adenocarcinoma is a high-malignant variant of adenocarcinoma with a hepatic or fetal-intestinal phenotype. The number of cases of AFP-producing adenocarcinomas is increasing, but the molecular mechanism underlying the aberrant production of AFP is unclear. Here we sought to assess the role of Forkhead box A (FoxA)2, which is a pioneer transcription factor in the differentiation of hepatoblasts. FoxA2 expression was investigated in five cases of AFP-producing gastric adenocarcinomas by immunohistochemistry, and all cases showed FoxA2 expression. Chromatin immunoprecipitation revealed the DNA binding of FoxA2 on the regulatory element of AFP gene in AFP-producing adenocarcinoma cells. The inhibition of FoxA2 expression with siRNA reduced the mRNA expression of liver-specific proteins, including AFP, albumin, and transferrin. The inhibition of FoxA2 also reduced the expressions of liver-enriched nuclear factors, i.e., hepatocyte nuclear factor (HNF) 4α and HNF6, although the expressions of HNF1α and HNF1β were not affected. The same effect as FoxA2 knockdown in AFP producing adenocarcinoma cells was also observed in hepatocellular carcinoma cells. Our results suggest that FoxA2 plays a key role in the expression of hepatic phenotype of AFP-producing adenocarcinomas. Copyright © 2017 Elsevier GmbH. All rights reserved.
-
Shih, Angela; Lauwers, Gregory Y; Balabaud, Charles; Bioulac-Sage, Paulette; Misdraji, Joseph
2015-09-01
Mixed focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) within a single tumor mass is rarely reported, and most of these cases are examples of tumors with features intermediate between FNH and HCA. Although a few reported cases are probably examples of true mixed tumors, none was evaluated immunohistochemically or confirmed by molecular analysis. We report a mixed FNH and HCA arising in a woman with several HNF1A-inactivated adenomas. Our case is the first case of mixed FNH and HNF1A-inactivated HCA documented by immunohistochemistry.
-
Liao, Shunyao; Liu, Yunqiang; Zheng, Bing; Cho, Pyo Yun; Song, Hyun Ok; Lee, Yun-Seok; Jung, Suk-Yul; Park, Hyun
2011-12-01
The onset, severity, and ultimate outcome of malaria infection are influenced by parasite-expressed virulence factors as well as by individual host responses to these determinants. In both humans and mice, liver injury follows parasite entry, persisting to the erythrocytic stage in the case of infection with the fatal strain of Plasmodium falciparum. Hepatic nuclear factor (HNF)-1α is a master regulator of not only the liver damage and adaptive responses but also diverse metabolic functions. In this study, we analyzed the expression of host HNF-1α in relation to malaria infection and evaluated its interaction with the 5'-untranslated region of subtilisin-like protease 2 (subtilase, Sub2). Recombinant human HNF-1α expressed by a lentiviral vector (LV HNF-1α) was introduced into mice. Interestingly, differences in the activity of the 5'-untranslated region of the Pf-Sub2 promoter were detected in 293T cells, and LV HNF-1α was observed to influence promoter activity, suggesting that host HNF-1α interacts with the Sub2 gene.
-
Fadare, Oluwole; Liang, Sharon X
2012-12-01
Hepatocyte nuclear factor 1-beta (HNF1β) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1β protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1β expression was found to be present in a wide spectrum of tissues. Twenty-seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1β expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1β expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1β, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear
-
Szopa, Magdalena; Kapusta, Maria; Matejko, Bartlomiej; Klupa, Tomasz; Koblik, Teresa; Kiec-Wilk, Beata; Borowiec, Maciej; Malecki, Maciej T
2015-01-01
We previously showed that in HNF1A-MODY the cystatin C-based glomerular filtration rate (GFR) estimate is higher than the creatinine-based estimate. Currently, we aimed to replicate this finding and verify its clinical significance. The study included 72 patients with HNF1A-MODY, 72 with GCK-MODY, 53 with type 1 diabetes (T1DM), 70 with type 2 diabetes (T2DM), and 65 controls. Serum creatinine and cystatin C levels were measured. GFR was calculated from creatinine and cystatin C using the CKD-EPI creatinine equation (eGRF-cr) and CKD-EPI cystatin C equation (eGFR-cys), respectively. Cystatin C levels were lower (p < 0.001) in the control (0.70 ± 0.13 mg/L), HNF1A (0.75 ± 0.21), and GCK (0.72 ± 0.16 mg/L) groups in comparison to those with either T1DM (0.87 ± 0.15 mg/L) or T2DM (0.9 ± 0.23 mg/L). Moreover, eGFR-cys was higher than eGRF-cr in HNF1A-MODY, GCK-MODY, and the controls (p = 0.004; p = 0.003; p < 0.0001). This corresponded to 8.9 mL/min/1.73 m2, 9.7 mL/min/1.73 m2, and 16.9 mL/min/1.73 m2 of difference. Additionally, T1DM patients had higher eGFR-cr than eGFR-cys (11.6 mL/min/1.73 m(2); p = 0.0004); no difference occurred in T2DM (p = 0.91). We confirmed that eGFR-cys values in HNF1A-MODY patients are higher compared to eGFR-cr. Some other differences were also described in diabetic groups. However, none of them appears to be clinically relevant.
-
Pinés Corrales, Pedro José; López Garrido, María P; Aznar Rodríguez, Silvia; Louhibi Rubio, Lynda; López Jiménez, Luz M; Lamas Oliveira, Cristina; Alfaro Martínez, Jose J; Lozano García, Jose J; Hernández López, Antonio; Requejo Castillo, Ramón; Escribano Martínez, Julio; Botella Romero, Francisco
2010-01-01
The aim of our study was to describe and evaluate the clinical and metabolic characteristics of patients with MODY-3, MODY-2 or type 2 diabetes who presented I27L polymorphism in the HNF1alpha gene. The study included 31 previously diagnosed subjects under follow-up for MODY-3 (10 subjects from 5 families), MODY-2 (15 subjects from 9 families), or type 2 diabetes (6 subjects) with I27L polymorphism in the HNF1alpha gene. The demographic, clinical, metabolic, and genetic characteristics of all patients were analyzed. No differences were observed in distribution according to sex, age of onset, or form of diagnosis. All patients with MODY-2 or MODY-3 had a family history of diabetes. In contrast, 33.3% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene had no family history of diabetes (p < 0.05). No differences were observed in body mass index, prevalence of hypertension, or microvascular or macrovascular complications. Drug therapy was required by 100% of MODY-3 patients, but not required by 100% of MODY-2 patients or 16.7% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene (p < 0.05). Occasional difficulties may be encountered when classifying patients with MODY-2, MODY-3 or type 2 diabetes of atypical characteristics, in this case patients who present I27L polymorphism in the HNF1alpha gene. Copyright 2010 Sociedad Española de Endocrinología y Nutrición. Published by Elsevier Espana. All rights reserved.
-
López-Garrido, M P; Herranz-Antolín, S; Alija-Merillas, M J; Giralt, P; Escribano, J
2013-09-01
To determine the genetic basis of dominant early-onset diabetes mellitus in two families. Molecular analysis by PCR sequencing of the promoter, the 5' untranslated region (UTR) and exons of both GCK and HNF1A genes was carried out in two families with clinically diagnosed dominant diabetes mellitus. The novel HNF1A c.-154_-160TGGGGGT mutation, located in the 5' UTR, was present in several members of the two families in the heterozygous state. Interestingly, the GCK p.Y61X mutation was also identified in three members of one of the families, and two of them carried both mutations in heterozygosis. To the best of our knowledge, this is the first report of the co-inheritance of GCK and HNF1A mutations and the coexistence of maturity-onset diabetes of the young (MODY) 2, MODY 3 and unusual MODY 2-3 genotypes in the same family. Carriers of both GCK and HNF1A mutations manifested a typical MODY 3 phenotype and showed that the presence of a second mutation in the GCK gene apparently did not modify the clinical outcome, at least at the time of this study. Our data show that co-inheritance of MODY 2 and MODY 3 mutations should be considered, at least in some cases, for accurate genetic testing. © 2012 John Wiley & Sons Ltd.
-
7Be(p,gamma)8B S-factor from Ab Initio Wave Functions
DOE Office of Scientific and Technical Information (OSTI.GOV)
Navratil, P; Bertulani, C A; Caurier, E
2006-10-12
There has been a significant progress in ab initio approaches to the structure of light nuclei. Starting from realistic two- and three-nucleon interactions the ab initio no-core shell model (NCSM) predicts low-lying levels in p-shell nuclei. It is a challenging task to extend ab initio methods to describe nuclear reactions. We present here a brief overview of the first steps taken toward nuclear reaction applications. In particular, we discuss our calculation of the {sup 7}Be(p,{gamma}){sup 8}B S-factor. We also present our first results of the {sup 3}He({alpha},{gamma}){sup 7}Be S-factor and of the S-factor of the mirror reaction {sup 3}H({alpha},{gamma}){sup 7}Li.more » The {sup 7}Be(p,{gamma}){sup 8}B and {sup 3}He({alpha},{gamma}){sup 7}Be reactions correspond to the most important uncertainties in solar model predictions of neutrino fluxes.« less
-
Matsui, Chieko; Deng, Lin; Minami, Nanae; Abe, Takayuki; Koike, Kazuhiko; Shoji, Ikuo
2018-07-01
Hepatitis C virus (HCV) infection is closely associated with type 2 diabetes. We reported that HCV infection induces the lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) via interaction with HCV nonstructural protein 5A (NS5A) protein, thereby suppressing GLUT2 gene expression. The molecular mechanisms of selective degradation of HNF-1α caused by NS5A are largely unknown. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway. Here, we investigated whether CMA is involved in the selective degradation of HNF-1α in HCV-infected cells and observed that the pentapeptide spanning from amino acid (aa) 130 to aa 134 of HNF-1α matches the rule for the CMA-targeting motif, also known as KFERQ motif. A cytosolic chaperone protein, heat shock cognate protein of 70 kDa (HSC70), and a lysosomal membrane protein, lysosome-associated membrane protein type 2A (LAMP-2A), are key components of CMA. Immunoprecipitation analysis revealed that HNF-1α was coimmunoprecipitated with HSC70, whereas the Q130A mutation (mutation of Q to A at position 130) of HNF-1α disrupted the interaction with HSC70, indicating that the CMA-targeting motif of HNF-1α is important for the association with HSC70. Immunoprecipitation analysis revealed that increasing amounts of NS5A enhanced the association of HNF-1α with HSC70. To determine whether LAMP-2A plays a role in the degradation of HNF-1α protein, we knocked down LAMP-2A mRNA by RNA interference; this knockdown by small interfering RNA (siRNA) recovered the level of HNF-1α protein in HCV J6/JFH1-infected cells. This result suggests that LAMP-2A is required for the degradation of HNF-1α. Immunofluorescence study revealed colocalization of NS5A and HNF-1α in the lysosome. Based on our findings, we propose that HCV NS5A interacts with HSC70 and recruits HSC70 to HNF-1α, thereby promoting the lysosomal degradation of HNF-1α via CMA. IMPORTANCE Many viruses use a protein degradation system, such as
-
Genetic Predictors of Interindividual Variability in Hepatic CYP3A4 ExpressionS⃞
Lamba, Vishal; Panetta, John C.; Strom, Stephen
2010-01-01
Variability in hepatic CYP3A4 cannot be explained by common CYP3A4 coding variants. We previously identified polymorphisms in pregnane X receptor (PXR) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with CYP3A4 mRNA levels in small cohorts of human livers. However, the relative contributions of these genetic variations or of polymorphisms in other CYP3A4 regulators to variable CYP3A4 expression were not known. We phenotyped livers from white donors (n = 128) by quantitative real-time polymerase chain reaction for expression of CYP3A4, CYP3A5, and CYP3A7 and nine transcriptional regulators, coactivators, and corepressors. We resequenced hepatic nuclear factor-3-β (HNF3β, FoxA2), HNF4α, HNF3γ (FoxA3), nuclear receptor corepressor 2 (NCoR2), and regions of the CYP3A4 promoter and genotyped informative single-nucleotide polymorphisms in PXR and ABCB1 in the same livers. CYP3A4 mRNA was positively correlated with PXR and FoxA2 and negatively correlated with NCoR2 mRNA. A common silent polymorphism and a polymorphic trinucleotide (CCT) repeat in FoxA2 were associated with CYP3A4 expression. The transcriptional activity of the FoxA2 polymorphic CCT repeat alleles (wild-type, n = 14 and variant, n = 13, 15, and 19) when assayed by luciferase reporter transactivation assays was greatest for the wild-type repeat, with deviations from this number having decreased transcriptional activity. This corresponded with higher expression of FoxA2 mRNA and its targets PXR and CYP3A4 in human livers with (CCT) n = 14 genotypes. Multiple linear regression analysis was used to quantify the contributions of selected genetic polymorphisms to variable CYP3A4 expression. This approach identified sex and polymorphisms in FoxA2, HNF4α, FoxA3, PXR, ABCB1, and the CYP3A4 promoter that together explained as much as 24.6% of the variation in hepatic CYP3A4 expression. PMID:19934400
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Beggs, Kevin M., E-mail: kbeggs2@kumc.edu
Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), chemicals present in a multitude of consumer products, are persistent organic pollutants. Both compounds induce hepatotoxic effects in rodents, including steatosis, hepatomegaly and liver cancer. The mechanisms of PFOA- and PFOS-induced hepatic dysfunction are not completely understood. We present evidence that PFOA and PFOS induce their hepatic effects via targeting hepatocyte nuclear factor 4-alpha (HNF4α). Human hepatocytes treated with PFOA and PFOS at a concentration relevant to occupational exposure caused a decrease in HNF4α protein without affecting HNF4α mRNA or causing cell death. RNA sequencing analysis combined with Ingenuity Pathway Analysis of globalmore » gene expression changes in human hepatocytes treated with PFOA or PFOS indicated alterations in the expression of genes involved in lipid metabolism and tumorigenesis, several of which are regulated by HNF4α. Further investigation of specific HNF4α target gene expression revealed that PFOA and PFOS could promote cellular dedifferentiation and increase cell proliferation by down regulating positive targets (differentiation genes such as CYP7A1) and inducing negative targets of HNF4α (pro-mitogenic genes such as CCND1). Furthermore, in silico docking simulations indicated that PFOA and PFOS could directly interact with HNF4α in a similar manner to endogenous fatty acids. Collectively, these results highlight HNF4α degradation as novel mechanism of PFOA and PFOS-mediated steatosis and tumorigenesis in human livers. - Highlights: • PFOA and PFOS cause decreased HNF4α protein expression in human hepatocytes. • PFOA and PFOS promote changes associated with lipid metabolism and carcinogenesis. • PFOA and PFOS induced changes in gene expression associated with cellular dedifferentiation. • PFOA and PFOS induce expression of Nanog, a transcription factor involved in stem cell development.« less
-
Utley, Sarah; James, David; Mavila, Nirmala; Nguyen, Marie V.; Vendryes, Christopher; Salisbury, S. Michael; Phan, Jennifer; Wang, Kasper S.
2014-01-01
Background & Aims Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent β-catenin activation. Moreover, the emergence of hepatocytes expressing the HPC marker A6 during 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury is mediated partly by FGF and β-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated β-catenin activation in acute DDC liver injury. Methods Transgenic mice were fed DDC chow for 14 days concurrent with either Fgf10 over-expression or inhibition of FGF signaling via expression of soluble dominant-negative FGF Receptor (R)-2IIIb. Results After 14 days of DDC treatment, there was an increase in periportal cells expressing FGFR1, FGFR2, and AKT-activated phospho-Serine 552 (pSer552) β-CATENIN in association with up-regulation of genes encoding FGFR2IIIb ligands, Fgf7, Fgf10, and Fgf22. In response to Fgf10 over-expression, there was an increase in the number of pSer552-β-CATENIN(positive)+ive periportal cells as well as cells co-positive for A6 and hepatocyte marker, Hepatocyte Nuclear Factor-4α (HNF4α). A similar expansion of A6+ive cells was observed after Fgf10 over-expression with regular chow and after partial hepatectomy during ethanol toxicity. Inhibition of FGF signaling increased the periportal A6+iveHNF4α+ive cell population while reducing centrolobular A6+ive HNF4α+ive cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6+iveHNF4α+ive cell expansion. In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT-mediated β-CATENIN activation but not enhanced cell migration. Conclusion During acute DDC treatment, FGF signaling promotes the expansion of A6-expressing liver cells partly via AKT-dependent activation of β-CATENIN expansion of A6+ive periportal cells and possibly by reprogramming of centrolobular hepatocytes. PMID:24365171
-
Yang, Jaewook; Hutchinson, Ian I; Shah, Tariq; Min, David I
2011-05-27
New-onset diabetes after transplantation (NODAT) is one of the major complications after transplantation and is associated with reduced overall patient and graft survival. The objective of this study was to determine the genetic and clinical risk factors for NODAT in Hispanic kidney transplant recipients. Hispanic kidney allograft recipients without evidence of preexisting diabetes who developed NODAT (n=133) were studied using Hispanic kidney transplant recipients with no evidence of diabetes as a control group (n=170). NODAT was defined as fasting glucose levels ≥126 mg/dL on two or more occasions or patients taking any insulin or oral hypoglycemic agents 1 month or later after kidney transplantation. Fourteen alleles in nine genes were genotyped and other patients' clinical data with genotype data were analyzed by logistic regression. Among 14 alleles, hepatocyte nuclear factor 4 alpha (HNF4A) AA (rs2144908, odds ratio [OR]=1.96, confidence interval [CI]=1.08-3.50, P=0.010), HNF4A TT (rs1884614, OR=2.44, CI=1.42-4.48, P=0.002), and insulin receptor substrate 1 AA+AG (rs1801278, OR=2.71, CI=1.16-6.89, P=0.021) remained significant after logistic regression. Among the clinical factors, average age (OR=1.01, CI=1.00-1.08, P=0.048), sirolimus (OR=5.36, CI=3.02-10.4, P=0.001), deceased donor (OR=1.96, CI=1.16-2.94, P=0.015), and acute rejection (OR=2.92, CI=1.31-5.77, P=0.009) remained significant after logistic regression. This study indicates that polymorphism of two alleles of HNF-4A gene (rs2144908 and rs1884614) and insulin receptor substrate 1 (rs1801278) are significantly associated with NODAT in kidney transplant patients with Hispanic ethnicity. In the case of clinical factors, older age (>50 year), deceased donor type, acute rejection, and sirolimus use are associated with NODAT in Hispanic kidney transplant recipients.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
HAMMERS, J.S.
The purpose of the test was to verify that the AN Tank Farm B Pit Leak Detector components are functionally integrated and operate in accordance with engineering design specifications. The Acceptance Test Procedure HNF-4646,241-AN-B-Pit Leak Detection ANB-WT-LDSTA-231 was conducted between 26 June and 02 July 1999 at the 200E AN Tank Farm. The test has been completed with no open test exceptions. The test was conducted prior to final engineering ''as built'' activities being completed this had no impact on the procedure or test results. All components, identified in the procedure were found to be labeled and identified as writtenmore » in the procedure.« less
-
Grau, G E; Heremans, H; Piguet, P F; Pointaire, P; Lambert, P H; Billiau, A; Vassalli, P
1989-01-01
Experimental cerebral malaria (ECM), a lethal hyperacute neurological syndrome associated with high blood levels of tumor necrosis factor, develops in genetically susceptible (CBA/Ca) mice 7 days after infection with Plasmodium berghei ANKA strain. Injections of neutralizing monoclonal antibody against recombinant murine interferon gamma, not later than 4 days after infection, markedly reduced the incidence of ECM and the elevation in serum levels of tumor necrosis factor. This treatment prevented the cerebral lesions (plugging of brain vessels by monocytes, lymphocytes, and parasitized erythrocytes). In contrast, the extent of macrophage infiltration in lymphoid organs (which is a characteristic feature of mice developing ECM), as well as the course of infection, remained unaffected by the antibody treatment. Protected mice died at a later time of severe anemia and overwhelming parasitemia, the usual outcome of P. berghei infection in mice that are not susceptible to ECM. The present data indicate that interferon gamma constitutes an important link in the cytokine network that leads to brain vessel inflammation in experimental malaria. It is proposed that interferon gamma released by activated CD4+ T cells acts by augmenting both production and action of tumor necrosis factor. PMID:2501793
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki
The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1{alpha} and CYP2A5 mRNAsmore » in murine primary hepatocytes. Furthermore, the elevation of the PGC-1{alpha} expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1{alpha} expression vector demonstrated that PGC-1{alpha} is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4{alpha} response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1{alpha} binds, together with HNF-4{alpha}, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1{alpha} mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4{alpha}. This strongly suggests that PGC-1{alpha} is the major factor mediating the fasting response of CYP2A5.« less
-
Snykers, Sarah; Vanhaecke, Tamara; De Becker, Ann; Papeleu, Peggy; Vinken, Mathieu; Van Riet, Ivan; Rogiers, Vera
2007-01-01
Background The capability of human mesenchymal stem cells (hMSC) derived of adult bone marrow to undergo in vitro hepatic differentiation was investigated. Results Exposure of hMSC to a cocktail of hepatogenic factors [(fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF), insulin-transferrin-sodium-selenite (ITS) and dexamethasone)] failed to induce hepatic differentiation. Sequential exposure to these factors (FGF-4, followed by HGF, followed by HGF+ITS+dexamethasone), however, resembling the order of secretion during liver embryogenesis, induced both glycogen-storage and cytokeratin (CK)18 expression. Additional exposure of the cells to trichostatin A (TSA) considerably improved endodermal differentiation, as evidenced by acquisition of an epithelial morphology, chronological expression of hepatic proteins, including hepatocyte-nuclear factor (HNF)-3β, alpha-fetoprotein (AFP), CK18, albumin (ALB), HNF1α, multidrug resistance-associated protein (MRP)2 and CCAAT-enhancer binding protein (C/EBP)α, and functional maturation, i.e. upregulated ALB secretion, urea production and inducible cytochrome P450 (CYP)-dependent activity. Conclusion hMSC are able to undergo mesenchymal-to-epithelial transition. TSA is hereby essential to promote differentiation of hMSC towards functional hepatocyte-like cells. PMID:17407549
-
The POPOP4 library and codes for preparing secondary gamma-ray production cross sections
NASA Technical Reports Server (NTRS)
Ford, W. E., III
1972-01-01
The POPOP4 code for converting secondary gamma ray yield data to multigroup secondary gamma ray production cross sections and the POPOP4 library of secondary gamma ray yield data are described. Recent results of the testing of uranium and iron data sets from the POPOP4 library are given. The data sets were tested by comparing calculated secondary gamma ray pulse height spectra measured at the ORNL TSR-II reactor.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
HAMMERS, J.S.
1999-09-22
The purpose of the test was to verify that the AN Tank Farm Manifold Valves can be manually manipulated to the required operating position and that the electrical and visual indications accurately reflect that position. Physical locking devices were also verified to function. The Acceptance Test Procedure HNF-4642, 241-AN-A Valve Pit Manifold Valves and Position Indication was conducted between 23 June and 10 August 1999 at the 200E AN Tank Farm. The test has no open test exceptions. The test was conducted prior to final engineering ''as built'' activities being completed, this had an impact on the procedure and testmore » results, ECN 653752 was written to correct the mismatch between the procedure and actual field conditions. P&ID H-14-100941 was changed via ECN-W-314-4C-120. All components, identified in the procedure, were not found to be labeled and identified as written in the procedure, temporary tags were used for operational identification. A retest of valve ANA-WT-V 318 was required because it was removed from its installed position and modified after testing was completed.« less
-
Supervised Gamma Process Poisson Factorization
DOE Office of Scientific and Technical Information (OSTI.GOV)
Anderson, Dylan Zachary
This thesis develops the supervised gamma process Poisson factorization (S- GPPF) framework, a novel supervised topic model for joint modeling of count matrices and document labels. S-GPPF is fully generative and nonparametric: document labels and count matrices are modeled under a uni ed probabilistic framework and the number of latent topics is controlled automatically via a gamma process prior. The framework provides for multi-class classification of documents using a generative max-margin classifier. Several recent data augmentation techniques are leveraged to provide for exact inference using a Gibbs sampling scheme. The first portion of this thesis reviews supervised topic modeling andmore » several key mathematical devices used in the formulation of S-GPPF. The thesis then introduces the S-GPPF generative model and derives the conditional posterior distributions of the latent variables for posterior inference via Gibbs sampling. The S-GPPF is shown to exhibit state-of-the-art performance for joint topic modeling and document classification on a dataset of conference abstracts, beating out competing supervised topic models. The unique properties of S-GPPF along with its competitive performance make it a novel contribution to supervised topic modeling.« less
-
Non-equilibrium effects in steady relativistic e^+e^-gamma winds
NASA Astrophysics Data System (ADS)
Grimsrud, Ole M.; Wasserman, Ira
1998-11-01
We consider an ultrarelativistic wind consisting of electron-positron pairs and photons with the principal goal of finding the asymptotic Lorentz factor gamma_∞ for zero baryon number. The wind is assumed to originate at radius r_i where it has a Lorentz factor gamma_i and a temperature T_i sufficiently high to maintain pair equilibrium. As r increases, T decreases and becomes less than the temperature corresponding to the electron mass m_e, after which non-equilibrium effects become important. The pairs, which carry only a small fraction of the total energy, may be accelerated by the photons until tau falls below ~2x10^-5gamma^3/4_i. Radiative transfer calculations show that only at this point do the radiation flux and pressure start to deviate significantly from their blackbody values. The acceleration of the pairs increases gamma by a factor ~45 compared with its value at the photosphere; it is shown to approach gamma_∞~1.4x10^3(r^6_i/10cm)^1/4gamma^{3/4}_iT_i/m_e. The limit of zero baryon number is a good approximation when the mass injection rate Msolar in the flow is below a critical value corresponding to (Esolar/MsolarM)_c,0~5x10^7(r^6_i/10cm)T_i/m_e for fixed energy injection rate E/E. For large baryon loading, (Esolar/Msolar<~Esolar/Msolar)_c,M~350(r_i/10^6cm)^1/4gamma^3/4_iT_i/ m_e, the asymptotic Lorentz factor is gamma_∞~Esolar/Msolar. Surprisingly, increasing Esolar/Msolar from (Esolar/Msolar)_c,M to ∞ only increases gamma_∞ by a factor ~(m_p/m_e)^1/4~6.5, less than an order of magnitude. As Esolar/Msolar increases, the fraction of the energy carried by pairs decreases, reaching ~10^-5gamma^3/4_i as Esolar/Msolar to ∞.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chiba, Takuya, E-mail: takuya@nagasaki-u.ac.jp; Tsuchiya, Tomoshi; Komatsu, Toshimitsu
2010-10-15
Research highlights: {yields} We identified four sequence motifs lying upstream of putative pro-longevity genes. {yields} One of these motifs binds to HNF-4{alpha}. {yields} HNF-4{alpha}/PGC-1{alpha} could up-regulate the transcription of a reporter gene linked to this motif. {yields} The reporter system described here could be used to screen candidate anti-aging molecules. -- Abstract: Suppression of the growth hormone/insulin-like growth factor-I pathway in Ames dwarf (DF) mice, and caloric restriction (CR) in normal mice extends lifespan and delays the onset of age-related disorders. In combination, these interventions have an additive effect on lifespan in Ames DF mice. Therefore, common signaling pathways regulatedmore » by DF and CR could have additive effects on longevity. In this study, we tried to identity the signaling mechanism and develop a system to assess pro-longevity status in cells and mice. We previously identified genes up-regulated in the liver of DF and CR mice by DNA microarray analysis. Motif analysis of the upstream sequences of those genes revealed four major consensus sequence motifs, which have been named dwarfism and calorie restriction-responsive elements (DFCR-REs). One of the synthesized sequences bound to hepatocyte nuclear factor-4{alpha} (HNF-4{alpha}), an important transcription factor involved in liver metabolism. Furthermore, using this sequence information, we developed a highly sensitive bioassay to identify chemicals mimicking the anti-aging effects of CR. When the reporter construct, containing an element upstream of a secreted alkaline phosphatase (SEAP) gene, was co-transfected with HNF-4{alpha} and its regulator peroxisome proliferator-activated receptor (PPAR) {gamma} coactivator-1{alpha} (PGC-1{alpha}), SEAP activity was increased compared with untransfected controls. Moreover, transient transgenic mice established using this construct showed increased SEAP activity in CR mice compared with ad libitum-fed mice. These
-
Initial Gamma Spectrometry Examination of the AGR-3/4 Irradiation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Harp, Jason M.; Demkowicz, Paul A.; Stempien, John D.
2016-11-01
The initial results from gamma spectrometry examination of the different components from the combined third and fourth US Advanced Gas Reactor Fuel Development TRISO-coated particle fuel irradiation tests (AGR-3/4) have been analyzed. This experiment was designed to provide information about in-pile fission product migration. In each of the 12 capsules, a single stack of four compacts with designed-to-fail particles surrounded by two graphitic diffusion rings (inner and outer) and a graphite sink were irradiated in the Idaho National Laboratory’s Advanced Test Reactor. Gamma spectrometry has been used to evaluate the gamma-emitting fission product inventory of compacts from the irradiation andmore » evaluate the burnup of these compacts based on the activity of the radioactive cesium isotopes (Cs-134 and Cs-137) in the compacts. Burnup from gamma spectrometry compares well with predicted burnup from simulations. Additionally, inner and outer rings were also examined by gamma spectrometry both to evaluate the fission product inventory and the distribution of gamma-emitting fission products within the rings using gamma emission computed tomography. The cesium inventory of the scanned rings compares acceptably well with the expected inventory from fission product transport modeling. The inventory of the graphite fission product sinks is also being evaluated by gamma spectrometry.« less
-
Shi, Xiaohe; Cui, Bin; Wang, Zhugang; Weng, Lin; Xu, Zhongping; Ma, Jinjin; Xu, Guotong; Kong, Xiangyin; Hu, Landian
2009-02-19
Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the Hsf4 gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. However, neither the relationship between HSF4 and crystallins nor the detailed mechanism of maintenance of lens transparency by HSF4 is fully understood. In an attempt to determine how the underlying biomedical and physiological mechanisms resulting from loss of HSF4 contribute to cataract formation, we generated an Hsf4 knockout mouse model. We showed that the Hsf4 knockout mouse (Hsf4-/-) partially mimics the human cataract caused by HSF4 mutations. Q-PCR analysis revealed down-regulation of several cataract-relevant genes, including gamma S-crystallin (Crygs) and lens-specific beaded filament proteins 1 and 2 (Bfsp1 and Bfsp2), in the lens of the Hsf4-/- mouse. Transcription activity analysis using the dual-luciferase system suggested that these cataract-relevant genes are the direct downstream targets of HSF4. The effect of HSF4 on gamma S-crystallin is exemplified by the cataractogenesis seen in the Hsf4-/-,rncat intercross. The 2D electrophoretic analysis of whole-lens lysates revealed a different expression pattern in 8-week-old Hsf4-/- mice compared with their wild-type counterparts, including the loss of some alpha A-crystallin modifications and reduced expression of gamma-crystallin proteins. Our results indicate that HSF4 is sufficiently important to lens development and disruption of the Hsf4 gene leads to cataracts via at least three pathways: 1) down-regulation of gamma-crystallin, particularly gamma S-crystallin; 2) decreased lens beaded filament expression; and 3) loss of post-translational modification of alpha A-crystallin.
-
The Gamma Gap and All-Cause Mortality
Juraschek, Stephen P.; Moliterno, Alison R.; Checkley, William; Miller, Edgar R.
2015-01-01
Background The difference between total serum protein and albumin, i.e. the gamma gap, is a frequently used clinical screening measure for both latent infection and malignancy. However, there are no studies defining a positive gamma gap. Further, whether it is an independent risk factor of mortality is unknown. Methods and Findings This study examined the association between gamma gap, all-cause mortality, and specific causes of death (cardiovascular, cancer, pulmonary, or other) in 12,260 participants of the National Health and Nutrition Examination Survey (NHANES) from 1999–2004. Participants had a comprehensive metabolic panel measured, which was linked with vital status data from the National Death Index. Cause of death was based on ICD10 codes from death certificates. Analyses were performed with Cox proportional hazards models adjusted for mortality risk factors. The mean (SE) age was 46 (0.3) years and the mean gamma gap was 3.0 (0.01) g/dl. The population was 52% women and 10% black. During a median follow-up period of 4.8 years (IQR: 3.3 to 6.2 years), there were 723 deaths. The unadjusted 5-year cumulative incidences across quartiles of the gamma gap (1.7–2.7, 2.8–3.0, 3.1–3.2, and 3.3–7.9 g/dl) were 5.7%, 4.2%, 5.5%, and 7.8%. After adjustment for risk factors, participants with a gamma gap of ≥3.1 g/dl had a 30% higher risk of death compared to participants with a gamma gap <3.1 g/dl (HR: 1.30; 95%CI: 1.08, 1.55; P = 0.006). Gamma gap (per 1.0 g/dl) was most strongly associated with death from pulmonary causes (HR 2.22; 95%CI: 1.19, 4.17; P = 0.01). Conclusions The gamma gap is an independent risk factor for all-cause mortality at values as low as 3.1 g/dl (in contrast to the traditional definition of 4.0 g/dl), and is strongly associated with death from pulmonary causes. Future studies should examine the biologic pathways underlying these associations. PMID:26629820
-
Docena, Maricor K; Faiman, Charles; Stanley, Christine M; Pantalone, Kevin M
2014-02-01
An estimated 1 to 2% of cases of diabetes mellitus have a monogenic basis; however, delayed diagnosis and misdiagnosis as type 1 and 2 diabetes are common. Correctly identifying the molecular basis of an individual's diabetes may significantly alter the management approach to both the patient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-α) mutation as a cause of MODY-3. A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.
-
NASA Astrophysics Data System (ADS)
Aim-O, P.; Wongsawaeng, D.; Tancharakorn, S.; Sophon, M.
2017-09-01
High-density cement mixed with crumb rubber has been studied to be a gamma ray and neutron shielding material, especially for photonuclear reactions that may occur from accelerators where both types of radiation exist. The Buildup factors from gamma ray scattering, prompt and secondary gamma ray emissions from neutron capture and mechanical properties were evaluated. For buildup factor studies, two different geometries were used: narrow beam and broad beam. Prompt Gamma Neutron Activation Analysis (PGNAA) was carried out to determine the prompt and secondary gamma ray emissions. The compressive strength of samples was evaluated by using compression testing machine which was central point loading crushing test. The results revealed that addition of crumb rubber increased the buildup factor. Gamma ray spectra following PGNAA revealed no prompt or secondary gamma ray emission. Mechanical testing indicated that the compressive strength of the shielding material decreased with increasing volume percentage of crumb rubber.
-
Modeling the Martian neutron and gamma-ray leakage fluxes using Geant4
NASA Astrophysics Data System (ADS)
Pirard, Benoit; Desorgher, Laurent; Diez, Benedicte; Gasnault, Olivier
A new evaluation of the Martian neutron and gamma-ray (continuum and line) leakage fluxes has been performed using the Geant4 code. Even if numerous studies have recently been carried out with Monte Carlo methods to characterize planetary radiation environments, only a few however have been able to reproduce in detail the neutron and gamma-ray spectra observed in orbit. We report on the efforts performed to adapt and validate the Geant4-based PLAN- ETOCOSMICS code for use in planetary neutron and gamma-ray spectroscopy data analysis. Beside the advantage of high transparency and modularity common to Geant4 applications, the new code uses reviewed nuclear cross section data, realistic atmospheric profiles and soil layering, as well as specific effects such as gravity acceleration for low energy neutrons. Results from first simulations are presented for some Martian reference compositions and show a high consistency with corresponding neutron and gamma-ray spectra measured on board Mars Odyssey. Finally we discuss the advantages and perspectives of the improved code for precise simulation of planetary radiation environments.
-
Nie, Ya-Li; He, Hang; Li, Jiang-Feng; Meng, Xiang-Guang; Yan, Liang; Wang, Pei; Wang, Shu-Jie; Bi, Hong-Zheng; Zhang, Li-Rong; Kan, Quan-Cheng
2017-01-01
Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.
-
Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels
NASA Technical Reports Server (NTRS)
Pierangeli, Silvia S.; Sonnenfeld, Gerald
1989-01-01
Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.
-
Gamma-radiation effects on luminescence properties of Eu3+ activated LaPO4 phosphor
NASA Astrophysics Data System (ADS)
Vujčić, Ivica; Gavrilović, Tamara; Sekulić, Milica; Mašić, Slobodan; Putić, Slaviša; Papan, Jelena; Dramićanin, Miroslav D.
2018-05-01
Eu3+ activated LaPO4 phosphors were prepared by a high-temperature solid-state method and irradiated to different high-doses gamma-radiation in the 0-4 MGy range. No effects of high-doses of high-energy radiation on phosphor's morphology and structure were observed, as documented by electron microscopy and X-ray diffraction measurements. On the other hand, photoluminescence measurements showed that emission properties of phosphor were affected by gamma-radiation; changes in radiative properties being prominent for absorbed radiation doses up to 250 kGy after which no additional changes are observed. Judd-Ofelt analysis of emission spectra is performed to thoroughly investigate radiative properties of phosphors. Analysis showed that radiative transition probability of Eu3+ emission decreases while non-radiative probability increases upon gamma-irradiation. Quantum efficiency of emission is decreased from about 46% to 35% when Eu3+ doped LaPO4 powders are exposed to gamma-radiation of 250 kGy dose, showing no additional decrease for higher gamma-radiation doses.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bohm, A.; Teese, R.B.
1976-01-01
Using SU(4) as a spectrum generating group the radiative decay rates of the charmed vector mesons and of J(psi) are calculated. With the known decay rates of the old mesons GAMMA(..omega.. ..-->.. ..pi gamma..), GAMMA(phi ..-->.. eta ..gamma..), GAMMA(rho ..-->.. ..pi gamma..), GAMMA(K/sup 0/* ..-->.. K/sup 0/..gamma..) as input one obtains GAMMA(K/sup +/* ..-->.. K/sup +/..gamma..) = 2.6 keV, GAMMA(..omega.. ..-->.. eta ..gamma..) = 220 eV, GAMMA(rho ..-->.. eta ..gamma..) = 4.8 keV, GAMMA(psi ..-->.. chi ..gamma..) = 1.6 keV, GAMMA(D/sup 0/* ..-->.. D/sup 0/..gamma..) = 350 eV and GAMMA(D/sup +/* ..-->.. D/sup +/..gamma..) = 22 eV.
-
NASA Astrophysics Data System (ADS)
Raut, S. D.; Awasarmol, V. V.; Shaikh, S. F.; Ghule, B. G.; Ekar, S. U.; Mane, R. S.; Pawar, P. P.
2018-04-01
The gamma ray energy absorption and exposure buildup factors (EABF and EBF) were calculated for ferrites such as cobalt ferrite (CoFe2O4), zinc ferrite (ZnFe2O4), nickel ferrite (NiFe2O4) and magnesium ferrite (MgFe2O4) using five parametric geometric progression (G-P fitting) formula in the energy range 0.015-15.00 MeV up to the penetration depth 40 mean free path (mfp). The obtained data of absorption and exposure buildup factors have been studied as a function of incident photon energy and penetration depth. The obtained EABF and EBF data are useful for radiation dosimetry and radiation therapy.
-
Reuter, Simone; Schnekenburger, Michael; Cristofanon, Silvia; Buck, Isabelle; Teiten, Marie-Hélène; Daubeuf, Sandrine; Eifes, Serge; Dicato, Mario; Aggarwal, Bharat B; Visvikis, Athanase; Diederich, Marc
2009-02-01
Gamma-glutamyltransferase (GGT) cleaves the gamma-glutamyl moiety of glutathione (GSH), an endogenous antioxidant, and is involved in mercapturic acid metabolism and in cancer drug resistance when overexpressed. Moreover, GGT converts leukotriene (LT) C4 into LTD4 implicated in various inflammatory pathologies. So far the effect of inflammatory stimuli on regulation of GGT expression and activity remained to be addressed. We found that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) induced GGT promoter transactivation, mRNA and protein synthesis, as well as enzymatic activity. Remicade, a clinically used anti-TNFalpha antibody, small interfering RNA (siRNA) against p50 and p65 nuclear factor-kappaB (NF-kappaB) isoforms, curcumin, a well characterized natural NF-kappaB inhibitor, as well as a dominant negative inhibitor of kappaB alpha (IkappaBalpha), prevented GGT activation at various levels, illustrating the involvement of this signaling pathway in TNFalpha-induced stimulation. Over-expression of receptor of TNFalpha-1 (TNFR1), TNFR-associated factor-2 (TRAF2), TNFR-1 associated death domain (TRADD), dominant negative (DN) IkappaBalpha or NF-kappaB p65 further confirmed GGT promoter activation via NF-kappaB. Linker insertion mutagenesis of 536 bp of the proximal GGT promoter revealed NF-kappaB and Sp1 binding sites at -110 and -78 relative to the transcription start site, responsible for basal GGT transcription. Mutation of the NF-kappaB site located at -110 additionally inhibited TNFalpha-induced promoter induction. Chromatin immunoprecipitation (ChIP) assays confirmed mutagenesis results and further demonstrated that TNFalpha treatment induced in vivo binding of both NF-kappaB and Sp1, explaining increased GGT expression, and led to RNA polymerase II recruitment under inflammatory conditions.
-
Constraints onthe bulk Lorentz factor of gamma-ray burstswith the detection rate by Fermi LAT
NASA Astrophysics Data System (ADS)
Chen, Ye; Liu, Ruo-Yu; Wang, Xiang-Yu
2018-07-01
The bulk Lorentz factor (Γ) of the outflow is an essential parameter for understanding the physics of gamma-ray burst (GRB). Informations about the Lorentz factors of some individual GRBs have been obtained from the spectral features of the high-energy gamma-ray emissions (>100 MeV), assuming that the spectral breaks or cutoffs are due to the pair-production attenuation (i.e. γγ → e+e-). In this paper, we attempt to interpret the dependence of the Large Area Telescope (LAT) detection rate of GRBs on the number of high-energy gamma-rays, taking into account the attenuation effect. We first simulate a long-GRB sample with Monte Carlo method using the luminosity function, rate distribution with redshift, and properties of the GRB spectrum. To characterize the distribution of the Lorentz factors, we assume that the Lorentz factors follow the relation Γ =Γ _0E_{iso, 52}k, where Eiso,52 is the isotropic photon energy in unit of 1052 erg. After taking into account the attenuation effect related with the above Lorentz factor distribution, we are able to reproduce the LAT-detected rate of GRBs as the function of the number of gamma-rays for suitable choice of the values of Γ0 and k. The result suggests that the distribution of the bulk Lorentz factor for the majority of GRBs is in the range of 50-250.
-
Rogers, M B
1996-01-01
The effect of retinoids on malignant cells and embryos indicates that retinoids influence the expression of growth factors or alter the response of cells to growth factors. The bone morphogenetic proteins, Bmp-2 and Bmp-4, are candidates for such growth factors because retinoic acid (RA) treatment of F9 embryonal carcinoma cells induced Bmp-2 mRNA, while simultaneously repressing Bmp-4 levels. Also, recombinant Bmp-2 affected the growth and differentiation of these cells. Regulation of each gene was concentration dependent and required continuous RA treatment. The short half-lives of the Bmp-2 (75 +/- 11 min) and Bmp-4 (70 +/- 4 min) mRNAs suggest that their abundance is primarily controlled at the transcriptional level. To determine which RA receptor (RAR) controls bmp-2 and bmp-4 expression, F9 cells were exposed to various receptor-selective retinoids. RAR alpha- and gamma-selective retinoids induced Bmp-2 and repressed Bmp-4 equally as well as all-trans RA. In contrast, a RAR beta-selective retinoid had little effect on Bmp-2 induction but repressed Bmp-4. A RAR alpha-selective antagonist inhibited all-trans RA stimulation of Bmp-2, although not as dramatically as a RAR beta gamma-selective antagonist. No differences were observed between Bmp levels in all-trans RA and 9-cis RA-treated cells, indicating that the RXRs play little part in controlling these genes. The results are consistent with RAR alpha and gamma-controlled Bmp-2 and Bmp-4 regulation.
-
Synthesis of urease hybrid nanoflowers and their enhanced catalytic properties.
Somturk, Burcu; Yilmaz, Ismail; Altinkaynak, Cevahir; Karatepe, Aslıhan; Özdemir, Nalan; Ocsoy, Ismail
2016-05-01
Increasing numbers of materials have been extensively used as platforms for enzyme immobilization to enhance catalytic activity and stability. Although stability of enzyme was accomplished with immobilization approaches, activity of the most of the enzymes was declined after immobilization. Herein, we synthesize the flower shaped-hybrid nanomaterials called hybrid nanoflower (HNF) consisting of urease enzyme and copper ions (Cu(2+)) and report a mechanistic elucidation of enhancement in both activity and stability of the HNF. We demonstrated how experimental factors influence morphology of the HNF. We proved that the HNF (synthesized from 0.02mgmL(-1) urease in 10mM PBS (pH 7.4) at +4°C) exhibited the highest catalytic activity of ∼2000% and ∼4000% when stored at +4°C and RT, respectively compared to free urease. The highest stability was also achieved by this HNF by maintaining 96.3% and 90.28% of its initial activity within storage of 30 days at +4°C and RT, respectively. This dramatically enhanced activity is attributed to high surface area, nanoscale-entrapped urease and favorable urease conformation of the HNF. The exceptional catalytic activity and stability properties of HNF can be taken advantage of to use it in fields of biomedicine and chemistry. Copyright © 2015 Elsevier Inc. All rights reserved.
-
Dubey, Vikas; Kaur, Jagjeet; Parganiha, Yogita; Suryanarayana, N S; Murthy, K V R
2016-04-01
This paper reports the thermoluminescence properties of Eu(3+) doped different host matrix phosphors (SrY2O4 and Y4Al2O9). The phosphor is prepared by high temperature solid state reaction method. The method is suitable for large scale production and fixed concentration of boric acid using as a flux. The prepared samples were characterized by X-ray diffraction technique and the crystallite size calculated by Scherer's formula. The prepared phosphor characterized by Scanning Electron Microscopic (SEM), Fourier Transform Infrared (FTIR), Energy Dispersive X-ray analysis (EDX), thermoluminescence (TL) and Transmission Electron Microscopic (TEM) techniques. The prepared phosphors for different concentration of Eu(3+) ions were examined by TL glow curve for UV, beta and gamma irradiation. The UV 254nm source used for UV irradiation, Sr(90) source was used for beta irradiation and Co(60) source used for gamma irradiation. SrY2O4:Eu(3+)and Y4Al2O9:Eu(3+) phosphors which shows both higher temperature peaks and lower temperature peaks for UV, beta and gamma irradiation. Here UV irradiated sample shows the formation of shallow trap (surface trapping) and the gamma irradiated sample shows the formation of deep trapping. The estimation of trap formation was evaluated by knowledge of trapping parameters. The trapping parameters such as activation energy, order of kinetics and frequency factor were calculated by peak shape method. Here most of the peak shows second order of kinetics. The effect of gamma, beta and UV exposure on TL studies was also examined and it shows linear response with dose which indicate that the samples may be useful for TL dosimetry. Formation of deep trapping mechanism by UV, beta and gamma irradiated Eu(3+) activated SrY2O4 and Y4Al2O9 phosphors is discussed in this paper. Copyright © 2015 Elsevier Ltd. All rights reserved.
-
Cytoskeletal actin genes function downstream of HNF-3beta in ascidian notochord development.
Jeffery, W R; Ewing, N; Machula, J; Olsen, C L; Swalla, B J
1998-11-01
We have examined the expression and regulation of cytoskeletal actin genes in ascidians with tailed (Molgula oculata) and tailless larvae (Molgula occulta). Four cDNA clones were isolated representing two pairs of orthologous cytoskeletal actin genes (CA1 and CA2), which encode proteins differing by five amino acids in the tailed and tailless species. The CA1 and CA2 genes are present in one or two copies, although several related genes may also be present in both species. Maternal CA1 and CA2 mRNA is present in small oocytes but transcript levels later decline, suggesting a role in early oogenesis. In the tailed species, embryonic CA1 and CA2 mRNAs first appear in the presumptive mesenchyme and muscle cells during gastrulation, subsequently accumulate in the presumptive notochord cells, and can be detected in these tissues through the tadpole stage. CA1 mRNAs accumulate initially in the same tissues in the tailless species but subsequently disappear, in concert with the arrest of notochord and tail development. In contrast, CA2 mRNAs were not detected in embryos of the tailless species. Fertilization of eggs of the tailless species with sperm of the tailed species, which restores the notochord and the tail, also results in the upregulation of CA1 and CA2 gene expression in hybrid embryos. Antisense oligodeoxynucleotide experiments suggest that CA1 and CA2 expression in the notochord, but not in the muscle cells, is dependent on prior expression of Mocc FHI, an ascidian HNF-3beta-like gene. The expression of the CA1 and CA2 genes in the notochord in the tailed species, downregulation in the tailless species, upregulation in interspecific hybrids, and dependence on HNF-3beta activity is consistent with a role of these genes in development of the ascidian notochord.
-
Vercelli, D; Jabara, H H; Lauener, R P; Geha, R S
1990-01-15
The T cell-derived lymphokine IL-4 is essential for the induction of IgE synthesis by human lymphocytes. The IgE-inducing effect of IL-4 is antagonized by IFN-gamma. The secretion of IFN-gamma is vigorously triggered in MLC. Thus, IL-4-stimulated MLC represent a suitable model to characterize the functional antagonism between IL-4 and IFN-gamma. In this report, we show that rIL-4 consistently induced IgE synthesis when added to human primary MLC. IL-4-dependent IgE production required cognate T/B cell recognition, because it was inhibited by antibodies to CD3 and MHC class II (HlA-DR) Ag. A neutralizing anti-IFN-gamma mAb dramatically enhanced IL-4-dependent IgE synthesis by MLC, indicating that endogenous IFN-gamma is a major inhibitor of IgE production. More importantly, addition of rIL-4 markedly inhibited the release of IFN-gamma in supernatants of MLC and Con A-activated PBMC. The decrease in IFN-gamma protein was accompanied by a decreased expression of IFN-gamma mRNA transcripts. The downregulation of IFN-gamma by IL-4 is likely to play an important role in the IL-4-dependent induction of IgE synthesis.
-
Phospholipase C-gamma 1 binding to intracellular receptors for activated protein kinase C.
Disatnik, M H; Hernandez-Sotomayor, S M; Jones, G; Carpenter, G; Mochly-Rosen, D
1994-01-18
Phospholipase C-gamma 1 (PLC-gamma 1; EC 3.1.4.11) hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol and inositol 1,4,5-trisphosphate and is activated in response to growth factor stimulation and tyrosine phosphorylation. Concomitantly, the enzyme translocates from the cytosol to the particulate cell fraction. A similar process of activation-induced translocation from the cytosol to the cell particulate fraction has also been described for protein kinase C (PKC). We have previously shown that activated PKC binds to specific receptor proteins, receptors for activated C kinase, or RACKs, of approximately 30 kDa. Here, we show that PLC-gamma 1 bound to these RACKs and inhibited subsequent PKC binding to RACKs. However, unlike PKC, the binding of PLC-gamma 1 to RACKs did not require phospholipids and calcium. After epidermal growth factor treatment of intact A-431 cells, the binding of PLC-gamma 1 to RACKs increased as compared with PLC-gamma 1 from control cells. This increase in PLC-gamma 1 binding to RACKs was due to the phosphorylation of PLC-gamma 1. Additional data indicated that PLC-gamma 1 binds to RACKs in solution; epidermal growth factor receptor-dependent PLC-gamma 1 phosphorylation and activation decreased in the presence of RACKs. It is possible that, in vivo, PLC-gamma 1 associates with RACKs or with other PLC-gamma 1-specific anchoring proteins in the particulate cell fraction. Since a PKC C2 homologous region is present in PLC-gamma 1, the C2 region may mediate the activation-induced translocation of the enzyme to the cell particulate fraction and the anchoring protein-PLC-gamma 1 complex may be the active translocated form of PLC-gamma 1.
-
Constraints on the bulk Lorentz factor of gamma-ray bursts with the detection rate by Fermi LAT
NASA Astrophysics Data System (ADS)
Chen, Ye; Liu, Ruo-Yu; Wang, Xiang-Yu
2018-05-01
The bulk Lorentz factor(Γ) of the outflow is an essential parameter to understanding the physics of gamma-ray burst (GRB). Informations about the Lorentz factors of some individual GRBs have been obtained from the spectral features of the high-energy gamma-ray emissions (>100 MeV), assuming that the spectral breaks or cutoffs are due to the pair-production attenuation (i.e., γγ → e+e-). In this paper, we attempt to interpret the dependence of the LAT detection rate of GRBs on the number of high-energy gamma-rays, taking into account the attenuation effect. We first simulate a long-GRB sample with Monte Carlo method using the luminosity function, rate distribution with redshift and properties of the GRB spectrum. To characterize the distribution of the Lorentz factors, we assume that the Lorentz factors follow the relation Γ =Γ _0E_iso,52k, where Eiso, 52 is the isotropic photon energy in unit of 1052erg. After taking into account the attenuation effect related with the above Lorentz factor distribution, we are able to reproduce the LAT-detected rate of GRBs as the function of the number of gamma-rays for suitable choice of the values of Γ0 and k. The result suggests that the distribution of the bulk Lorentz factor for the majority of GRBs is in the range of 50 - 250.
-
TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway.
Zheng, Jian; Liu, Xiaobai; Xue, Yixue; Gong, Wei; Ma, Jun; Xi, Zhuo; Que, Zhongyou; Liu, Yunhui
2017-02-20
Circular RNAs are a subgroup of non-coding RNAs and generated by a mammalian genome. Herein, the expression and function of circular RNA circ-TTBK2 were investigated in human glioma cells. Fluorescence in situ hybridization and quantitative real-time PCR were conducted to profile the cell distribution and expression of circ-TTBK2 and microRNA-217 (miR-217) in glioma tissues and cells. Immunohistochemical and western blot were used to determine the expression of HNF1β and Derlin-1 in glioma tissues and cells. Stable knockdown of circ-TTBK2 or overexpression of miR-217 glioma cell lines (U87 and U251) were established to explore the function of circ-TTBK2 and miR-217 in glioma cells. Further, luciferase reports and RNA immunoprecipitation were used to investigate the correlation between circ-TTBK2 and miR-217. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate circ-TTBK2 and miR-217 function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between HNF1β and Derlin-1. We found that circ-TTBK2 was upregulated in glioma tissues and cell lines, while linear TTBK2 was not dysregulated in glioma tissues and cells. Enhanced expression of circ-TTBK2 promoted cell proliferation, migration, and invasion, while inhibited apoptosis. MiR-217 was downregulated in glioma tissues and cell lines. We also found that circ-TTBK2, but not linear TTBK2, acted as miR-217 sponge in a sequence-specific manner. In addition, upregulated circ-TTBK2 decreased miR-217 expression and there was a reciprocal negative feedback between them in an Argonaute2-dependent manner. Moreover, reintroduction of miR-217 significantly reversed circ-TTBK2-mediated promotion of glioma progression. HNF1β was a direct target of miR-217, and played oncogenic role in glioma cells. Remarkably, circ-TTBK2 knockdown combined with miR-217 overexpression led to tumor regression in vivo. These results
-
Fendler, Wojciech; Borowiec, Maciej; Antosik, Karolina; Szadkowska, Agnieszka; Deja, Grazyna; Jarosz-Chobot, Przemyslawa; Mysliwiec, Malgorzata; Wyka, Krystyna; Pietrzak, Iwona; Skupien, Jan; Malecki, Maciej T; Mlynarski, Wojciech
2011-09-01
Confirmation of monogenic diabetes caused by glucokinase mutations (GCK-MODY) allows pharmacogenetic intervention in the form of insulin discontinuation. This is especially important among paediatric and young adult populations where GCK-MODY is most prevalent. The study evaluated the utility of lipid parameters in screening for patients with GCK-MODY. Eighty-nine children with type 1 diabetes and 68 with GCK-MODY were screened for triglyceride (TG), total and HDL cholesterol levels. Standardization against a control group of 171 healthy children was applied to eliminate the effect of development. Clinical applicability and cut-off value were evaluated in all available patients with GCK-MODY (n = 148), hepatocyte nuclear factor 1-alpha-MODY (HNF1A MODY) (n = 37) or type 1 diabetes (n = 221). Lower lipid parameter values were observed in GCK-MODY than in patients with type 1 diabetes. Standard deviation scores were -0·22 ± 2·24 vs 1·31 ± 2·17 for HDL cholesterol (P < 0·001), -0·16 ± 2·14 vs 0·60 ± 1·77 for total cholesterol (P = 0·03) and -0·57 ± 0·97 vs-0·22 ± 0·97 for TG (P = 0·05). Validation analysis confirmed that HDL cholesterol was the best parameter for GCK-MODY selection [sensitivity 87%, specificity 54%, negative predictive value (NPV) 86%, positive PV 56%]. A threshold HDL concentration of 1·56 mm offered significantly better diagnostic efficiency than total cholesterol (cut-off value 4·51 mm; NPV 80%; PPV 38%; P < 0·001). TG did not offer a meaningful cut-off value. HDL cholesterol levels measured in individuals with likely monogenic diabetes may be useful in screening for GCK-MODY and differentiation from T1DM and HNF1A-MODY, regardless of treatment or metabolic control. © 2011 Blackwell Publishing Ltd.
-
Wang, L M; Michieli, P; Lie, W R; Liu, F; Lee, C C; Minty, A; Sun, X J; Levine, A; White, M F; Pierce, J H
1995-12-01
Interleukin-13 (IL-13) induced a potent mitogenic response in IL-3-dependent TF-1 cells and DNA synthesis to a lesser extent in MO7E and FDC-P1 cells. IL-13 stimulation of these lines, like IL-4 and insulin-like growth factor-1 (IGF-1), resulted in tyrosine phosphorylation of a 170-kD substrate. The tyrosine-phosphorylated 170-kD substrate strongly associated with the 85-kD subunit of phosphoinositol-3 (PI-3) kinase and with Grb-2. Anti-4PS serum readily detected the 170-kD substrate in lysates from both TF-1 and FDC-P1 cells stimulated with IL-13 or IL-4. These data provide evidence that IL-13 induces tyrosine phosphorylation of the 4PS substrate, providing an essential interface between the IL-13 receptor and signaling molecules containing SH2 domains. IL-13 and IL-4 stimulation of murine L cell fibroblasts, which endogenously express the IL-4 receptor (IL-4R alpha) and lack expression of the IL-2 receptor gamma subunit (IL-2R gamma), resulted in tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1)/4PS. Enhanced tyrosine phosphorylation of IRS-1/4PS was observed in response to IL-4, but not IL-13 treatment of L cells transfected with the IL-2R gamma chain. These results indicate that IL-13 does not use the IL-2R gamma subunit in its receptor complex and that expression of IL-2R gamma enhances, but is not absolutely required for mediating IL-4-induced tyrosine phosphorylation of IRS-1/4PS.
-
Genetic risk factors for ovarian cancer and their role for endometriosis risk.
Burghaus, Stefanie; Fasching, Peter A; Häberle, Lothar; Rübner, Matthias; Büchner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif B; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias W; Renner, Stefan P
2017-04-01
Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions. In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray™ analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors. rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis. As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer. Copyright © 2017 Elsevier Inc. All rights reserved.
-
Xu, Jinghua; Christian, Barbara; Jump, Donald B.
2009-01-01
Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X(MLX), and hepatic nuclear factor-4α (HNF-4α)are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferator-activated receptor α (PPARα) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNAL-PK but did not suppress hepatic ChREBP or HNF-4α nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNALPK and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4α. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4α-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4α-LPK promoter interaction. Although overexpressed ChREBP or HNF-4α did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNAL-PK abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA
-
NASA Astrophysics Data System (ADS)
Dedes, G.; Pinto, M.; Dauvergne, D.; Freud, N.; Krimmer, J.; Létang, J. M.; Ray, C.; Testa, E.
2014-04-01
Monte Carlo simulations are nowadays essential tools for a wide range of research topics in the field of radiotherapy. They also play an important role in the effort to develop a real-time monitoring system for quality assurance in proton and carbon ion therapy, by means of prompt-gamma detection. The internal theoretical nuclear models of Monte Carlo simulation toolkits are of decisive importance for the accurate description of neutral or charged particle emission, produced by nuclear interactions between beam particles and target nuclei. We assess the performance of Geant4 nuclear models in the context of prompt-gamma emission, comparing them with experimental data from proton and carbon ion beams. As has been shown in the past and further indicated in our study, the prompt-gamma yields are consistently overestimated by Geant4 by a factor of about 100% to 200% over an energy range from 80 to 310 MeV/u for the case of 12C, and to a lesser extent for 160 MeV protons. Furthermore, we focus on the quantum molecular dynamics (QMD) modeling of ion-ion collisions, in order to optimize its description of light nuclei, which are abundant in the human body and mainly anticipated in hadrontherapy applications. The optimization has been performed by benchmarking QMD free parameters with well established nuclear properties. In addition, we study the effect of this optimization on charged particle emission. With the usage of the proposed parameter values, discrepancies reduce to less than 70%, with the highest values being attributed to the nucleon-ion induced prompt-gammas. This conclusion, also confirmed by the disagreement we observe in the case of proton beams, indicates the need for further investigation on nuclear models which describe proton and neutron induced nuclear reactions.
-
The solar gamma ray spectrum between 4 and 8 MeV
NASA Technical Reports Server (NTRS)
Ramaty, R.; Kozlovsky, B.; Suri, A. N.
1976-01-01
The properties of nuclear gamma ray emission in the 4 to 8 MeV range were evaluated. This emission consists of broad and narrow lines resulting from nuclear reactions of energetic H, He, C and O nuclei with ambient matter. Calculations were compared with observations of the 1972, August 4 flare and show that: (1) essentially all the observed radiation in the 4 to 8 MeV region is to the superposition of broad and narrow lines of nuclear origin with almost no contribution from other mechanisms; (2) the accelerated particles in the energy region from about 10 to 100 MeV/amu have a relatively flat Energy spectrum; (3) the calculated gamma ray spectrum, obtained from an isotropic distribution of accelerated particles, fits the observed spectrum better than the spectrum derived from an anisotropic distribution for which the particles' velocity vectors point towards the photosphere; and (4) it is possible to set a stringent upper limit on the ratio of relativistic electrons to protons in flares, consistent with the small, but finite, electron-to-proton ratio in galactic cosmic rays.
-
Gupta, Kanupriya; Ogendi, Brian M. O.; Bakshi, Rakesh K.; Kapil, Richa; Press, Christen G.; Sabbaj, Steffanie; Lee, Jeannette Y.
2017-01-01
ABSTRACT Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and can cause significant reproductive morbidity in women. There is insufficient knowledge of C. trachomatis-specific immune responses in humans, which could be important in guiding vaccine development efforts. In contrast, murine models have clearly demonstrated the essential role of T helper type 1 (Th1) cells, especially interferon gamma (IFN-γ)-producing CD4+ T cells, in protective immunity to chlamydia. To determine the frequency and magnitude of Th1 cytokine responses elicited to C. trachomatis infection in humans, we stimulated peripheral blood mononuclear cells from 90 chlamydia-infected women with C. trachomatis elementary bodies, Pgp3, and major outer membrane protein and measured IFN-γ-, tumor necrosis factor alpha (TNF-α)-, and interleukin-2 (IL-2)-producing CD4+ and CD8+ T-cell responses using intracellular cytokine staining. The majority of chlamydia-infected women elicited CD4+ TNF-α responses, with frequency and magnitude varying significantly depending on the C. trachomatis antigen used. CD4+ IFN-γ and IL-2 responses occurred infrequently, as did production of any of the three cytokines by CD8+ T cells. About one-third of TNF-α-producing CD4+ T cells coproduced IFN-γ or IL-2. In summary, the predominant Th1 cytokine response elicited to C. trachomatis infection in women was a CD4+ TNF-α response, not CD4+ IFN-γ, and a subset of the CD4+ TNF-α-positive cells produced a second Th1 cytokine. PMID:28100498
-
New Fermi-LAT event reconstruction reveals more high-energy gamma rays from gamma-ray bursts
Atwood, W. B.; Baldini, L.; Bregeon, J.; ...
2013-08-19
Here, based on the experience gained during the four and a half years of the mission, the Fermi-LAT Collaboration has undertaken a comprehensive revision of the event-level analysis going under the name of Pass 8. Although it is not yet finalized, we can test the improvements in the new event reconstruction with the special case of the prompt phase of bright gamma-ray bursts (GRBs), where the signal-to-noise ratio is large enough that loose selection cuts are sufficient to identify gamma rays associated with the source. Using the new event reconstruction, we have re-analyzed 10 GRBs previously detected by the Largemore » Area Telescope (LAT) for which an X-ray/optical follow-up was possible and found four new gamma rays with energies greater than 10 GeV in addition to the seven previously known. Among these four is a 27.4 GeV gamma ray from GRB 080916C, which has a redshift of 4.35, thus making it the gamma ray with the highest intrinsic energy (~147 GeV) detected from a GRB. We present here the salient aspects of the new event reconstruction and discuss the scientific implications of these new high-energy gamma rays, such as constraining extragalactic background light models, Lorentz invariance violation tests, the prompt emission mechanism, and the bulk Lorentz factor of the emitting region.« less
-
A search for low energy gamma rays from CG 195+4
NASA Technical Reports Server (NTRS)
Haymes, R. C.; Meegan, C. A.; Fishman, G. J.
1979-01-01
A 13-deg-wide region of sky containing the high-energy gamma-ray source CG 195+4 was searched for X-ray and gamma-ray emission in the energy interval from 0.035 to 8.737 MeV. The balloon-altitude measurements were undertaken on October 4, 1977, at Palestine, Texas, and used an actively collimated scintillation counter. As a result of the measurements, low upper limits have been found for the spectrum from the source. Combined with the positive detections made with satellites at high energies, the measurements show that the photon number spectrum must have a spectral index harder than 2.0. The data appear inconsistent with models of the source in which the presumed neutron star is surrounded by a cloud thick to X-rays. Negative results of the search for periodicity are discussed.
-
Zheng, Shizhong; Chen, Anping
2007-01-01
Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-beta (TGF-beta) and a dramatic reduction in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-gamma in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-gamma activation suppressed gene expression of TGF-beta receptors in activated HSC, leading to the interruption of TGF-beta signaling. This observation supported our assumption of an antagonistic relationship between PPAR-gamma activation and TGF-beta signaling in HSC. In this study, we further hypothesize that TGF-beta signaling might negatively regulate gene expression of PPAR-gamma in activated HSC. The present report demonstrates that exogenous TGF-beta1 inhibits gene expression of PPAR-gamma in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-beta signaling. Transfection assays further indicate that blocking TGF-beta signaling by dominant negative type II TGF-beta receptor increases the promoter activity of PPAR-gamma gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-gamma gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-gamma gene promoter and TGF-beta signaling. Taken together, these results demonstrate that the interruption of TGF
-
Gamma-ray flares from the Crab Nebula.
Abdo, A A; Ackermann, M; Ajello, M; Allafort, A; Baldini, L; Ballet, J; Barbiellini, G; Bastieri, D; Bechtol, K; Bellazzini, R; Berenji, B; Blandford, R D; Bloom, E D; Bonamente, E; Borgland, A W; Bouvier, A; Brandt, T J; Bregeon, J; Brez, A; Brigida, M; Bruel, P; Buehler, R; Buson, S; Caliandro, G A; Cameron, R A; Cannon, A; Caraveo, P A; Casandjian, J M; Çelik, Ö; Charles, E; Chekhtman, A; Cheung, C C; Chiang, J; Ciprini, S; Claus, R; Cohen-Tanugi, J; Costamante, L; Cutini, S; D'Ammando, F; Dermer, C D; de Angelis, A; de Luca, A; de Palma, F; Digel, S W; do Couto e Silva, E; Drell, P S; Drlica-Wagner, A; Dubois, R; Dumora, D; Favuzzi, C; Fegan, S J; Ferrara, E C; Focke, W B; Fortin, P; Frailis, M; Fukazawa, Y; Funk, S; Fusco, P; Gargano, F; Gasparrini, D; Gehrels, N; Germani, S; Giglietto, N; Giordano, F; Giroletti, M; Glanzman, T; Godfrey, G; Grenier, I A; Grondin, M-H; Grove, J E; Guiriec, S; Hadasch, D; Hanabata, Y; Harding, A K; Hayashi, K; Hayashida, M; Hays, E; Horan, D; Itoh, R; Jóhannesson, G; Johnson, A S; Johnson, T J; Khangulyan, D; Kamae, T; Katagiri, H; Kataoka, J; Kerr, M; Knödlseder, J; Kuss, M; Lande, J; Latronico, L; Lee, S-H; Lemoine-Goumard, M; Longo, F; Loparco, F; Lubrano, P; Madejski, G M; Makeev, A; Marelli, M; Mazziotta, M N; McEnery, J E; Michelson, P F; Mitthumsiri, W; Mizuno, T; Moiseev, A A; Monte, C; Monzani, M E; Morselli, A; Moskalenko, I V; Murgia, S; Nakamori, T; Naumann-Godo, M; Nolan, P L; Norris, J P; Nuss, E; Ohsugi, T; Okumura, A; Omodei, N; Ormes, J F; Ozaki, M; Paneque, D; Parent, D; Pelassa, V; Pepe, M; Pesce-Rollins, M; Pierbattista, M; Piron, F; Porter, T A; Rainò, S; Rando, R; Ray, P S; Razzano, M; Reimer, A; Reimer, O; Reposeur, T; Ritz, S; Romani, R W; Sadrozinski, H F-W; Sanchez, D; Saz Parkinson, P M; Scargle, J D; Schalk, T L; Sgrò, C; Siskind, E J; Smith, P D; Spandre, G; Spinelli, P; Strickman, M S; Suson, D J; Takahashi, H; Takahashi, T; Tanaka, T; Thayer, J B; Thompson, D J; Tibaldo, L; Torres, D F; Tosti, G; Tramacere, A; Troja, E; Uchiyama, Y; Vandenbroucke, J; Vasileiou, V; Vianello, G; Vitale, V; Wang, P; Wood, K S; Yang, Z; Ziegler, M
2011-02-11
A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (10(15) electron volts) electrons in a region smaller than 1.4 × 10(-2) parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.
-
Gamma-Ray Flares from the Crab Nebula
NASA Astrophysics Data System (ADS)
Abdo, A. A.; Ackermann, M.; Ajello, M.; Allafort, A.; Baldini, L.; Ballet, J.; Barbiellini, G.; Bastieri, D.; Bechtol, K.; Bellazzini, R.; Berenji, B.; Blandford, R. D.; Bloom, E. D.; Bonamente, E.; Borgland, A. W.; Bouvier, A.; Brandt, T. J.; Bregeon, J.; Brez, A.; Brigida, M.; Bruel, P.; Buehler, R.; Buson, S.; Caliandro, G. A.; Cameron, R. A.; Cannon, A.; Caraveo, P. A.; Casandjian, J. M.; Çelik, Ö.; Charles, E.; Chekhtman, A.; Cheung, C. C.; Chiang, J.; Ciprini, S.; Claus, R.; Cohen-Tanugi, J.; Costamante, L.; Cutini, S.; D'Ammando, F.; Dermer, C. D.; de Angelis, A.; de Luca, A.; de Palma, F.; Digel, S. W.; do Couto e Silva, E.; Drell, P. S.; Drlica-Wagner, A.; Dubois, R.; Dumora, D.; Favuzzi, C.; Fegan, S. J.; Ferrara, E. C.; Focke, W. B.; Fortin, P.; Frailis, M.; Fukazawa, Y.; Funk, S.; Fusco, P.; Gargano, F.; Gasparrini, D.; Gehrels, N.; Germani, S.; Giglietto, N.; Giordano, F.; Giroletti, M.; Glanzman, T.; Godfrey, G.; Grenier, I. A.; Grondin, M.-H.; Grove, J. E.; Guiriec, S.; Hadasch, D.; Hanabata, Y.; Harding, A. K.; Hayashi, K.; Hayashida, M.; Hays, E.; Horan, D.; Itoh, R.; Jóhannesson, G.; Johnson, A. S.; Johnson, T. J.; Khangulyan, D.; Kamae, T.; Katagiri, H.; Kataoka, J.; Kerr, M.; Knödlseder, J.; Kuss, M.; Lande, J.; Latronico, L.; Lee, S.-H.; Lemoine-Goumard, M.; Longo, F.; Loparco, F.; Lubrano, P.; Madejski, G. M.; Makeev, A.; Marelli, M.; Mazziotta, M. N.; McEnery, J. E.; Michelson, P. F.; Mitthumsiri, W.; Mizuno, T.; Moiseev, A. A.; Monte, C.; Monzani, M. E.; Morselli, A.; Moskalenko, I. V.; Murgia, S.; Nakamori, T.; Naumann-Godo, M.; Nolan, P. L.; Norris, J. P.; Nuss, E.; Ohsugi, T.; Okumura, A.; Omodei, N.; Ormes, J. F.; Ozaki, M.; Paneque, D.; Parent, D.; Pelassa, V.; Pepe, M.; Pesce-Rollins, M.; Pierbattista, M.; Piron, F.; Porter, T. A.; Rainò, S.; Rando, R.; Ray, P. S.; Razzano, M.; Reimer, A.; Reimer, O.; Reposeur, T.; Ritz, S.; Romani, R. W.; Sadrozinski, H. F.-W.; Sanchez, D.; Parkinson, P. M. Saz; Scargle, J. D.; Schalk, T. L.; Sgrò, C.; Siskind, E. J.; Smith, P. D.; Spandre, G.; Spinelli, P.; Strickman, M. S.; Suson, D. J.; Takahashi, H.; Takahashi, T.; Tanaka, T.; Thayer, J. B.; Thompson, D. J.; Tibaldo, L.; Torres, D. F.; Tosti, G.; Tramacere, A.; Troja, E.; Uchiyama, Y.; Vandenbroucke, J.; Vasileiou, V.; Vianello, G.; Vitale, V.; Wang, P.; Wood, K. S.; Yang, Z.; Ziegler, M.
2011-02-01
A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (1015 electron volts) electrons in a region smaller than 1.4 × 10-2 parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.
-
Sun, Kai; Montana, Vedrana; Chellappa, Karthikeyani; Brelivet, Yann; Moras, Dino; Maeda, Yutaka; Parpura, Vladimir; Paschal, Bryce M; Sladek, Frances M
2007-06-01
Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4alpha (HNF4alpha). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4alpha and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4alpha (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4alpha as well as decreased endogenous HNF4alpha protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor alpha, retinoid X receptor alpha, and thyroid hormone receptor beta) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor alpha and peroxisome proliferator-activated receptor alpha. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.
-
Resetting the transcription factor network reverses terminal chronic hepatic failure
Nishikawa, Taichiro; Bell, Aaron; Brooks, Jenna M.; Setoyama, Kentaro; Melis, Marta; Han, Bing; Fukumitsu, Ken; Handa, Kan; Tian, Jianmin; Kaestner, Klaus H.; Vodovotz, Yoram; Locker, Joseph; Soto-Gutierrez, Alejandro; Fox, Ira J.
2015-01-01
The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement. PMID:25774505
-
Effect of interferon-gamma on complement gene expression in different cell types.
Lappin, D F; Guc, D; Hill, A; McShane, T; Whaley, K
1992-01-15
We have studied the expression of the complement components C2, C3, factor B, C1 inhibitor (C1-inh), C4-binding protein (C4-bp) and factor H in human peripheral blood monocytes, skin fibroblasts, umbilical vein endothelial cells (HUVEC) and the human hepatoma cell line G2 (Hep G2) in the absence and the presence of interferon-gamma (IFN-gamma). E.l.i.s.a. performed on culture fluids, run-on transcription assays, Northern blot and double-dilution dot-blot techniques confirmed that monocytes expressed all six components, whereas fibroblasts, HUVEC and HepG2 each expressed five of the six components. Fibroblasts and HUVEC did not synthesize C4-bp, and Hep G2 did not produce factor H. In addition to these differences, the synthesis rates of C3, C1-inh and factor H were not the same in all cell types. However, the synthesis rates of C2 and factor B were similar in all four cell types. The half-lives of the mRNAs were shorter in monocytes than in other cell types. Monocyte factor H mRNA had a half-life of 12 min in monocytes, compared with over 3 h in fibroblasts and HUVEC. The instability of factor H mRNA in monocytes may contribute to their low factor H secretion rate. IFN-gamma produced dose-dependent stimulation of C2, factor B, C1-inh, C4-bp and factor H synthesis by all cell types expressing these proteins, but decreased C3 synthesis in all four cell types. Cell-specific differences in the response to IFN-gamma were observed. The increased rates of transcription of the C1-inh and factor H genes in HUVEC were greater than in other cell types, while the increased rate of transcription of the C2, factor B and C1-inh genes in Hep G2 cells was less than in other cell types. IFN-gamma did not affect the stability of C3, factor H or C4 bp mRNAs, but increased the stability of factor B and C1-inh mRNAs and decreased the stability of C2 mRNA. Although these changes occurred in all four cell types studied, the half-life of C1-inh mRNA in monocytes was increased almost 4-fold
-
Gamma-Ray Flares from the Crab Nebula
Abdo, A. A.; Ackermann, M.; Ajello, M.; ...
2010-01-06
A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega–electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta–electron-volt (10more » 15 electron volts) electrons in a region smaller than 1.4 × 10 -2 parsecs. In conclusion, these are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.« less
-
SAX J1808.4$-$3658, an accreting millisecond pulsar shining in gamma rays?
de Oña Wilhelmi, E.; Papitto, A.; Li, J.; ...
2015-12-31
We report the detection of a possible gamma-ray counterpart of the accreting millisec- ond pulsar SAXJ1808.4–3658. The analysis of ~6 years of data from the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (Fermi-LAT) within a re- gion of 15° radius around the position of the pulsar reveals a point gamma-ray source detected at a significance of ~6σ (Test Statistic TS = 32), with position compatible with that of SAXJ1808.4–3658 within 95% Confidence Level. The energy flux in the energy range between 0.6 GeV and 10 GeV amounts to (2.1 ± 0.5) × 10 -12 erg cm -2more » s -1 and the spectrum is well-represented by a power-law function with photon index 2.1±0.1. We searched for significant variation of the flux at the spin frequency of the pulsar and for orbital modulation, taking into account the trials due to the uncertain- ties in the position, the orbital motion of the pulsar and the intrinsic evolution of the pulsar spin. No significant deviation from a constant flux at any time scale was found, preventing a firm identification via time variability. Nonetheless, the association of the LAT source as the gamma-ray counterpart of SAXJ1808.4–3658 would match the emission expected from the millisecond pulsar, if it switches on as a rotation-powered source during X-ray quiescence.« less
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kwon, Deug-Nam; Park, Mi-Ryung; Park, Jong-Yi
Highlights: {yields} The sequences of -604 to -84 bp of the pUPII promoter contained the region of a putative negative cis-regulatory element. {yields} The core promoter was located in the 5F-1. {yields} Transcription factor HNF4 can directly bind in the pUPII core promoter region, which plays a critical role in controlling promoter activity. {yields} These features of the pUPII promoter are fundamental to development of a target-specific vector. -- Abstract: Uroplakin II (UPII) is a one of the integral membrane proteins synthesized as a major differentiation product of mammalian urothelium. UPII gene expression is bladder specific and differentiation dependent, butmore » little is known about its transcription response elements and molecular mechanism. To identify the cis-regulatory elements in the pig UPII (pUPII) gene promoter region, we constructed pUPII 5' upstream region deletion mutants and demonstrated that each of the deletion mutants participates in controlling the expression of the pUPII gene in human bladder carcinoma RT4 cells. We also identified a new core promoter region and putative negative cis-regulatory element within a minimal promoter region. In addition, we showed that hepatocyte nuclear factor 4 (HNF4) can directly bind in the pUPII core promoter (5F-1) region, which plays a critical role in controlling promoter activity. Transient cotransfection experiments showed that HNF4 positively regulates pUPII gene promoter activity. Thus, the binding element and its binding protein, HNF4 transcription factor, may be involved in the mechanism that specifically regulates pUPII gene transcription.« less
-
Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J; Hontecillas, Raquel
2009-01-01
Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) gamma agonist. Hence, we hypothesized that F4/80(hi) and F4/80(lo) ATM differentially express PPAR gamma. This study phenotypically and functionally characterizes F4/80(hi) and F4/80(lo) ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80(lo) and F4/80(hi) ATM by quantitative real-time RT-PCR. We show that while F4/80(lo) macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80(lo) and F4/80(hi) ATM. Moreover, accumulation of F4/80(hi) ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80(hi) ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-alpha, MCP-1, and IL-10 than F4/80(lo) ATM. Gene expression analyses of the sorted populations revealed that only the F4/80(lo) population produced IL-4, whereas the F4/80(hi) ATM expressed greater amounts of PPAR gamma, delta, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR gamma in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR gamma is differentially expressed in F4/80(hi) versus F4/80(low) ATM subsets and its deficiency favors a predominance of M1 markers in WAT.
-
Gamma non-ionizing energy loss: Comparison with the damage factor in silicon devices
NASA Astrophysics Data System (ADS)
El Allam, E.; Inguimbert, C.; Meulenberg, A.; Jorio, A.; Zorkani, I.
2018-03-01
The concept of non-ionizing energy loss (NIEL) has been demonstrated to be a successful approach to describe the displacement damage effects in silicon materials and devices. However, some discrepancies exist in the literature between experimental damage factors and theoretical NIELs. 60Co gamma rays having a low NIEL are an interesting particle source that can be used to validate the NIEL scaling approach. This paper presents different 60Co gamma ray NIEL values for silicon targets. They are compared with the radiation-induced increase in the thermal generation rate of carriers per unit fluence. The differences between the different models, including one using molecular dynamics, are discussed.
-
Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A.
MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation ofmore » miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR
-
Comparison of SensL and Hamamatsu 4×4 channel SiPM arrays in gamma spectrometry with scintillators
NASA Astrophysics Data System (ADS)
Grodzicka-Kobylka, M.; Szczesniak, T.; Moszyński, M.
2017-06-01
The market of Silicon Photomultipliers (SiPMs) consists of many manufacturers that produce their detectors in different technology. Hamamatsu (Japan) and SensL (Ireland) seems to be the most popular companies that produce large SiPM arrays. The aim of this work is characterization and comparison of 4×4 channel SiPM arrays produced by these two producers. Both of the tested SiPMs are made in through-silicon via (TSV) technology, consist of 16, 3×3 mm avalanche photodiode (APD) cells and have fill factor slightly above 60%. The largest difference is a single APD cell size and hence total number of APD cells (55,424 for Hamamatsu, 76,640 for SensL). In the case of SensL SiPM, its spectral response characteristics is shifted slightly toward shorter wavelengths with maximum at 420 nm (450 nm for Hamamatsu). The presented measurements cover selection of the SiPM optimum operating voltage (in respect to energy resolution), verification of the excess noise factor and check of the linearity characteristics. Moreover, the gamma spectrometry with LSO, BGO and CsI:Tl scintillators together with pulse characteristics for these crystals (rise time and fall time) is reported, as well as temperature dependence. The presented measurements show better performance of the SensL array comparing to the Hamamatsu detector.
-
Cortical volume and sex influence visual gamma.
van Pelt, Stan; Shumskaya, Elena; Fries, Pascal
2018-06-05
Visually induced gamma-band activity (GBA) has been implicated in several central cognitive functions, in particular perceptual binding, the feedforward routing of attended stimulus information and memory encoding. Several studies have documented that the strength and frequency of GBA are influenced by both subject-intrinsic factors like age, and subject-extrinsic factors such as stimulus contrast. Here, we investigated the relative contributions of previously tested factors, additional factors, and their interactions, in a cohort of 158 subjects recorded with magnetoencephalography (MEG). In agreement with previous studies, we found that gamma strength and gamma peak frequency increase with stimulus contrast and stimulus velocity. Also in confirmation of previous findings, we report that gamma peak frequency declines with subject age. In addition, we found that gamma peak frequency is higher for subjects with thicker occipital cortex, but lower for larger occipital cortices. Also, gamma peak frequency is higher in female than male subjects. Extrinsic factors (stimulus contrast and velocity) and intrinsic factors (age, cortical thickness and sex) together explained 21% of the variance in gamma peak frequency and 20% of the variance in gamma strength. These results can contribute to our understanding of the mechanisms, by which gamma is generated, and the mechanisms, through which it affects the cognitive performance of a given individual subject. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
-
Calcio-olivine {gamma}-Ca{sub 2}SiO{sub 4}: I. Rietveld refinement of the crystal structure
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gobechiya, E. R., E-mail: elgob@mail.ru; Yamnova, N. A.; Zadov, A. E.
2008-05-15
The structure of the natural mineral calcio-olivine ({gamma}-Ca{sub 2}SiO{sub 4}) found in skarn xenoliths in the region of the Lakargi Mountain (North Caucasus, Kabardino-Balkaria, Russia) is refined by the Rietveld method [a = 5.07389(7) A, b = 11.21128(14) A, c = 6.75340(9) A, V = 384.170(5) A{sup 3}, Z = 4, {rho}{sub calcd} = 2.98 g/cm{sup 3}, space group Pbnm]. The X-ray diffraction pattern of a powdered sample is recorded on a STOE STADI MP diffractometer [{lambda}CuK{sub {alpha}1}; Ge(111) primary monochromator; 6.00{sup o} < 2{theta} < 100.88{sup o}; step width, 2.5{sup o} in 2{theta}; number of reflections, 224]. All calculationsmore » are performed with the WYRIET (version 3.3) software package. The structural model is refined in the anisotropic approximation to R{sub p} = 6.44, R{sub wp} = 8.52, R{sub exp} = 5.85, R{sub B} = 4.98, R{sub F} = 6.90, and s = 1.46. It is shown that the sample under investigation is a mixture of several mineral phases, among which calcio-olivine (the natural analogue of the {gamma}-Ca{sub 2}SiO{sub 4} compound) (83%), hillebrandite (13%), and wadalite (4%) are dominant. Only the scale factors and the unit cell parameters are refined for hillebrandite Ca{sub 2}SiO{sub 3}(OH){sub 2} [a = 3.63472(16) A, b = 16.4140(10) A, c = 11.7914(8) A, space group Cmc2{sub 1}, Z = 6] and wadalite Ca{sub 6}Al{sub 5}Si{sub 2}O{sub 16}Cl{sub 3} (a = 12.0088 A, space group, I 4 bar 3d, Z = 4). The results of the structure refinement of the main component of the sample confirm that the mineral calcio-olivine is isostructural to the synthetic compound {gamma}-Ca{sub 2}SiO{sub 4}. The structure of this compound is formed by the heteropolyhedral framework composed of Ca octahedra joined together into olivine-like ribbons and isolated Si tetrahedra.« less
-
Asher, C; Chigaev, A; Garty, H
2001-09-07
Cell surface expression of the epithelial Na(+) channel ENaC is regulated by the ubiquitin ligase Nedd4. Binding of the WW domains of Nedd4 to the PY region in the carboxy tails of beta and gammaENaC, results in channel ubiquitination and degradation. Kinetic analysis of these interactions has been done using surface plasmon resonance. Synthetic peptides corresponding to the PY regions of beta and gammaENaC were immobilized on a sensor chip and "real-time" kinetics of their binding to recombinant WW proteins was determined. Specificity of the interactions was established by competition experiment, as well as by monitoring effects of a point mutation known to impair Nedd4/ENaC binding. These data provides the first determination of association, dissociation and equilibrium constants for the interactions between WW2 and beta or gammaENaC. Copyright 2001 Academic Press.
-
BC404 scintillators as gamma locators studied via Geant4 simulations
NASA Astrophysics Data System (ADS)
Cortés, M. L.; Hoischen, R.; Eisenhauer, K.; Gerl, J.; Pietralla, N.
2014-05-01
In many applications in industry and academia, an accurate determination of the direction from where gamma rays are emitted is either needed or desirable. Ion-beam therapy treatments, the search for orphan sources, and homeland security applications are examples of fields that can benefit from directional sensitivity to gamma-radiation. Scintillation detectors are a good option for these types of applications as they have relatively low cost, are easy to handle and can be produced in a large range of different sizes. In this work a Geant4 simulation was developed to study the directional sensitivity of different BC404 scintillator geometries and arrangements. The simulation includes all the physical processes relevant for gamma detection in a scintillator. In particular, the creation and propagation of optical photons inside the scintillator was included. A simplified photomultiplier tube model was also simulated. The physical principle exploited is the angular dependence of the shape of the energy spectrum obtained from thin scintillator layers when irradiated from different angles. After an experimental confirmation of the working principle of the device and a check of the simulation, the possibilities and limitations of directional sensitivity to gamma radiation using scintillator layers was tested. For this purpose, point-like sources of typical energies expected in ion-beam therapy were used. Optimal scintillator thicknesses for different energies were determined and the setup efficiencies calculated. The use of arrays of scintillators to reconstruct the direction of incoming gamma rays was also studied. For this case, a spherical source emitting Bremsstrahlung radiation was used together with a setup consisting of scintillator layers. The capability of this setup to identify the center of the extended source was studied together with its angular resolution.
-
Agosti, J M; Coombs, R W; Collier, A C; Paradise, M A; Benedetti, J K; Jaffe, H S; Corey, L
1992-05-01
To determine safety and efficacy of tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-related complex, a randomized, double-blind study was conducted. Twenty-five patients with AIDS-related complex and CD4 lymphocytes less than or equal to 500 x 10(6)/L attended an AIDS Clinical Trials Unit of a tertiary referral center. Patients were administered tumor necrosis factor (TNF) (10 micrograms/m2) or IFN gamma (10 micrograms/m2), or both intramuscularly three times weekly for 16 weeks. Side effects from all three preparations included fever, constitutional symptoms, and local reactions. No significant hematologic, hepatic, renal, or coagulation abnormalities were observed. CD4 lymphocyte counts, beta 2-microglobulin, p24 antigen levels, and anti-p24 antibody did not change significantly during therapy. Similarly, no significant change was noted in rates of HIV isolation from peripheral blood mononuclear cells or plasma. TNF and IFN gamma were tolerable after premedication with acetaminophen; however, no significant change in markers of human immunodeficiency virus infection was demonstrated. These cytokines alone do not appear to be of benefit, nor do they appear to hasten the progression of HIV infection.
-
MODY in Ukraine: genes, clinical phenotypes and treatment.
Globa, Evgenia; Zelinska, Nataliya; Elblova, Lenka; Dusatkova, Petra; Cinek, Ondrej; Lebl, Jan; Colclough, Kevin; Ellard, Sian; Pruhova, Stepanka
2017-10-26
Maturity-onset diabetes of the young (MODY) has not been previously studied in Ukraine. We investigated the genetic etiology in a selected cohort of patients with diabetes diagnosed before 18 years of age, and in their family members. Genetic testing of the most prevalent MODY genes (GCK, HNF1A, HNF4A, HNF1B and INS) was undertaken for 36 families (39 affected individuals) by Sanger or targeted next generation sequencing. A genetic diagnosis of MODY was made in 15/39 affected individuals from 12/36 families (33%). HNF1A and HNF4A MODY were the most common subtypes, accounting for 9/15 of MODY cases. Eight patients with HNF1A or HNF4A MODY and inadequate glycemic control were successfully transferred to sulfonylureas. Median HbA1c decreased from 67 mmol/mol (range 58-69) to 47 mmol/mol (range 43-50) (8.3% [7.5-8.5] to 6.4% [6.1-6.7]) 3 months after transfer (p=0.006). Genetic testing identified pathogenic HNF1A and HNF4A variants as the most common cause of MODY in Ukraine. Transfer to sulfonylureas substantially improved the glycemic control of these patients.
-
Pathophysiologic roles of the fibrinogen gamma chain.
Farrell, David H
2004-05-01
Fibrinogen binds through its gamma chains to cell surface receptors, growth factors, and coagulation factors to perform its key roles in fibrin clot formation, platelet aggregation, and wound healing. However, these binding interactions can also contribute to pathophysiologic processes, including inflammation and thrombosis. This review summarizes the latest findings on the role of the fibrinogen gamma chain in these processes, and illustrates the potential for therapeutic intervention. Novel gamma chain epitopes that bind platelet integrin alpha IIbbeta3 and leukocyte integrin alphaMbeta2 have been characterized, leading to the revision of former dogma regarding the processes of platelet aggregation, clot retraction, inflammation, and thrombosis. A series of studies has shown that the gamma chain serves as a depot for fibroblast growth factor-2 (FGF-2), which is likely to play an important role in wound healing. Inhibition of gamma chain function with the monoclonal antibody 7E9 has been shown to interfere with multiple fibrinogen activities, including factor XIIIa crosslinking, platelet adhesion, and platelet-mediated clot retraction. The role of the enigmatic variant fibrinogen gamma chain has also become clearer. Studies have shown that gamma chain binding to thrombin and factor XIII results in clots that are mechanically stiffer and resistant to fibrinolysis, which may explain the association between gammaA/gamma' fibrinogen levels and cardiovascular disease. The identification of new interactions with gamma chains has revealed novel targets for the treatment of inflammation and thrombosis. In addition, several exciting studies have shown new functions for the variant gamma chain that may contribute to cardiovascular disease.
-
Measurement of the branching fraction of Gamma(4S) --> B0B0.
Aubert, B; Barate, R; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges-Pous, E; Palano, A; Pappagallo, M; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Borgland, A W; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Fritsch, M; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Chevalier, N; Cottingham, W N; Kelly, M P; Cuhadar-Donszelmann, T; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Thiessen, D; Khan, A; Kyberd, P; Teodorescu, L; Blinov, A E; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Ivanchenko, V N; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bondioli, M; Bruinsma, M; Chao, M; Eschrich, I; Kirkby, D; Lankford, A J; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Weinstein, A J R; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; Del Re, D; Hadavand, H K; Hill, E J; MacFarlane, D B; Paar, H P; Rahatlou, Sh; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Lu, A; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Yang, S; Jayatilleke, S; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P; Chen, S; Ford, W T; Nauenberg, U; Olivas, A; Rankin, P; Ruddick, W O; Smith, J G; Ulmer, K A; Zhang, J; Chen, A; Eckhart, E A; Harton, J L; Soffer, A; Toki, W H; Wilson, R J; Zeng, Q; Spaan, B; Altenburg, D; Brandt, T; Brose, J; Dickopp, M; Feltresi, E; Hauke, A; Lacker, H M; Maly, E; Nogowski, R; Otto, S; Petzold, A; Schott, G; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Bernard, D; Bonneaud, G R; Grenier, P; Schrenk, S; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Xie, Y; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Sarti, A; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Patteri, P; Peruzzi, I M; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Bailey, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Won, E; Dubitzky, R S; Langenegger, U; Marks, J; Uwer, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Gaillard, J R; Morton, G W; Nash, J A; Nikolich, M B; Taylor, G P; Charles, M J; Grenier, G J; Mallik, U; Cochran, J; Crawley, H B; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Yi, J; Arnaud, N; Davier, M; Giroux, X; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Petersen, T C; Pierini, M; Plaszczynski, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wormser, G; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Chavez, C A; Coleman, J P; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Parry, R J; Payne, D J; Touramanis, C; Cormack, C M; Di Lodovico, F; Brown, C L; Cowan, G; Flack, R L; Flaecher, H U; Green, M G; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Winter, M A; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Hodgkinson, M C; Lafferty, G D; Naisbit, M T; Williams, J C; Chen, C; Farbin, A; Hulsbergen, W D; Jawahery, A; Kovalskyi, D; Lae, C K; Lillard, V; Roberts, D A; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Kofler, R; Koptchev, V B; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Taylor, F; Yamamoto, R K; Patel, P M; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Taras, P; Nicholson, H; Cavallo, N; De Nardo, G; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Wilden, L; Jessop, C P; Losecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Lu, M; Potter, C T; Sinev, N B; Strom, D; Torrence, E; Colecchia, F; Dorigo, A; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; John, M J J; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Biasini, M; Covarelli, R; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Morganti, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Simi, G; Walsh, J; Haire, M; Judd, D; Paick, K; Wagoner, D E; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Tehrani, F Safai; Voena, C; Christ, S; Schröder, H; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Gopal, G P; Olaiya, E O; Wilson, F F; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Giraud, P-F; Graziani, G; de Monchenault, G Hamel; Kozanecki, W; Legendre, M; London, G W; Mayer, B; Vasseur, G; Yèche, Ch; Zito, M; Purohit, M V; Weidemann, A W; Wilson, J R; Yumiceva, F X; Abe, T; Allen, M; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Claus, R; Convery, M R; Cristinziani, M; Dingfelder, J C; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Fan, S; Field, R C; Glanzman, T; Gowdy, S J; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Mohapatra, A K; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Soha, A; Stelzer, J; Strube, J; Su, D; Sullivan, M K; Thompson, J; Va'vra, J; Wagner, S R; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Ahmed, M; Ahmed, S; Alam, M S; Ernst, J A; Saeed, M A; Saleem, M; Wappler, F R; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Kim, H; Ritchie, J L; Satpathy, A; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Ricca, G Della; Dittongo, S; Grancagnolo, S; Lanceri, L; Poropat, P; Vitale, L; Vuagnin, G; Martinez-Vidal, F; Panvini, R S; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Jackson, P D; Kowalewski, R; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Graham, M; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mellado, B; Mihalyi, A; Pan, Y; Prepost, R; Tan, P; von Wimmersperg-Toeller, J H; Wu, J; Wu, S L; Yu, Z; Greene, M G; Neal, H
2005-07-22
We report the first measurement of the branching fraction f(00) for Gamma(4S) --> B(0)B(0). The data sample consists of 81.7 fb(-1) collected at the Gamma(4S) resonance with the BABAR detector at the SLAC PEP-II asymmetric-energy e(+)e(-) storage ring. Using partial reconstruction of the decay B(0) --> D(*+) l(-)nu(l) in which only the charged lepton and the soft pion from the decay D(*+) --> D(0)pi(+) are reconstructed, we obtain f(00) = 0.487 +/- 0.010(stat) +/- 0.008(syst). Our result does not depend on the branching fractions of B(0) --> D(*+)l(-)nu(l) and D(*+) --> D(0)pi(+) decays, on the ratio of the charged and neutral B meson lifetimes, nor on the assumption of isospin symmetry.
-
Thermally stimulated capacitance in gamma irradiated epitaxial 4H-SiC Schottky barrier diodes
NASA Astrophysics Data System (ADS)
Vigneshwara Raja, P.; Narasimha Murty, N. V. L.
2018-04-01
Deep level defects in 4H-SiC Schottky barrier diodes (SBDs) fabricated on n-type epitaxial 4H-SiC have been identified by thermally stimulated capacitance (TSCAP) spectroscopy prior to and after 60Co-gamma irradiation. The TSCAP measurements on the non-irradiated SBDs reveal two electron traps at Ec-0.63 eV (˜250 K) and Ec-1.13 eV (˜525 K), whereas only one trap at Ec-0.63 eV is identified by conventional thermally stimulated current (TSC) measurements. Hence, TSCAP spectroscopy is more effective in identifying deep level defects in epitaxial 4 H-SiC SBDs as compared to the TSC spectroscopy. Upon exposure to 60Co-gamma rays up to a dose of 100 Mrad, significant changes in the concentration of the traps at Ec-0.63 eV, Ec-1.13 eV, and one new trap at Ec-0.89 eV (˜420 K) are observed. The electrical characteristics of the SBDs are considerably changed after gamma irradiation. The dominant mechanisms responsible for the irradiation induced changes in the SBD electrical characteristics are analyzed by incorporating the trap signatures in the commercial Silvaco® TCAD device simulator. The extracted trap parameters of the irradiated SBDs may be helpful in predicting the survival of 4H-SiC SBD detectors at higher irradiation levels.
-
Paciello, O; Borzacchiello, G; Varricchio, E; Papparella, S
2007-10-01
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. PPAR-gamma is expressed in multiple normal and neoplastic tissues, such as the breast, colon, lung, ovary and placenta. In addition to adipogenic and anti-inflammatory effects, PPAR-gamma activation has been shown to be anti-proliferative by its differentiation-promoting effect, suggesting that activation of PPAR-gamma may be useful in slowing or arresting the proliferation of de-differentiated tumour cells. In this study, we investigated the expression of PPAR-gamma in normal and neoplastic canine nasal epithelium. Twenty-five samples composed of five normal nasal epithelia and 20 canine nasal carcinomas, were immunohistochemically stained for PPAR-gamma. The specificity of the antibody was verified by Western Blot analysis. Confocal laser scanning microscopical investigation was also performed. In normal epithelium, the staining pattern was cytoplasmic and polarized at the cellular free edge. In carcinomas, the neoplastic cells showed mainly strong cytoplasmatic PPAR-gamma expression; moreover, perinuclear immunoreactivity was also detected and few neoplastic cells exhibited a nuclear positivity. Our results demonstrate different patterns of PPAR-gamma expression in normal canine nasal epithelium when compared with canine nasal carcinoma. The importance of this transcription factor in the pathophysiology of several different tumours has stimulated much research in this field and has opened new opportunities for the treatment of the tumours.
-
Gamma spectrometry in the ITWG CMX-4 exercise
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lakosi, L.; Zsigrai, J.; Kocsonya, A.
Low enriched uranium samples of unknown origin were analyzed by 16 laboratories in the context of a Collaborative Materials Exercise (CMX), organized by the Nuclear Forensics International Technical Working Group (ITWG). The purpose was to compare and prioritize nuclear forensic methods and techniques, and to evaluate attribution capabilities among participants. This paper gives a snapshot of the gamma spectrometric capabilities of the participating laboratories and summarizes the results achieved by gamma spectrometry.
-
Gamma spectrometry in the ITWG CMX-4 exercise
Lakosi, L.; Zsigrai, J.; Kocsonya, A.; ...
2018-01-05
Low enriched uranium samples of unknown origin were analyzed by 16 laboratories in the context of a Collaborative Materials Exercise (CMX), organized by the Nuclear Forensics International Technical Working Group (ITWG). The purpose was to compare and prioritize nuclear forensic methods and techniques, and to evaluate attribution capabilities among participants. This paper gives a snapshot of the gamma spectrometric capabilities of the participating laboratories and summarizes the results achieved by gamma spectrometry.
-
Design and Performance of the GAMMA-400 Gamma-Ray Telescope for Dark Matter Searches
NASA Technical Reports Server (NTRS)
Galper, A.M.; Adriani, O.; Aptekar, R. L.; Arkhangelskaja, I. V.; Arkhangelskiy, A.I.; Boezio, M.; Bonvicini, V.; Boyarchuk, K. A.; Fradkin, M. I.; Gusakov, Yu. V.;
2012-01-01
The GAMMA-400 gamma-ray telescope is designed to measure the fluxes of gamma-rays and cosmic-ray electrons + positrons, which can be produced by annihilation or decay of the dark matter particles, as well as to survey the celestial sphere in order to study point and extended sources of gamma-rays, measure energy spectra of Galactic and extragalactic diffuse gamma-ray emission, gamma-ray bursts, and gamma-ray emission from the Sun. GAMMA-400 covers the energy range from 100 MeV to 3000 GeV. Its angular resolution is approx. 0.01 deg (E(sub gamma) > 100 GeV), the energy resolution approx. 1% (E(sub gamma) > 10 GeV), and the proton rejection factor approx 10(exp 6). GAMMA-400 will be installed on the Russian space platform Navigator. The beginning of observations is planned for 2018.
-
Transversal inducing differentiation of human amniotic epithelial cells into hepatocyte-like cells.
Luo, Hongwu; Huang, Xiangjun; Huang, Feizhou; Liu, Xunyang
2011-06-01
To evaluate the in vitro differentiation of human amniotic epithelial cells (hAECs ) into hepatocyte-like cells. Combined approach of dexamethasone, HGF, IGF and other cytokines were used to induce the differentiation of hAECs into hepatocyte-like cells. The induction lasted 2 weeks. During the induction, the expression of albumin ALB, CYP1A1, CYP1A2, IGFR, c-met and key functional genes related to liver cells as well as transcription factors HNF3, HNF4 and C/EBPa were monitored by RT-PCR. Time dependent changes of the surface marker colony ALB, AFP and CK18 were analyzed by cell flow cytometry. After the 2 week induction, the expressions of liver hepatocyte-like cell functional genes such as albumin, CYP1A1, CYP1A2, c-met, and transcription factors such as HNF3, HNF4, C/EBPa and HNF1 were observed. Six days after the induction, hAECs mainly were stained AFP+, and the positive rate was (15.1 ± 2.1)%. While 10 days after the induction, part of the hAECs showed AFP+/ALB+ (6.5 ± 1.4)%; and on 14th day, hAECs only showed ALB+, and the rate was (13.9 ± 2.3)%. ALB+ cell increase indicated a gradual functional maturation from the hAECs to hepatocyte-like cells. Similaritly, the number of CK18+ cells in the whole population was also increased: On 10th day, the rate was (16.1 ± 1.2)%; on 14th day, that was (21.3 ± 4.6)%, which proved the above hypothesis of the trandifferentiation. By extending the induction time, the expression of functional genes increased gradually, and a maturing process of hAECs was detected by cell surface markers. The differentiation of hAECs induced in vitro has the characteristics of hepatocyte-like cells.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sadhasivam, S.; Rajesh, N.P., E-mail: rajeshnp@hotmail.com
2016-02-15
Highlights: • Inorganic NdPO{sub 4} crystal was grown first time using potassium polyphosphate (K{sub 6}P{sub 4}O{sub 13}) flux. • NdPO{sub 4} crystal is insoluble in water, non-hygroscopic and high radiation resistance favoring for actinides host. • Actinide immobilization can be made at 1273 K. • High yield of 1061 nm photon emission. - Abstract: Rare earth orthophosphate (NdPO{sub 4}) monazite single crystals were grown using high temperature flux growth method employing K{sub 6}P{sub 4}O{sub 13} (K{sub 6}) as molten solvent. Their structural parameters were studied using single crystal X-ray diffraction (XRD) method. The grown crystals were examined by SEM andmore » EDX techniques for their homogeniousity and inclusion in the crystals. The influence of gamma irradiation in structural and optical absorption properties were studied by the powder XRD, FTIR and reflectance spectroscopy. The effect of gamma irradiation on luminescence properties was recorded. No significant structural change is observed up to 150 kGy gamma dose. The gamma ray induced charge trap in the crystal was saturated to 40 kGy dose. The luminescence intensity decreases with an increase in the irradiation. The emission of luminescence intensity stabilizes above 40 kGy gamma dose.« less
-
Barbon, Elena; Pignani, Silvia; Branchini, Alessio; Bernardi, Francesco; Pinotti, Mirko; Bovolenta, Matteo
2016-06-24
Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the -94C > G or -61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20-40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.
-
NASA Technical Reports Server (NTRS)
Helgason, Kari; Kashlinsky, Alexander
2012-01-01
Reconstructing the Gamma-Ray Photon Optical Depth of the Universe To Z Approx. 4fFrom Multiwavelength Galaxy Survey Data We reconstruct the gamma-ray opacity of the universe out to z approx. < 3–4 using an extensive library of 342 observed galaxy luminosity function (LF) surveys extending to high redshifts .We cover the whole range from UV to mid-IR (0.15–25 micron ) providing for the first time a robust empirical calculation of the gamma gamma optical depth out to several TeV. Here, we use the same database as Helgason et al. where the extragalactic background light was reconstructed from LFs out to 4.5 micron and was shown to recover observed galaxy counts to high accuracy. We extend our earlier library Of LFs to 25micron such that it covers the energy range of pair production with gamma -rays (1) in the entire Fermi/LAT energy range, and (2) at higher TeV energies probed by ground-based Cherenkov telescopes. In the absence of significant contributions to the cosmic diffuse background from unknown populations, such as the putative Population III era sources, the universe appears to be largely transparent to gamma-rays at all Fermi/LAT energies out to z approx.. 2 whereas it becomes opaque to TeV photons already at z approx. < 0.2 and reaching tau approx 10 at z = 1. Comparing with the currently available Fermi/LAT gamma-ray burst and blazar data shows that there is room for significant emissions originating in the first stars era.
-
Design and performance of the GAMMA-400 gamma-ray telescope for dark matter searches
NASA Astrophysics Data System (ADS)
Galper, A. M.; Adriani, O.; Aptekar, R. L.; Arkhangelskaja, I. V.; Arkhangelskiy, A. I.; Boezio, M.; Bonvicini, V.; Boyarchuk, K. A.; Fradkin, M. I.; Gusakov, Yu. V.; Kaplin, V. A.; Kachanov, V. A.; Kheymits, M. D.; Leonov, A. A.; Longo, F.; Mazets, E. P.; Maestro, P.; Marrocchesi, P.; Mereminskiy, I. A.; Mikhailov, V. V.; Moiseev, A. A.; Mocchiutti, E.; Mori, N.; Moskalenko, I. V.; Naumov, P. Yu.; Papini, P.; Picozza, P.; Rodin, V. G.; Runtso, M. F.; Sparvoli, R.; Spillantini, P.; Suchkov, S. I.; Tavani, M.; Topchiev, N. P.; Vacchi, A.; Vannuccini, E.; Yurkin, Yu. T.; Zampa, N.; Zverev, V. G.; Zirakashvili, V. N.
2013-02-01
The GAMMA-400 gamma-ray telescope is designed to measure the fluxes of gamma-rays and cosmic-ray electrons + positrons, which can be produced by annihilation or decay of the dark matter particles, as well as to survey the celestial sphere in order to study point and extended sources of gamma-rays, measure energy spectra of Galactic and extragalactic diffuse gamma-ray emission, gamma-ray bursts, and gamma-ray emission from the Sun. GAMMA-400 covers the energy range from 100 MeV to 3000 GeV. Its angular resolution is ~0.01° (Eγ > 100 GeV), the energy resolution ~1% (Eγ > 10 GeV), and the proton rejection factor ~106. GAMMA-400 will be installed on the Russian space platform Navigator. The beginning of observations is planned for 2018.
-
Tsukamoto, Yumiko; Uehara, Shoji; Mizoguchi, Chieko; Sato, Atsushi; Horikawa, Keisuke; Takatsu, Kiyoshi
2005-10-21
Mature B-2 cells expressing surface IgM and IgD proliferate upon stimulation by CD38, CD40 or lipopolysaccharide (LPS) and differentiate into IgG1-producing plasma cells in the presence of cytokines. The process of class switch recombination (CSR) from IgM to other isotypes is highly regulated by cytokines and activation-induced cytidine deaminase (AID). Blimp-1 and XBP-1 play an essential role in the terminal differentiation of switched B-2 cells to Ig-producing plasma cells. IL-5 induces AID and Blimp-1 expression in CD38- and CD40-activated B-2 cells, leading to mu to gamma1 CSR at DNA level and IgG1 production. IL-4, a well-known IgG1-inducing factor, does not induce mu to gamma1 CSR in CD38-activated B-2 cells or Blimp-1, while IL-4 induces mu to gamma1 CSR, XBP-1 expression, and IgG1 production expression in CD40-activated B-2 cells. Interestingly, the addition of 8-mercaptoguanosine (8-SGuo) with IL-4 to the culture of CD38-activated B cells can induce mu to gamma1 CSR, Blimp-1 expression, and IgG1 production. Intriguingly, 8-SGuo by itself induces AID expression in CD38-activated B cells. However, it does not induce mu to gamma1 CSR. These results imply that the mode of B-cell activation for extracellular stimulation affects the outcome of cytokine stimulation with respect to the efficiency and direction of CSR, and the requirements of the transcriptional regulator and the generation of antibody-secreting cells. Furthermore, our data suggest the requirement of additional molecules in addition to AID for CSR.
-
Design and Performance of the GAMMA-400 Gamma-Ray Telescope for Dark Matter Searches
NASA Technical Reports Server (NTRS)
Galper, A. M.; Adriani, O.; Aptekar, R. L.; Arkhangelskaja, I. V.; Arkhangelskiy, A. I.; Boezio, M.; Bonvicini, V.; Boyarchuk, K. A.; Fradkin, M. I.; Gusakov, Yu V.;
2012-01-01
The GAMMA-400 gamma-ray telescope is designed to measure the fluxes of gamma-rays and cosmic-ray electrons (+) positrons, which can be produced by annihilation or decay of the dark matter particles, as well as to survey the celestial sphere in order to study point and extended sources of gamma-rays, measure energy spectra of Galactic and extragalactic diffuse gamma-ray emission, gamma-ray bursts, and gamma-ray emission from the Sun. GAMMA-400 covers the energy range from 100 MeV to 3000 GeV. Its angular resolution is approximately 0.01deg (E(sub gamma) greater than 100 GeV), the energy resolution approximately 1% (E(sub gamma) greater than 10 GeV), and the proton rejection factor approximately 10(exp 6). GAMMA-400 will be installed on the Russian space platform Navigator. The beginning of observations is planned for 2018.
-
Involvement of {gamma}-secretase in postnatal angiogenesis
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hayashi, Hiroki; Nakagami, Hironori; Takami, Yoichi
2007-11-23
{gamma}-Secretase cleaves the transmembrane domains of several integral membrane proteins involved in vasculogenesis. Here, we investigated the role of {gamma}-secretase in the regulation of postnatal angiogenesis using {gamma}-secretase inhibitors (GSI). In endothelial cell (EC), {gamma}-secretase activity was up-regulated under hypoxia or the treatment of vascular endothelial growth factor (VEGF). The treatment of GSI significantly attenuated growth factor-induced EC proliferation and migration as well as c-fos promoter activity in a dose-dependent manner. In vascular smooth muscle cell (VSMC), treatment of GSI significantly attenuated growth factor-induced VEGF and fibroblast growth factor-2 (FGF-2) expression. Indeed, GSI attenuated VEGF-induced tube formation and inhibited FGF-2-inducedmore » angiogenesis on matrigel in mice as quantified by FITC-lectin staining of EC. Overall, we demonstrated that {gamma}-secretase may be key molecule in postnatal angiogenesis which may be downstream molecule of growth factor-induced growth and migration in EC, and regulate the expression of angiogenic growth factors in VSMC.« less
-
Kuriyama, Ryoko; Bettencourt-Dias, Monica; Hoffmann, Ingrid; Arnold, Marc; Sandvig, Lisa
2009-06-15
Cancer cells frequently induce aberrant centrosomes, which have been implicated in cancer initiation and progression. Human colorectal cancer cells, HCT116, contain aberrant centrioles composed of disorganized cylindrical microtubules and displaced appendages. These cells also express unique centrosome-related structures associated with a subset of centrosomal components, including gamma-tubulin, centrin and PCM1. During hydroxyurea treatment, these abnormal structures become more abundant and undergo a change in shape from small dots to elongated fibers. Although gamma-tubulin seems to exist as a ring complex, the abnormal structures do not support microtubule nucleation. Several lines of evidence suggest that the fibers correspond to a disorganized form of centriolar microtubules. Plk4, a mammalian homolog of ZYG-1 essential for initiation of centriole biogenesis, is not associated with the gamma-tubulin-specific abnormal centrosomes. The amount of Plk4 at each centrosome was less in cells with abnormal centrosomes than cells without gamma-tubulin-specific abnormal centrosomes. In addition, the formation of abnormal structures was abolished by expression of exogenous Plk4, but not SAS6 and Cep135/Bld10p, which are downstream regulators required for the organization of nine-triplet microtubules. These results suggest that HCT116 cells fail to organize the ninefold symmetry of centrioles due to insufficient Plk4.
-
NASA Astrophysics Data System (ADS)
Kumar, Sandeep; Kaur, Ramanpreet; Singh, Tejbir; Singh, Sukhpal
2018-05-01
The gamma ray buildup factors of Bismuth-Ground granulated blast furnace slag (Bi-GGBFS) concrete in the composition of (0.6 cement + x Bi2O3+ (0.4-x) GGBFS, x = 0.05, 0.10, 0.15, 0.20 and 0.25) has been calculated by using Geometrical Progression formula in the energy region of 0.015-15 MeV as well as up to a penetration depth of 40 mean free paths, and have been studied as a function of incident photon energy. From the obtained results it is found that the fixed penetration depth values of buildup factor are very large in the medium energy region and in the low and high energy regions are low. The investigation was carried out to explore the advantages of the Bismuth-Ground granulated blast furnace slag (Bi-GGBFS) concrete in different radiation shielding applications.
-
Proton and Gamma Radiation Effects in Undoped, Single-doped and co-doped YLiF4 and LuLiF4
NASA Technical Reports Server (NTRS)
Lee, Hyung; Bai, Yingxin; Yu, Kirong; Singh, U.
2009-01-01
Proton and gamma radiation effects in various YLiF4 and LuLiF4 crystals have been investigated. The radiation induced color centers compared with six different kinds of crystal samples in ranges up to 200 krads and 200 MeV. The radiation induced absorption coefficients are strongly dependent on polarization and concentration of rare-earth ions.
-
The effect of alloying on gamma and gamma prime in nickel-base superalloys
NASA Technical Reports Server (NTRS)
Dreshfield, R. L.; Wallace, J. F.
1972-01-01
An investigation was conducted to determine the compositional limits of gamma and gamma prime phases in nickel-base superalloys. Fifty-one nickel-base alloys were melted under vacuum and heat treated for 4 hours at 1190 C followed by 1008 hours at 850 C. The alloys had the following composition ranges: A1 4.0 to 13 atomic percent, Cr 6.5 to 20.5 percent, Ti 0.25 to 4.75 percent, Mo 0.0 to 6.0 percent, and W 0.0 to 4.0 percent. The residues from the ammonium sulfate electrolytic extraction for the two-phase alloys were analyzed chemically and by X-ray diffraction. The results of the investigation were used to assemble a mathematical model of the gamma-gamma prime region of the Ni-Al-Cr-Ti-Mo-W system. A computer program was written to analyze the model of the phase diagram. Some of these results are also presented graphically. The resulting model is capable of satisfactorily predicting the compositions of conjugate gamma-gamma prime phases in the alloys investigated and twelve of fifteen commercial superalloys studied.
-
Day, Yuan-Ji; Huang, Liping; Ye, Hong; Li, Li; Linden, Joel; Okusa, Mark D
2006-03-01
A(2A) adenosine receptor (A(2A)R)-expressing bone marrow (BM)-derived cells contribute to the renal protective effect of A(2A) agonists in renal ischemia-reperfusion injury (IRI). We performed IRI in mice lacking T and B cells to determine whether A(2A)R expressed in CD4+ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A(2A) agonist, did not confer additional protection. IFN-gamma is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN-gamma is produced by kidney cells and T cells we performed IRI in BM chimeras in which the BM of WT mice was reconstituted with BM from IFN-gamma KO mice (IFN-gamma KO-->WT chimera). We observed marked reduction in IRI in comparison to WT-->WT chimeras providing additional indirect support for the role of T cells. To confirm the role of CD4+ A(2A)R in mediating protection from IRI, Rag-1 KO mice were subjected to ischemia-reperfusion. The protection observed in Rag-1 KO mice was reversed in Rag-1 KO mice that were adoptively transferred WT CD4+ cells (WT CD4+-->Rag-1 KO) or A(2A) KO CD4+ cells (A(2A) KO CD4+-->Rag-1 KO). ATL146e reduced injury in WT CD4+-->Rag-1 KO mice but not in A(2A) KO CD4+-->Rag-1 KO mice. Rag-1 KO mice reconstituted with CD4+ cells derived from IFN-gamma KO mice (IFN-gamma CD4+-->Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4+ IFN-gamma contributes to IRI and that A(2A) agonists mediate protection from IRI through action on CD4+ cells.
-
NASA Astrophysics Data System (ADS)
Konno, Chikara; Tada, Kenichi; Kwon, Saerom; Ohta, Masayuki; Sato, Satoshi
2017-09-01
We have studied reasons of differences of KERMA factors and DPA cross-section data among nuclear data libraries. Here the KERMA factors and DPA cross-section data included in the official ACE files of JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 are examined in more detail. As a result, it is newly found out that the KERMA factors and DPA cross-section data of a lot of nuclei are different among JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 and reasons of the differences are the followings: 1) large secondary particle production yield, 2) no secondary gamma data, 3) secondary gamma data in files12-15 mt = 3, 4) mt = 103-107 data without mt = 600 s-800 s data in file6. The issue 1) is considered to be due to nuclear data, while the issues 2)-4) seem to be due to NJOY. The ACE files of JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 with these problems should be revised after correcting wrong nuclear data and NJOY problems.
-
Gillman, Aaron N; Breshears, Laura M; Kistler, Charles K; Finnegan, Patrick M; Torres, Victor J; Schlievert, Patrick M; Peterson, Marnie L
2017-06-28
Staphylococcus aureus ( S. aureus ) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma-toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of S. aureus infections.
-
Simulating Terrestrial Gamma-ray Flashes using SWORD (Invited)
NASA Astrophysics Data System (ADS)
Gwon, C.; Grove, J.; Dwyer, J. R.; Mattson, K.; Polaski, D.; Jackson, L.
2013-12-01
We report on simulations of the relativistic feedback discharges involved with the production of terrestrial gamma-ray flashes (TGFs). The simulations were conducted using Geant4 using the SoftWare for the Optimization of Radiation Detectors (SWORD) framework. SWORD provides a graphical interface for setting up simulations in select high-energy radiation transport engines. Using Geant4, we determine avalanche length, the energy spectrum of the electrons and gamma-rays as they leave the field region, and the feedback factor describing the degree to which the production of energetic particles is self-sustaining. We validate our simulations against previous work in order to determine the reliability of our results. This work is funded by the Office of Naval Research.
-
The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver
DOE Office of Scientific and Technical Information (OSTI.GOV)
Oiso, Hiroshi; Furukawa, Noboru, E-mail: n-furu@gpo.kumamoto-u.ac.jp; Suefuji, Mihoshi
2011-01-07
Research highlights: {yields} A novel class I HDAC inhibitor decreased hepatic PEPCK mRNA and gluconeogenesis. {yields} Inhibition of HDAC decreased PEPCK by reducing HNF4{alpha} expression and FoxO1 activity. {yields} siRNA knockdown of HDAC1 in HepG2 cells reduced the expression of PEPCK and HNF4{alpha}. {yields} Inhibition of class I HDAC improves glucose homeostasis in HFD mice. -- Abstract: Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role ofmore » class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4{alpha} expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4{alpha} protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.« less
-
Characterization of LWRS Hybrid SiC-CMC-Zircaloy-4 Fuel Cladding after Gamma Irradiation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Isabella J van Rooyen
2012-09-01
The purpose of the gamma irradiation tests conducted at the Idaho National Laboratory (INL) was to obtain a better understanding of chemical interactions and potential changes in microstructural properties of a mock-up hybrid nuclear fuel cladding rodlet design (unfueled) in a simulated PWR water environment under irradiation conditions. The hybrid fuel rodlet design is being investigated under the Light Water Reactor Sustainability (LWRS) program for further development and testing of one of the possible advanced LWR nuclear fuel cladding designs. The gamma irradiation tests were performed in preparation for neutron irradiation tests planned for a silicon carbide (SiC) ceramic matrixmore » composite (CMC) zircaloy-4 (Zr-4) hybrid fuel rodlet that may be tested in the INL Advanced Test Reactor (ATR) if the design is selected for further development and testing« less
-
Purushotham, Aparna; Xu, Qing; Lu, Jing; Foley, Julie F.; Yan, Xingjian; Kim, Dong-Hyun; Kemper, Jongsook Kim
2012-01-01
SIRT1, a highly conserved NAD+-dependent protein deacetylase, is a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although SIRT1 has been implicated in a number of hepatic metabolic processes, the mechanisms by which hepatic SIRT1 modulates bile acid metabolism are still not well understood. Here we report that deletion of hepatic SIRT1 reduces the expression of farnesoid X receptor (FXR), a nuclear receptor that regulates bile acid homeostasis. We provide evidence that SIRT1 regulates the expression of FXR through hepatocyte nuclear factor 1α (HNF1α). SIRT1 deficiency in hepatocytes leads to decreased binding of HNF1α to the FXR promoter. Furthermore, we show that hepatocyte-specific deletion of SIRT1 leads to derangements in bile acid metabolism, predisposing the mice to development of cholesterol gallstones on a lithogenic diet. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of hepatic bile acid homeostasis through the HNF1α/FXR signaling pathway. PMID:22290433
-
SU-F-T-294: The Analysis of Gamma Criteria for Delta4 Dosimetry Using Statistical Process Control
DOE Office of Scientific and Technical Information (OSTI.GOV)
Cho, S; Ahn, S; Kim, J
Purpose: To evaluate the sensitivity of gamma criteria for patient-specific volumetric modulated arc therapy(VMAT) quality assurance of the Delta{sup 4} dosimetry program using the statistical process control(SPC) methodology. Methods: The authors selected 20 patient-specific VMAT QA cases which were undertaken MapCHECK and ArcCHECK with gamma pass rate better than 97%. The QAs data were collected Delta4 Phantom+ and Elekta Agility six megavolts without using an angle incrementer. The gamma index(GI) were calculated in 2D planes with normalizing deviation to local dose(local gamma). The sensitivity of the GI methodology using criterion of 3%/3mm, 3%/2mm and 2%/3mm was analyzed with using processmore » acceptability indices. We used local confidence(LC) level, the upper control limit(UCL) and lower control limit(LCL) of I-MR chart for process capability index(Cp) and a process acceptability index (Cpk). Results: The lower local confidence levels of 3%/3mm, 3%/2mm and 2%/3mm were 92.0%, 83.6% and 78.8% respectively. All of the calculated Cp and Cpk values that used LC level were under 1.0 in this study. The calculated LCLs of I-MR charts were 89.5%, 79.0% and 70.5% respectively. These values were higher than 1.0 which means good quality of QA. For the generally used lower limit of 90%, we acquired over 1.3 of Cp value for the gamma index of 3%/3mm and lower than 1.0 in the rest of GI. Conclusion: We applied SPC methodology to evaluate the sensitivity of gamma criteria and could see the lower control limits of VMAT QA for the Delta 4 dosimetry and could see that Delta 4 phantom+ dosimetry more affected by the position error and the I-MR chart derived values are more suitable for establishing lower limits. Acknowledgement: This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (No. 2015R1D1A1A01060463)« less
-
Baicalin benefits the anti-HBV therapy via inhibiting HBV viral RNAs
DOE Office of Scientific and Technical Information (OSTI.GOV)
Huang, Hai, E-mail: HHai3552@sina.cn
Background: Although current antiviral treatments (nucleoside analogs, NAs) for chronic hepatitis B virus (HBV) infection are effective in suppressing HBV-DNA replication, their clinical outcomes can be compromised by the increasing drug resistance and the inefficiency in promoting HBsAg/HBeAg seroconversion. Objectives: In this study, we will explore possible effects and mechanism of a natural product baicalin (BA) with the anti-HBV efficacy of entecavir (ETV), a first-line anti-HBV drug, in HBV-DNA, HBsAg/HBeAg seroconversion and drug-resistance. Methods: The co-effects of BA and ETV were conducted in wild-type/NA-resistance mutant HBV cell lines and DHBV-infected duckling models. HBV-DNA/RNAs, HBsAg/HBeAg, host factors (hepatocyte nuclear factors) weremore » explored for possible anti-HBV mechanism. Results and discussion: BA could significantly enhance and reduced HBsAg and HBeAg in hepG2.2.15, a wild-type HBV cell line. Co-treatment of BA and ETV had a more dramatic effect in NA-resistant HBV{sup rtM204V/rtLl80M} transfected hepG2 cells. Our study further revealed that BA mainly inhibited the production of HBV RNAs (3.5, 2.4, 2.1 kb), the templates for viral proteins and HBV-DNA synthesis. BA blocked HBV RNAs transcription possibly by down-regulating transcription and expression of HBV replication dependent hepatocyte nuclear factors (HNF1α and HNF4α). Thus, BA may benefit the anti-HBV therapy via inhibiting HBV viral RNAs. - Highlights: • Baicalin benefits the anti-HBV therapy. • Baicalin enhances ETV antiviral efficacy and overcomes NA-resistant HBV mutation. • The anti-HBV effect of baicalin is achieved by inhibiting HBV RNAs. • Baicalin down-regulates HBV replication-dependent host factors HNF 1α and HNF 4α.« less
-
Wajih, Nadeem; Owen, John; Wallin, Reidar
2008-01-01
Recombinant members of the vitamin K-dependent protein family (factors IX and VII and protein C) have become important pharmaceuticals in treatment of bleeding disorders and sepsis. However, because the in vivo gamma-carboxylation system in stable cell lines used for transfection has a limited capacity of post translational gamma-carboxylation, the recovery of fully gamma-carboxylated and functional proteins is low. In this work we have engineered recombinant factor VII producing HEK 293 cells to stably overexpress VKORC1, the reduced vitamin K gamma-carboxylase cofactor and in addition stably silenced the gamma-carboxylase inhibitory protein calumenin. Stable cell lines transfected with only a factor VII cDNA had a 9% production of functional recombinant factor VII. On the other hand, these recombinant factor VII producing cells when engineered to overexpress VKORC1 and having calumenin stably suppressed more than 80% by shRNA expression, produced 68% functional factor VII. The technology presented should be applicable to all vertebrae members of the vitamin K-dependent protein family and should lower the production cost of the clinically used factors VII, IX and protein C.
-
The Andromeda galaxy in gamma-rays
NASA Technical Reports Server (NTRS)
Oezel, M. E.; Berkhuijsen, E. M.
1987-01-01
Implications of high-energy gamma-ray observations of the Andromeda galaxy with the next generation of satellites Gamma-1 and GRO are discussed in the context of the origin of cosmic rays and gamma-ray processes. The present estimate of the total gamma-ray flux of this galaxy at energies above 100 MeV is a factor of about three less than previous estimates.
-
Bonner, Caroline; Bacon, Siobhán; Concannon, Caoimhín G.; Rizvi, Syed R.; Baquié, Mathurin; Farrelly, Angela M.; Kilbride, Seán M.; Dussmann, Heiko; Ward, Manus W.; Boulanger, Chantal M.; Wollheim, Claes B.; Graf, Rolf; Byrne, Maria M.; Prehn, Jochen H.M.
2010-01-01
OBJECTIVE In diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A–maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells. RESEARCH DESIGN AND METHODS DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay. RESULTS We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A–induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A–expressing cells, but not DN-HNF1A–expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V–positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A–induced cells by stimulating cell proliferation and increasing insulin gene expression. CONCLUSIONS Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY. PMID:20682686
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sirunyan, A. M.; Tumasyan, A.; Adam, W.
Here, measurements are presented ofmore » $$ \\mathrm{ W \\gamma\\gamma } $$ and $$ \\mathrm{ Z \\gamma\\gamma } $$ production in proton-proton collisions. Fiducial cross sections are reported based on a data sample corresponding to an integrated luminosity of 19.4 fb$$^{-1}$$ collected with the CMS detector at a center-of-mass energy of 8 TeV. Signal is identified through the $$\\mathrm{ W } \\to \\ell\
-
Sirunyan, A. M.; Tumasyan, A.; Adam, W.; ...
2017-10-11
Here, measurements are presented ofmore » $$ \\mathrm{ W \\gamma\\gamma } $$ and $$ \\mathrm{ Z \\gamma\\gamma } $$ production in proton-proton collisions. Fiducial cross sections are reported based on a data sample corresponding to an integrated luminosity of 19.4 fb$$^{-1}$$ collected with the CMS detector at a center-of-mass energy of 8 TeV. Signal is identified through the $$\\mathrm{ W } \\to \\ell\
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Yamamoto, Keiko; Ninomiya, Yuichi; Iseki, Mioko
2008-03-14
(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and antidiabetic agent as has been previously reported. As PPAR{gamma} agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice whenmore » compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.« less
-
Rosowsky, A; Bader, H; Freisheim, J H
1991-01-01
Analogues of methotrexate (MTX) and aminopterin (AMT) modified at the gamma-position of the glutamate side chain were synthesized and evaluated as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. Condesations of 4-amino-4-deoxy-N10-methylpteroic acid (mAPA) with dimethyl DL-4-methyleneglutamate in the presence of diethyl phosphorocyanidate (DEPC) followed by alkaline hydrolysis yielded N-(4-amino-4-deoxy-N10-methylpteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneMTX). Condensation of 4-amino-4-deoxy-N10-formylpteroic acid (fAPA) with dimethyl-DL-4-methyleneglutamate by the mixed carboxylic-carbonic anhydride method yielded N-4-amino-4-deoxypteroyl)-DL-4-methyleneglutamic acid (gamma-methyleneAMT). Also prepared via DEPC coupling was a mixture of the four possible diastereomers of N-(4-amino-4-deoxy-N10-methylpteroyl)-4-cyanoglutamic acid (gamma-cyanoMTX). The requisite intermediate gamma-tert-butyl alpha-methyl 4-cyanoglutamate, as a DL-threo/DL-erythro mixture, was prepared from methyl N alpha-Boc-O-tosyl-L-serinate by reaction with sodium tert-butyl cyanoacetate followed by mild trifluoroacetic treatment to selectively remove the Boc group. The gamma-methylene derivatives of MTX and AMT are attractive because of their potential to act as Michael acceptors within the DHFR active site. gamma-CyanoMTX may be viewed as a congener of the nonpolyglutamated MTX analogue gamma-fluoroMTX. In vitro bioassay data for the gamma-methylene and gamma-cyano compounds support the idea that the active site of DHFR, already known for its ability to tolerate modification of the gamma-carboxyl group of MTX and AMT, can likewise accommodate substitution on the gamma-carbon itself.
-
Influence of gamma-radiation on the nutritional and functional qualities of lotus seed flour.
Bhat, Rajeev; Sridhar, Kandikere Ramaiah; Karim, Alias A; Young, Chiu C; Arun, Ananthapadmanabha B
2009-10-28
In the present study, we investigated the physicochemical and functional properties of lotus seed flour exposed to low and high doses of gamma-radiation (0-30 kGy; the dose recommended for quarantine and hygienic purposes). The results indicated raw seed flour to be rich in nutrients with minimal quantities of antinutritional factors. Irradiation resulted in a dose-dependent increase in some of the proximal constituents. The raw and gamma-irradiated seeds meet the Food and Agricultural Organization-World Health Organization recommended pattern of essential amino acids. Some of the antinutritional factors (phytic acid, total phenolics, and tannins) were lowered with gamma-irradiation, while the seed flours were devoid of lectins, L-3,4-dihydroxyphenylalanine, and polonium-210. The functional properties of the seed flour were significantly improved with gamma-radiation. gamma-radiation selectively preserved or improved the desired nutritional and functional traits of lotus seeds, thus ensuring a safe production of appropriate nutraceutically valued products.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ahdjoudj, S.; Kaabeche, K.; Holy, X.
2005-02-01
The molecular mechanisms regulating the adipogenic differentiation of bone marrow stromal cells in vivo remain largely unknown. In this study, we investigated the regulatory effects of transforming growth factor beta-2 (TGF-{beta}2) on transcription factors involved in adipogenic differentiation induced by hind limb suspension in rat bone marrow stromal cells in vivo. Time course real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis of gene expression showed that skeletal unloading progressively increases the expression of CCAAT/enhancer-binding protein (C/EBP){alpha} and C/EBP{beta} {alpha} at 5 days in bone marrow stromal cells resulting in increased peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}2) transcripts at 7 days. TGF-{beta}2more » administration in unloaded rats corrected the rise in C/EBP{alpha} and C/EBP{beta} transcripts induced by unloading in bone marrow stromal cells. This resulted in inhibition of PPAR{gamma}2 expression that was associated with increased Runx2 expression. Additionally, the inhibition of C/EBP{alpha} and C/EBP{beta} expression by TGF-{beta}2 was associated with increased PPAR{gamma} serine phosphorylation in bone marrow stromal cells, a mechanism that inhibits PPAR{gamma} transactivating activity. The sequential inhibitory effect of TGF-{beta}2 on C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma}2 resulted in reduced LPL expression and abolition of bone marrow stromal cell adipogenic differentiation, which contributed to prevent bone loss induced by skeletal unloading. We conclude that TGF-{beta}2 inhibits the excessive adipogenic differentiation of bone marrow stromal cells induced by skeletal unloading by inhibiting C/EBP{alpha}, C/EBP{beta}, and PPAR{gamma} expression and activity, which provides a sequential mechanism by which TGF-{beta}2 regulates adipogenic differentiation of bone marrow stromal cells in vivo.« less
-
Régis, Jean; Tamura, Manabu; Guillot, Cécile; Yomo, Shoji; Muraciolle, Xavier; Nagaje, Mariko; Arka, Yasser; Porcheron, Denis
2009-02-01
The world's first Leksell Gamma Knife PerfeXion (Elekta Instrument AB, Stockholm, Sweden) for radiosurgery of the head and neck became operational at Timone University Hospital in Marseille on July 10, 2006. To allow strict evaluation of the capabilities, advantages, disadvantages, and limitations of this new technology, patients were enrolled in a prospective, randomized trial. In 66 working days, between July 10 and December 20, 2006, 363 patients were treated by gamma knife surgery at Timone University Hospital, Marseille. Of these patients, 200 were eligible for the comparative prospective study (inclusion criteria were informed consent obtained, tumor or vascular indication, and no previous radiosurgery or radiotherapy). In accordance with the blinded randomization process, 100 patients were treated with the Leksell Gamma Knife 4C (Elekta Instrument AB) and Gamma Knife 100 (Elekta Instrument AB) with the Leksell Gamma Knife PerfeXion. Dose planning parameters, dosimetry measurements on the patient's body, workflow, patient comfort, quality assurance procedure, and a series of other treatment-related parameters were systematically and prospectively evaluated in both arms of the trial. No technical failure of the treatment procedure was encountered. The new dose-planning system led to the use of composite shots in 39.4% of the patients. The median number of different collimator sizes used was larger with the PerfeXion than with the 4C (2 and 1, respectively). The mean number of isocenters used was lower (10.67 and 13.08, respectively). The median total treatment time was significantly shorter with the PerfeXion (40 and 60 minutes, respectively), but there was no significant difference in the median radiation time (34.02 and 33.40 minutes, respectively). The procedure was performed using only a single run in 98.99% of the PerfeXion cases and in 42% of the 4C cases. Collision risk on the 4C forced us to change the frame gamma angle for at least 1 shot in 24% of
-
Effect of gamma-ray irradiation on the device process-induced defects in 4H-SiC epilayers
NASA Astrophysics Data System (ADS)
Miyazaki, T.; Makino, T.; Takeyama, A.; Onoda, S.; Ohshima, T.; Tanaka, Y.; Kandori, M.; Yoshie, T.; Hijikata, Y.
2016-11-01
We investigated the gamma-ray irradiation effect on 4H-SiC device process-induced defects by photoluminescence (PL) imaging and deep level transient spectroscopy (DLTS). We found that basal plane dislocations (BPDs) that were present before the irradiation were eliminated by gamma-ray irradiation of 1 MGy. The reduction mechanism of BPD was discussed in terms of BPD-threading edge dislocation (TED) transformation and shrinkage of stacking faults. In addition, the entire PL image was gradually darkened with increasing absorbed dose, which is presumably due to the point defects generated by gamma-ray irradiation. We obtained DLTS peaks that could be assigned to complex defects, termed RD series, and found that the peaks increased with absorbed dose.
-
Kumar, Ramadhar; Balaji, S; Uma, T S; Sehgal, P K
2009-12-10
Momordica charantia fruit is a widely used traditional medicinal herb as, anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor. The present study is undertaken to investigate the possible mode of action of fruit extracts derived from Momordica charantia (MC) and study its pharmacological effects for controlling diabetic mellitus. Effects of aqueous and chloroform extracts of Momordica charantia fruit on glucose uptake and up-regulation of glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPAR gamma) and phosphatidylinositol-3 kinase (PI3K), were investigated to show its efficacy as a hypoglycaemic agent. Dose dependent glucose uptake assay was performed on L6 myotubes using 2-deoxy-D-[1-(3)H] glucose. Up-regulatory effects of the extracts on the mRNA expression level of Glut-4, PPAR gamma and PI3K have been studied. The association of Momordica charantia with the aqueous and chloroform extracts of Momordica charantia fruit at 6 microg/ml has shown significant up-regulatory effect, respectively, by 3.6-, 2.8- and 3.8-fold on the battery of targets Glut-4, PPAR gamma and PI3K involved in glucose transport. The up-regulation of glucose uptake was comparable with insulin and rosiglitazone which was approximately 2-fold over the control. Moreover, the inhibitory effect of the cyclohexamide on Momordica charantia fruit extract mediated glucose uptake suggested the requirement of new protein synthesis for the enhanced glucose uptake. This study demonstrated the significance of Glut-4, PPAR gamma and PI3K up-regulation by Momordica charantia in augmenting the glucose uptake and homeostasis.
-
2006-09-01
The aim of the two parts of the experiment was identical: To explore concepts and supporting tools for Effects Based Approach to Operations (EBAO...feedback on the PMESII factors over time and the degree of achievement of the Operational Endstate. Modelling & Simulation Support to the Effects ...specific situation depends also on his interests. GAMMA provides two different methods: 1. The importance for different PMESII factors (ie potential
-
Gamma ray energy tracking in GRETINA
NASA Astrophysics Data System (ADS)
Lee, I. Y.
2011-10-01
The next generation of stable and exotic beam accelerators will provide physics opportunities to study nuclei farther away from the line of stability. However, these experiments will be more demanding on instrumentation performance. These come from the lower production rate for more exotic beams, worse beam impurities, and large beam velocity from the fragmentation and inverse reactions. Gamma-ray spectroscopy will be one of the most effective tools to study exotic nuclei. However, to fully exploit the physics reach provided by these new facilities, better gamma-ray detector will be needed. In the last 10 years, a new concept, gamma-ray energy tracking array, was developed. Tracking arrays will increase the detection sensitivity by factors of several hundred compared to current arrays used in nuclear physics research. Particularly, the capability of reconstructing the position of the interaction with millimeters resolution is needed to correct the Doppler broadening of gamma rays emitted from high velocity nuclei. GRETINA is a gamma-ray tracking array which uses 28 Ge crystals, each with 36 segments, to cover ¼ of the 4 π of the 4 π solid angle. The gamma ray tracking technique requires detailed pulse shape information from each of the segments. These pulses are digitized using 14-bit 100 MHz flash ADCs, and digital signal analysis algorithms implemented in the on-board FPGAs provides energy, time and selection of pulse traces. A digital trigger system, provided flexible trigger functions including a fast trigger output, and also allows complicated trigger decisions to be made up to 20 microseconds. Further analyzed, carried out in a computer cluster, determine the energy, time, and three-dimensional positions of all gamma-ray interactions in the array. This information is then utilized, together with the characteristics of Compton scattering and pair-production processes, to track the scattering sequences of the gamma rays. GRETINA construction is completed in
-
COMPTEL gamma-ray observations of the C4 solar flare on 20 January 2000
NASA Astrophysics Data System (ADS)
Young, C. A.; Arndt, M. B.; Bennett, K.; Connors, A.; Debrunner, H.; Diehl, R.; McConnell, M.; Miller, R. S.; Rank, G.; Ryan, J. M.; Schoenfelder, V.; Winkler, C.
2001-10-01
The ``Pre-SMM'' (Vestrand and Miller 1998) picture of gamma-ray line (GRL) flares was that they are relatively rare events. This picture was quickly put in question with the launch of the Solar Maximum Mission (SMM). Over 100 GRL flares were seen with sizes ranging from very large GOES class events (X12) down to moderately small events (M2). It was argued by some (Bai 1986) that this was still consistent with the idea that GRL events are rare. Others, however, argued the opposite (Vestrand 1988; Cliver, Crosby and Dennis 1994), stating that the lower end of this distribution was just a function of SMM's sensitivity. They stated that the launch of the Compton Gamma-ray Observatory (CGRO) would in fact continue this distribution to show even smaller GRL flares. In response to a BACODINE cosmic gamma-ray burst alert, COMPtonTELescope on the CGRO recorded gamma rays above 1 MeV from the C4 flare at 0221 UT 20 January 2000. This event, though at the limits of COMPTEL's sensitivity, clearly shows a nuclear line excess above the continuum. Using new spectroscopy techniques we were able to resolve individual lines. This has allowed us to make a basic comparison of this event with the GRL flare distribution from SMM and also compare this flare with a well-observed large GRL flare seen by OSSE. .
-
Designing a new type of neutron detector for neutron and gamma-ray discrimination via GEANT4.
Shan, Qing; Chu, Shengnan; Ling, Yongsheng; Cai, Pingkun; Jia, Wenbao
2016-04-01
Design of a new type of neutron detector, consisting of a fast neutron converter, plastic scintillator, and Cherenkov detector, to discriminate 14-MeV fast neutrons and gamma rays in a pulsed n-γ mixed field and monitor their neutron fluxes is reported in this study. Both neutrons and gamma rays can produce fluorescence in the scintillator when they are incident on the detector. However, only the secondary charged particles of the gamma rays can produce Cherenkov light in the Cherenkov detector. The neutron and gamma-ray fluxes can be calculated by measuring the fluorescence and Cherenkov light. The GEANT4 Monte Carlo simulation toolkit is used to simulate the whole process occurring in the detector, whose optimum parameters are known. Analysis of the simulation results leads to a calculation method of neutron flux. This method is verified by calculating the neutron fluxes using pulsed n-γ mixed fields with different n/γ ratios, and the results show that the relative errors of all calculations are <5%. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
Human Cells as Platform to Produce Gamma-Carboxylated Proteins.
de Sousa Bomfim, Aline; de Freitas, Marcela Cristina Corrêa; Covas, Dimas Tadeu; de Sousa Russo, Elisa Maria
2018-01-01
The gamma-carboxylated proteins belong to a family of proteins that depend on vitamin K for normal biosynthesis. The major representative gamma-carboxylated proteins are the coagulation system proteins, for example, factor VII, factor IX, factor X, prothrombin, and proteins C, S, and Z. These molecules have harbored posttranslational modifications, such as glycosylation and gamma-carboxylation, and for this reason they need to be produced in mammalian cell lines. Human cells lines have emerged as the most promising alternative to the production of gamma-carboxylated proteins. In this chapter, the methods to generate human cells as a platform to produce gamma-carboxylated proteins, for example the coagulation factors VII and IX, are presented. From the cell line modification up to the vitamin K adaptation of the produced cells is described in the protocols presented in this chapter.
-
NASA Astrophysics Data System (ADS)
Rujiwarodom, Rachanee
2010-05-01
To study the Equilibrium between radon-222 and its daughters in Bangkok atmosphere by Gamma-ray spectrometry, air sample were collected on 48 activated charcoal canister and 360 glass fiber filters by using a high volume jet-air sampler during December 2007 to November 2008.The Spectra of gamma-ray were measured by using a HPGe (Hyper Pure Germanium Detector). In the condition of secular equilibrium obtaining between Radon-222 and its decay products, radon-222 on activated charcoal canister and its daughters on glass fiber filters collected in the same time interval were calculated. The equilibrium factor (F) in the open air had a value of 0.38 at the minimum ,and 0.75 at the maximum. The average value of equilibrium factor (F) was 0.56±0.12. Based on the results, F had variations with a maximum value in the night to the early morning and decreased in the afternoon. In addition, F was higher in the winter than in the summer. This finding corresponds with the properties of the Earth atmosphere. The equilibrium factor (F) also depended on the concentration of dust in the atmosphere. People living in Bangkok were exposed to average value of 30 Bq/m3 of Radon-222 in the atmosphere. The equilibrium factor (0.56±0.12) and the average value of Radon-222 showed that people were exposed to alpha energy from radon-222 and its daughters decay at 0.005 WL(Working Level) which is lower than the safety standard at 0.02 WL. Keywords: Radon, Radon daughters , equilibrium factor, Gamma -ray spectrum analysis ,Bangkok ,Thailand
-
The 4U 0115+63: Another energetic gamma ray binary pulsar
NASA Technical Reports Server (NTRS)
Chadwick, P. M.; Dipper, N. A.; Dowthwaite, J. C.; Kirkman, I. W.; Mccomb, T. J. L.; Orford, K. J.; Turver, K. E.
1985-01-01
Following the discovery of Her X-1 as a source of pulsed 1000 Gev X-rays, a search for emission from an X-ray binary containing a pulsar with similar values of period, period derivative and luminosity was successful. The sporadic X-ray binary 4U 0115-63 has been observed, with probability 2.5 x 10 to the minus 6 power ergs/s to emit 1000 GeV gamma-rays with a time averaged energy flux of 6 to 10 to the 35th power.
-
SU-G-IeP4-12: Performance of In-111 Coincident Gamma-Ray Counting: A Monte Carlo Simulation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pahlka, R; Kappadath, S; Mawlawi, O
2016-06-15
Purpose: The decay of In-111 results in a non-isotropic gamma-ray cascade, which is normally imaged using a gamma camera. Creating images with a gamma camera using coincident gamma-rays from In-111 has not been previously studied. Our objective was to explore the feasibility of imaging this cascade as coincidence events and to determine the optimal timing resolution and source activity using Monte Carlo simulations. Methods: GEANT4 was used to simulate the decay of the In-111 nucleus and to model the gamma camera. Each photon emission was assigned a timestamp, and the time delay and angular separation for the second gamma-ray inmore » the cascade was consistent with the known intermediate state half-life of 85ns. The gamma-rays are transported through a model of a Siemens dual head Symbia “S” gamma camera with a 5/8-inch thick crystal and medium energy collimators. A true coincident event was defined as a single 171keV gamma-ray followed by a single 245keV gamma-ray within a specified time window (or vice versa). Several source activities (ranging from 10uCi to 5mCi) with and without incorporation of background counts were then simulated. Each simulation was analyzed using varying time windows to assess random events. The noise equivalent count rate (NECR) was computed based on the number of true and random counts for each combination of activity and time window. No scatter events were assumed since sources were simulated in air. Results: As expected, increasing the timing window increased the total number of observed coincidences albeit at the expense of true coincidences. A timing window range of 200–500ns maximizes the NECR at clinically-used source activities. The background rate did not significantly alter the maximum NECR. Conclusion: This work suggests coincident measurements of In-111 gamma-ray decay can be performed with commercial gamma cameras at clinically-relevant activities. Work is ongoing to assess useful clinical applications.« less
-
Status of the GAMMA-400 Project
NASA Technical Reports Server (NTRS)
Galper, A. M.; Adriani, O.; Aptekar, R. L.; Arkhangelskaja, I. V.; Arkhangelskiy, A. I.; Boezio, M.; Bonvicini, V.; Boyarchuk, K. A.; Gusakov, Yu. V.; Farber, M. O.;
2013-01-01
The preliminary design of the new space gamma-ray telescope GAMMA-400 for the energy range 100 MeV-3 TeV is presented. The angular resolution of the instrument, 1-2 deg at E(gamma) approximately 100 MeV and approximately 0.01 at E(gamma) greater than 100 GeV, its energy resolution is approximately 1% at E(gamma) greater than 100 GeV, and the proton rejection factor is approximately 10(exp 6) are optimized to address a broad range of science topics, such as search for signatures of dark matter, studies of Galactic and extragalactic gamma-ray sources, Galactic and extragalactic diffuse emission, gamma-ray bursts, as well as high-precision measurements of spectra of cosmic-ray electrons, positrons, and nuclei.
-
Areas V1 and V2 show microsaccade-related 3-4-Hz covariation in gamma power and frequency.
Lowet, E; Roberts, M J; Bosman, C A; Fries, P; De Weerd, P
2016-05-01
Neuronal gamma-band synchronization (25-80 Hz) in visual cortex appears sustained and stable during prolonged visual stimulation when investigated with conventional averages across trials. However, recent studies in macaque visual cortex have used single-trial analyses to show that both power and frequency of gamma oscillations exhibit substantial moment-by-moment variation. This has raised the question of whether these apparently random variations might limit the functional role of gamma-band synchronization for neural processing. Here, we studied the moment-by-moment variation in gamma oscillation power and frequency, as well as inter-areal gamma synchronization, by simultaneously recording local field potentials in V1 and V2 of two macaque monkeys. We additionally analyzed electrocorticographic V1 data from a third monkey. Our analyses confirm that gamma-band synchronization is not stationary and sustained but undergoes moment-by-moment variations in power and frequency. However, those variations are neither random and nor a possible obstacle to neural communication. Instead, the gamma power and frequency variations are highly structured, shared between areas and shaped by a microsaccade-related 3-4-Hz theta rhythm. Our findings provide experimental support for the suggestion that cross-frequency coupling might structure and facilitate the information flow between brain regions. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
-
A method to describe inelastic gamma field distribution in neutron gamma density logging.
Zhang, Feng; Zhang, Quanying; Liu, Juntao; Wang, Xinguang; Wu, He; Jia, Wenbao; Ti, Yongzhou; Qiu, Fei; Zhang, Xiaoyang
2017-11-01
Pulsed neutron gamma density logging (NGD) is of great significance for radioprotection and density measurement in LWD, however, the current methods have difficulty in quantitative calculation and single factor analysis for the inelastic gamma field distribution. In order to clarify the NGD mechanism, a new method is developed to describe the inelastic gamma field distribution. Based on the fast-neutron scattering and gamma attenuation, the inelastic gamma field distribution is characterized by the inelastic scattering cross section, fast-neutron scattering free path, formation density and other parameters. And the contribution of formation parameters on the field distribution is quantitatively analyzed. The results shows the contribution of density attenuation is opposite to that of inelastic scattering cross section and fast-neutron scattering free path. And as the detector-spacing increases, the density attenuation gradually plays a dominant role in the gamma field distribution, which means large detector-spacing is more favorable for the density measurement. Besides, the relationship of density sensitivity and detector spacing was studied according to this gamma field distribution, therefore, the spacing of near and far gamma ray detector is determined. The research provides theoretical guidance for the tool parameter design and density determination of pulsed neutron gamma density logging technique. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
Regulation of gamma-Secretase in Alzheimer's Disease
DOE Office of Scientific and Technical Information (OSTI.GOV)
Zhou, Shuxia; Zhou, Hua; Walian, Peter
2007-02-07
The {gamma}-secretase complex is an intramembrane aspartyl protease that cleaves its substrates along their transmembrane regions. Sequential proteolytic processing of amyloid precursor protein by {beta}- and {gamma}-secretase produces amyloid {beta}-peptides, which are the major components of amyloid plaques in the brains of Alzheimer's disease patients. The {gamma}-secretase complex is therefore believed to be critical in the pathogenesis of Alzheimer's disease. Here we review the range of factors found to affect the nature and degree of {gamma}-secretase complex activity; these include {gamma}-secretase complex assembly and activation, the integral regulatory subunit CD147, transient or weak binding partners, the levels of cholesterol andmore » sphingolipids in cell membranes, and inflammatory cytokines. Integrated knowledge of the molecular mechanisms supporting the actions of these factors is expected to lead to a comprehensive understanding of the functional regulation of the {gamma}-secretase complex, and this, in turn, should facilitate the development of novel therapeutic strategies for the treatment of Alzheimer's disease.« less
-
Hyrsova, Lucie; Smutny, Tomas; Carazo, Alejandro; Moravcik, Stefan; Mandikova, Jana; Trejtnar, Frantisek; Gerbal‐Chaloin, Sabine
2016-01-01
Background and Purpose The organic cation transporter 1 (OCT1) transports cationic drugs into hepatocytes. The high hepatic expression of OCT1 is controlled by the HNF4α and USF transcription factors. Pregnane X receptor (PXR) mediates induction of the principal xenobiotic metabolizing enzymes and transporters in the liver. Here, we have assessed the down‐regulation of OCT1 expression by PXR activation. Experimental Approach We used primary human hepatocytes and related cell lines to measure OCT1 expression and activity, by assaying MPP+ accumulation. Western blotting, qRT‐PCR, the OCT1 promoter gene reporter constructs and chromatin immunoprecipitation assays were also used. Key Results OCT1 mRNA in human hepatocytes was down‐regulated along with reduced [3H]MPP+ accumulation in differentiated HepaRG cells after treatment with rifampicin. Rifampicin and hyperforin as well as the constitutively active PXR mutant T248D suppressed activity of the 1.8 kb OCT1 promoter construct in gene reporter assays. Silencing of both PXR and HNF4α in HepaRG cells blocked the PXR ligand‐mediated down‐regulation of OCT1 expression. The mutation of HNF4α and USF1 (E‐box) responsive elements reversed the PXR‐mediated inhibition in gene reporter assays. Chromatin immunoprecipitation assays indicated that PXR activation sequestrates the SRC‐1 coactivator from the HNF4α response element and E‐box of the OCT1 promoter. Consistent with these findings, exogenous overexpression of the SRC‐1, but not the PGC1α coactivator, relieved the PXR‐mediated repression of OCT1 transactivation. Conclusions and Implications PXR ligands reduced the HNF4α‐mediated and USF‐mediated transactivation of OCT1 gene expression by competing for SRC‐1 and decreased delivery of a model OCT1 substrate into hepatocytes. PMID:26920453
-
Laser pyrolysis fabrication of ferromagnetic gamma'-Fe4N and FeC nanoparticles
NASA Technical Reports Server (NTRS)
Grimes, C. A.; Qian, D.; Dickey, E. C.; Allen, J. L.; Eklund, P. C.
2000-01-01
Using the laser pyrolysis method, single phase gamma'-Fe4N nanoparticles were prepared by a two step method involving preparation of nanoscale iron oxide and a subsequent gas-solid nitridation reaction. Single phase Fe3C and Fe7C3 could be prepared by laser pyrolysis from Fe(CO)5 and 3C2H4 directly. Characterization techniques such as XRD, TEM and vibrating sample magnetometer were used to measure phase structure, particle size and magnetic properties of these nanoscale nitride and carbide particles. c2000 American Journal of Physics.
-
Higashi, Kiyoshi; Inagaki, Yutaka; Fujimori, Ko; Nakao, Atsuhito; Kaneko, Hideo; Nakatsuka, Iwao
2003-10-31
Transforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma) exert antagonistic effects on collagen synthesis in human dermal fibroblasts. We have recently shown that Y box-binding protein YB-1 mediates the inhibitory effects of IFN-gamma on alpha2(I) procollagen gene (COL1A2) transcription through the IFN-gamma response element located between -161 and -150. Here we report that YB-1 counter-represses TGF-beta-stimulated COL1A2 transcription by interfering with Smad3 bound to the upstream sequence around -265 and subsequently by interrupting the Smad3-p300 interaction. Western blot and immunofluorescence analyses using inhibitors for Janus kinases or casein kinase II suggested that the casein kinase II-dependent signaling pathway mediates IFN-gamma-induced nuclear translocation of YB-1. Down-regulation of endogenous YB-1 expression by double-stranded YB-1-specific RNA abrogated the transcriptional repression of COL1A2 by IFN-gamma in the absence and presence of TGF-beta. In transient transfection assays, overexpression of YB-1 in human dermal fibroblasts exhibited antagonistic actions against TGF-beta and Smad3. Physical interaction between Smad3 and YB-1 was demonstrated by immunoprecipitation-Western blot analyses, and electrophoretic mobility shift assays using the recombinant Smad3 and YB-1 proteins indicated that YB-1 forms a complex with Smad3 bound to the Smad-binding element. Glutathione S-transferase pull-down assays showed that YB-1 binds to the MH1 domain of Smad3, whereas the central and carboxyl-terminal regions of YB-1 were required for its interaction with Smad3. YB-1 also interferes with the Smad3-p300 interaction by its preferential binding to p300. Altogether, the results provide a novel insight into the mechanism by which IFN-gamma/YB-1 counteracts TGF-beta/Smad3. They also indicate that IFN-gamma/YB-1 inhibits COL1A2 transcription by dual actions: via the IFN-gamma response element and through a cross-talk with the TGF
-
NASA Technical Reports Server (NTRS)
Lockwood, J. A.; Webber, W. R.; Friling, L. A.; Macri, J.; Hsieh, L.
1981-01-01
Balloon-borne measurements of the atmospheric and diffuse gamma-ray flux in the energy range 0.4-7.0 MeV with a Compton telescope, which included pulse-shape discrimination of the first scattering detector and a time-of-flight system between the first and second detector elements, are reported. Comparison of the diffuse cosmic gamma-ray flux to the atmospheric gamma rays indicates that 0.2-5.0 MeV is the optimum energy range for measurements made at the top of the earth's atmosphere. The measured total atmospheric gamma-ray flux between zero and 40 deg has an energy spectrum that agrees with the calculations of Ling (1975). Observations indicate that the ratio of the diffuse to atmospheric gamma ray fluxes at 3.5 g/sq cm is a maximum, about 1.0, between 0.7 and 3.0 MeV.
-
Nagahashi, Kotomi; Umemura, Kazuo; Kanayama, Naohiro; Iwaki, Takayuki
2017-04-01
Mammalian gamma-glutamyl carboxylase and reduced vitamin K are indispensable for synthesis of mature mammalian vitamin K dependent proteins including some of blood coagulation factors (factors II, VII, IX, and X). It was well known that Drosophila melanogaster expressed gamma-glutamyl carboxylase and possessed a vit.K cycle although native substrates for them have not been identified yet. Despite the potential capability of gamma carboxylation in D. melanogaster derived cells such as S2 cells, Drosophila gamma-glutamyl carboxylase failed to gamma carboxylate a peptide fused to the human coagulation factor IX propeptide. Thus, it had been believed that the Drosophila system was not adequate to synthesize mammalian vit.K dependent proteins. Indeed, we previously attempted to synthesize biologically active factor VII in S2 cells although we were not able to obtain it. However, recently, a successful transient expression of biologically active human factor IX from S2 cells was reported. In the present study, several expression vectors which enable expressing mammalian GGCX, VKORC1, and/or PDIA2 along with F7 were developed. S2 cells transfected with pMKA85, pMAK86, and pMAK219 successfully synthesized active FVII. Thus, mammalian GGCX was indispensable to synthesize active FVII while mammalian VKORC1 and PDIA2 were not critical but supportive factors for S2 cells.
-
Z{gamma}{gamma}{gamma} {yields} 0 Processes in SANC
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bardin, D. Yu., E-mail: bardin@nu.jinr.ru; Kalinovskaya, L. V., E-mail: kalinov@nu.jinr.ru; Uglov, E. D., E-mail: corner@nu.jinr.ru
2013-11-15
We describe the analytic and numerical evaluation of the {gamma}{gamma} {yields} {gamma}Z process cross section and the Z {yields} {gamma}{gamma}{gamma} decay rate within the SANC system multi-channel approach at the one-loop accuracy level with all masses taken into account. The corresponding package for numeric calculations is presented. For checking of the results' correctness we make a comparison with the other independent calculations.
-
Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma
Jang, Chang Ki; Jung, Hyun Ho; Chang, Jong Hee; Chang, Jin Woo; Park, Yong Gou
2015-01-01
Background The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or cannot be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. Methods We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imaging, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multiple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient's age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage was 13.9 Gy. Results The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evidence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema (PTE) after gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had craniotomy and tumor removal after gamma knife surgery. Conclusion Gamma knife surgery for intracranial meningioma has proven to be a safe and effective treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially effective in cases of remnant meningioma after surgical resection or where PTE is not present. PMID:26605265
-
Long-Term Results of Gamma Knife Radiosurgery for Intracranial Meningioma.
Jang, Chang Ki; Jung, Hyun Ho; Chang, Jong Hee; Chang, Jin Woo; Park, Yong Gou; Chang, Won Seok
2015-10-01
The predominant treatment modality for meningioma is surgical resection. However, gamma knife radiosurgery is also an important treatment modality for meningioma that is small or cannot be completely removed because of its location. In this study, we evaluated the effectiveness and long-term results of radiosurgical treatment for meningioma in our institution. We studied 628 patients (130 men and 498 women) who underwent gamma knife radiosurgery for intracranial meningioma, which is radiologically diagnosed, from Jan 2008 to Nov 2012. We included patients with single lesion meningioma, and followed up after 6 months with imaging, and then at 24 months with a clinical examination. Patients with high-grade meningioma or multiple meningiomas were excluded. We analyzed each of the factors associated with progression free survival. The median patient's age was 56.8 years. Maximal dosage was 27.8 Gy and marginal dosage was 13.9 Gy. The overall tumor control rate was 95%. Twenty-eight patients (4.4%) showed evidence of tumor recurrence. Ninety-eight patients (15%) developed peritumoral edema (PTE) after gamma-knife surgery; two of them (2%) underwent surgical resections due to PTE. Nine patients had craniotomy and tumor removal after gamma knife surgery. Gamma knife surgery for intracranial meningioma has proven to be a safe and effective treatment tool with successful long-term outcomes. Gamma knife radiosurgery can be especially effective in cases of remnant meningioma after surgical resection or where PTE is not present.
-
Sneaky Gamma-Rays: Using Gravitational Lensing to Avoid Gamma-Gamma-Absorption
NASA Astrophysics Data System (ADS)
Boettcher, Markus; Barnacka, Anna
2014-08-01
It has recently been suggested that gravitational lensing studies of gamma-ray blazars might be a promising avenue to probe the location of the gamma-ray emitting region in blazars. Motivated by these prospects, we have investigated potential gamma-gamma absorption signatures of intervening lenses in the very-high-energy gamma-ray emission from lensedblazars. We considered intervening galaxies and individual stars within these galaxies. We find that the collective radiation field of galaxies acting as sources of macrolensing are not expected to lead to significant gamma-gamma absorption. Individual stars within intervening galaxies could, in principle, cause a significant opacity to gamma-gamma absorption for VHE gamma-rays if the impact parameter (the distance of closest approach of the gamma-ray to the center of the star) is small enough. However, we find that the curvature of the photon path due to gravitational lensing will cause gamma-ray photons to maintain a sufficiently large distance from such stars to avoid significant gamma-gamma absorption. This re-inforces the prospect of gravitational-lensing studies of gamma-ray blazars without interference due to gamma-gamma absorption due to the lensing objects.
-
Dust reddening and extinction curves toward gamma-ray bursts at z > 4
NASA Astrophysics Data System (ADS)
Bolmer, J.; Greiner, J.; Krühler, T.; Schady, P.; Ledoux, C.; Tanvir, N. R.; Levan, A. J.
2018-01-01
Context. Dust is known to be produced in the envelopes of asymptotic giant branch (AGB) stars, the expanded shells of supernova (SN) remnants, and in situ grain growth within the interstellar medium (ISM), although the corresponding efficiency of each of these dust formation mechanisms at different redshifts remains a topic of debate. During the first Gyr after the Big Bang, it is widely believed that there was not enough time to form AGB stars in high numbers, hence the dust at this epoch is expected to be purely from SNe or subsequent grain growth in the ISM. The time period corresponding to z 5-6 is thus expected to display the transition from SN-only dust to a mixture of both formation channels as is generally recognized at present. Aims: Here we aim to use afterglow observations of gamma-ray bursts (GRBs) at redshifts larger than z > 4 to derive host galaxy dust column densities along their line of sight and to test if a SN-type dust extinction curve is required for some of the bursts. Methods: We performed GRB afterglow observations with the seven-channel Gamma-Ray Optical and Near-infrared Detector (GROND) at the 2.2 m MPI telescope in La Silla, Chile (ESO), and we combined these observations with quasi-simultaneous data gathered with the XRT telescope on board the Swift satellite. Results: We increase the number of measured AV values for GRBs at z > 4 by a factor of 2-3 and find that, in contrast to samples at mostly lower redshift, all of the GRB afterglows have a visual extinction of AV < 0.5 mag. Analysis of the GROND detection thresholds and results from a Monte Carlo simulation show that although we partly suffer from an observational bias against highly extinguished sight-lines, GRB host galaxies at 4 < z < 6 seem to contain on average less dust than at z 2. Additionally, we find that all of the GRBs can be modeled with locally measured extinction curves and that the SN-like dust extinction curve, as previously found toward GRB 071025, provides a
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp; Haniu, Hisao
2012-08-03
Highlights: Black-Right-Pointing-Pointer We examined the correlation between PPAR{gamma} expression and cell proliferation. Black-Right-Pointing-Pointer PPAR{gamma} overexpression reduces cell viability. Black-Right-Pointing-Pointer We show the synergistic effect of cell growth inhibition by a PPAR{gamma} agonist. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPAR{gamma} is expressed at considerable levels in human colon cancer cells. This suggests that PPAR{gamma} expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPAR{gamma} expression in 4 human colon cancer cell lines, HT-29, LOVO,more » DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPAR{gamma} mRNA and protein in these cells were in the order HT-29 > LOVO > Caco-2 > DLD-1. We also found that PPAR{gamma} overexpression promoted cell growth inhibition in PPAR{gamma} lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPAR{gamma} expression and the cells' sensitivity for proliferation.« less
-
Wiedmann, Mareike M.; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F.; Verma, Chandra S.; Itzhaki, Laura; Stewart, Murray; Brenton, James D.
2016-01-01
Abstract There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum‐based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA‐mediated knockdown of the target protein, HNF1β, in five high‐ and low‐HNF1β‐expressing CCC lines. To inhibit the protein function, cell‐permeable, non‐helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X‐ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. PMID:27918136
-
Terrestrial Gamma-Ray Flashes (TGFs)
NASA Technical Reports Server (NTRS)
Fishman, Gerald J.
2010-01-01
This slide presentation reviews the observation of Terrestrial Gamma Ray Flashes (TGFs) by Gamma-Ray Telescopes. These were: (1) BATSE /Compton Observatory, (2) Solar Spectroscopic Imager, (3) AGILE Gamma-ray Telescope, and (4) Gamma-ray Burst Monitor (GBM) on the Fermi Gamma-ray Space Telescope. It contains charts which display the counts over time, a map or the TGFs observed by the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI). and a map showing the latitude and longitude of 85 of the TGFs observed by the Fermi GBM.
-
Simulation of prompt gamma-ray emission during proton radiotherapy.
Verburg, Joost M; Shih, Helen A; Seco, Joao
2012-09-07
The measurement of prompt gamma rays emitted from proton-induced nuclear reactions has been proposed as a method to verify in vivo the range of a clinical proton radiotherapy beam. A good understanding of the prompt gamma-ray emission during proton therapy is key to develop a clinically feasible technique, as it can facilitate accurate simulations and uncertainty analysis of gamma detector designs. Also, the gamma production cross-sections may be incorporated as prior knowledge in the reconstruction of the proton range from the measurements. In this work, we performed simulations of proton-induced nuclear reactions with the main elements of human tissue, carbon-12, oxygen-16 and nitrogen-14, using the nuclear reaction models of the GEANT4 and MCNP6 Monte Carlo codes and the dedicated nuclear reaction codes TALYS and EMPIRE. For each code, we made an effort to optimize the input parameters and model selection. The results of the models were compared to available experimental data of discrete gamma line cross-sections. Overall, the dedicated nuclear reaction codes reproduced the experimental data more consistently, while the Monte Carlo codes showed larger discrepancies for a number of gamma lines. The model differences lead to a variation of the total gamma production near the end of the proton range by a factor of about 2. These results indicate a need for additional theoretical and experimental study of proton-induced gamma emission in human tissue.
-
Abozaid, Omayma A R; Moawed, Fatma S M; Farrag, Mostafa A; Abdel Aziz, Abdel Aziz A
2017-12-01
Cellular exposure to ionising radiation leads to oxidative stress events, which refer to elevated intracellular levels of reactive oxygen species (ROS). The elevated levels of ROS significantly contributed to γ-radiation (IR) induced cytotoxicity. In an attempt to minimise these cytotoxic effects, antioxidant compounds have been identified to counteract radiation- associated toxicities. We mainly aimed to study the protective effect of 4-(4-hydroxy-3-methoxyphenyl)-2-butanone (HMB) on IR-induced nephrotoxicity, whereas it was previously shown to have anti-inflammatory effects in different inflammation models. Animals were treated orally with HMB (25 mg/kg b.wt daily) then performed by whole-body gamma-irradiation of animals with 6 Gy; a single dose applied on the 15th day and animals were sacrificed at the end of the 23rd day. It was found that IR exposure significantly induced renal oxidative injury that accompanied by inflammatory disturbance. Also, NADPH oxidase and iNOS gene expressions were significantly up-regulated, while the mitochondrial enzymes (complex I & II) were significantly down-regulated in IR exposed animals. Additionally, Western immunoblotting analysis of signalling growth factor protein; p38 MAPK was significantly overexpressed. Interestingly, HMB treatment showed statistically significant amelioration in parameters with an improved histological structure upon the IR-induced nephrotoxicity. It can be concluded that modulation of NADPH-oxidase, iNOS and mitochondrial enzymes by HMB might be responsible for the amendment of the antioxidant status and impairment of p38 MAPK signal, thus attenuate the nephrotoxicity induced post IR exposure.
-
Laouar, Yasmina; Sutterwala, Fayyaz S; Gorelik, Leonid; Flavell, Richard A
2005-06-01
Interferon-gamma and interleukin 12 produced by the innate arm of the immune system are important regulators of T helper type 1 (T(H)1) cell development, but signals that negatively regulate their expression remain controversial. Here we show that transforming growth factor-beta (TGF-beta) controlled T(H)1 differentiation through the regulation of interferon-gamma produced by natural killer (NK) cells. Blockade of TGF-beta signaling in NK cells caused the accumulation of a large pool of NK cells secreting copious interferon-gamma, responsible for T(H)1 differentiation and protection from leishmania infection. In contrast, blockade of TGF-beta signaling in dendritic cells did not affect dendritic cell homeostasis or interleukin 12 production, thus indicating a previously undescribed demarcation of the function of TGF-beta in NK cells versus dendritic cells.
-
Efficiency transfer using the GEANT4 code of CERN for HPGe gamma spectrometry.
Chagren, S; Tekaya, M Ben; Reguigui, N; Gharbi, F
2016-01-01
In this work we apply the GEANT4 code of CERN to calculate the peak efficiency in High Pure Germanium (HPGe) gamma spectrometry using three different procedures. The first is a direct calculation. The second corresponds to the usual case of efficiency transfer between two different configurations at constant emission energy assuming a reference point detection configuration and the third, a new procedure, consists on the transfer of the peak efficiency between two detection configurations emitting the gamma ray in different energies assuming a "virtual" reference point detection configuration. No pre-optimization of the detector geometrical characteristics was performed before the transfer to test the ability of the efficiency transfer to reduce the effect of the ignorance on their real magnitude on the quality of the transferred efficiency. The obtained and measured efficiencies were found in good agreement for the two investigated methods of efficiency transfer. The obtained agreement proves that Monte Carlo method and especially the GEANT4 code constitute an efficient tool to obtain accurate detection efficiency values. The second investigated efficiency transfer procedure is useful to calibrate the HPGe gamma detector for any emission energy value for a voluminous source using one point source detection efficiency emitting in a different energy as a reference efficiency. The calculations preformed in this work were applied to the measurement exercise of the EUROMET428 project. A measurement exercise where an evaluation of the full energy peak efficiencies in the energy range 60-2000 keV for a typical coaxial p-type HpGe detector and several types of source configuration: point sources located at various distances from the detector and a cylindrical box containing three matrices was performed. Copyright © 2015 Elsevier Ltd. All rights reserved.
-
Polyfunctional CD4 T cells in the response to bovine tuberculosis
USDA-ARS?s Scientific Manuscript database
CD4 T cells are crucial in immunity to tuberculosis (TB). Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), Interleukin-2 (IL-2) and Tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB and HIV. However, the a...
-
Yanagida, M; Fukamachi, H; Takei, M; Hagiwara, T; Uzumaki, H; Tokiwa, T; Saito, H; Iikura, Y; Nakahata, T
1996-01-01
We examined the effects of interferon-gamma (IFN-gamma) on 100% pure human mast cells generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6). When mast cells were suspended in serum-free medium without any cytokine after the withdrawal of SCF and IL-6, they died over a period of 5 days because of apoptosis. IFN-gamma in the cultures suppressed apoptosis and prolonged their survival in a dose-dependent manner. This survival-promoting effect of IFN-gamma was blocked by neutralizing antibodies to IFN-gamma or to IFN-gamma receptor (IFN-gamma R). When mast cells were incubated with IFN-gamma in serum-free medium for more than 4 hr during sensitization, immunoglobulin E (IgE)/anti-IgE antibody-induced histamine release was effectively enhanced. Polymerase chain reaction (PCR) amplification of the alpha-chain of IFN-gamma R (IFN-gamma R alpha) yielded products of the correct size predicted from the sequence of the receptor. In addition, flow cytometry using anti-IFN-gamma R monoclonal antibodies (mAbs) indicated that these mast cells bear IFN-gamma R on their surface. These findings suggested that IFN-gamma activates human mast cells via specific receptors in certain aspects of inflammatory reactions. Images Figure 2 Figure 4 PMID:9014819
-
Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity
1984-01-01
Gamma-interferon (IFN-gamma) is the macrophage-activating factor (MAF) produced by normal murine splenic cells and the murine T cell hybridoma 24/G1 that induces nonspecific tumoricidal activity in macrophages. Incubation of 24/G1 supernatants diluted to 8.3 IRU IFN-gamma/ml with 6 X 10(6) elicited peritoneal macrophages or bone marrow-derived macrophages for 4 h at 37 degrees C, resulted in removal of 80% of the MAF activity from the lymphokine preparation. Loss of activity appeared to result from absorption and not consumption because (a) 40% of the activity was removed after exposure to macrophage for 30 min at 4 degrees C, (b) no reduction of MAF activity was detected when the 24/G1 supernatant was incubated with macrophage culture supernatants, and (c) macrophage-treated supernatants showed a selective loss of MAF activity but not interleukin 2 (IL-2) activity. Absorption was dependent on the input of either IFN-gamma or macrophages and was time dependent at 37 degrees C but not at 4 degrees C. With four rodent species tested, absorption of murine IFN-gamma displayed species specificity. However, cultured human peripheral blood monocytes and the human histiocytic lymphoma cell line U937 were able to absorb the murine lymphokine. Although the majority of murine cell lines tested absorbed 24/G1 MAF activity, two murine macrophage cell lines, P388D1 and J774, were identified which absorbed significantly reduced amounts of natural IFN- gamma. Purified murine recombinant IFN-gamma was absorbed by elicited macrophages but not by P388D1. Normal macrophages but not P388D1 bound fluoresceinated microspheres coated with recombinant IFN-gamma and binding was inhibited by pretreatment of the normal cells with 24/G1 supernatants. Scatchard plot analysis showed that 12,000 molecules of soluble 125I-recombinant IFN-gamma bound per bone marrow macrophage with a Ka of 0.9 X 10(8) M-1. Binding was quantitatively inhibitable by natural IFN-gamma but not by murine IFN alpha. IFN
-
Radon-222 related influence on ambient gamma dose.
Melintescu, A; Chambers, S D; Crawford, J; Williams, A G; Zorila, B; Galeriu, D
2018-04-03
Ambient gamma dose, radon, and rainfall have been monitored in southern Bucharest, Romania, from 2010 to 2016. The seasonal cycle of background ambient gamma dose peaked between July and October (100-105 nSv h -1 ), with minimum values in February (75-80 nSv h -1 ), the time of maximum snow cover. Based on 10 m a.g.l. radon concentrations, the ambient gamma dose increased by around 1 nSv h -1 for every 5 Bq m -3 increase in radon. Radon variability attributable to diurnal changes in atmospheric mixing contributed less than 15 nSv h -1 to the overall variability in ambient gamma dose, a factor of 4 more than synoptic timescale changes in air mass fetch. By contrast, precipitation-related enhancements of the ambient gamma dose were 15-80 nSv h -1 . To facilitate routine analysis, and account in part for occasional equipment failure, an automated method for identifying precipitation spikes in the ambient gamma dose was developed. Lastly, a simple model for predicting rainfall-related enhancement of the ambient gamma dose is tested against rainfall observations from events of contrasting duration and intensity. Results are also compared with those from previously published models of simple and complex formulation. Generally, the model performed very well. When simulations underestimated observations the absolute difference was typically less than the natural variability in ambient gamma dose arising from atmospheric mixing influences. Consequently, combined use of the automated event detection method and the simple model of this study could enable the ambient gamma dose "attention limit" (which indicates a potential radiological emergency) to be reduced from 200 to 400% above background to 25-50%. Copyright © 2018 Elsevier Ltd. All rights reserved.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Achasov, N. N., E-mail: achasov@math.nsc.ru
2011-03-15
The approach to the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decay study is presented in detail, based on the sum rules for the Z {yields} cc-bar {yields} {gamma}{gamma}* and Z {yields} bb-bar {yields} {gamma}{gamma}* amplitudes and their derivatives. The branching ratios of the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decays are calculated for different hypotheses on saturation of the sum rules. The lower bounds of {Sigma}{sub {psi}} BR(Z {yields} {gamma}{psi}) = 1.95 Multiplication-Sign 10{sup -7} and {Sigma}{sub {upsilon}} BR(Z {yields} {gamma}Y) = 7.23 Multiplication-Sign 10{sup -7} are found. Deviations from the lower bounds are discussed, including the possibilitymore » of BR(Z {yields} {gamma}J/{psi}(1S)) {approx} BR(Z {yields} {gamma}Y(1S)) {approx} 10{sup -6}, that could be probably measured in LHC. The angular distributions in the Z {yields} {gamma}{psi} and Z {yields} {gamma}Y decays are also calculated.« less
-
NASA Technical Reports Server (NTRS)
Schneid, E. J.; Bertsch, D. L.; Fichtel, C. E.; Hartman, R. C.; Hunter, S. D.; Kwok, P. W.; Mattox, J. R.; Sreekumar, P.; Thompson, D. J.; Kanbach, G.
1992-01-01
The Energetic Gamma Ray Experiment Telescope (EGRET) on the Compton Gamma Ray Observatory has observed energetic gamma ray bursts and flares. On May 3, 1991, EGRET detected a gamma ray burst both in the energy measuring NaI (Tl) scintillator and independently in the spark chamber imaging assembly. The NaI spectra were accumulated by a special BURST mode of EGRET. The spectra were measured over a range from 1 to 200 MeV, in three sequential spectra of 1,2, and 4 seconds. During the peak of the burst, six individual gamma rays were detected in the spark chamber, allowing a determination of the burst arrival direction. The intense flares of June were also detected. A solar flare on June 4 was observed to last for several minutes and for a brief time, less than a minute, had significant emission of gamma rays exceeding 150 MeV.
-
Elliott, Simon P
2003-04-23
The endogenous nature of the drug of abuse gamma hydroxybutyric acid (GHB) has caused various interpretative problems for toxicologists. In order to obtain data for the presence of endogenous GHB in humans and to investigate any factors that may affect this, a volunteer study was undertaken. The GHB concentrations in 119 urine specimens from GHB-free subjects and 25 urine specimens submitted for toxicological analysis showed maximal urinary GHB concentrations of 3mg/l. Analysis of 15 plasma specimens submitted for toxicological analysis detected no measurable GHB (less than 2.5mg/l). Studies in a male and female volunteer in which different dietary food groups were ingested at weekly intervals, showed significant creatinine-independent intra-individual fluctuation with overall urine GHB concentrations between 0 and 2.55, and 0 and 2.74mg/l, respectively. Urinary concentrations did not appear to be affected by the particular dietary groups studied. The concentrations measured by gas chromatography with flame ionisation detection (GC-FID) and gas chromatography with mass spectrometry (GC-MS) lend further support to the proposed urinary and plasma interpretative cut-offs of 10 and 4mg/l, respectively, where below this it is not possible to determine whether any GHB detected is endogenous or exogenous in nature.
-
Wiedmann, Mareike M; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F; Verma, Chandra S; Itzhaki, Laura; Stewart, Murray; Brenton, James D; Spring, David R
2017-01-09
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
-
Han, Guangming; Soslow, Robert A; Wethington, Stephanie; Levine, Douglas A; Bogomolniy, Faina; Clement, Philip B; Köbel, Martin; Gilks, Blake; DeLair, Deborah
2015-07-01
Endometrial clear cell carcinoma (CC) is an uncommon tumor and often carries a poor prognosis. It has histologic features that overlap with other endometrial carcinomas and is frequently misclassified. Accurate classification is crucial, however, to improve treatment options. The objectives of this study were (1) to assess diagnostic interobserver variability among 5 gynecologic pathologists for tumors originally diagnosed as CC or with a component of CC (n=44); (2) to determine the utility of immunohistochemical markers estrogen receptor and HNF-1β; and (3) to detect mutations in select genes. Clinical data and morphologic features were also recorded. Agreement among reviewers was only moderate: only 46% of the original CC remained classified as such. After reclassification, estrogen receptor was positive in 8% of CC, 67% of endometrioid carcinomas (EC), and 47% of serous carcinomas (SC). Sensitivities of HNF-1β in CC, SC, and EC were 62%, 27%, and 17%, respectively, whereas specificity for CC versus EC or SC was 78%. Mutations in PIK3CA, PIK3R1, PTEN, KRAS, and NRAS were detected in 41% of 37 cases that had adequate material for study. At least 1 mutation was identified in 33% of CC, 67% of EC, and 33% of SC. This group of patients had poor outcomes: 72% of the patients with follow-up information had died of disease. In summary, this study suggests that the current pool of CC is a heterogeneous group of tumors from the morphologic, immunophenotypic, and molecular point of views and that only a percentage of them represent true CC.
-
Kilbride, Seán M.; Farrelly, Angela M.; Bonner, Caroline; Ward, Manus W.; Nyhan, Kristine C.; Concannon, Caoimhín G.; Wollheim, Claes B.; Byrne, Maria M.; Prehn, Jochen H. M.
2010-01-01
Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKα gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation. PMID:20841353
-
Visual stimulus eccentricity affects human gamma peak frequency.
van Pelt, Stan; Fries, Pascal
2013-09-01
The peak frequency of neuronal gamma-band synchronization has received much attention in recent years. Gamma peak frequency shifts to higher frequency values for higher contrast, faster moving, and attended stimuli. In monkey V1, gamma peak frequency for a drifting grating is higher for a parafoveal as compared to an eccentric stimulus (Lima et al., 2010). This effect might be due to the cortical magnification factor: the higher cortical magnification for parafoveal stimuli increases the velocity with which the cortical representations of the moving grating stripes move across the cortical surface. Since faster moving stimuli lead to higher gamma frequency, a faster moving cortical representation might do the same. This explanation predicts that the eccentricity effect on gamma peak frequency is absent for stationary stimuli. To test this, we investigated the effect of eccentricity on gamma peak frequency by recording magnetoencephalography in human subjects while they viewed moving or stationary gratings. We found that both the moving and the stationary stimuli induced lower peak frequencies for larger eccentricities, arguing against an explanation based on the cortical magnification factor. We further investigated whether this eccentricity effect was explained by differences in the size or the spatial frequency of the expected cortical activation. Neither of those explained the eccentricity effect. We propose that the different stimulus and top-down factors leading to higher gamma peak frequency all result in higher stimulus salience, that salience is translated into gamma peak frequency, and that gamma peak frequency might subserve the preferential processing of neuronal activity induced by salient stimuli. Copyright © 2013 Elsevier Inc. All rights reserved.
-
[Maturity onset diabetes of the young (MODY) - screening, diagnostic and therapy].
Kaser, Susanne; Resl, Michael
2016-04-01
Maturity onset diabetes of the young (MODY) is a group of monogenetic diabetes types affecting up to 2% all known diabetics. Transcription factor MODY (HNF1α, HNF4α), the most frequent forms of MODY, allow treatment with sulfonylureas, mutations of glucokinase (GCK-MODY) usually do not require any therapy. Especially in younger patients correct diagnosis of MODY often results in discontinuation of insulin therapy and initiation of a sulfonylurea. Accordingly, in patients with diabetes onset below age of 25 years, with a positive family history for diabetes and negative autoantibodies screening for MODY is recommended.
-
Gamma emission of the atmosphere in the vicinity of the Earth. [28 keV to 4. 1 MeV
DOE Office of Scientific and Technical Information (OSTI.GOV)
Golenetskii, S.V.; Gur'yan, Yu.A.; Il'inskii, V.N.
1975-01-01
The X-ray and ..gamma..-emissions of the earth's atmosphere were measured on Kosmos 461 in the range of 28 keV to 4.1 MeV. The energy spectrum of the emission was measured and the geomagnetic dependence of intensity in the continuous spectrum and in the 0.511-MeV line was determined. Measurements on Kosmos 135 yielded data on the height dependence of the atmospheric ..gamma..-quantum flux. 10 references.
-
NASA Technical Reports Server (NTRS)
Forrest, D. J.
1978-01-01
The SMM gamma ray experiment and the important scientific capabilities of the instrument are discussed. The flare size detectable as a function of spectrum integration time was studied. A preliminary estimate indicates that a solar gamma ray line at 4.4 MeV one-fifth the intensity of that believed to have been emitted on 4 August 1972 can be detected in approximately 1000 sec with a confidence level of 99%.
-
Martins, Marcia Valéria B S; Lima, Mônica Cristina B S; Duppre, Nadia C; Matos, Haroldo J; Spencer, John S; Brennan, Patrick J; Sarno, Euzenir N; Fonseca, Leila; Pereira, Geraldo M B; Pessolani, Maria Cristina V
2007-05-01
There are no reliable means for detecting subclinical mycobacterial infections. The recent sequencing of several mycobacterial genomes has now afforded new opportunities for the development of pathogen-specific diagnostic tests, critical in the context of leprosy and tuberculosis control. In the present study, we applied a multi-parametric flow cytometric analysis that allowed the investigation of T-cell functions in order to define immunological markers that measure previous exposure to mycobacteria. We compared the in vivo response to PPD, the gold standard skin test reagent for measuring previous exposure to Mycobacterium tuberculosis, with in vitro parameters of leukocyte activation in five PPD positive and five PPD negative healthy volunteers. PPD-stimulated peripheral leukocytes expressing CD4, CD69, cutaneous lymphocyte-associated antigen (CLA) and intracellular IFN-gamma were enumerated in whole blood and compared with the size of in vivo PPD-induced induration and IFN-gamma production levels as measured by ELISA in supernatants of PPD-stimulated peripheral blood mononuclear cells. The reactivity to the tuberculin skin test (TST) was associated with markedly increased frequencies of PPD-responsive activated (CD69+) and IFN-gamma-producing CD4+T cells. Detection of PPD-specific IFN-gamma producing leukocytes was restricted to CD4+T cells and a subset of these cells was shown to express the skin homing molecule CLA. Multiple linear regression modeling of responses to PPD showed the highest association between skin test indurations and frequencies of PPD-responsive IFN-gamma-producing CD4+CD69+ T cells. Our data show that the in vitro enumeration of antigen-specific IFN-gamma-producing CD4+ T cells can provide an alternative to the in vivo tuberculin test for the detection of latent Mycobacterium tuberculosis infection. Moreover, the measurement of these immunological parameters can be useful for the screening of new specific antigens defined by the genome
-
Arza, Elvira; Alvarez-Barrientos, Alberto; Fabregat, Isabel; Garcia-Bravo, Maria; Meza, Nestor W.; Segovia, Jose C.
2012-01-01
The fusion of bone marrow (BM) hematopoietic cells with hepatocytes to generate BM derived hepatocytes (BMDH) is a natural process, which is enhanced in damaged tissues. However, the reprogramming needed to generate BMDH and the identity of the resultant cells is essentially unknown. In a mouse model of chronic liver damage, here we identify a modification in the chromatin structure of the hematopoietic nucleus during BMDH formation, accompanied by the loss of the key hematopoietic transcription factor PU.1/Sfpi1 (SFFV proviral integration 1) and gain of the key hepatic transcriptional regulator HNF-1A homeobox A (HNF-1A/Hnf1a). Through genome-wide expression analysis of laser captured BMDH, a differential gene expression pattern was detected and the chromatin changes observed were confirmed at the level of chromatin regulator genes. Similarly, Tranforming Growth Factor-β1 (TGF-β1) and neurotransmitter (e.g. Prostaglandin E Receptor 4 [Ptger4]) pathway genes were over-expressed. In summary, in vivo BMDH generation is a process in which the hematopoietic cell nucleus changes its identity and acquires hepatic features. These BMDHs have their own cell identity characterized by an expression pattern different from hematopoietic cells or hepatocytes. The role of these BMDHs in the liver requires further investigation. PMID:22457803
-
Spontaneous Gamma Activity in Schizophrenia.
Hirano, Yoji; Oribe, Naoya; Kanba, Shigenobu; Onitsuka, Toshiaki; Nestor, Paul G; Spencer, Kevin M
2015-08-01
A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30
-
The PPAR{gamma} coding region and its role in visceral obesity
DOE Office of Scientific and Technical Information (OSTI.GOV)
Boon Yin, Khoo; Institute for Research in Molecular Medicine; Najimudin, Nazalan
Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a ligand activated transcription factor, plays many essential roles of biological function in higher organisms. The PPAR{gamma} is mainly expressed in adipose tissue. It regulates the transcriptional activity of genes by binding with other transcription factor. The PPAR{gamma} coding region has been found to be closest to that of monkey in ours and other research groups. Thus, monkey is a more suitable animal model for future PPAR{gamma} studying, although mice and rat are frequently being used. The PPAR{gamma} is involved in regulating alterations of adipose tissue masses result from changes in mature adipocyte sizemore » and/or number through a complex interplay process called adipogenesis. However, the role of PPAR{gamma} in negatively regulating the process of adipogenesis remains unclear. This review may help we investigate the differential expression of key transcription factor in adipose tissue in response to visceral obesity-induced diet in vivo. The study may also provide valuable information to define a more appropriate physiological condition in adipogenesis which may help to prevent diseases cause by negative regulation of the transcription factors in adipose tissue.« less
-
Studying the response of a plastic scintillator to gamma rays using the Geant4 Monte Carlo code.
Ghadiri, Rasoul; Khorsandi, Jamshid
2015-05-01
To determine the gamma ray response function of an NE-102 scintillator and to investigate the gamma spectra due to the transport of optical photons, we simulated an NE-102 scintillator using Geant4 code. The results of the simulation were compared with experimental data. Good consistency between the simulation and data was observed. In addition, the time and spatial distributions, along with the energy distribution and surface treatments of scintillation detectors, were calculated. This simulation makes us capable of optimizing the photomultiplier tube (or photodiodes) position to yield the best coupling to the detector. Copyright © 2015 Elsevier Ltd. All rights reserved.
-
MCNP-based computational model for the Leksell gamma knife.
Trnka, Jiri; Novotny, Josef; Kluson, Jaroslav
2007-01-01
We have focused on the usage of MCNP code for calculation of Gamma Knife radiation field parameters with a homogenous polystyrene phantom. We have investigated several parameters of the Leksell Gamma Knife radiation field and compared the results with other studies based on EGS4 and PENELOPE code as well as the Leksell Gamma Knife treatment planning system Leksell GammaPlan (LGP). The current model describes all 201 radiation beams together and simulates all the sources in the same time. Within each beam, it considers the technical construction of the source, the source holder, collimator system, the spherical phantom, and surrounding material. We have calculated output factors for various sizes of scoring volumes, relative dose distributions along basic planes including linear dose profiles, integral doses in various volumes, and differential dose volume histograms. All the parameters have been calculated for each collimator size and for the isocentric configuration of the phantom. We have found the calculated output factors to be in agreement with other authors' works except the case of 4 mm collimator size, where averaging over the scoring volume and statistical uncertainties strongly influences the calculated results. In general, all the results are dependent on the choice of the scoring volume. The calculated linear dose profiles and relative dose distributions also match independent studies and the Leksell GammaPlan, but care must be taken about the fluctuations within the plateau, which can influence the normalization, and accuracy in determining the isocenter position, which is important for comparing different dose profiles. The calculated differential dose volume histograms and integral doses have been compared with data provided by the Leksell GammaPlan. The dose volume histograms are in good agreement as well as integral doses calculated in small calculation matrix volumes. However, deviations in integral doses up to 50% can be observed for large
-
COMPTEL Gamma-Ray Observations of the C4 Solar Flare on 20 January 2000
NASA Astrophysics Data System (ADS)
Young, C. A.; COMPTEL Collaboration
2003-05-01
The Solar Maximum Mission (SMM) greatly changed the picture of gamma-ray line (GRL) flares. Once thought to be relatively rare and confined to only the largest of flares, SMM observations put this view in question. SMM observed over 100 GRL flares from very large (GOES class X12) to several orders of magnitude smaller (GOES class M2). It was argued by some (Bai 1986) that this was still consistent with the idea that GRL events are rare. Others, however, argued the opposite (Vestrand 1988; Cliver, Crosby and Dennis 1994), stating that the lower end of this distribution was just a function of SMM's sensitivity. They stated that the launch of the Compton Gamma-ray Observatory (CGRO) would in fact continue this distribution to show even smaller GRL flares. In response to a BACODINE cosmic gamma-ray burst alert, COMPTEL on the CGRO recorded gamma rays above 1 MeV from the C4 flare at 0221 UT 20 January 2000. This event, though at the limits of COMPTEL's sensitivity, clearly showed a nuclear line excess above the continuum. Using new spectroscopy techniques we were able to resolve individual lines. This has allowed us to make a basic comparison of this event with the GRL flare distribution from SMM and also compare this flare with a well-observed large GRL flare seen by OSSE. We show that this flare is normal, i.e., it is a natural extension of the SMM distribution of flares. The analysis of this flare means there is no evidence for a lower flare size for proton acceleration. Protons even in small flares contain a large part of the accelerated particle energy.
-
Spatial distribution and cognitive correlates of gamma noise power in schizophrenia.
Díez, A; Suazo, V; Casado, P; Martín-Loeches, M; Molina, V
2013-06-01
Brain activity is less organized in patients with schizophrenia than in healthy controls (HC). Noise power (scalp-recorded electroencephalographic activity unlocked to stimuli) may be of use for studying this disorganization. Method Fifty-four patients with schizophrenia (29 minimally treated and 25 stable treated), 23 first-degree relatives and 27 HC underwent clinical and cognitive assessments and an electroencephalographic recording during an oddball P300 paradigm to calculate noise power magnitude in the gamma band. We used a principal component analysis (PCA) to determine the factor structure of gamma noise power values across electrodes and the clinical and cognitive correlates of the resulting factors. The PCA revealed three noise power factors, roughly corresponding to the default mode network (DMN), frontal and occipital regions respectively. Patients showed higher gamma noise power loadings in the first factor when compared to HC and first-degree relatives. In the patients, frontal gamma noise factor scores related significantly and inversely to working memory and problem-solving performance. There were no associations with symptoms. There is an elevated gamma activity unrelated to task processing over regions coherent with the DMN topography in patients with schizophrenia. The same type of gamma activity over frontal regions is inversely related to performance in tasks with high involvement in these frontal areas. The idea of gamma noise as a possible biological marker for schizophrenia seems promising. Gamma noise might be of use in the study of underlying neurophysiological mechanisms involved in this disease.
-
Phenotypic and in vivo functional characterization of immortalized human fetal liver cells.
Patil, Pradeep B; Begum, Setara; Joshi, Meghnad; Kleman, Marika I; Olausson, Michael; Sumitran-Holgersson, Suchitra
2014-06-01
We report the establishment and characterization of immortalized human fetal liver progenitor cells by expression of the Simian virus 40 large T (SV40 LT) antigen. Well-characterized cells at various passages were transplanted into nude mice with acute liver injury and tested for functional capacity. The SV40LT antigen-immortalized fetal liver cells showed a morphology similar to primary cells. Cultured cells demonstrated stable phenotypic expression in various passages, of hepatic markers such as albumin, CK 8, CK18, transcription factors HNF-4α and HNF-1α and CYP3A/7. The cells did not stain for any of the tested cancer-associated markers. Albumin, HNF-4α and CYP3A7 expression was confirmed by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry showed expression of some progenitor cell markers. In vivo study showed that the cells expressed both fetal and differentiated hepatocytes markers. Our study suggests new approaches to expand hepatic progenitor cells, analyze their fate in animal models aiming at cell therapy of hepatic diseases.
-
4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors.
Churcher, Ian; Beher, Dirk; Best, Jonathan D; Castro, José L; Clarke, Earl E; Gentry, Amy; Harrison, Timothy; Hitzel, Laure; Kay, Euan; Kerrad, Sonia; Lewis, Huw D; Morentin-Gutierrez, Pablo; Mortishire-Smith, Russell; Oakley, Paul J; Reilly, Michael; Shaw, Duncan E; Shearman, Mark S; Teall, Martin R; Williams, Susie; Wrigley, Jonathan D J
2006-01-15
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
-
Continuous versus pulse neutron induced gamma spectroscopy for soil carbon analysis
USDA-ARS?s Scientific Manuscript database
Neutron induced gamma spectra analysis (NGA) provides a means of measuring carbon in large soil volumes without destructive sampling. Calibration of the NGA system must account for system background and the interference of other nuclei on the carbon peak at 4.43 MeV. Accounting for these factors pro...
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Nikolic, Rebecca J.; Conway, Adam M.; Heineck, Daniel
2013-10-15
Methods for manufacturing solid-state thermal neutron detectors with simultaneous high thermal neutron detection efficiency (>50%) and neutron to gamma discrimination (>10.sup.4) are provided. A structure is provided that includes a p+ region on a first side of an intrinsic region and an n+ region on a second side of the intrinsic region. The thickness of the intrinsic region is minimized to achieve a desired gamma discrimination factor of at least 1.0E+04. Material is removed from one of the p+ region or the n+ region and into the intrinsic layer to produce pillars with open space between each pillar. The openmore » space is filed with a neutron sensitive material. An electrode is placed in contact with the pillars and another electrode is placed in contact with the side that is opposite of the intrinsic layer with respect to the first electrode.« less
-
NASA Astrophysics Data System (ADS)
Mahfouz, R. M.; Siddiqui, M. R. H.; Al-Wassil, A. I.; Al-Resayes, S. I.; Al-Otaibi, A. M.
2005-05-01
The present work is a study on radiolyses of 4-iodophenol in aqueous methanol solutions. The radiolysis products are separated and identified using spectrophotometric and chromatographic techniques. The radiolytic products (I-2, I- and IO3-) formed in aerated solutions at room temperature were identified and the yields are investigated as a function of absorbed gamma-ray dose. The formation of I-2 is mainly dependent on the acidity of solution and produced via the pathway of secondary free radical reactions. Aromatic products of lower and higher molecular weight than the corresponding investigated compound were analysed and separated by HPLC. The results have been discussed in view of mechanisms based on free radicals and ion-molecule interactions. The chemical effects induced by gamma-irradiation in solid 4-iodophenol have also been investigated and the degradation products were identified in solid state by NMR, GC/MS experiments and HPLC after dissolution in aqueous methanol. The results were evaluated and compared with radiolysis data.
-
Jabbari, Keyvan; Pashaei, Fakhereh; Ay, Mohammad R.; Amouheidari, Alireza; Tavakoli, Mohammad B.
2018-01-01
Background: MapCHECK2 is a two-dimensional diode arrays planar dosimetry verification system. Dosimetric results are evaluated with gamma index. This study aims to provide comprehensive information on the impact of various factors on the gamma index values of MapCHECK2, which is mostly used for IMRT dose verification. Methods: Seven fields were planned for 6 and 18 MV photons. The azimuthal angle is defined as any rotation of collimators or the MapCHECK2 around the central axis, which was varied from 5 to −5°. The gantry angle was changed from −8 to 8°. Isodose sampling resolution was studied in the range of 0.5 to 4 mm. The effects of additional buildup on gamma index in three cases were also assessed. Gamma test acceptance criteria were 3%/3 mm. Results: The change of azimuthal angle in 5° interval reduced gamma index value by about 9%. The results of putting buildups of various thicknesses on the MapCHECK2 surface showed that gamma index was generally improved in thicker buildup, especially for 18 MV. Changing the sampling resolution from 4 to 2 mm resulted in an increase in gamma index by about 3.7%. The deviation of the gantry in 8° intervals in either directions changed the gamma index only by about 1.6% for 6 MV and 2.1% for 18 MV. Conclusion: Among the studied parameters, the azimuthal angle is one of the most effective factors on gamma index value. The gantry angle deviation and sampling resolution are less effective on gamma index value reduction. PMID:29535922
-
NASA Astrophysics Data System (ADS)
Sharaf, J. M.; Saleh, H.
2015-05-01
The shielding properties of three different construction styles, and building materials, commonly used in Jordan, were evaluated using parameters such as attenuation coefficients, equivalent atomic number, penetration depth and energy buildup factor. Geometric progression (GP) method was used to calculate gamma-ray energy buildup factors of limestone, concrete, bricks, cement plaster and air for the energy range 0.05-3 MeV, and penetration depths up to 40 mfp. It has been observed that among the examined building materials, limestone offers highest value for equivalent atomic number and linear attenuation coefficient and the lowest values for penetration depth and energy buildup factor. The obtained buildup factors were used as basic data to establish the total equivalent energy buildup factors for three different multilayer construction styles using an iterative method. The three styles were then compared in terms of fractional transmission of photons at different incident photon energies. It is concluded that, in case of any nuclear accident, large multistory buildings with five layers exterior walls, style A, could effectively attenuate radiation more than small dwellings of any construction style.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Baluev, V. V.; Bogdanova, L. N.; Bom, V. R.
2011-07-15
A search for the muon-catalyzed fusion reaction d + d {yields} {sup 4}He + {gamma} in the dd{mu} muonic molecule was performed using the experimental installation TRITON with BGO detectors for {gamma}-quanta. A high-pressure target filled with deuterium was exposed to the negative muon beam of the JINR Phasotron to detect {gamma}-quanta with the energy 23.8 MeV. An experimental estimation for the yield of radiative deuteron capture from the dd{mu} state J = 1 was obtained at the level of {eta}{sub {gamma}} {<=} 8 Multiplication-Sign 10{sup -7} per fusion.
-
Graw, J; Liebstein, A; Pietrowski, D; Schmitt-John, T; Werner, T
1993-12-22
The murine genes, gamma B-cry and gamma C-cry, encoding the gamma B- and gamma C-crystallins, were isolated from a genomic DNA library. The complete nucleotide (nt) sequences of both genes were determined from 661 and 711 bp, respectively, upstream from the first exon to the corresponding polyadenylation sites, comprising more than 2650 and 2890 bp, respectively. The new sequences were compared to the partial cDNA sequences available for the murine gamma B-cry and gamma C-cry, as well as to the corresponding genomic sequences from rat and man, at both the nt and predicted amino acid (aa) sequence levels. In the gamma B-cry promoter region, a canonical CCAAT-box, a TATA-box, putative NF-I and C/EBP sites were detected. An R-repeat is inserted 366 bp upstream from the transcription start point. In contrast, the gamma C-cry promoter does not contain a CCAAT-box, but some other putative binding sites for transcription factors (AP-2, UBP-1, LBP-1) were located by computer analysis. The promoter regions of all six gamma-cry from mouse, rat and human, except human psi gamma F-cry, were analyzed for common sequence elements. A complex sequence element of about 70-80 bp was found in the proximal promoter, which contains a gamma-cry-specific and almost invariant sequence (crygpel) of 14 nt, and ends with the also invariant TATA-box. Within the complex sequence element, a minimum of three further features specific for the gamma A-, gamma B- and gamma D/E/F-cry genes can be defined, at least two of which were recently shown to be functional. In addition to these four sequence elements, a subtype-specific structure of inverted repeats with different-sized spacers can be deduced from the multiple sequence alignment. A phylogenetic analysis based on the promoter region, as well as the complete exon 3 of all gamma-cry from mouse, rat and man, suggests separation of only five gamma-cry subtypes (gamma A-, gamma B-, gamma C-, gamma D- and gamma E/F-cry) prior to species separation.
-
Study of SMM flares in gamma-rays and neutrons
NASA Technical Reports Server (NTRS)
Dunphy, Philip P.; Chupp, Edward L.
1992-01-01
This report summarizes the results of the research supported by NASA grant NAGW-2755 and lists the papers and publications produced through the grant. The objective of the work was to study solar flares that produced observable signals from high-energy (greater than 10 MeV) gamma-rays and neutrons in the Solar Maximum Mission (SMM) Gamma-Ray Spectrometer (GRS). In 3 of 4 flares that had been studied previously, most of the neutrons and neutral pions appear to have been produced after the 'main' impulsive phase as determined from hard x-rays and gamma-rays. We, therefore, proposed to analyze the timing of the high-energy radiation, and its implications for the acceleration, trapping, and transport of flare particles. It was equally important to characterize the spectral shapes of the interacting energetic electrons and protons - another key factor in constraining possible particle acceleration mechanisms. In section 2.0, we discuss the goals of the research. In section 3.0, we summarize the results of the research. In section 4.0, we list the papers and publications produced under the grant. Preprints or reprints of the publications are attached as appendices.
-
[Allergic asthma and interleukins 2, 4, 5, 6 and 12 and gamma interferon levels].
Bastida Segura, Diana Lyzbeth; López Velásquez, Benjamin; Castrejón Vázquez, María Isabel; Galicia Tapía, Jorge; Cano Altamirano, Silvia; Miranda Feria, Alfonso Javier
2004-01-01
Asthma is an inflammatory chronic illness, in which mastocyt cells, basophils, T lymphocytes, eosinophils and cytokines play a role. Its association with the production of TH2 cytokines is not well known, but it is considered an aberrant immune response, yielding the activation and recruitment of a number of effector cells (mastocyts/eosinophils) and the appearance of clinical symptoms. To determine the serum values of the interleukins 2, 4, 5, 6 and 12 and gamma interferon in relation to the severity degree of asthma and the time of immunotherapy in patients with stable chronic allergic bronchial asthma. Clinical records of allergic asthmatic patients from the external consultation at Servicio de Alergia e Immunología Clínica were reviewed in a period of 12 months (1st January 2002 to 1st January 2003) and those of healthy volunteers, forming three groups: Group 1, allergic asthmatics with immunotherapy less than 24 months; Group 2, allergic asthmatics with more than 24 months of immunotherapy, and Group 3, healthy volunteers (control group). Previous informed consent, a serum sample was taken of all subjects. Ninety-two subjects were included: 41 (45%) allergic asthmatics and 51 (55%) healthy volunteers. Significant differences were found in interleukins 2, 4, 5, 6 and 12 levels between healthy volunteers and asthmatics without relating the immunotherapy time. In the total group gamma interferon levels were not found. A relation of interleukins Th2 levels with the severity degree of asthma was not found. Differences of serum interleukins Th1 and Th2 in allergic patients related to immunotherapy time were not significant; even though, irrespective of immunotherapy time, IgG levels were always high. Patients with allergic asthma have a predominance of serum interleukins Th2 and, despite of the immunotherapy, in the maintaining phase, these continue high, which may be due to an immune system dysregulation maybe including other factors. Immunotherapy continues
-
NASA Technical Reports Server (NTRS)
Wu, S. T.
2000-01-01
The project has progressed successfully during this period of performance. The highlights of the Gamma Ray Astronomy teams efforts are: (1) Support daily BATSE data operations, including receipt, archival and dissemination of data, quick-look science analysis, rapid gamma-ray burst and transient monitoring and response efforts, instrument state-of-health monitoring, and instrument commanding and configuration; (2) On-going scientific analysis, including production and maintenance of gamma-ray burst, pulsed source and occultation source catalogs, gamma-ray burst spectroscopy, studies of the properties of pulsars and black holes, and long-term monitoring of hard x-ray sources; (3) Maintenance and continuous improvement of BATSE instrument response and calibration data bases; (4) Investigation of the use of solid state detectors for eventual application and instrument to perform all sky monitoring of X-Ray and Gamma sources with high sensitivity; and (5) Support of BATSE outreach activities, including seminars, colloquia and World Wide Web pages. The highlights of this efforts can be summarized in the publications and presentation list.
-
Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells
NASA Technical Reports Server (NTRS)
Mazumder, B.; Mukhopadhyay, C. K.; Prok, A.; Cathcart, M. K.; Fox, P. L.
1997-01-01
Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma. It has multiple in vitro activities, including copper transport, lipid pro- and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain. Although ceruloplasmin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported. We here show that IFN-gamma is a potent inducer of ceruloplasmin synthesis by monocytic cells. Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold. The identity of the protein was confirmed by plasmin fingerprinting. IFN-gamma also increased ceruloplasmin mRNA. Induction followed a 2- to 4-h lag and was partially blocked by cycloheximide, indicating a requirement for newly synthesized factors. Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-4, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective. The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthesis in endothelial or smooth muscle cells. In contrast, IFN-gamma was stimulatory in other monocytic cells, including THP-1 cells and human peripheral blood monocytes, and also in HepG2 cells. Ceruloplasmin secreted by IFN-gamma-stimulated U937 cells had ferroxidase activity and was, in fact, the only secreted protein with this activity. Monocytic cell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.
-
Visser, J; Blauw, B; Hinloopen, B; Brommer, E; de Kloet, E R; Kluft, C; Nagelkerken, L
1998-02-01
A disturbed hypothalamus-pituitary-adrenal gland axis and alterations at the immune system level have been observed in patients with chronic fatigue syndrome (CFS). Glucocorticoids are known to modulate T cell responses; therefore, purified CD4 T cells from CFS patients were studied to determine whether they have an altered sensitivity to dexamethasone (DEX). CD4 T cells from CFS patients produced less interferon-gamma than did cells from controls; by contrast, interleukin-4 production and cell proliferation were comparable. With CD4 T cells from CFS patients (compared with cells from controls), a 10- to 20-fold lower DEX concentration was needed to achieve 50% inhibition of interleukin-4 production and proliferation, indicating an increased sensitivity to DEX in CFS patients. Surprisingly, interferon-gamma production in patients and controls was equally sensitive to DEX. A differential sensitivity of cytokines or CD4 T cell subsets to glucocorticoids might explain an altered immunologic function in CFS patients.
-
Thorne, James L; Ouboussad, Lylia; Lefevre, Pascal F
2012-09-01
IκB kinase α (IKKα) is part of the cytoplasmic IKK complex regulating nuclear factor-κB (NF-κB) release and translocation into the nucleus in response to pro-inflammatory signals. IKKα can also be recruited directly to the promoter of NF-κB-dependent genes by NF-κB where it phosphorylates histone H3 at serine 10, triggering recruitment of the bromodomain-containing protein 4 and the positive transcription elongation factor b. Herein, we report that IKKα travels with the elongating form of ribonucleic acid polymerase II together with heterochromatin protein 1 gamma (HP1γ) at NF-κB-dependent genes in activated macrophages. IKKα binds to and phosphorylates HP1γ, which in turn controls IKKα binding to chromatin and phosphorylation of the histone variant H3.3 at serine 31 within transcribing regions. Downstream of transcription end sites, IKKα accumulates with its inhibitor the CUE-domain containing protein 2, suggesting a link between IKKα inactivation and transcription termination.
-
Tran, Van; Little, Mark P
2017-11-01
Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5 mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p < 0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant
-
Characteristics of gamma-ray line flares
NASA Technical Reports Server (NTRS)
Bai, T.; Dennis, B.
1983-01-01
Observations of solar gamma rays by the Solar Maximum Mission (SMM) demonstrate that energetic protons and ions are rapidly accelerated during the impulsive phase. To understand the acceleration mechanisms for these particles, the characteristics of the gamma ray line flares observed by SMM were studied. Some very intense hard X-ray flares without detectable gamma ray lines were also investigated. Gamma ray line flares are distinguished from other flares by: (1) intense hard X-ray and microwave emissions; (2) delay of high energy hard X-rays; (3) emission of type 2 and/or type 4 radio bursts; and (4) flat hard X-ray spectra (average power law index: 3.1). The majority of the gamma ray line flares shared all these characteristics, and the remainder shared at least three of them. Positive correlations were found between durations of spike bursts and spatial sizes of flare loops as well as between delay times and durations of spike bursts.
-
Deckert-Schlüter, M; Rang, A; Weiner, D; Huang, S; Wiestler, O D; Hof, H; Schlüter, D
1996-12-01
Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of
-
A dizygotic twin pregnancy in a MODY 3-affected woman.
Bitterman, O; Iafusco, D; Torcia, F; Tinto, N; Napoli, A
2016-10-01
MODY diabetes includes rare familiar forms due to genetic mutations resulting in β-cell dysfunction. MODY 3 is due to mutations in the gene transcription factor HNF-1α, with diabetes diagnosis in adolescence or early adult life. Few data are available about MODY 3 in pregnancy. A 36-year-old Italian woman came to our unit at the 5th week of pregnancy. She was diagnosed with diabetes at 18 years, with negative autoimmunity and a strong familiarity for diabetes. She was treated with gliclazide and metformin. She had a previous pregnancy in which she was treated with insulin, giving birth at 38 weeks to a 3.210 kg baby girl, who showed neonatal hypoglycemia. We switched her to insulin treatment according to guidelines. We asked for genetic molecular testing, resulting in a HNF-1α gene mutation. A US examination at 7 weeks revealed a twin, bicorial, biamniotic pregnancy. At 37 weeks of gestation, she gave birth to two normal-weight baby girls; only one showed neonatal hypoglycemia and a genetic test revealed that she was affected by HNF-1α gene mutation. Subsequently, entire family of the woman was tested, showing that the father, the sister and the first daughter had the same HNF-1α mutation. A MODY 3 foetus needs a near-normal maternal glycemic control, because the exposure to intrauterine hyperglycemia can lead to an earlier age of diabetes onset. Neonatal hypoglycemia is generally observed in MODY 1 infants, but it is possible to hypothesize that some HNF-1α mutations could lead to a functionally impaired protein that might dysregulate HNF-4α expression determining hypoglycemia.
-
Banaee, Nooshin; Asgari, Sepideh; Nedaie, Hassan Ali
2018-07-01
The accuracy of penumbral measurements in radiotherapy is pivotal because dose planning computers require accurate data to adequately modeling the beams, which in turn are used to calculate patient dose distributions. Gamma knife is a non-invasive intracranial technique based on principles of the Leksell stereotactic system for open deep brain surgeries, invented and developed by Professor Lars Leksell. The aim of this study is to compare the penumbra widths of Leksell Gamma Knife model C and Gamma ART 6000. Initially, the structure of both systems were simulated by using Monte Carlo MCNP6 code and after validating the accuracy of simulation, beam profiles of different collimators were plotted. MCNP6 beam profile calculations showed that the penumbra values of Leksell Gamma knife model C and Gamma ART 6000 for 18, 14, 8 and 4 mm collimators are 9.7, 7.9, 4.3, 2.6 and 8.2, 6.9, 3.6, 2.4, respectively. The results of this study showed that since Gamma ART 6000 has larger solid angle in comparison with Gamma Knife model C, it produces better beam profile penumbras than Gamma Knife model C in the direct plane. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
Airflow-aligned helical nanofilament (B4) phase in topographic confinement
Gim, Min-Jun; Kim, Hanim; Chen, Dong; Shen, Yongqiang; Yi, Youngwoo; Korblova, Eva; Walba, David M.; Clark, Noel A.; Yoon, Dong Ki
2016-01-01
We investigated a controlled helical nanofilament (HNF: B4) phase under topographic confinement with airflow that can induce a shear force and temperature gradient on the sample. The resulting orientation and ordering of the B4 phase in this combinational effort was directly investigated using microscopy. The structural freedom of the complex B7 phase, which is a higher temperature phase than the B4 phase, can result in relatively complex microscopic arrangements of HNFs compared with the B4 phase generated from the simple layer structure of the B2 phase. This interesting chiral/polar nanofilament behaviour offers new opportunities for further exploration of the exotic physical properties of the B4 phase. PMID:27384747
-
Amara Konaté, Ahmed; Pan, Heping; Ma, Huolin; Qin, Zhen; Guo, Bo; Yevenyo Ziggah, Yao; Kounga, Claude Ernest Moussounda; Khan, Nasir; Tounkara, Fodé
2017-10-01
The main purpose of the Wenchuan Earthquake Fault Scientific drilling project (WFSD) was to produce an in-depth borehole into the Yingxiu-Beichuan (YBF) and Anxian-Guanxian faults in order to gain a much better understanding of the physical and chemical properties as well as the mechanical faulting involved. Five boreholes, namely WFSD-1, WFSD-2, WFSD-3P, WFSD-3 and WFSD-4, were drilled during the project entirety. This study, therefore, presents first-hand WFSD-4 data on the lithology (original rocks) and fault rocks that have been obtained from the WFSD project. In an attempt to determine the physical properties and the clay minerals of the lithology and fault rocks, this study analyzed the spectral gamma ray logs (Total gamma ray, Potassium, Thorium and Uranium) recorded in WFSD-4 borehole on the Northern segment of the YBF. The obtained results are presented as cross-plots and statistical multi log analysis. Both lithology and fault rocks show a variability of spectral gamma ray (SGR) logs responses and clay minerals. This study has shown the capabilities of the SGR logs for well-logging of earthquake faults and proves that SGR logs together with others logs in combination with drill hole core description is a useful method of lithology and fault rocks characterization. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
Polyfunctional cytokine responses by central memory CD4*T cells in response to bovine tuberculosis
USDA-ARS?s Scientific Manuscript database
CD4 T cells are crucial in immunity to tuberculosis (TB). Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB. Mycobacterium bovis in...
-
Polyfunctional cytokine responses by central memory CD4+T cells in response to bovine tuberculosis
USDA-ARS?s Scientific Manuscript database
CD4 T cells are crucial in immunity to tuberculosis (TB). Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB and HIV. Mycobacterium ...
-
Takizawa, F; Adamczewski, M; Kinet, J P
1992-08-01
In addition to their well characterized high affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) mast cells have long been suspected to express undefined Fc receptors capable of binding IgE with low affinity. In this paper, we show that Fc gamma RII and Fc gamma RIII, but not Mac-2, on mouse mast cells and macrophages bind IgE-immune complexes. This binding is efficiently competed by 2.4G2, a monoclonal antibody against the extracellular homologous region of both Fc gamma RII and Fc gamma RIII. Furthermore, IgE-immune complexes bind specifically to Fc gamma RII or Fc gamma RIII transfected into COS-7 cells. The association constants of IgE binding estimated from competition experiments are about 3.1 x 10(5) M-1 for Fc gamma RII, and 4.8 x 10(5) M-1 for Fc gamma RIII. Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin. This release is inhibited by 2.4G2, and at maximum, reaches 30-40% of the intracellular content, about half of the maximal release (60-80%) obtained after Fc epsilon RI engagement. These data demonstrate that mouse Fc gamma RII and Fc gamma RIII are not isotype specific, and that the binding of IgE-immune complexes to these receptors induces cell activation.
-
Electron Acceleration and Efficiency in Nonthermal Gamma-Ray Sources
NASA Astrophysics Data System (ADS)
Bykov, A. M.; Meszaros, P.
1996-04-01
In energetic nonthermal sources such as gamma-ray bursts, active galactic nuclei, or galactic jets, etc., one expects both relativistic and transrelativistic shocks accompanied by violent motions of moderately relativistic plasma. We present general considerations indicating that these sites are electron and positron accelerators leading to a modified power-law spectrum. The electron (or e+/-) energy index is very hard, ~ gamma -1 or flatter, up to a comoving frame break energy gamma *, and becomes steeper above that. In the example of gamma-ray bursts, the Lorentz factor reaches gamma * ~ 103 for e+/- accelerated by the internal shock ensemble on subhydrodynamical timescales. For pairs accelerated on hydrodynamical timescales in the external shocks, similar hard spectra are obtained, and the break Lorentz factor can be as high as gamma * <~ 105. Radiation from the nonthermal electrons produces photon spectra with shapes and characteristic energies in qualitative agreement with observed generic gamma-ray burst and blazar spectra. The scenario described here provides a plausible way to solve one of the crucial problems of nonthermal high-energy sources, namely, the efficient transfer of energy from the proton flow to an appropriate nonthermal lepton component.
-
{gamma}-RAY AND PARSEC-SCALE JET PROPERTIES OF A COMPLETE SAMPLE OF BLAZARS FROM THE MOJAVE PROGRAM
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lister, M. L.; Hovatta, T.; Aller, M.
We investigate the Fermi Large Area Telescope {gamma}-ray and 15 GHz Very Long Baseline Array radio properties of a joint {gamma}-ray and radio-selected sample of active galactic nuclei (AGNs) obtained during the first 11 months of the Fermi mission (2008 August 4-2009 July 5). Our sample contains the brightest 173 AGNs in these bands above declination -30 Degree-Sign during this period, and thus probes the full range of {gamma}-ray loudness ({gamma}-ray to radio band luminosity ratio) in the bright blazar population. The latter quantity spans at least 4 orders of magnitude, reflecting a wide range of spectral energy distribution (SED)more » parameters in the bright blazar population. The BL Lac objects, however, display a linear correlation of increasing {gamma}-ray loudness with synchrotron SED peak frequency, suggesting a universal SED shape for objects of this class. The synchrotron self-Compton model is favored for the {gamma}-ray emission in these BL Lac objects over external seed photon models, since the latter predict a dependence of Compton dominance on Doppler factor that would destroy any observed synchrotron SED-peak-{gamma}-ray-loudness correlation. The high-synchrotron peaked (HSP) BL Lac objects are distinguished by lower than average radio core brightness temperatures, and none display large radio modulation indices or high linear core polarization levels. No equivalent trends are seen for the flat-spectrum radio quasars (FSRQs) in our sample. Given the association of such properties with relativistic beaming, we suggest that the HSP BL Lac objects have generally lower Doppler factors than the lower-synchrotron peaked BL Lac objects or FSRQs in our sample.« less
-
Oke, Olaleke O; Magony, Andor; Anver, Himashi; Ward, Peter D; Jiruska, Premysl; Jefferys, John G R; Vreugdenhil, Martin
2010-04-01
Synchronization of neuronal activity in the visual cortex at low (30-70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-gamma; peak frequency approximately 80 Hz at 37 degrees C) that can coexist with low-frequency gamma oscillations (slow-gamma; peak frequency approximately 50 Hz at 37 degrees C) in the same column. Current-source density analysis showed that fast-gamma was associated with rhythmic current sink-source sequences in layer III and slow-gamma with rhythmic current sink-source sequences in layer V. Fast-gamma and slow-gamma were not phase-locked. Slow-gamma power fluctuations were unrelated to fast-gamma power fluctuations, but were modulated by the phase of theta (3-8 Hz) oscillations generated in the deep layers. Fast-gamma was spatially less coherent than slow-gamma. Fast-gamma and slow-gamma were dependent on gamma-aminobutyric acid (GABA)(A) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and gap-junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast-gamma and slow-gamma power were differentially modulated by thiopental and adenosine A(1) receptor blockade, and their frequencies were differentially modulated by N-methyl-D-aspartate (NMDA) receptors, GluK1 subunit-containing receptors and persistent sodium currents. Our data indicate that fast-gamma and slow-gamma both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co-existence of fast-gamma and slow-gamma allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high-frequency gamma oscillations.
-
NASA Astrophysics Data System (ADS)
Medley, S. S.; Cecil, F. E.; Cole, D.; Conway, M. A.; Wilkinson, F. J., III
1985-05-01
Nuclear reactions of interest in fusion research often possess a branch yielding prompt emission of gamma radiation in excess of 15 MeV which can be exploited to provide a new fusion reaction diagnostic having applications similar to conventional neutron emission measurements. Conceptual aspects of fusion gamma diagnostics are discussed with emphasis on application to the Tokamak Fusion Test Reactor (TFTR) during deuterium neutral beam heating of D-T and D-3He plasmas. Recent measurements of the D (T, γ)5He, D(3He, γ)5Li, and D(D, γ)4He branching ratios at low center-of-mass energy (30-100 keV) and of the response of a large volume Ne226 detector for gamma detection in high neutron backgrounds are presented. Using a well-shielded Ne226 detector during 20 MW-120 kV deuterium beam heating of a tritium plasma in TFTR, the D(T, γ)5He gamma signal level is estimated to be 3.5×105 cps.
-
Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines
Terasawa, K; Toyota, M; Sagae, S; Ogi, K; Suzuki, H; Sonoda, T; Akino, K; Maruyama, R; Nishikawa, N; Imai, K; Shinomura, Y; Saito, T; Tokino, T
2006-01-01
Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1β (HNF1β), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2′deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4α, a transcriptional target of HNF1β, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment. PMID:16479257
-
Polyfunctional CD4 T cells in the response to bovine tuberculosis
USDA-ARS?s Scientific Manuscript database
Polyfunctional CD4 T cells simultaneously produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) and play relevant roles in several chronic infections, including human TB and HIV. However, the assessment of this response in bovine infections was not fe...
-
Komohara, Yoshihiro; Takemura, Kenichi; Lei, Xiao Feng; Sakashita, Naomi; Harada, Mamoru; Suzuki, Hiroshi; Kodama, Tatsuhiko; Takeya, Motohiro
2009-11-01
Class A scavenger receptors (SR-A, CD204) are highly expressed in tumor-associated macrophages (TAM). To investigate the function of SR-A in TAM, wild-type and SR-A-deficient (SR-A(-/-)) mice were injected with EL4 cells. Although these groups of mice did not differ in the numbers of infiltrating macrophages and lymphocytes and in neovascularization, SR-A(-/-) mice had delayed growth of EL4 tumors. Expression of inducible nitric oxide (NO) synthase and interferon (IFN)-gamma mRNA increased significantly in tumor tissues from SR-A(-/-) mice. Engulfment of necrotic EL4 cells induced upregulation of NO and IFN-gamma production by cultured macrophages, and production of NO and IFN-gamma increased in SR-A(-/-) macrophages in vitro. IFN-beta production by cultured macrophages was also elevated in SR-A(-/-) macrophages in vitro. These results suggested that the antitumor activity of macrophages increased in SR-A(-/-) mice because of upregulation of NO and IFN-gamma production. These data indicate an important role of SR-A in regulating TAM function by inhibiting toll-like receptor (TLR)4-IFN-beta signaling.
-
Gamma-ray burster recurrence timescales
NASA Technical Reports Server (NTRS)
Schaefer, B. E.; Cline, T. L.
1984-01-01
Three optical transients have been found which are associated with gamma-ray bursters (GRBs). The deduced recurrence timescale for these optical transients (tau sub opt) will depend on the minimum brightness for which a flash would be detected. A detailed analysis using all available data of tau sub opt as a function of E(gamma)/E(opt) is given. For flashes similar to those found in the Harvard archives, the best estimate of tau sub opt is 0.74 years, with a 99% confidence interval from 0.23 years to 4.7 years. It is currently unclear whether the optical transients from GRBs also give rise to gamma-ray events. One way to test this association is to measure the recurrence timescale of gamma-ray events tau sub gamma. A total of 210 gamma-ray error boxes were examined and it was found that the number of observed overlaps is not significantly different from the number expected from chance coincidence. This observation can be used to place limits on tau sub gamma for an assumed luminosity function. It was found that tau sub gamma is approx. 10 yr if bursts are monoenergetic. However, if GRBs have a power law luminosity function with a wide dynamic range, then the limit is tau sub gamma 0.5 yr. Hence, the gamma-ray data do not require tau sub gamma and tau sub opt to be different.
-
Attentional modulation of cell-class specific gamma-band synchronization in awake monkey area V4
Vinck, Martin; Womelsdorf, Thilo; Buffalo, Elizabeth A.; Desimone, Robert; Fries, Pascal
2013-01-01
Summary Selective visual attention is subserved by selective neuronal synchronization, entailing precise orchestration among excitatory and inhibitory cells. We tentatively identified these as broad (BS) and narrow spiking (NS) cells and analyzed their synchronization to the local field potential in two macaque monkeys performing a selective visual attention task. Across cells, gamma phases scattered widely but were unaffected by stimulation or attention. During stimulation, NS cells lagged BS cells on average by ~60° and gamma synchronized twice as strongly. Attention enhanced and reduced the gamma locking of strongly and weakly activated cells, respectively. During a pre-stimulus attentional cue period, BS cells showed weak gamma synchronization, while NS cells gamma synchronized as strongly as with visual stimulation. These analyses reveal the cell-type specific dynamics of the gamma cycle in macaque visual cortex and suggest that attention affects neurons differentially depending on cell type and activation level. PMID:24267656
-
Silva, J S; Vespa, G N; Cardoso, M A; Aliberti, J C; Cunha, F Q
1995-01-01
Cell invasion by Trypanosoma cruzi and its intracellular replication are essential for continuation of the parasite life cycle and for production of Chagas' disease. T. cruzi is able to replicate in nucleated cells and can be killed by activated macrophages. Gamma interferon (IFN-gamma) is one of the major stimuli for the activation of macrophages and has been shown to be a key activation factor for the killing of intracellular parasites through a mechanism dependent upon nitric oxide (NO) biosynthesis. We show that although the addition of exogenous tumor necrosis factor alpha (TNF-alpha) does not potentiate the trypanocidal activity of IFN-gamma in vitro, treatment of resistant C57BI/6 mice with an anti-TNF-alpha monoclonal antibody increased parasitemia and mortality. In addition, the anti-TNF-alpha-treated animals had decreased NO production, both in vivo and in vitro, suggesting an important role for TNF-alpha in controlling infection. In order to better understand the role of TNF-alpha in the macrophage-mediating killing of parasites, cultures of T. cruzi-infected macrophages were treated with an anti-TNF-alpha monoclonal antibody. IFN-gamma-activated macrophages failed to kill intracellular parasites following treatment with 100 micrograms of anti-TNF-alpha. In these cultures, the number of parasites released at various time points after infection was significantly increased while NO production was significantly reduced. We conclude that IFN-gamma-activated macrophages produce TNF-alpha after infection by T. cruzi and suggest that this cytokine plays a role in amplifying NO production and parasite killing. PMID:7591147
-
Modulation of PPAR-Gamma Signaling in Prostatic Carcinogenesis
2009-09-01
AD_________________ AWARD NUMBER: W81XWH-07-1-0479 TITLE: Modulation of PPAR -Gamma Signaling in...REPORT TYPE Annual 3. DATES COVERED 1 Sep 2008 – 1 Sep 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Modulation of PPAR -Gamma Signaling in...4 Annual Report PCRP Idea Development Award W81XWH-07-1-0479 Modulation of PPAR -Gamma Signaling in Prostatic Carcinogenesis P.I. Simon W
-
Anticonvulsant properties of alpha, gamma, and alpha, gamma-substituted gamma-butyrolactones.
Klunk, W E; Covey, D F; Ferrendelli, J A
1982-09-01
Derivatives of gamma-butyrolactone (GBL) substituted on the alpha- and/or gamma-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), alpha, alpha-dimethyl GBL, alpha, gamma-diethyl-alpha, gamma-dimethyl GBL, and gamma-ethyl-gamma-methyl GBL, prevented seizures induced by pentylenetetrazol, beta-ethyl-beta-methyl-gamma-butyrolactone (beta-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither gamma-hydroxybutyrate (GHB) nor alpha-isopropylidine GBL had any anticonvulsant activity. The anticonvulsant alpha-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of beta-EMGBL, alpha-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by beta-EMGBL. These results demonstrate that alpha-alkyl-substituted GBL and, to a lesser extent, gamma-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or beta-alkyl-substituted GBLs, which are epileptogenic. Possibly beta- and alpha-substituted GBLs act at the same site as agonists and antagonists, respectively.
-
Xie, Yan-Hui; Chen, Qin-Fen; Xie, Yi; Xie, Hong
2002-12-01
To observe the proliferation of T lymphocytes stimulated by CML and AML cells which were induced by rhGM-CSF and rhIL-4, and the secretion of IFN-gamma from proliferated T lymphocytes, the expression of CD80, CD86 and HLA-DR on CML and AML cells induced by GM-CSF and IL-4 was assayed by flow cytometry in vitro. Then one-way mixed lymphocyte reaction was carried out, with induced leukemia cells as stimulating cells and auto-T lymphocytes as reactive cells. The secretion of IFN-gamma from T lymphocytes was determined by double antibody sandwich ELISA. The results showed that GM-CSF and IL-4 significantly upregulated the expression of CD80, CD86 and HLA-DR on CML cells and CD80 and CD86 on AML cells, which could stimulate the T lymphocyte proliferation and high secretion of IFN-gamma (in CML group) of autologous T lymphocytes. It is concluded that the CML and AML cells induced by GM-CSF and IL-4 have the ability to present tumor specific antigen to auto-T lymphocyte.
-
1992-01-01
In addition to their well characterized high affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) mast cells have long been suspected to express undefined Fc receptors capable of binding IgE with low affinity. In this paper, we show that Fc gamma RII and Fc gamma RIII, but not Mac-2, on mouse mast cells and macrophages bind IgE-immune complexes. This binding is efficiently competed by 2.4G2, a monoclonal antibody against the extracellular homologous region of both Fc gamma RII and Fc gamma RIII. Furthermore, IgE-immune complexes bind specifically to Fc gamma RII or Fc gamma RIII transfected into COS-7 cells. The association constants of IgE binding estimated from competition experiments are about 3.1 x 10(5) M-1 for Fc gamma RII, and 4.8 x 10(5) M-1 for Fc gamma RIII. Engagement of Fc gamma RII and Fc gamma RIII with IgE-immune complexes (after blocking access to Fc epsilon RI) or with IgG-immune complexes triggers C57.1 mouse mast cells to release serotonin. This release is inhibited by 2.4G2, and at maximum, reaches 30-40% of the intracellular content, about half of the maximal release (60-80%) obtained after Fc epsilon RI engagement. These data demonstrate that mouse Fc gamma RII and Fc gamma RIII are not isotype specific, and that the binding of IgE-immune complexes to these receptors induces cell activation. PMID:1386873
-
Early optical emission from the gamma-ray burst of 4 October 2002.
Fox, D W; Yost, S; Kulkarni, S R; Torii, K; Kato, T; Yamaoka, H; Sako, M; Harrison, F A; Sari, R; Price, P A; Berger, E; Soderberg, A M; Djorgovski, S G; Barth, A J; Pravdo, S H; Frail, D A; Gal-Yam, A; Lipkin, Y; Mauch, T; Harrison, C; Buttery, H
2003-03-20
Observations of the long-lived emission--or 'afterglow'--of long-duration gamma-ray bursts place them at cosmological distances, but the origin of these energetic explosions remains a mystery. Observations of optical emission contemporaneous with the burst of gamma-rays should provide insight into the details of the explosion, as well as into the structure of the surrounding environment. One bright optical flash was detected during a burst, but other efforts have produced negative results. Here we report the discovery of the optical counterpart of GRB021004 only 193 seconds after the event. The initial decline is unexpectedly slow and requires varying energy content in the gamma-ray burst blastwave over the course of the first hour. Further analysis of the X-ray and optical afterglow suggests additional energy variations over the first few days.
-
Olsen, J; Lefebvre, O; Fritsch, C; Troelsen, J T; Orian-Rousseau, V; Kedinger, M; Simon-Assmann, P
2000-01-01
Laminin-5 is a trimer of laminin alpha3, beta3 and gamma2 chains that is found in the intestinal basement membrane. Deposition of the laminin gamma2 chain at the basement membrane is of great interest because it undergoes a developmental shift in its cellular expression. Here we study the regulatory elements that control basal and cytokine-activated transcriptional expression of the LAMC2 gene, which encodes the laminin gamma2 chain. By using transient transfection experiments we demonstrated the presence of constitutive and cytokine-responsive cis-elements. Comparison of the transcriptional activity of the LAMC2 promoter in the epithelial HT29mtx cells with that in small-intestinal fibroblastic cells (C20 cells) led us to conclude that two regions with constitutive epithelium-specific activity are present between positions -1.2 and -0.12 kb. This was further validated by transfections of primary foetal intestinal endoderm and mesenchyme. A 2.5 kb portion of the LAMC2 5' flanking region was equally responsive to PMA and hepatocyte growth factor (HGF), whereas it was less responsive to transforming growth factor beta1. A minimal promoter limited to the initial 120 bp upstream of the transcriptional start site maintained inducibility by PMA and HGF. This short promoter fragment contains two activator protein 1 (AP-1) elements and the 5'-most of these is a composite AP-1/Sp1 element. The 5'AP-1 element is crucial to the HGF-mediated activity of the promoter; analysis of interacting nuclear proteins demonstrated that AP-1 proteins containing JunD mediate the response to HGF. PMID:10749670
-
MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β*
Hao, Jielu; Lou, Qiang; Wei, Qingqing; Mei, Shuqin; Li, Lin; Wu, Guangyu; Mi, Qing-Sheng; Mei, Changlin; Dong, Zheng
2017-01-01
Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity. PMID:28119452
-
de Alencar, Bruna C G; Persechini, Pedro M; Haolla, Filipe A; de Oliveira, Gabriel; Silverio, Jaline C; Lannes-Vieira, Joseli; Machado, Alexandre V; Gazzinelli, Ricardo T; Bruna-Romero, Oscar; Rodrigues, Mauricio M
2009-10-01
A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4(+) and CD8(+) T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4(+) and CD8(+) T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-gamma) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8(+) T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-gamma or IFN-gamma/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-gamma in the presence of highly cytotoxic T cells. Vaccinated IFN-gamma-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-gamma in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy.
-
Maturity-onset diabetes of the young (MODY): an update.
Anık, Ahmet; Çatlı, Gönül; Abacı, Ayhan; Böber, Ece
2015-03-01
Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders characterized by autosomal dominantly inherited non-insulin dependent form of diabetes classically presenting in adolescence or young adults before the age of 25 years. MODY is a rare cause of diabetes (1% of all cases) and is frequently misdiagnosed as Type 1 diabetes (T1DM) or Type 2 diabetes (T2DM). A precise molecular diagnosis is essential because it leads to optimal treatment of the patients and allows early diagnosis for their asymptomatic family members. Mutations in the glucokinase (GCK) (MODY 2) and hepatocyte nuclear factor (HNF)1A/4A (MODY 3 and MODY 1) genes are the most common causes of MODY. GCK mutations cause a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment. However, mutations in the HNF1A and HNF4A cause a progressive pancreatic β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in these patients by acting on adenosine triphosphate (ATP)-sensitive potassium channels, although insulin therapy may be required later in life. Mutations in the HNF1B (MODY 5) is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction. Compared to MODY 1, 2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. In this review, we summarize the main clinical and laboratory characteristics of the common and rarer causes of MODY.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Richard, Cynthia Lee; Lowthers, Erica Lauren; Blay, Jonathan
2007-10-01
The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE{sub 2}, PGA{sub 2}, PGD{sub 2}, PGJ{sub 2} and 15dPGJ{sub 2} each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD{sub 2} and its metabolites PGJ{sub 2} and 15dPGJ{sub 2}. Down-regulation was most rapid with the end-product 15dPGJ{sub 2} and was accompanied bymore » a marked reduction in CXCR4 mRNA. 15dPGJ{sub 2} is known to be a ligand for the nuclear receptor PPAR{gamma}. Down-regulation of CXCR4 was also observed with the PPAR{gamma} agonist rosiglitazone, while 15dPGJ{sub 2}-induced CXCR4 down-regulation was substantially diminished by the PPAR{gamma} antagonists GW9662 and T0070907. These data support the involvement of PPAR{gamma}. However, the 15dPGJ{sub 2} analogue CAY10410, which can act on PPAR{gamma} but which lacks the intrinsic cyclopentenone structure found in 15dPGJ{sub 2}, down-regulated CXCR4 substantially less potently than 15dPGJ{sub 2}. The cyclopentenone grouping is known to inhibit the activity of NF{kappa}B. Consistent with an additional role for NF{kappa}B, we found that the cyclopentenone prostaglandin PGA{sub 2} and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NF{kappa}B p50 and that 15dPGJ{sub 2} interfered with this p50 nuclear localization. These data suggest that 15dPGJ{sub 2} can down-regulate CXCR4 on cancer cells through both PPAR{gamma} and NF{kappa}B. 15dPGJ{sub 2}, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.« less
-
Wüst, F; Hultsch, C; Bergmann, R; Johannsen, B; Henle, T
2003-07-01
The isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine 4 was labelled with 18F via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). A modified approach for the convenient synthesis of [18F]SFB was used, and [18F]SFB could be obtained in decay-corrected radiochemical yields of 44-53% (n = 20) and radiochemical purity >95% within 40 min after EOB. For labelling N(epsilon)-(gamma-glutamyl)-L-lysine with [18F]SFB the effects of isopeptide concentration, temperature, and pH were studied to determine the optimum reaction conditions. The coupling reaction was shown to be temperature and pH independent while being strongly affected by the isopeptide concentration. Using the optimized labelling conditions, in a typical experiment 1.3GBq of [18F]SFB could be converted into 447MBq (46%, decay-corrected) of [18F]fluorobenzoylated isopeptide within 45 min, including HPLC purification.
-
Platelet factor-4 (CXCL4/PF-4): an angiostatic chemokine for cancer therapy.
Wang, Zhe; Huang, He
2013-05-01
Platelet factor-4 (CXCL4/PF-4) is the first chemokine identified to have several biological functions. Notably, CXCL4/PF-4 inhibits endothelial cell proliferation and migration, leading to suppression of angiogenesis. Since angiogenesis is essential for the growth of most primary tumors and their subsequent metastases, it is a target for cancer therapy; due to its multiple functions, CXCL4/PF-4 is a potential clinical anti-tumor agent. This report reviews the mechanisms of CXCL4/PF-4 angiostatic activity, including interference with angiogenic growth factors bFGF-2 and VEGF165, activation of CXCR3B, interactions with integrins, interference with cell cycle, interactions with factors such as VEGF121 and CXCL8/IL-8, and derived molecules of CXCL4/PF-4 with angiostatic and anti-tumoral activities in different models in vivo or in vitro. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Artemov, S. V.; Igamov, S. B., E-mail: igamov@inp.uz; Tursunmakhatov, Q. I.
2012-03-15
The astrophysical S factors for the radiative-capture reaction {sup 14}N(p, {gamma}){sup 15}O in the region of ultralow energies were calculated on the basis of the R-matrix approach. The values of the radiative and protonic widths were fitted to new experimental data. The contribution of direct radiative capture to bound states of the {sup 15}O nucleus was determined with the aid of asymptotic normalization coefficients, whose values were refined in the present study on the basis of the results obtained from an analysis of the reaction {sup 14}N({sup 3}He, d){sup 15}O at three different energies of incident helium ions. A valuemore » of S(0) = 1.79 {+-} 0.31 keV b was obtained for the total astrophysical S factor, and the reaction rate was determined for the process {sup 14}N(p, {gamma}){sup 15}O.« less
-
Maddens, Stéphane; Charruyer, Alexandra; Plo, Isabelle; Dubreuil, Patrice; Berger, Stuart; Salles, Bernard; Laurent, Guy; Jaffrézou, Jean-Pierre
2002-08-15
Previous studies demonstrated that Kit activation confers radioprotection. However, the mechanism by which Kit signaling interferes with cellular response to ionizing radiation (IR) has not been firmly established. Based on the role of the sphingomyelin (SM) cycle apoptotic pathway in IR-induced apoptosis, we hypothesized that one of the Kit signaling components might inhibit IR-induced ceramide production or ceramide-induced apoptosis. Results show that, in both Ba/F3 and 32D murine cell lines transfected with wild-type c-kit, stem cell factor (SCF) stimulation resulted in a significant reduction of IR-induced apoptosis and cytotoxicity, whereas DNA repair remained unaffected. Moreover, SCF stimulation inhibited IR-induced neutral sphingomyelinase (N-SMase) stimulation and ceramide production. The SCF inhibitory effect on SM cycle was not influenced by wortmannin, a phosphoinositide-3 kinase (PI3K) inhibitor. The SCF protective effect was maintained in 32D-KitYF719 cells in which the PI3K/Akt signaling pathway is abolished due to mutation in Kit docking site for PI3K. In contrast, phospholipase C gamma (PLC gamma) inhibition by U73122 totally restored IR-induced N-SMase stimulation, ceramide production, and apoptosis in Kit-activated cells. Moreover, SCF did not protect 32D-KitYF728 cells (lacking a functional docking site for PLC gamma 1), from IR-induced SM cycle. Finally, SCF-induced radioprotection of human CD34(+) bone marrow cells was also inhibited by U73122. Altogether, these results suggest that SCF radioprotection is due to PLC gamma 1-dependent negative regulation of IR-induced N-SMase stimulation. Beyond the scope of Kit-expressing cells, it suggests that PLC gamma 1 status could greatly influence the post-DNA damage cellular response to IR, and perhaps, to other genotoxic agents.
-
NASA Astrophysics Data System (ADS)
Kumar Dixit, Amit; Kumar, Vineet; Rani, Anita; Manjaya, J. G.; Bhatnagar, Deepak
2011-04-01
Three soybean genotypes Kalitur, Hara soya and NRC37 with black, green and yellow seed coat color, respectively, were gamma irradiated at 0.5, 2.0 and 5.0 kGy and tested for antinutritional and nutritional factors. Gamma irradiation at all doses reduced the level of lipoxygenase isomers, trypsin inhibitor (TI) and ascorbic acid in all the 3 soybean genotypes as compared to the unirradiated control. However, irradiation dose of 5.0 kGy increased the sucrose content of the soybean genotypes. No significant change was observed in oil, protein fatty acids and total tocopherol content of the 3 genotypes at any irradiation dose. It is suggested that inhibition of lipoxygenase, reduction in TI and ascorbic acid may be due to the breakage or oxidation of protein structure by the gamma irradiation. Similarly, gamma irradiation at higher doses may break glycosidic linkages in oligosaccharides to produce more sucrose and decrease the content of flatulence causing oligosaccharides.
-
Bulk Lorentz factors of gamma-ray bursts
NASA Astrophysics Data System (ADS)
Ghirlanda, G.; Nappo, F.; Ghisellini, G.; Melandri, A.; Marcarini, G.; Nava, L.; Salafia, O. S.; Campana, S.; Salvaterra, R.
2018-01-01
Knowledge of the bulk Lorentz factor Γ0 of gamma-ray bursts (GRBs) allows us to compute their comoving frame properties shedding light on their physics. Upon collisions with the circumburst matter, the fireball of a GRB starts to decelerate, producing a peak or a break (depending on the circumburst density profile) in the light curve of the afterglow. Considering all bursts with known redshift and with an early coverage of their emission, we find 67 GRBs (including one short event) with a peak in their optical or GeV light curves at a time tp. For another 106 GRBs we set an upper limit tpUL. The measure of tp provides the bulk Lorentz factor Γ0 of the fireball before deceleration. We show that tp is due to the dynamics of the fireball deceleration and not to the passage of a characteristic frequency of the synchrotron spectrum across the optical band. Considering the tp of 66 long GRBs and the 85 most constraining upper limits, we estimate Γ0 or a lower limit Γ0LL. Using censored data analysis methods, we reconstruct the most likely distribution of tp. All tp are larger than the time Tp,γ when the prompt γ-ray emission peaks, and are much larger than the time Tph when the fireball becomes transparent, that is, tp>Tp,γ>Tph. The reconstructed distribution of Γ0 has median value 300 (150) for a uniform (wind) circumburst density profile. In the comoving frame, long GRBs have typical isotropic energy, luminosity, and peak energy ⟨ Eiso ⟩ = 3(8) × 1050 erg, ⟨ Liso ⟩ = 3(15) × 1047 erg s-1, and ⟨ Epeak ⟩ = 1(2) keV in the homogeneous (wind) case. We confirm that the significant correlations between Γ0 and the rest frame isotropic energy (Eiso), luminosity (Liso), and peak energy (Ep) are not due to selection effects. When combined, they lead to the observed Ep-Eiso and Ep-Liso correlations. Finally, assuming a typical opening angle of 5 degrees, we derive the distribution of the jet baryon loading which is centered around a few 10-6M⊙.
-
Fermi LAT detection of enhanced gamma-ray emission from the Crab Nebula region
NASA Astrophysics Data System (ADS)
Ojha, Roopesh; Buehler, Rolf; Hays, Elizabeth; Dutka, Michael
2012-07-01
The Large Area Telescope (LAT), one of the two instruments on the Fermi Gamma-ray Space Telescope, has observed a significant increase in the gamma-ray activity from a source positionally consistent with the Crab Nebula on July 3, 2012. Preliminary LAT analysis indicates that the daily-averaged gamma-ray emission (E >100 MeV) from the direction of the Crab doubled from (2.4 +/- 0.5) x 10^-6 ph/cm2/sec (statistical errors only) on July 2nd to (5.5 +/- 0.7) x 10^-6 ph/cm2/sec on July 3rd, a factor of 2 greater than the average flux of (2.75 +/- 0.10) x 10^-6 ph/cm2/sec reported in the second Fermi LAT catalog (2FGL, Nolan et al.
-
Directional detector of gamma rays
Cox, Samson A.; Levert, Francis E.
1979-01-01
A directional detector of gamma rays comprises a strip of an electrical cuctor of high atomic number backed with a strip of a second electrical conductor of low atomic number. These elements are enclosed within an electrical conductor that establishes an electrical ground, maintains a vacuum enclosure and screens out low-energy gamma rays. The detector exhibits a directional sensitivity marked by an increased output in the favored direction by a factor of ten over the output in the unfavored direction.
-
Lee, Seunghoon; Seo, Seong-Wook; Hwang, Juyoung; Seol, Ho Jun; Nam, Do-Hyun; Lee, Jung-Il; Kong, Doo-Sik
2016-12-01
Communicating hydrocephalus (HCP) in vestibular schwannomas (VS) after gamma knife radiosurgery (GKRS) has been reported in the literature. However, little information about its incidence and risk factors after GKRS for intracranial schwannomas is yet available. The objective of this study was to identify the incidence and risk factors for developing communicating HCP after GKRS for intracranial schwannomas. We retrospectively reviewed a total of 702 patients with intracranial schwannomas who were treated with GKRS between January 2002 and December 2015. We investigated patients' age, gender, tumor origin, previous surgery history, tumor volume, marginal radiation dose, and presence of tumor control to identify associations with communicating HCP following GKRS. To make predictive models of communicating HCP, we performed Cox regression analyses and constructed a decision tree for risk factors. In total, 29 of the 702 patients (4.1%) developed communicating HCP following GKRS, which required ventriculo-peritoneal (VP) shunt surgery. Multivariate analyses indicated that age (P = 0.0011), tumor origin (P = 0.0438), and tumor volume (P < 0.0001) were significant predictors of communicating HCP in patients with intracranial schwannoma after GKRS. Using machine-learning methods, we fit an optimal predictive model. We found that developing communicating HCP following GKRS was most likely if the tumor was vestibular origin and had a volume ≥13.65 cm 3 . Communicating HCP is not a rare complication of GKRS for intracranial schwannomas. Under specific conditions, communicating HCP following GKRS is warranted for this patient group, and this patient group should be closely followed up. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
-
Accurate Wavelength Measurement of High-Energy Gamma Rays from the 35Cl(n,{gamma}) Reactions
DOE Office of Scientific and Technical Information (OSTI.GOV)
Belgya, T.; Molnar, G.L.; Mutti, P.
2005-05-24
The energies of eight gamma rays in the 36Cl level scheme have been measured with high precision using the 35Cl(n,{gamma}) reaction and the GAMS4 spectrometer. From these energies, a skeleton decay scheme for 36Cl was constructed, and the binding energy of 36Cl was determined to higher precision than previously. It is shown that using this new information, binding energy determination from Ge detector experiments for other nuclei can also be made with higher precision than now available. The measurement of additional weaker 36Cl gamma rays is continuing.
-
Dynamic gamma knife radiosurgery
NASA Astrophysics Data System (ADS)
Luan, Shuang; Swanson, Nathan; Chen, Zhe; Ma, Lijun
2009-03-01
Gamma knife has been the treatment of choice for various brain tumors and functional disorders. Current gamma knife radiosurgery is planned in a 'ball-packing' approach and delivered in a 'step-and-shoot' manner, i.e. it aims to 'pack' the different sized spherical high-dose volumes (called 'shots') into a tumor volume. We have developed a dynamic scheme for gamma knife radiosurgery based on the concept of 'dose-painting' to take advantage of the new robotic patient positioning system on the latest Gamma Knife C™ and Perfexion™ units. In our scheme, the spherical high dose volume created by the gamma knife unit will be viewed as a 3D spherical 'paintbrush', and treatment planning reduces to finding the best route of this 'paintbrush' to 'paint' a 3D tumor volume. Under our dose-painting concept, gamma knife radiosurgery becomes dynamic, where the patient moves continuously under the robotic positioning system. We have implemented a fully automatic dynamic gamma knife radiosurgery treatment planning system, where the inverse planning problem is solved as a traveling salesman problem combined with constrained least-square optimizations. We have also carried out experimental studies of dynamic gamma knife radiosurgery and showed the following. (1) Dynamic gamma knife radiosurgery is ideally suited for fully automatic inverse planning, where high quality radiosurgery plans can be obtained in minutes of computation. (2) Dynamic radiosurgery plans are more conformal than step-and-shoot plans and can maintain a steep dose gradient (around 13% per mm) between the target tumor volume and the surrounding critical structures. (3) It is possible to prescribe multiple isodose lines with dynamic gamma knife radiosurgery, so that the treatment can cover the periphery of the target volume while escalating the dose for high tumor burden regions. (4) With dynamic gamma knife radiosurgery, one can obtain a family of plans representing a tradeoff between the delivery time and the
-
NASA Astrophysics Data System (ADS)
Zoros, E.; Moutsatsos, A.; Pappas, E. P.; Georgiou, E.; Kollias, G.; Karaiskos, P.; Pantelis, E.
2017-09-01
Detector-, field size- and machine-specific correction factors are required for precise dosimetry measurements in small and non-standard photon fields. In this work, Monte Carlo (MC) simulation techniques were used to calculate the k{{Qmsr},{{Q}0}}{{fmsr},{{f}ref}} and k{{Qclin},{{Q}msr}}{{fclin},{{f}msr}} correction factors for a series of ionization chambers, a synthetic microDiamond and diode dosimeters, used for reference and/or output factor (OF) measurements in the Gamma Knife Perfexion photon fields. Calculations were performed for the solid water (SW) and ABS plastic phantoms, as well as for a water phantom of the same geometry. MC calculations for the k{{Qclin},{{Q}msr}}{{fclin},{{f}msr}} correction factors in SW were compared against corresponding experimental results for a subset of ionization chambers and diode detectors. Reference experimental OF data were obtained through the weighted average of corresponding measurements using TLDs, EBT-2 films and alanine pellets. k{{Qmsr},{{Q}0}}{{fmsr},{{f}ref}} values close to unity (within 1%) were calculated for most of ionization chambers in water. Greater corrections of up to 6.0% were observed for chambers with relatively large air-cavity dimensions and steel central electrode. A phantom correction of 1.006 and 1.024 (breaking down to 1.014 from the ABS sphere and 1.010 from the accompanying ABS phantom adapter) were calculated for the SW and ABS phantoms, respectively, adding up to k{{Qmsr},{{Q}0}}{{fmsr},{{f}ref}} corrections in water. Both measurements and MC calculations for the diode and microDiamond detectors resulted in lower than unit k{{Qclin},{{Q}msr}}{{fclin},{{f}msr}} correction factors, due to their denser sensitive volume and encapsulation materials. In comparison, higher than unit k{{Qclin},{{Q}msr}}{{fclin},{{f}msr}} results for the ionization chambers suggested field size depended dose underestimations (being significant for the 4 mm field), with magnitude depending on the combination of
-
Toward an understanding of the pathophysiology of clear cell carcinoma of the ovary (Review)
UEKURI, CHIHARU; SHIGETOMI, HIROSHI; ONO, SUMIRE; SASAKI, YOSHIKAZU; MATSUURA, MIYUKI; KOBAYASHI, HIROSHI
2013-01-01
Endometriosis-associated ovarian cancers demonstrate substantial morphological and genetic diversity. The transcription factor, hepatocyte nuclear factor (HNF)-1β, may be one of several key genes involved in the identity of ovarian clear cell carcinoma (CCC). The present study reviews a considerably expanded set of HNF-1β-associated genes and proteins that determine the pathophysiology of CCC. The current literature was reviewed by searching MEDLINE/PubMed. Functional interpretations of gene expression profiling in CCC are provided. Several important CCC-related genes overlap with those known to be regulated by the upregulation of HNF-1β expression, along with a lack of estrogen receptor (ER) expression. Furthermore, the genetic expression pattern in CCC resembles that of the Arias-Stella reaction, decidualization and placentation. HNF-1β regulates a subset of progesterone target genes. HNF-1β may also act as a modulator of female reproduction, playing a role in endometrial regeneration, differentiation, decidualization, glycogen synthesis, detoxification, cell cycle regulation, implantation, uterine receptivity and a successful pregnancy. In conclusion, the present study focused on reviewing the aberrant expression of CCC-specific genes and provided an update on the pathological implications and molecular functions of well-characterized CCC-specific genes. PMID:24179489
-
Dammermann, Alexander; Maddox, Paul S; Desai, Arshad; Oegema, Karen
2008-02-25
Centrioles are surrounded by pericentriolar material (PCM), which is proposed to promote new centriole assembly by concentrating gamma-tubulin. Here, we quantitatively monitor new centriole assembly in living Caenorhabditis elegans embryos, focusing on the conserved components SAS-4 and SAS-6. We show that SAS-4 and SAS-6 are coordinately recruited to the site of new centriole assembly and reach their maximum levels during S phase. Centriolar SAS-6 is subsequently reduced by a mechanism intrinsic to the early assembly pathway that does not require progression into mitosis. Centriolar SAS-4 remains in dynamic equilibrium with the cytoplasmic pool until late prophase, when it is stably incorporated in a step that requires gamma-tubulin and microtubule assembly. These results indicate that gamma-tubulin in the PCM stabilizes the nascent daughter centriole by promoting microtubule addition to its outer wall. Such a mechanism may help restrict new centriole assembly to the vicinity of preexisting parent centrioles that recruit PCM.
-
Veselsky, T; Novotny, J; Pastykova, V; Koniarova, I
2017-12-01
The aim of this study was to determine small field correction factors for a synthetic single-crystal diamond detector (PTW microDiamond) for routine use in clinical dosimetric measurements. Correction factors following small field Alfonso formalism were calculated by comparison of PTW microDiamond measured ratio M Qclin fclin /M Qmsr fmsr with Monte Carlo (MC) based field output factors Ω Qclin,Qmsr fclin,fmsr determined using Dosimetry Diode E or with MC simulation itself. Diode measurements were used for the CyberKnife and Varian Clinac 2100C/D linear accelerator. PTW microDiamond correction factors for Leksell Gamma Knife (LGK) were derived using MC simulated reference values from the manufacturer. PTW microDiamond correction factors for CyberKnife field sizes 25-5 mm were mostly smaller than 1% (except for 2.9% for 5 mm Iris field and 1.4% for 7.5 mm fixed cone field). The correction of 0.1% and 2.0% for 8 mm and 4 mm collimators, respectively, needed to be applied to PTW microDiamond measurements for LGK Perfexion. Finally, PTW microDiamond M Qclin fclin /M Qmsr fmsr for the linear accelerator varied from MC corrected Dosimetry Diode data by less than 0.5% (except for 1 × 1 cm 2 field size with 1.3% deviation). Regarding low resulting correction factor values, the PTW microDiamond detector may be considered an almost ideal tool for relative small field dosimetry in a large variety of stereotactic and radiosurgery treatment devices. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.
-
Constraining Gamma-Ray Pulsar Gap Models with a Simulated Pulsar Population
NASA Technical Reports Server (NTRS)
Pierbattista, Marco; Grenier, I. A.; Harding, A. K.; Gonthier, P. L.
2012-01-01
With the large sample of young gamma-ray pulsars discovered by the Fermi Large Area Telescope (LAT), population synthesis has become a powerful tool for comparing their collective properties with model predictions. We synthesised a pulsar population based on a radio emission model and four gamma-ray gap models (Polar Cap, Slot Gap, Outer Gap, and One Pole Caustic). Applying gamma-ray and radio visibility criteria, we normalise the simulation to the number of detected radio pulsars by a select group of ten radio surveys. The luminosity and the wide beams from the outer gaps can easily account for the number of Fermi detections in 2 years of observations. The wide slot-gap beam requires an increase by a factor of 10 of the predicted luminosity to produce a reasonable number of gamma-ray pulsars. Such large increases in the luminosity may be accommodated by implementing offset polar caps. The narrow polar-cap beams contribute at most only a handful of LAT pulsars. Using standard distributions in birth location and pulsar spin-down power (E), we skew the initial magnetic field and period distributions in a an attempt to account for the high E Fermi pulsars. While we compromise the agreement between simulated and detected distributions of radio pulsars, the simulations fail to reproduce the LAT findings: all models under-predict the number of LAT pulsars with high E , and they cannot explain the high probability of detecting both the radio and gamma-ray beams at high E. The beaming factor remains close to 1.0 over 4 decades in E evolution for the slot gap whereas it significantly decreases with increasing age for the outer gaps. The evolution of the enhanced slot-gap luminosity with E is compatible with the large dispersion of gamma-ray luminosity seen in the LAT data. The stronger evolution predicted for the outer gap, which is linked to the polar cap heating by the return current, is apparently not supported by the LAT data. The LAT sample of gamma-ray pulsars
-
Gamma-telescopes Fermi/LAT and GAMMA-400 Trigger Systems Event Recognizing Methods Comparison
NASA Astrophysics Data System (ADS)
Arkhangelskaja, I. V.; Murchenko, A. E.; Chasovikov, E. N.; Arkhangelskiy, A. I.; Kheymits, M. D.
value because of its calorimeter thickness is only ∼10 X0 and energy of registered particles is defined by shower profile analysis. Less than 3% photons will be wrongly recognized as electrons or protons in double-layer ACtop taking into account both temporal and amplitude trigger marker analysis methods during onboard processing in the counting and triggers signals formation system of GAMMA-400. The proton rejection factor will be ∼10-5. The Fermi/LAT based on a 4 × 4 array of identical towers each contains a tracker, calorimeter and data acquisition module. Each tracker consists of 18 x-y silicon-strip layers. The calorimeter in each tower made of eight layers in a hodoscopic arrangement for measure the three-dimensional profiles of showers permits corrections for energy leakage and enhances the capability to discriminate hadronic cosmic rays. The each layer consists of 12 CsI(Tl) based bars. The segmented anticoincidence shield covers the array of towers. Unfortunately, several types of biases lead to systematic effects caused high values of relative systematic uncertainties of the exposure, the number of signal events, the induced fractional signal and so on. For example non confirmed announcement of ∼133 GeV line detection and lost sources in different Fermi catalogues (1FGL, 2FGL, 3FGL) - just well seen in 2FGL Cygnus X-3 (J2032.1+4049) does not appear in 3FGL. It allows to conclude sufficient biases in LAT characteristics obtained methods and event recognized algorithms. Now Fermi/LAT operates during ∼ 7 years but effective caveats methods continuously to be proposed. Respectively, continuation of measurements with use of other telescopes is necessary, and realization of GAMMA-400 will allow improving the results.
-
Igarashi, Ikuo; Suzuki, Reiko; Waki, Seiji; Tagawa, Yoh-Ichi; Seng, Seyha; Tum, Sothyra; Omata, Yoshitaka; Saito, Atsushi; Nagasawa, Hideyuki; Iwakura, Yohichiro; Suzuki, Naoyoshi; Mikami, Takeshi; Toyoda, Yutaka
1999-01-01
Babesia microti produces a self-limiting infection in mice, and recovered mice are resistant to reinfection. In the present study, the role of T cells in protective immunity against challenge infection was examined. BALB/c mice which recovered from primary infection showed strong protective immunity against challenge infection. In contrast, nude mice which failed to control the primary infection and were cured with an antibabesial drug did not show protection against challenge infection. Treatment of immune mice with anti-CD4 monoclonal antibody (MAb) diminished the protective immunity against challenge infection, but treatment with anti-CD8 MAb had no effect on the protection. Transfer of CD4+ T-cell-depleted spleen cells resulted in higher parasitemia than transfer of CD8+ T-cell-depleted spleen cells. A high level of gamma interferon (IFN-γ), which was produced by CD4+ T cells, was observed for the culture supernatant of spleen cells from immune mice, and treatment of immune mice with anti-IFN-γ MAb partially reduced the protection. Moreover, no protection against challenge infection was found in IFN-γ-deficient mice. On the other hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or tumor necrosis factor alpha did not affect protective immunity. These results suggest essential requirements for CD4+ T cells and IFN-γ in protective immunity against challenge infection with B. microti. PMID:10417185
-
van Ooij, C; Snyder, R C; Paeper, B W; Duester, G
1992-01-01
The human class I alcohol dehydrogenase (ADH) gene family consists of ADH1, ADH2, and ADH3, which are sequentially activated in early fetal, late fetal, and postnatal liver, respectively. Analysis of ADH promoters revealed differential activation by several factors previously shown to control liver transcription. In cotransfection assays, the ADH1 promoter, but not the ADH2 or ADH3 promoter, was shown to respond to hepatocyte nuclear factor 1 (HNF-1), which has previously been shown to regulate transcription in early liver development. The ADH2 promoter, but not the ADH1 or ADH3 promoter, was shown to respond to CCAAT/enhancer-binding protein alpha (C/EBP alpha), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADH1, ADH2, and ADH3 promoters all responded to the liver transcription factors liver activator protein (LAP) and D-element-binding protein (DBP), which are most active in postnatal liver. For all three promoters, the activation by LAP or DBP was higher than that seen by HNF-1 or C/EBP alpha, and a significant synergism between C/EBP alpha and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBP alpha and LAP homo- and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBP alpha (i.e., -160, -120, -40, and -20 bp), but DBP bound strongly only to the site located at -40 bp relative to the transcriptional start. Mutational analysis of ADH2 indicated that the -40 bp element accounts for most of the promoter regulation by the bZIP factors analyzed. These studies suggest that HNF-1 and C/EBP alpha help establish ADH gene family transcription in fetal liver and that LAP and DBP help maintain high-level ADH gene family transcription in postnatal liver. Images PMID:1620113
-
Zhang, Weihua; Ungar, Kurt; Stukel, Matthew; Mekarski, Pawel
2014-04-01
In this study, a digital gamma-gamma coincidence/anticoincidence spectrometer was developed and examined for low-level cosmogenic (22)Na and (7)Be in air-filter sample monitoring. The spectrometer consists of two bismuth germanate scintillators (BGO) and an XIA LLC Digital Gamma Finder (DGF)/Pixie-4 software and card package. The spectrometer design allows a more selective measurement of (22)Na with a significant background reduction by gamma-gamma coincidence events processing. Hence, the system provides a more sensitive way to quantify trace amounts of (22)Na than normal high resolution gamma spectrometry providing a critical limit of 3 mBq within a 20 h count. The use of a list-mode data acquisition technique enabled simultaneous determination of (22)Na and (7)Be activity concentrations using a single measurement by coincidence and anticoincidence mode respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.
-
Application of mobile gamma-ray spectrometry for soil mapping
NASA Astrophysics Data System (ADS)
Werban, Ulrike; Lein, Claudia; Pohle, Marco; Dietrich, Peter
2017-04-01
Gamma-ray measurements have a long tradition for geological surveys and deposit exploration using airborne and borehole logging systems. For these applications, the relationships between the measured physical parameter - the concentration of natural gamma emitters 40K, 238U and 232Th - and geological origin or sedimentary developments are well described. Thus, Gamma-ray spectrometry seems a useful tool for carrying out spatial mapping of physical parameters related to soil properties. The isotope concentration in soils depends on different soil parameters (e.g. geochemical composition, grain size fractions), which are a result of source rock properties and processes during soil geneses. There is a rising interest in the method for application in Digital Soil Mapping or as input data for environmental, ecological or hydrological modelling, e.g. as indicator for clay content. However, the gamma-ray measurement is influenced by endogenous factors and processes like soil moisture variation, erosion and deposition of material or cultivation. We will present results from a time series of car borne gamma-ray measurements to observe heterogeneity of soil on a floodplain area in Central Germany. The study area is characterised by high variations in grain size distribution and occurrence of flooding events. For the survey, we used a 4 l NaI(Tl) detector with GPS connection mounted on a sledge, which is towed across the field sites by a four-wheel-vehicle. The comparison of data from different dates shows similar structures with small variation between the data ranges and shape of structures. We will present our experiences concerning the application of gamma-ray measurements under variable field conditions and their impacts on data quality.
-
Gamma ray shielding and structural properties of PbO-P2O5-Na2WO4 glass system
NASA Astrophysics Data System (ADS)
Dogra, Mridula; Singh, K. J.; Kaur, Kulwinder; Anand, Vikas; Kaur, Parminder
2017-05-01
The present work has been undertaken to study the gamma ray shielding properties of PbO-P2O5-Na2WO4 glass system. The values of mass attenuation coefficient and half value layer parameter at photon energies 511, 662 and 1173 KeV have been determined using XCOM computer software developed by National Institute of Standards and Technology. The density, molar volume, XRD, UV-VIS and Raman studies have been performed to study the structural properties of the prepared glass system to check the possibility of the use of prepared samples as an alternate to conventional concrete for gamma ray shielding applications.
-
Urbanová, Jana; Rypáčková, Blanka; Kučera, Petr; Anděl, Michal; Heneberg, Petr
2013-01-01
It was recently suggested that routine islet cell autoantibody testing should be performed to discriminate maturity-onset diabetes of the young (MODY) from type 1 diabetes mellitus (T1DM). This is the first report ever to describe the familial manifestation of T1DM autoimmunity in nonobese HNF1A-MODY subjects and the presence of islet antigen-2 (IA-2) antibodies in MODY subjects. Three nonobese subjects in an age range of 14-35 years were diagnosed with HNF1A-MODY (p. Arg159Gln mutation). All the tested subjects had detectable (but varying) levels of islet cell autoantibodies (i.e., antibodies against glutamate decarboxylase or IA-2) in the absence of other T1DM characteristics. They displayed long-term expression of intermediate fasting C-peptide levels, ketoacidosis was absent even in periods of spontaneous insulin withdrawal, and full dependence on externally administered insulin was not detected in any of them although better glycemic control was achieved when insulin was supplemented. The course of the disease was similar to that of the autoantibody-negative HNF1A-MODY subjects. The case questions the selectivity of autoantibodies as a marker of T1DM or late-onset autoimmune diabetes of adulthood (LADA) over MODY and challenges the use of autoantibodies as a universal negative marker of MODY in an effort to decrease the cost of health care, as it may eventually lead to the wrong diagnosis and thus to the incorrect treatment. Further research should involve examination of the autoantibody titers and prevalence in large and geographically diverse cohorts of MODY subjects selected for genetic testing (regardless of their autoantibody titers) as well as determination of the islet cell autoantibody kinetics in the course of MODY onset and progression. Copyright © 2013 S. Karger AG, Basel.
-
A Spherical Active Coded Aperture for 4π Gamma-ray Imaging
Hellfeld, Daniel; Barton, Paul; Gunter, Donald; ...
2017-09-22
Gamma-ray imaging facilitates the efficient detection, characterization, and localization of compact radioactive sources in cluttered environments. Fieldable detector systems employing active planar coded apertures have demonstrated broad energy sensitivity via both coded aperture and Compton imaging modalities. But, planar configurations suffer from a limited field-of-view, especially in the coded aperture mode. In order to improve upon this limitation, we introduce a novel design by rearranging the detectors into an active coded spherical configuration, resulting in a 4pi isotropic field-of-view for both coded aperture and Compton imaging. This work focuses on the low- energy coded aperture modality and the optimization techniquesmore » used to determine the optimal number and configuration of 1 cm 3 CdZnTe coplanar grid detectors on a 14 cm diameter sphere with 192 available detector locations.« less
-
Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A.; Krause, James S.; Banik, Naren L.
2014-01-01
Insulin-like growth factor-1 (IGF-1) is a neuroprotective growth factor that promotes neuronal survival by inhibition of apoptosis. In order to examine whether IGF-1 exerts cytoprotective effects against extracellular inflammatory stimulation, ventral spinal cord 4.1 (VSC4.1) motoneuron cells were treated with interferon-gamma (IFN-γ). Our data demonstrated apoptotic changes, increased calpain:calpastatin and Bax:Bcl-2 ratios, and expression of apoptosis related proteases (caspase-3 and −12) in motoneurons rendered by IFN-γ in a dose-dependent manner. Post-treatment with IGF-1 attenuated these changes. In addition, IGF-1 treatment of motoneurons exposed to IFN-γ decreased expression of inflammatory markers (cyclooxygenase-2 and nuclear factor-kappa B:inhibitor of kappa B ratio). Furthermore, IGF-1 attenuated the loss of expression of IGF-1 receptors (IGF-1Rα and IGF-1Rβ) and estrogen receptors (ERα and ERβ) induced by IFN-γ. To determine whether the protective effects of IGF-1 are associated with ERs, ERs antagonist ICI and selective siRNA targeted against ERα and ERβ were used in VSC4.1 motoneurons. Distinctive morphological changes were observed following siRNA knockdown of ERα and ERβ. In particular, apoptotic cell death assessed by TUNEL assay was enhanced in both ERα and ERβ-silenced VSC4.1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ. PMID:24188094
-
Yoo, J C; Pae, H O; Choi, B M; Kim, W I; Kim, J D; Kim, Y M; Chung, H T
2000-02-01
The effects of ionizing irradiation on the nitric oxide (NO) production in murine embryonic liver cell line, BNL CL.2 cells, were investigated. Various doses (5-40 Gy) of radiation made BNL CL.2 cells responsive to interferon-gamma alone for the production of NO in a dose-dependent manner. Small amounts of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) synergized with IFN-gamma in the production of NO from irradiated BNL CL.2 cells, even though LPS or TNF-alpha alone did not induce NO production from the same cells. Immunoblots showed parallel induction of inducible nitric oxide synthase (iNOS). NO production in irradiated BNL CL.2 cells by IFN-gamma or IFN-gamma plus LPS was decreased by the addition of catalase, suggesting that H(2)O(2) produced by ionizing irradiation primed the cells to trigger NO production in response to IFN-gamma or IFN-gamma plus LPS. Furthermore, the treatment of nongamma-irradiated BNL CL.2 cells with H(2)O(2) made the cells responsive to IFN-gamma or IFN-gamma plus LPS for the production of NO. This study shows that ionizing irradiation has the ability to induce iNOS gene expression in responsive to IFN-gamma via the formation of H(2)O(2) in BNL CL.2 murine embryonic liver cells.
-
Rodewald, H R; Awad, K; Moingeon, P; D'Adamio, L; Rabinowitz, D; Shinkai, Y; Alt, F W; Reinherz, E L
1993-04-01
We have recently identified a dominant wave of CD4-CD8- (double-negative [DN]) thymocytes in early murine fetal development that express low affinity Fc gamma receptors (Fc gamma RII/III) and contain precursors for Ti alpha/beta lineage T cells. Here we show that Fc gamma RII/III is expressed in very immature CD4low single-positive (SP) thymocytes and that Fc gamma RII/III expression is downregulated within the DN subpopulation and before the CD3-CD8low SP stage in T cell receptor (TCR)-alpha/beta lineage-committed thymocytes. DN Fc gamma RII/III+ thymocytes also contain a small fraction of TCR-gamma/delta lineage cells in addition to TCR-alpha/beta progenitors. Fetal day 15.5 DN TCR-alpha/beta lineage progenitors can be subdivided into three major subpopulations as characterized by cell surface expression of Fc gamma RII/III vs. CD2 (Fc gamma RII/III+CD2-, Fc gamma RII/III+CD2+, Fc gamma RII/III-CD2+). Phenotypic analysis during fetal development as well as adoptive transfer of isolated fetal thymocyte subpopulations derived from C57B1/6 (Ly5.1) mice into normal, nonirradiated Ly5.2 congenic recipient mice identifies one early differentiation sequence (Fc gamma RII/III+CD2(-)-->Fc gamma RII/III+CD2(+)-->Fc gamma RII/III-CD2+) that precedes the entry of DN thymocytes into the CD4+CD8+ double-positive (DP) TCRlow/- stage. Unseparated day 15.5 fetal thymocytes develop into DP thymocytes within 2.5 d and remain at the DP stage for > 48 h before being selected into either CD4+ or CD8+ SP thymocytes. In contrast, Fc gamma RII/III+CD2- DN thymocytes follow this same developmental pathway but are delayed by approximately 24 h before entering the DP compartment, while Fc gamma RII/III-CD2+ display accelerated development by approximately 24 h compared with total day 15.5 thymocytes. Fc gamma RII/III-CD2+ are also more developmentally advanced than Fc gamma RII/III+CD2- fetal thymocytes with respect to their TCR beta chain V(D)J rearrangement. At day 15.5 in gestation, beta
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan
2013-03-07
Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partialmore » PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.« less
-
Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G
2000-10-31
We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.
-
Activation measurement of the 3He(alpha,gamma)7Be cross section at low energy.
Bemmerer, D; Confortola, F; Costantini, H; Formicola, A; Gyürky, Gy; Bonetti, R; Broggini, C; Corvisiero, P; Elekes, Z; Fülöp, Zs; Gervino, G; Guglielmetti, A; Gustavino, C; Imbriani, G; Junker, M; Laubenstein, M; Lemut, A; Limata, B; Lozza, V; Marta, M; Menegazzo, R; Prati, P; Roca, V; Rolfs, C; Alvarez, C Rossi; Somorjai, E; Straniero, O; Strieder, F; Terrasi, F; Trautvetter, H P
2006-09-22
The nuclear physics input from the 3He(alpha,gamma)7Be cross section is a major uncertainty in the fluxes of 7Be and 8B neutrinos from the Sun predicted by solar models and in the 7Li abundance obtained in big-bang nucleosynthesis calculations. The present work reports on a new precision experiment using the activation technique at energies directly relevant to big-bang nucleosynthesis. Previously such low energies had been reached experimentally only by the prompt-gamma technique and with inferior precision. Using a windowless gas target, high beam intensity, and low background gamma-counting facilities, the 3He(alpha,gamma)7Be cross section has been determined at 127, 148, and 169 keV center-of-mass energy with a total uncertainty of 4%. The sources of systematic uncertainty are discussed in detail. The present data can be used in big-bang nucleosynthesis calculations and to constrain the extrapolation of the 3He(alpha,gamma)7Be astrophysical S factor to solar energies.
-
gamma-Hexachlorocyclohexane (gamma-HCH)
Integrated Risk Information System (IRIS)
gamma - Hexachlorocyclohexane ( gamma - HCH ) ; CASRN 58 - 89 - 9 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Asse
-
Human antirabies gamma globulin*
Hosty, Thomas S.; Kissling, R. E.; Schaeffer, M.; Wallace, Gordon A.; Dibble, E. H.
1959-01-01
To obviate the foreign protein reactions experienced with the use of hyperimmune serum in rabies-exposed individuals, an attempt was made to produce a rabies antiserum of human origin. Five doses of an inactivated rabies virus duck-egg vaccine were administered to 34 volunteers at 4-day intervals (i.e., on days 0, 4, 8, 12 and 16). An additional dose of chick-embryo attenuated virus vaccine—Flury HEP (high egg passage)—was given on the 46th day, followed by a final booster dose of duck-egg vaccine on the 288th day. Twenty-four days later, i.e., on the 312th day after the first dose, the participants were bled and the serum pooled and converted to gamma globulin. These volunteers, having no initial antibody, responded with variable titres, the pooled serum having a titre of 1: 100 against 50 LD50 of rabies virus in neutralization tests and the gamma globulin prepared from this pool a titre of 1: 300. In five individuals inoculated with the antirabies gamma globulin, blood samples tested at intervals for residual antibody showed significant titres through 21 days. While the passive antibody levels resulting from the administration of a more potent immune horse serum were much higher than those achieved by the weaker human antirabies gamma globulin used, the decrease in titre was more gradual with the human globulin. With more booster inoculations in a larger group of human volunteers, it is believed that a human rabies immune gamma globulin could be produced which would be equal in effect to immune horse serum. The advantages of a human source of antibody in rabies prophylaxis are discussed. PMID:14403320
-
Chakraborty, Chiranjib; Bandyopadhyay, Sanghamitra; Doss, C George Priya; Agoramoorthy, Govindasamy
2015-04-01
Maturity onset diabetes of the young (MODY) is a metabolic and genetic disorder. It is different from type 1 and type 2 diabetes with low occurrence level (1-2%) among all diabetes. This disorder is a consequence of β-cell dysfunction. Till date, 11 subtypes of MODY have been identified, and all of them can cause gene mutations. However, very little is known about the gene mapping, molecular phylogenetics, and co-expression among MODY genes and networking between cascades. This study has used latest servers and software such as VarioWatch, ClustalW, MUSCLE, G Blocks, Phylogeny.fr, iTOL, WebLogo, STRING, and KEGG PATHWAY to perform comprehensive analyses of gene mapping, multiple sequences alignment, molecular phylogenetics, protein-protein network design, co-expression analysis of MODY genes, and pathway development. The MODY genes are located in chromosomes-2, 7, 8, 9, 11, 12, 13, 17, and 20. Highly aligned block shows Pro, Gly, Leu, Arg, and Pro residues are highly aligned in the positions of 296, 386, 437, 455, 456 and 598, respectively. Alignment scores inform us that HNF1A and HNF1B proteins have shown high sequence similarity among MODY proteins. Protein-protein network design shows that HNF1A, HNF1B, HNF4A, NEUROD1, PDX1, PAX4, INS, and GCK are strongly connected, and the co-expression analyses between MODY genes also show distinct association between HNF1A and HNF4A genes. This study has used latest tools of bioinformatics to develop a rapid method to assess the evolutionary relationship, the network development, and the associations among eleven MODY genes and cascades. The prediction of sequence conservation, molecular phylogenetics, protein-protein network and the association between the MODY cascades enhances opportunities to get more insights into the less-known MODY disease.
-
Rat brain gamma-secretase activity is highly influenced by detergents.
Frånberg, Jenny; Welander, Hedvig; Aoki, Mikio; Winblad, Bengt; Tjernberg, Lars O; Frykman, Susanne
2007-06-26
Gamma-secretase is important for the development of Alzheimer's disease, since it is a crucial enzyme for the generation of the pathogenic amyloid beta-peptide (Abeta). Most data on gamma-secretase is derived from studies in cell lines overexpressing gamma-secretase components or amyloid precursor protein (APP), and since gamma-secretase is a transmembrane protein complex, detergents have been frequently used to facilitate the studies. However, no extensive comparison of the influence of different detergents at different concentrations on gamma-secretase activity in preparations from brain has been made. Here, we establish the optimal conditions for gamma-secretase activity in rat brain, using an activity assay detecting endogenous production of the APP intracellular domain, which is generated when gamma-secretase cleaves the APP C-terminal fragments. We performed a subcellular fractionation and noted the highest gamma-secretase activity in the 100000g pellet and that the optimal pH was around 7. We found that gamma-secretase was active for at least 16 h at 37 degrees C and that the endogenous substrate levels were sufficient for activity measurements. The highest activity was obtained in 0.4% CHAPSO, which is slightly below the critical micelle concentration (0.5%) for this detergent, but the complex was not solubilized efficiently at this concentration. On the other hand, 1% CHAPSO solubilized a substantial amount of the gamma-secretase components, but the activity was low. The activity was fully restored by diluting the sample to 0.4% CHAPSO. Therefore, using 1% CHAPSO for solubilization and subsequently diluting the sample to 0.4% is an appropriate procedure for obtaining a soluble, highly active gamma-secretase from rat brain.
-
Gamma-Ray and Parsec-Scale Jet Properties of a Complete Sample of Blazars from the MOJAVE Program
NASA Technical Reports Server (NTRS)
Lister, M.L.; Aller, M.; Aller, H.; Hovatta, T.; Kellermann, K. I.; Kovalev, Y. Y.; Meyer, E. T.; Pushkarev, A. B.; Ros, E.; Ackermann, M.;
2011-01-01
We investigate the Fermi LAT gamma-ray and 15 GHz VLBA radio properties of a joint gamma-ray- and radio-selected sample of AGNs obtained during the first 11 months of the Fermi mission (2008 Aug 4 - 2009 Jul 5). Our sample contains the brightest 173 AGNs in these bands above declination -300 during this period, and thus probes the full range of gamma-ray loudness (gamma-ray to radio band luminosity ratio) in the bright blazar population. The latter quantity spans at least four orders of magnitude, reflecting a wide range of spectral energy distribution (SED) parameters in the bright blazar population. The BL Lac objects, however, display a linear correlation of increasing gamma-ray loudness with synchrotron SED peak frequency, suggesting a universal SED shape for objects of this class. The synchrotron self-Compton model is favored for the gamma-ray emission in these BL Lacs over external seed photon models, since the latter predict a dependence of Compton dominance on Doppler factor that would destroy any observed synchrotron SED peak - gamma-ray loudness correlation. The high-synchrotron peaked (HSP) BL Lac objects are distinguished by lower than average radio core brightness temperatures, and none display large radio modulation indices or high linear core polarization levels. No equivalent trends are seen for the flat-spectrum radio quasars (FSRQ) in our sample. Given the association of such properties with relativistic beaming, we suggest that the HSP BL Lacs have generally lower Doppler factors than the lower-synchrotron peaked BL Lacs or FSRQs in our sample.
-
Zhang, Weihua; Yi, Jing; Mekarski, Pawel; Ungar, Kurt; Hauck, Barry; Kramer, Gary H
2011-06-01
The purpose of this study is to investigate the possibility of verifying depleted uranium (DU), natural uranium (NU), low enriched uranium (LEU) and high enriched uranium (HEU) by a developed digital gamma-gamma coincidence spectroscopy. The spectroscopy consists of two NaI(Tl) scintillators and XIA LLC Digital Gamma Finder (DGF)/Pixie-4 software and card package. The results demonstrate that the spectroscopy provides an effective method of (235)U and (238)U quantification based on the count rate of their gamma-gamma coincidence counting signatures. The main advantages of this approach over the conventional gamma spectrometry include the facts of low background continuum near coincident signatures of (235)U and (238)U, less interference from other radionuclides by the gamma-gamma coincidence counting, and region-of-interest (ROI) imagine analysis for uranium enrichment determination. Compared to conventional gamma spectrometry, the method offers additional advantage of requiring minimal calibrations for (235)U and (238)U quantification at different sample geometries. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.
-
Top-Down Beta Enhances Bottom-Up Gamma
Thompson, William H.
2017-01-01
Several recent studies have demonstrated that the bottom-up signaling of a visual stimulus is subserved by interareal gamma-band synchronization, whereas top-down influences are mediated by alpha-beta band synchronization. These processes may implement top-down control of stimulus processing if top-down and bottom-up mediating rhythms are coupled via cross-frequency interaction. To test this possibility, we investigated Granger-causal influences among awake macaque primary visual area V1, higher visual area V4, and parietal control area 7a during attentional task performance. Top-down 7a-to-V1 beta-band influences enhanced visually driven V1-to-V4 gamma-band influences. This enhancement was spatially specific and largest when beta-band activity preceded gamma-band activity by ∼0.1 s, suggesting a causal effect of top-down processes on bottom-up processes. We propose that this cross-frequency interaction mechanistically subserves the attentional control of stimulus selection. SIGNIFICANCE STATEMENT Contemporary research indicates that the alpha-beta frequency band underlies top-down control, whereas the gamma-band mediates bottom-up stimulus processing. This arrangement inspires an attractive hypothesis, which posits that top-down beta-band influences directly modulate bottom-up gamma band influences via cross-frequency interaction. We evaluate this hypothesis determining that beta-band top-down influences from parietal area 7a to visual area V1 are correlated with bottom-up gamma frequency influences from V1 to area V4, in a spatially specific manner, and that this correlation is maximal when top-down activity precedes bottom-up activity. These results show that for top-down processes such as spatial attention, elevated top-down beta-band influences directly enhance feedforward stimulus-induced gamma-band processing, leading to enhancement of the selected stimulus. PMID:28592697
-
Decomposition of 2,4,6-trinitrotoluene (TNT) by gamma irradiation.
Lee, Byungjin; Lee, Myunjoo
2005-12-01
The purpose of this study was to evaluate the potential of gamma irradiation to decompose 2,4,6-trinitrotoluene (TNT) in an aqueous solution; the concentration range of the TNT solution was 0.11-0.44 mmol/L. The decomposition rate of TNT by gamma irradiation was pseudo-first-order kinetic over the applied initial concentrations. The dose constant was strongly dependent on the initial concentration of TNT. Increasing the concentration of dissolved oxygen in the solution was more effective on the decomposition of TNT as well as its mineralization. The required irradiation dose to remove 90% of initial TNT (0.44 mmol/L) was 58, 41, 32, 28, and 25 kGy at the dissolved oxygen concentration of 0.025, 0.149, 0.3, 0.538, and 0.822 mmol/L, respectively. However, TOC still remained as 30% of the initial TOC (3.19 mmol/L) when 200 kGy irradiation dose was applied to the TNT solution (0.44 mmol/L) containing dissolved oxygen of 0.822 mmol/L. The removal of the TNT was more efficient at a pH below 3 and at a pH above 11 than at neutral pH (pH 5-9). The required irradiation dose to remove over 99% of the initial TNT (0.44 mmol/L) was 39, 76, and 10 kGy at pH 2, 7, and 13, respectively. The dose constant was increased 1.6-fold and over 15.6-fold at pH 2 and 13, respectively, compared to that at pH 7. When an irradiation dose of 200 kGy was applied, the removal efficiencies of the TOC (initial concentration 3.19 mmol/L) were 91, 46, and 53% at pH 2, 7, and 13, respectively. Ammonia and nitrate were detected as the main nitrogen byproducts of TNT, and glyoxalic acid and oxalic acid were detected as organic byproducts.
-
Astrophysical S factor for the {sup 15}N(p,{gamma}){sup 16}O reaction
DOE Office of Scientific and Technical Information (OSTI.GOV)
Mukhamedzhanov, A. M.; La Cognata, M.; Kroha, V.
2011-04-15
The R-matrix approach has proved to be very useful in extrapolating the astrophysical factor down to astrophysically relevant energies, since the majority of measurements are not available in this region. However, such an approach has to be critically considered when no complete knowledge of the reaction model is available. To get reliable results in such cases one has to use all the available information from independent sources and, accordingly, fix or constrain variations of the parameters. In this paper we present a thorough R-matrix analysis of the {sup 15}N(p,{gamma}){sup 16}O reaction, which provides a path from the CN cycle tomore » the CNO bi-cycle and CNO tri-cycle. The measured astrophysical factor for this reaction is dominated by resonant capture through two strong J{sup {pi}}=1{sup -} resonances at E{sub R}=312 and 962 keV and direct capture to the ground state. Recently, a new measurement of the astrophysical factor for the {sup 15}N(p,{gamma}){sup 16}O reaction has been published [P. J. LeBlanc et al., Phys. Rev. C 82, 055804 (2010)]. The analysis has been done using the R-matrix approach with unconstrained variation of all parameters including the asymptotic normalization coefficient (ANC). The best fit has been obtained for the square of the ANC C{sup 2}=539.2 fm{sup -1}, which exceeds the previously measured value by a factor of {approx_equal}3. Here we present a new R-matrix analysis of the Notre Dame-LUNA data with the fixed within the experimental uncertainties square of the ANC C{sup 2}=200.34 fm{sup -1}. Rather than varying the ANC we add the contribution from a background resonance that effectively takes into account contributions from higher levels. Altogether we present ten fits, seven unconstrained and three constrained. For the unconstrained fit with the boundary condition B{sub c}=S{sub c}(E{sub 2}), where E{sub 2} is the energy of the second level, we get S(0)=39.0{+-}1.1 keVb and normalized {chi}-tilde{sup 2}=1.84, i.e., the result
-
Average Emissivity Curve of Batse Gamma-Ray Bursts with Different Intensities
NASA Technical Reports Server (NTRS)
Mitrofanov, Igor G.; Litvak, Maxim L.; Briggs, Michael S.; Paciesas, William S.; Pendleton, Geoffrey N.; Preece, Robert D.; Meegan, Charles A.
1999-01-01
Six intensity groups with approximately 150 BATSE gamma-ray bursts each are compared using average emissivity curves. Time stretch factors for each of the dimmer groups are estimated with respect to the brightest group, which serves as the reference, taking into account the systematics of counts-produced noise effects and choice statistics. A stretching/intensity anticorrelation is found with good statistical significance during the average back slopes of bursts. A stretch factor approximately 2 is found between the 150 dimmest bursts, with peak flux less than 0.45 photons/sq cm.s, and the 147 brightest bursts, with peak flux greater than 4.1 photons/sq cm.s. On the other hand, while a trend of increasing stretching factor may exist for rise fronts for bursts with decreasing peak flux from greater than 4.1 photons/sq cm.s down to 0.7 photons/sq cm.s, the magnitude of the stretching factor is less than approximately 1.4 and is therefore inconsistent with stretching factor of back slope.
-
The Gamma-Ray Albedo of the Moon
DOE Office of Scientific and Technical Information (OSTI.GOV)
Moskalenko, I.V.; /Stanford U., HEPL /KIPAC, Menlo Park; Porter, T.A.
2008-03-25
We use the GEANT4 Monte Carlo framework to calculate the {gamma}-ray albedo of the Moon due to interactions of cosmic ray (CR) nuclei with moon rock. Our calculation of the albedo spectrum agrees with the EGRET data. We show that the spectrum of {gamma}-rays from the Moon is very steep with an effective cutoff around 3-4 GeV (600 MeV for the inner part of the Moon disk) and exhibits a narrow pion-decay line at 67.5 MeV, perhaps unique in astrophysics. Apart from other astrophysical sources, the albedo spectrum of the Moon is well understood, including its absolute normalization; this makesmore » it a useful 'standard candle' for {gamma}-ray telescopes. The steep albedo spectrum also provides a unique opportunity for energy calibration of {gamma}-ray telescopes, such as the forthcoming Gamma Ray Large Area Space Telescope (GLAST). Since the albedo flux depends on the incident CR spectrum which changes over the solar cycle, it is possible to monitor the CR spectrum using the albedo {gamma}-ray flux. Simultaneous measurements of CR proton and helium spectra by the Payload for Antimatter-Matter Exploration and Light-nuclei Astrophysics (PAMELA), and observations of the albedo {gamma}-rays by the GLAST Large Area Telescope (LAT), can be used to test the model predictions and will enable the LAT to monitor the CR spectrum near the Earth beyond the lifetime of the PAMELA.« less
-
The Gamma-ray Albedo of the Moon
DOE Office of Scientific and Technical Information (OSTI.GOV)
Moskalenko, Igor V.; /Stanford U., HEPL; Porter, Troy A.
2007-09-28
We use the GEANT4 Monte Carlo framework to calculate the {gamma}-ray albedo of the Moon due to interactions of cosmic ray (CR) nuclei with moon rock. Our calculation of the albedo spectrum agrees with the EGRET data. We show that the spectrum of {gamma}-rays from the Moon is very steep with an effective cutoff around 3-4 GeV (600 MeV for the inner part of the Moon disk) and exhibits a narrow pion-decay line at 67.5 MeV, perhaps unique in astrophysics. Apart from other astrophysical sources, the albedo spectrum of the Moon is well understood, including its absolute normalization; this makesmore » it a useful 'standard candle' for {gamma}-ray telescopes. The steep albedo spectrum also provides a unique opportunity for energy calibration of {gamma}-ray telescopes, such as the forthcoming Gamma Ray Large Area Space Telescope (GLAST). Since the albedo flux depends on the incident CR spectrum which changes over the solar cycle, it is possible to monitor the CR spectrum using the albedo {gamma}-ray flux. Simultaneous measurements of CR proton and helium spectra by the Payload for Antimatter-Matter Exploration and Light-nuclei Astrophysics (PAMELA), and observations of the albedo {gamma}-rays by the GLAST Large Area Telescope (LAT), can be used to test the model predictions and will enable the LAT to monitor the CR spectrum near the Earth beyond the lifetime of the PAMELA.« less
-
Unidentified Gamma-Ray Sources: Hunting Gamma-Ray Blazars
DOE Office of Scientific and Technical Information (OSTI.GOV)
Massaro, F.; D'Abrusco, R.; Tosti, G.
2012-04-02
One of the main scientific objectives of the ongoing Fermi mission is unveiling the nature of the unidentified {gamma}-ray sources (UGSs). Despite the large improvements of Fermi in the localization of {gamma}-ray sources with respect to the past {gamma}-ray missions, about one third of the Fermi-detected objects are still not associated to low energy counterparts. Recently, using the Wide-field Infrared Survey Explorer (WISE) survey, we discovered that blazars, the rarest class of Active Galactic Nuclei and the largest population of {gamma}-ray sources, can be recognized and separated from other extragalactic sources on the basis of their infrared (IR) colors. Basedmore » on this result, we designed an association method for the {gamma}-ray sources to recognize if there is a blazar candidate within the positional uncertainty region of a generic {gamma}-ray source. With this new IR diagnostic tool, we searched for {gamma}-ray blazar candidates associated to the UGS sample of the second Fermi {gamma}-ray catalog (2FGL). We found that our method associates at least one {gamma}-ray blazar candidate as a counterpart each of 156 out of 313 UGSs analyzed. These new low-energy candidates have the same IR properties as the blazars associated to {gamma}-ray sources in the 2FGL catalog.« less
-
UNIDENTIFIED {gamma}-RAY SOURCES: HUNTING {gamma}-RAY BLAZARS
DOE Office of Scientific and Technical Information (OSTI.GOV)
Massaro, F.; Ajello, M.; D'Abrusco, R.
2012-06-10
One of the main scientific objectives of the ongoing Fermi mission is unveiling the nature of unidentified {gamma}-ray sources (UGSs). Despite the major improvements of Fermi in the localization of {gamma}-ray sources with respect to the past {gamma}-ray missions, about one-third of the Fermi-detected objects are still not associated with low-energy counterparts. Recently, using the Wide-field Infrared Survey Explorer survey, we discovered that blazars, the rarest class of active galactic nuclei and the largest population of {gamma}-ray sources, can be recognized and separated from other extragalactic sources on the basis of their infrared (IR) colors. Based on this result, wemore » designed an association method for the {gamma}-ray sources to recognize if there is a blazar candidate within the positional uncertainty region of a generic {gamma}-ray source. With this new IR diagnostic tool, we searched for {gamma}-ray blazar candidates associated with the UGS sample of the second Fermi {gamma}-ray LAT catalog (2FGL). We found that our method associates at least one {gamma}-ray blazar candidate as a counterpart to each of 156 out of 313 UGSs analyzed. These new low-energy candidates have the same IR properties as the blazars associated with {gamma}-ray sources in the 2FGL catalog.« less
-
Ackermann, M.
2015-09-02
We search for evidence of dark matter (DM) annihilation in the isotropic gamma-ray background (IGRB) measured with 50 months of Fermi Large Area Telescope (LAT) observations. An improved theoretical description of the cosmological DM annihilation signal, based on two complementary techniques and assuming generic weakly interacting massive particle (WIMP) properties, renders more precise predictions compared to previous work. More specifically, we estimate the cosmologically-induced gamma-ray intensity to have an uncertainty of a factor ~ 20 in canonical setups. We consistently include both the Galactic and extragalactic signals under the same theoretical framework, and study the impact of the former onmore » the IGRB spectrum derivation. We find no evidence for a DM signal and we set limits on the DM-induced isotropic gamma-ray signal. Our limits are competitive for DM particle masses up to tens of TeV and, indeed, are the strongest limits derived from Fermi LAT data at TeV energies. This is possible thanks to the new Fermi LAT IGRB measurement, which now extends up to an energy of 820 GeV. As a result, we quantify uncertainties in detail and show the potential this type of search offers for testing the WIMP paradigm with a complementary and truly cosmological probe of DM particle signals.« less
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Collaboration: Fermi LAT Collaboration
2015-09-01
We search for evidence of dark matter (DM) annihilation in the isotropic gamma-ray background (IGRB) measured with 50 months of Fermi Large Area Telescope (LAT) observations. An improved theoretical description of the cosmological DM annihilation signal, based on two complementary techniques and assuming generic weakly interacting massive particle (WIMP) properties, renders more precise predictions compared to previous work. More specifically, we estimate the cosmologically-induced gamma-ray intensity to have an uncertainty of a factor ∼ 20 in canonical setups. We consistently include both the Galactic and extragalactic signals under the same theoretical framework, and study the impact of the former on themore » IGRB spectrum derivation. We find no evidence for a DM signal and we set limits on the DM-induced isotropic gamma-ray signal. Our limits are competitive for DM particle masses up to tens of TeV and, indeed, are the strongest limits derived from Fermi LAT data at TeV energies. This is possible thanks to the new Fermi LAT IGRB measurement, which now extends up to an energy of 820 GeV. We quantify uncertainties in detail and show the potential this type of search offers for testing the WIMP paradigm with a complementary and truly cosmological probe of DM particle signals.« less
-
AGILE detects enhanced gamma-ray emission above 100 MeV from the blazar S4 0554+58 region
NASA Astrophysics Data System (ADS)
Lucarelli, F.; Pittori, C.; Verrecchia, F.; Tavani, M.; Piano, G.; Bulgarelli, A.; Fioretti, V.; Striani, E.; Vercellone, S.; Donnarumma, I.; Cardillo, M.; Gianotti, F.; Trifoglio, M.; Giuliani, A.; Mereghetti, S.; Caraveo, P.; Perotti, F.; Chen, A.; Argan, A.; Costa, E.; Del Monte, E.; Evangelista, Y.; Feroci, M.; Lazzarotto, F.; Lapshov, I.; Pacciani, L.; Soffitta, P.; Sabatini, S.; Vittorini, V.; Pucella, G.; Rapisarda, M.; Di Cocco, G.; Fuschino, F.; Galli, M.; Labanti, C.; Marisaldi, M.; Pellizzoni, A.; Trois, A.; Pilia, M.; Barbiellini, G.; Vallazza, E.; Longo, F.; Morselli, A.; Picozza, P.; Prest, M.; Lipari, P.; Zanello, D.; Cattaneo, P. W.; Rappoldi, A.; Colafrancesco, S.; Parmiggiani, N.; Ferrari, A.; Giommi, P.; Salotti, L.; Valentini, G.; D'Amico, F.
2015-02-01
AGILE is detecting increased gamma-ray emission above 100 MeV from a source positionally consistent with the flat spectrum radio quasar S4 0554+58 (also known as BZQ J0559+5804), with radio coordinates R.A.: 89.8058092 deg, Dec.: 58.0676239 deg (J2000, A. J. Beasley et al., 2002ApJS..141...13B).
-
Gao, Y; Chenping; Lin, X P
1997-10-01
In order to determine whether interferon-gamma (IFN-gamma) inhibits eosinphil infiltration in the trachea of asthmatic guinea pigs induced by Rhizopus nigricans. We had administered aerosolized rIFN-gamma in the tracheas of 30 sensitized guinea pigs which had been divided into six groups, then teated animal inhaled rIFN-gamma of 5 x 10(4), 20 x 10(4), and 40 x 10(4) concentration, BDP and normal saline respectively at 24 h, 12 h, 2 h before being challenged. (1) Provocation positive rates decreased in 40 x 10(4) rIFN-gamma and BDP group compared with that in normal saline group and before intervention (P < 0.05), airway resistence decreased (P < 0.01). (2) The administration of aerosolized rIFN-gamma (40 x 10(4)) and BDP also decreased fungus-induced eosnophils but not other cells infiltration in the trachea. (3) In BALF, Eos count and ECP level were obviously lower than those in other groups. However, eosinophil numbers did not show significant change in the peripheral blood. Local administration of rIFN-gamma (40 x 10(4)) may reduce airway inflammation and intervene asthmatic attack by inhibition of Eos, ECP infiltration in airways.
-
Using gamma distribution to determine half-life of rotenone, applied in freshwater.
Rohan, Maheswaran; Fairweather, Alastair; Grainger, Natasha
2015-09-15
Following the use of rotenone to eradicate invasive pest fish, a dynamic first-order kinetic model is usually used to determine the half-life and rate at which rotenone dissipated from the treated waterbody. In this study, we investigate the use of a stochastic gamma model for determining the half-life and rate at which rotenone dissipates from waterbodies. The first-order kinetic and gamma models produced similar values for the half-life (4.45 days and 5.33 days respectively) and days to complete dissipation (51.2 days and 52.48 days respectively). However, the gamma model fitted the data better and was more flexible than the first-order kinetic model, allowing us to use covariates and to predict a possible range for the half-life of rotenone. These benefits are particularly important when examining the influence that different environmental factors have on rotenone dissipation and when trying to predict the rate at which rotenone will dissipate during future operations. We therefore recommend that in future the gamma distribution model is used when calculating the half-life of rotenone in preference to the dynamic first-order kinetics model. Copyright © 2015 Elsevier B.V. All rights reserved.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lockwood, J.A.; Webber, W.R.; Friling, L.A.
1981-09-15
Results are presented from a balloon flight at Palestine, Texas, in 1978 to measure the atmospheric and diffuse ..gamma..-ray flux in the energy range 0.4--7.0 MeV. The observations were made with a Compton telescope which included pulse-shape discrimination of the first scattering detector and a time-of-flight system between the first and second detector elements. The total downward ..gamma..-ray flux at 3.7 g cm/sup -2/ is given by the spectrum 3.1 x 10/sup -2/ x E/sup -1.74/ (photons cm/sup -2/ s/sup -1/ MeV/sup -1/ sr/sup -1/) for 0.5
-
Ağladıoğlu, Sebahat Yılmaz; Aycan, Zehra; Çetinkaya, Semra; Baş, Veysel Nijat; Önder, Aşan; Peltek Kendirci, Havva Nur; Doğan, Haldun; Ceylaner, Serdar
2016-04-01
Maturity-onset diabetes of the youth (MODY), is a genetically and clinically heterogeneous group of diseasesand is often misdiagnosed as type 1 or type 2 diabetes. The aim of this study is to investigate both novel and proven mutations of 11 MODY genes in Turkish children by using targeted next generation sequencing. A panel of 11 MODY genes were screened in 43 children with MODY diagnosed by clinical criterias. Studies of index cases was done with MISEQ-ILLUMINA, and family screenings and confirmation studies of mutations was done by Sanger sequencing. We identified 28 (65%) point mutations among 43 patients. Eighteen patients have GCK mutations, four have HNF1A, one has HNF4A, one has HNF1B, two have NEUROD1, one has PDX1 gene variations and one patient has both HNF1A and HNF4A heterozygote mutations. This is the first study including molecular studies of 11 MODY genes in Turkish children. GCK is the most frequent type of MODY in our study population. Very high frequency of novel mutations (42%) in our study population, supports that in heterogenous disorders like MODY sequence analysis provides rapid, cost effective and accurate genetic diagnosis.
-
López-Mejías, Raquel; Genre, Fernanda; Remuzgo-Martínez, Sara; González-Juanatey, Carlos; Robustillo-Villarino, Montserrat; Llorca, Javier; Corrales, Alfonso; Vicente, Esther; Miranda-Filloy, José A.; Magro, César; Tejera-Segura, Beatriz; Ramírez Huaranga, Marco A.; Pina, Trinitario; Blanco, Ricardo; Alegre-Sancho, Juan J.; Raya, Enrique; Mijares, Verónica; Ubilla, Begoña; Mínguez Sánchez, María D.; Gómez-Vaquero, Carmen; Balsa, Alejandro; Pascual-Salcedo, Dora; López-Longo, Francisco J.; Carreira, Patricia; González-Álvaro, Isidoro; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Ferraz-Amaro, Iván; Castañeda, Santos; Martín, Javier; González-Gay, Miguel A.
2016-01-01
Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA. PMID:27534721
-
López-Mejías, Raquel; Genre, Fernanda; Remuzgo-Martínez, Sara; González-Juanatey, Carlos; Robustillo-Villarino, Montserrat; Llorca, Javier; Corrales, Alfonso; Vicente, Esther; Miranda-Filloy, José A; Magro, César; Tejera-Segura, Beatriz; Ramírez Huaranga, Marco A; Pina, Trinitario; Blanco, Ricardo; Alegre-Sancho, Juan J; Raya, Enrique; Mijares, Verónica; Ubilla, Begoña; Mínguez Sánchez, María D; Gómez-Vaquero, Carmen; Balsa, Alejandro; Pascual-Salcedo, Dora; López-Longo, Francisco J; Carreira, Patricia; González-Álvaro, Isidoro; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Ferraz-Amaro, Iván; Castañeda, Santos; Martín, Javier; González-Gay, Miguel A
2016-08-18
Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA.
-
The Co-60 gamma-ray irradiation effects on the Al/HfSiO4/p-Si/Al MOS capacitors
NASA Astrophysics Data System (ADS)
Lok, R.; Kaya, S.; Karacali, H.; Yilmaz, E.
2017-12-01
In this work, the initial interface trap density (Nit) to examine device compability for microelectronics and then the Co-60 gamma irradiation responses of Al/HfSiO4/p-Si/Al (MOS) capacitors were investigated in various dose ranges up to 70 Gy. Pre-irradiation response of the devices was evaluated from high frequency (HF) and low frequency (LF) capacitance method and the Nit was calculated as 9.91 × 1011 cm-2 which shows that the HfSiO4/p-Si interface quality is convenient for microelectronics applications. The irradiation responses of the devices were carried out from flat-band and mid-gap voltage shifts obtained from stretch of capacitance characteristics prior to and after irradiation. The results show that the flat band voltages very slightly shifted to positive voltage values demonstrating the enhancement of negative charge trapping in device structure. The sensitivity of the Al/HfSiO4/p-Si/Al MOS capacitors was found to be 4.41 mV/Gy for 300 nm-thick HfSiO4 gate dielectrics. This value approximately 6.5 times smaller compared to the same thickness conventional SiO2 based MOS devices. Therefore, HfSiO4 exhibits crucial irradiation tolerance in gamma irradiation environment. Consequently, HfSiO4 dielectrics may have significant usage for microelectronic technology as a radiation hard material where radiation field exists such as in space applications.
-
Vogels, Neeltje; Mariman, Edwin C M; Bouwman, Freek G; Kester, Arnold D M; Diepvens, Kristel; Westerterp-Plantenga, Margriet S
2005-10-01
Genetic variation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2), glucocorticoid receptor (GRL), and ciliary neurotrophic factor (CNTF) genes may play a role in the etiology of obesity. We examined biological, psychological, and genetic determinants associated with weight maintenance (WM) after weight loss. Subjects (n = 120) followed a 6-wk diet and then a 1-y period of WM. Body weight (BW), body composition, leptin concentration, attitude toward eating (measured with the Three-Factor Eating Questionnaire), physical activity, and the polymorphisms of the PPARgamma2, GRL, and CNTF genes were measured. BW loss was 7.0 +/- 3.1 kg. After 1 y, 21 subjects showed successful WM (<10% regain); 99 were unsuccessful (> or =10% regain). Compared with unsuccessful subjects, successful subjects had a higher increase in dietary restraint over time (4.8 +/- 5.0 and 1.8 +/- 3.9, respectively; P < 0.01) but significantly less sensation of general hunger (-4.0 +/- 4.9 and -1.2 +/- 2.7, respectively; P < 0.05). Successful subjects had a significantly different frequency distribution for the PPARgamma2 (P = 0.05) and GRL (P < 0.05) genes than did unsuccessful subjects. The more successful genotypes showed a higher baseline body mass index and waist circumference (PPARgamma2), a greater decrease in disinhibition of dietary restraint (GRL), and less sensation of hunger (GRL). The G/G genotype (GRL) was an independent predictor of successful WM. The different genotypes of the PPARgamma2 and GRL genes contribute to WM, either directly (GRL) or indirectly (PPARgamma2 and GRL) via baseline body mass index and waist circumference, and to changes in Three-Factor Eating Questionnaire scores.
-
SAS 2 observations of the earth albedo gamma radiation above 35 MeV
NASA Technical Reports Server (NTRS)
Thompson, D. J.; Simpson, G. A.; Ozel, M. E.
1981-01-01
The earth albedo gamma radiation above 35 MeV in the equatorial region is investigated using observations from the second Small Astronomy Satellite. The zenith angle distribution of the gamma radiation has a peak toward the horizon which is about an order of magnitude more intense than the radiation coming from the nadir, and nearly two orders of magnitude more intense than the gamma radiation from most parts of the sky. The gamma radiation originating from the western horizon is a factor of four more intense than the radiation from the eastern horizon and a factor of three more intense than that from the northern and southern directions. This reflects the geomagnetic effects on the incident cosmic rays whose interactions produce the albedo gamma rays. The variation of the upcoming gamma ray intensity with vertical cutoff rigidity is consistent with the empirical relationship found by Gur'yan et al. (1979).
-
NASA Technical Reports Server (NTRS)
Tewari, S. N.
1976-01-01
A directionally solidified eutectic alloy (DSEA), of those viewed as potential candidates for the next generation of aircraft gas turbine blade materials, is studied for the gamma-prime growth kinetics, in the system Ni-Nb-Cr-Al, specifically: Ni-20 w/o Nb-6 w/o Cr-2.5 w/o Al gamma/gamma-prime-delta DSEA. Heat treatment, polishing and etching, and preparation for electron micrography are described, and the size distribution of gamma-prime phase following various anneals is plotted, along with gamma-prime growth kinetics in this specific DSEA, and the cube of gamma-prime particle size vs anneal time. Activation energies and coarsening kinetics are studied.
-
NASA Astrophysics Data System (ADS)
Chernikova, Dina; Axell, Kåre; Avdic, Senada; Pázsit, Imre; Nordlund, Anders; Allard, Stefan
2015-05-01
Two versions of the neutron-gamma variance to mean (Feynman-alpha method or Feynman-Y function) formula for either gamma detection only or total neutron-gamma detection, respectively, are derived and compared in this paper. The new formulas have particular importance for detectors of either gamma photons or detectors sensitive to both neutron and gamma radiation. If applied to a plastic or liquid scintillation detector, the total neutron-gamma detection Feynman-Y expression corresponds to a situation where no discrimination is made between neutrons and gamma particles. The gamma variance to mean formulas are useful when a detector of only gamma radiation is used or when working with a combined neutron-gamma detector at high count rates. The theoretical derivation is based on the Chapman-Kolmogorov equation with the inclusion of general reactions and corresponding intensities for neutrons and gammas, but with the inclusion of prompt reactions only. A one energy group approximation is considered. The comparison of the two different theories is made by using reaction intensities obtained in MCNPX simulations with a simplified geometry for two scintillation detectors and a 252Cf-source. In addition, the variance to mean ratios, neutron, gamma and total neutron-gamma are evaluated experimentally for a weak 252Cf neutron-gamma source, a 137Cs random gamma source and a 22Na correlated gamma source. Due to the focus being on the possibility of using neutron-gamma variance to mean theories for both reactor and safeguards applications, we limited the present study to the general analytical expressions for Feynman-alpha formulas.
-
Park, Sookyoung; Nozaki, Kenkichi; Smith, Joshua A; Krause, James S; Banik, Naren L
2014-03-01
Insulin-like growth factor-1 (IGF-1) is a neuroprotective growth factor that promotes neuronal survival by inhibition of apoptosis. To examine whether IGF-1 exerts cytoprotective effects against extracellular inflammatory stimulation, ventral spinal cord 4.1 (VSC4.1) motoneuron cells were treated with interferon-gamma (IFN-γ). Our data demonstrated apoptotic changes, increased calpain:calpastatin and Bax:Bcl-2 ratios, and expression of apoptosis-related proteases (caspase-3 and -12) in motoneurons rendered by IFN-γ in a dose-dependent manner. Post-treatment with IGF-1 attenuated these changes. In addition, IGF-1 treatment of motoneurons exposed to IFN-γ decreased expression of inflammatory markers (cyclooxygenase-2 and nuclear factor-kappa B:inhibitor of kappa B ratio). Furthermore, IGF-1 attenuated the loss of expression of IGF-1 receptors (IGF-1Rα and IGF-1Rβ) and estrogen receptors (ERα and ERβ) induced by IFN-γ. To determine whether the protective effects of IGF-1 are associated with ERs, ERs antagonist ICI and selective siRNA targeted against ERα and ERβ were used in VSC4.1 motoneurons. Distinctive morphological changes were observed following siRNA knockdown of ERα and ERβ. In particular, apoptotic cell death assessed by TUNEL assay was enhanced in both ERα and ERβ-silenced VSC4.1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ. © 2013 International Society for Neurochemistry.
-
Ruiz-Ruiz, Carmen; López-Rivas, Abelardo
2002-01-01
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/APO-2L) induces apoptosis in a variety of tumour cells upon binding to death receptors TRAIL-R1 and TRAIL-R2. Here we describe the sensitization by interferon (IFN)-gamma to TRAIL-induced apoptosis in the breast tumour cell lines MCF-7 and MDA-MB231. IFN-gamma promoted TRAIL-mediated activation of caspase-8, Bcl-2 interacting domain death agonist (Bid) degradation, Bcl-2-associated X protein (Bax) translocation to mitochondria, cytochrome c release to the cytosol and activation of caspase-9 in these cell lines. No changes in the expression of TRAIL receptors were observed upon IFN-gamma treatment. Overexpression of Bcl-2 in MCF-7 cells completely inhibited IFN-gamma-induced sensitization to TRAIL-mediated cell death. Interestingly, TRAIL-induced apoptosis was also clearly enhanced by IFN-gamma in caspase-3-overexpressing MCF-7 cells, in the absence of Bax translocation to mitochondria and cytochrome c release to the cytosol. In summary, our results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells. PMID:11936954
-
Gamma power and cognition in patients with schizophrenia and their first-degree relatives.
Díez, Álvaro; Suazo, Vanessa; Casado, Pilar; Martín-Loeches, Manuel; Molina, Vicente
2014-01-01
Gamma oscillations are essential for functional neural assembly formation underlying higher cerebral functions. Previous studies concerning gamma band power in schizophrenia have yielded diverse results. In this study, we assessed gamma band power in minimally treated patients with schizophrenia, their first-degree relatives and healthy controls during an oddball paradigm performance, as well as the relation between gamma power and cognitive performance. We found a higher gamma power in the patient group than in the healthy controls at the P3, P4, Fz, Pz and T5 sites. Compared with their relatives, gamma power in the patients was only marginally higher over P3 and P4. We found a nearly significant inverse association between gamma power at F4 and Tower of London performance in the patients, as well as a significant inverse association between gamma power at T5 and verbal memory and working memory scores in the relatives. These results support higher total gamma power in association with schizophrenia and its inverse association with cognitive performance in patients and their first-degree relatives.
-
NASA Astrophysics Data System (ADS)
Campos, Sandro X.; Vieira, Eny M.; Cordeiro, Paulo J. M.; Rodrigues-Fo, Edson; Murgu, Michael
2003-12-01
In this study, gamma radiation from cobalt-60 was used to degrade the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) dimethylamine salt in water in the presence of humic acid. The 2,4-D dimethylamine salt 1.13×10 -4 mol dm -3 solution was irradiated with different doses. HPLC was used as an analytical technique to determine the degradation rate of herbicide studied. The results showed that the herbicide was completely degraded at an absorbed dose of 3 kGy. Degradation decreased when humic acid was added to all the doses. ESI/MS and MS/MS were used to identify the radiolytic degradation products. A fragmentation path for production of 4.6-dichlororesorcinol, is suggested. The radiolytic yields ( G) were calculated.
-
Wong, L H; Hatzinisiriou, I; Devenish, R J; Ralph, S J
1998-06-01
IFN-stimulated gene factor 3 (ISGF3) mediates transcriptional activation of IFN-sensitive genes (ISGs). The component subunits of ISGF3, STAT1alphabeta, STAT2, and p48-ISGF3gamma, are tyrosine phosphorylated before their assembly into a complex. Subsequently, the ISGF3 complex is translocated to the nucleus. We have recently established that the responsiveness of human melanoma cell lines to type I IFNs correlates directly with their intracellular levels of ISGF3 components, particularly STAT1. In the present study, we show that pretreating IFN-resistant melanoma cell lines with IFN-gamma (IFN-gamma priming) before stimulation with type I IFN also results in increased levels of ISGF3 components and enhanced DNA-binding activation of ISGF3. In addition, IFN-gamma priming of IFN-resistant melanoma cell lines increased expression of type I IFN-induced ISG products, including ISG54, 2'-5'-oligoadenylate synthase, HLA class I, B7-1, and ICAM-1 Ags. Furthermore, IFN-gamma priming enhanced the antiviral effect of IFN-beta on the IFN-resistant melanoma cell line, MM96. These results support a role for IFN-gamma priming in up-regulating ISGF3, thereby augmenting the responsiveness of IFN-resistant melanoma cell lines to type I IFN and providing a molecular basis and justification for using sequential IFN therapy, as proposed by others, to enhance the use of IFNs in the treatment of melanoma.
-
ElAlfy, Mohsen Saleh; Adly, Amira Abdel Moneam; Ebeid, Fatma Soliman ElSayed; Eissa, Deena Samir; Ismail, Eman Abdel Rahman; Mohammed, Yasser Hassan; Ahmed, Manar Elsayed; Saad, Aya Sayed
2018-06-20
Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4 + CD28 null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4 + CD28 null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4 + CD28 null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4 + CD28 null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4 + CD28 null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4 + CD28 null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4 + CD28 null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.
-
Athanasas-Platsis, S; Hoskin, M J; Rolfe, B E; Cavanagh, A C; Morton, H
1995-03-01
The importance of EPF during pregnancy has been established previously but the importance of the EPF-induced suppressor factor EPF-S1 in pregnancy has to date been unaddressed. Investigations were therefore conducted in order to study this. Monoclonal antibodies to EPF-S1 were produced, and one antibody, designated R2T gamma, was characterized. Mated mice were passively immunized with R2T gamma and the effect on implantation determined. Characterization of anti-EPF-S1 R2T gamma revealed that it cross-reacted with EPF-S1 of different MHC restriction but not with EPF or EPF-S2. When injected into mated mice on days 1 to 4, R2T gamma had no effect on pregnancy but when injections continued to day 5, pregnancy was affected; the number of embryos implanted on day 7 were significantly less than the number of corpora lutea counted, signifying embryonic loss. These studies show that anti-EPF-S1 R2T gamma disrupts implantation in mice when injected on days 1 to 5 of pregnancy but not when injected on days 1 to 4, demonstrating that EPF-S1 exerts its effects around the time of implantation.
-
Pai, Madhukar; Gokhale, Kaustubh; Joshi, Rajnish; Dogra, Sandeep; Kalantri, Shriprakash; Mendiratta, Deepak K; Narang, Pratibha; Daley, Charles L; Granich, Reuben M; Mazurek, Gerald H; Reingold, Arthur L; Riley, Lee W; Colford, John M
2005-06-08
Mycobacterium tuberculosis infection in health care workers has not been adequately studied in developing countries using newer diagnostic tests. To estimate latent tuberculosis infection prevalence in health care workers using the tuberculin skin test (TST) and a whole-blood interferon gamma (IFN-gamma) assay; to determine agreement between the tests; and to compare their correlation with risk factors. A cross-sectional comparison study of 726 health care workers aged 18 to 61 years (median age, 22 years) with no history of active tuberculosis conducted from January to May 2004, at a rural medical school in India. A total of 493 (68%) of the health care workers had direct contact with patients with tuberculosis and 514 (71%) had BCG vaccine scars. Tuberculin skin testing was performed using 1-TU dose of purified protein derivative RT23, and the IFN-gamma assay was performed by measuring IFN-gamma response to early secreted antigenic target 6, culture filtrate protein 10, and a portion of tuberculosis antigen TB7.7. Agreement between TST and the IFN-gamma assay, and comparison of the tests with respect to their association with risk factors. A large proportion of the health care workers were latently infected; 360 (50%) were positive by either TST or IFN-gamma assay, and 226 (31%) were positive by both tests. The prevalence estimates of TST and IFN-gamma assay positivity were comparable (41%; 95% confidence interval [CI], 38%-45% and 40%; 95% CI, 37%-43%, respectively). Agreement between the tests was high (81.4%; kappa = 0.61; 95% CI, 0.56-0.67). Increasing age and years in the health profession were significant risk factors for both IFN-gamma assay and TST positivity. BCG vaccination had little impact on TST and IFN-gamma assay results. Our study showed high latent tuberculosis infection prevalence in Indian health care workers, high agreement between TST and IFN-gamma assay, and similar association between positive test results and risk factors. Although TST and
-
[Determination of exogenous gamma-amylase residue in honey].
Fei, Xiaoqing; Wu, Bin; Shen, Chongyu; Zhang, Rui; Ding, Tao; Li, Lihua
2012-08-01
A novel method for the determination of exogenous gamma-amylase residue in honey using liquid chromatography-isotope ratio mass spectrometry (LC-IRMS) was established. After pre-separation by gel column chromatography, the gamma-amylase in honey samples was separated from the sugars. The gamma-amylase was then used to catalyze maltose into glucose. This enzymatic reaction was under the conditions of 55 degrees C and 0.03 mol/L phosphate buffer solution (pH 4.5) for 48 h. The maltose and glucose in the above enzymatic reaction solution were separated using liquid chromatography. By measuring the content of glucose with isotope ratio mass spectrometry, the gamma-amylase in honey can be determined. The linear range of gamma-amylase was 5 - 200 U/kg with the quantification limit of 5 U/kg. The recoveries were between 89.6% and 108.2% with the relative standard deviations from 3.3% to 4.9%. This method was used to analyze 38 honey and rice syrup samples, and the detection rate of gamma-amylase was 76.3%. To further verify the detection capability of this method, an authentic honey was adulterated with 15% (mass fraction) rice syrup. The gamma-amylase content in this sample was 10.2 U/kg. This method can effectively identify honey adulteration with rice syrups from the perspective of enzymology.
-
Kumar, Munish; Sahani, G; Chourasiya, G
2010-06-01
Electron contamination from a sealed (60)Co radiation source has been investigated comprehensively using a CaSO(4):Dy based TLD badge and LiF crystals. It has been found that due to electron contamination, the thermoluminescence (TL) detectors exhibit over response which can be corrected by applying a magnetic field. It has also been found that for a source-to-dosimeter distance of 50 cm, the ratio of the TL readouts of the third to first discs of the TLD badge reduces from approximately 1.5 to approximately 1.00 after applying a magnetic field. Hence detectors which are sensitive to electrons as well as photons, and are capable of distinguishing them, can lead to an erroneous measurement. This happens because the contribution due to electron contamination interferes with pure gamma calibration. The study is helpful in establishing accurate calibration and appropriate correction factors for personnel monitoring carried out using CaSO(4):Dy based TLD badge. Copyright 2009 Elsevier Ltd. All rights reserved.
-
Wang, Juan; Shibayama, Yuki; Kobori, Hiroyuki; Liu, Ya; Kobara, Hideki; Masaki, Tsutomu; Wang, Zhiyu
2017-01-01
High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5’-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy. PMID:29053707
-
Computational techniques in gamma-ray skyshine analysis
DOE Office of Scientific and Technical Information (OSTI.GOV)
George, D.L.
1988-12-01
Two computer codes were developed to analyze gamma-ray skyshine, the scattering of gamma photons by air molecules. A review of previous gamma-ray skyshine studies discusses several Monte Carlo codes, programs using a single-scatter model, and the MicroSkyshine program for microcomputers. A benchmark gamma-ray skyshine experiment performed at Kansas State University is also described. A single-scatter numerical model was presented which traces photons from the source to their first scatter, then applies a buildup factor along a direct path from the scattering point to a detector. The FORTRAN code SKY, developed with this model before the present study, was modified tomore » use Gauss quadrature, recent photon attenuation data and a more accurate buildup approximation. The resulting code, SILOGP, computes response from a point photon source on the axis of a silo, with and without concrete shielding over the opening. Another program, WALLGP, was developed using the same model to compute response from a point gamma source behind a perfectly absorbing wall, with and without shielding overhead. 29 refs., 48 figs., 13 tabs.« less
-
Suppressing effect of low-dose gamma-ray irradiation on collagen-induced arthritis.
Nakatsukasa, Hiroko; Tsukimoto, Mitsutoshi; Ohshima, Yasuhiro; Tago, Fumitoshi; Masada, Ayako; Kojima, Shuji
2008-07-01
We previously reported attenuation of autoimmune disease by low-dose gamma-ray irradiation in MRL-lpr/lpr mice. Here, we studied the effect of low-dose gamma-ray irradiation on collagen-induced arthritis (CIA) in DBA/1J mice. Mice were immunized with type II collagen, and exposed to low-dose gamma-rays (0.5 Gy per week for 5 weeks). Paw swelling, redness, and bone degradation were suppressed by irradiation, which also delayed the onset of pathological change and reduced the severity of the arthritis. Production of tumor necrosis factor-alpha, interferon-gamma, and interleukin-6, which play important roles in the onset of CIA, was suppressed by the irradiation. The level of anti-type II collagen antibody, which is essential for the onset of CIA, was also lower in irradiated CIA mice. The population of plasma cells was increased in CIA mice, but irradiation blocked this increase. Since regulatory T cells are known to be involved in suppression of autoimmune disease, the population of CD4(+)CD25(+)Foxp3(+) regulatory T cells was measured. Intriguingly, a significant increase of these regulatory T cells was found in irradiated CIA mice. Overall, our data suggest that low-dose gamma-ray irradiation could attenuate CIA through suppression of pro-inflammatory cytokines and autoantibody production, and induction of regulatory T cells.
-
Two-year experience with the commercial Gamma Knife Check software.
Xu, Andy Yuanguang; Bhatnagar, Jagdish; Bednarz, Greg; Novotny, Josef; Flickinger, John; Lunsford, L Dade; Huq, M Saiful
2016-07-08
The Gamma Knife Check software is an FDA approved second check system for dose calculations in Gamma Knife radiosurgery. The purpose of this study was to evaluate the accuracy and the stability of the commercial software package as a tool for independent dose verification. The Gamma Knife Check software version 8.4 was commissioned for a Leksell Gamma Knife Perfexion and a 4C unit at the University of Pittsburgh Medical Center in May 2012. Independent dose verifications were performed using this software for 319 radiosurgery cases on the Perfexion and 283 radiosurgery cases on the 4C units. The cases on each machine were divided into groups according to their diagnoses, and an averaged absolute percent dose difference for each group was calculated. The percentage dose difference for each treatment target was obtained as the relative difference between the Gamma Knife Check dose and the dose from the tissue maximum ratio algorithm (TMR 10) from the GammaPlan software version 10 at the reference point. For treatment plans with imaging skull definition, results obtained from the Gamma Knife Check software using the measurement-based skull definition method are used for comparison. The collected dose difference data were also analyzed in terms of the distance from the treatment target to the skull, the number of treatment shots used for the target, and the gamma angles of the treatment shots. The averaged percent dose differences between the Gamma Knife Check software and the GammaPlan treatment planning system are 0.3%, 0.89%, 1.24%, 1.09%, 0.83%, 0.55%, 0.33%, and 1.49% for the trigeminal neuralgia, acoustic neuroma, arteriovenous malformation (AVM), meningioma, pituitary adenoma, glioma, functional disorders, and metastasis cases on the Perfexion unit. The corresponding averaged percent dose differences for the 4C unit are 0.33%, 1.2%, 2.78% 1.99%, 1.4%, 1.92%, 0.62%, and 1.51%, respectively. The dose difference is, in general, larger for treatment targets in the
-
Two‐year experience with the commercial Gamma Knife Check software
Bhatnagar, Jagdish; Bednarz, Greg; Novotny, Josef; Flickinger, John; Lunsford, L. Dade; Huq, M. Saiful
2016-01-01
The Gamma Knife Check software is an FDA approved second check system for dose calculations in Gamma Knife radiosurgery. The purpose of this study was to evaluate the accuracy and the stability of the commercial software package as a tool for independent dose verification. The Gamma Knife Check software version 8.4 was commissioned for a Leksell Gamma Knife Perfexion and a 4C unit at the University of Pittsburgh Medical Center in May 2012. Independent dose verifications were performed using this software for 319 radiosurgery cases on the Perfexion and 283 radiosurgery cases on the 4C units. The cases on each machine were divided into groups according to their diagnoses, and an averaged absolute percent dose difference for each group was calculated. The percentage dose difference for each treatment target was obtained as the relative difference between the Gamma Knife Check dose and the dose from the tissue maximum ratio algorithm (TMR 10) from the GammaPlan software version 10 at the reference point. For treatment plans with imaging skull definition, results obtained from the Gamma Knife Check software using the measurement‐based skull definition method are used for comparison. The collected dose difference data were also analyzed in terms of the distance from the treatment target to the skull, the number of treatment shots used for the target, and the gamma angles of the treatment shots. The averaged percent dose differences between the Gamma Knife Check software and the GammaPlan treatment planning system are 0.3%, 0.89%, 1.24%, 1.09%, 0.83%, 0.55%, 0.33%, and 1.49% for the trigeminal neuralgia, acoustic neuroma, arteriovenous malformation (AVM), meningioma, pituitary adenoma, glioma, functional disorders, and metastasis cases on the Perfexion unit. The corresponding averaged percent dose differences for the 4C unit are 0.33%, 1.2%, 2.78% 1.99%, 1.4%, 1.92%, 0.62%, and 1.51%, respectively. The dose difference is, in general, larger for treatment targets in the
-
Discovery of a Nonblazar Gamma-Ray Transient Source Near the Galactic Plane: GRO J1838-04
NASA Technical Reports Server (NTRS)
Tavani, M.; Oliversen, Ronald (Technical Monitor)
2001-01-01
We report the discovery of a remarkable gamma-ray transient source near the Galactic plane, GRO J1838-04. This source was serendipitously discovered by EGRET in 1995 June with a peak intensity of approx. (4 +/- 1) x 10(exp -6) photons/sq cm s (for photon energies larger than 100 MeV) and a 5.9 sigma significance. At that time, GRO J1838-04 was the second brightest gamma-ray source in the sky. A subsequent EGRET pointing in 1995 late September detected the source at a flux smaller than its peak value by a factor of approx. 7. We determine that no radio-loud spectrally flat blazar is within the error box of GRO J1838-04. We discuss the origin of the gamma-ray transient source and show that interpretations in terms of active galactic nuclei or isolated pulsars are highly problematic. GRO J1838-04 provides strong evidence for the existence of a new class of variable gamma-ray sources.
-
Very high-energy gamma rays from gamma-ray bursts.
Chadwick, Paula M
2007-05-15
Very high-energy (VHE) gamma-ray astronomy has undergone a transformation in the last few years, with telescopes of unprecedented sensitivity having greatly expanded the source catalogue. Such progress makes the detection of a gamma-ray burst at the highest energies much more likely than previously. This paper describes the facilities currently operating and their chances for detecting gamma-ray bursts, and reviews predictions for VHE gamma-ray emission from gamma-ray bursts. Results to date are summarized.
-
Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin.
Chaya, D; Hayamizu, T; Bustin, M; Zaret, K S
2001-11-30
Nucleosome-like particles and acetylated histones occur near active promoters and enhancers, and certain transcription factors can recognize their target sites on the surface of a nucleosome in vitro; yet it has been unclear whether transcription factors can occupy target sites on nucleosomes in native chromatin. We developed a method for sequential chromatin immunoprecipitation of distinct nuclear proteins that are simultaneously cross-linked to nucleosome-sized genomic DNA segments. We find that core histone H2A co-occupies, along with the FoxA (hepatocyte nuclear factor-3) transcription factor, DNA for the albumin transcriptional enhancer in native liver chromatin, where the enhancer is active. Because histone H2A on nuclear DNA is only known to exist in nucleosomes, we conclude that transcription factors can form a stable complex on nucleosomes at an active enhancer element in vivo.
-
Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.
Revelo, Monica P; Federspiel, Charles; Helderman, Harold; Fogo, Agnes B
2005-12-01
Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN. All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules. Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2
-
Gamma Radiation from PSR B1055-52
NASA Technical Reports Server (NTRS)
Thompson, D. J.; Bailes, M.; Bertsch, D. L.; Cordes, J.; DAmico, N. D.; Esposito, J. A.; Finley, J.; Hartman, R. C.; Hermsen, W.; Kanbach, G.;
1998-01-01
The telescopes on the Compton Gamma Ray Observatory (CCRO) have observed PSR B1055-52 a number of times between 1991 and 1998. From these data, a more detailed picture of the gamma radiation from this source has been developed, showing several characteristics which distinguish this pulsar: the light curve is complex; there is no detectable unpulsed emission; the energy spectrum is flat, with no evidence of a sharp high-energy cutoff up to greater than 4 GeV. Comparisons of the gamma-ray data with observations at longer wavelengths show that no two of the known gamma-ray pulsars have quite the same characteristics; this diversity makes interpretation in terms of theoretical models difficult.
-
Gamma Radiation from PSR B1055-52
NASA Technical Reports Server (NTRS)
Thompson, D. J.; Bailes, M.; Bertsch, D. L.; Cordes, J.; DAmico, N.; Esposito, J. A.; Finley, J.; Hartman, R. C.; Hermsen, W.; Kanbach, G.;
1999-01-01
The telescopes on the Compton Gamma Ray Observatory (CGRO) have observed PSR B1055-52 a number of times between 1991 and 1998. From these data, a more detailed picture of the gamma radiation from this source has been developed, showing several characteristics which distinguish this pulsar: the light curve is complex; there is no detectable unpulsed emission; the energy spectrum is flat, with no evidence of a sharp high-energy cutoff up to greater than 4 GeV. Comparisons of the gamma-ray data with observations at longer wavelengths show that no two of the known gamma-ray pulsars have quite the same characteristics; this diversity makes interpretation in terms of theoretical models difficult.
-
25 CFR 153.4 - Factors determining competency.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 25 Indians 1 2010-04-01 2010-04-01 false Factors determining competency. 153.4 Section 153.4 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER DETERMINATION OF COMPETENCY: CROW INDIANS § 153.4 Factors determining competency. Among the matters to be considered by the...
-
Anti-interferon-gamma antibodies in the treatment of autoimmune diseases.
Skurkovich, Boris; Skurkovich, Simon
2003-02-01
Interferon (IFN)-gamma is an important immune regulator in normal immunity. When IFN gamma production is disturbed, various autoimmune diseases (ADs) can develop, in which we suggest that anti-IFN gamma could have a beneficial effect. Depending on the cell type in which IFN gamma synthesis is disturbed, different clinical manifestations may result. We have also proposed to remove tumor necrosis factor (TNF)-alpha, together with certain types of IFNs, to treat various ADs and AIDS, also an autoimmune condition. Anti-IFN gamma has been tested in several T-helper cell (Th1) ADs, including rheumatoid arthritis (RA), multiple sclerosis (MS), corneal transplant rejection, uveitis, Type I diabetes, schizophrenia (anti-IFN gamma and anti-TNF alpha), and various autoimmune skin diseases (alopecia areata, psoriasis vulgaris, vitiligo, pemphigus vulgaris and epidermolysis bullosa). A strong, sometimes striking, therapeutic response followed administration of anti-IFN gamma, indicating that it may be a promising therapy for Th1 ADs.
-
Heterozygous ABCC8 mutations are a cause of MODY.
Bowman, P; Flanagan, S E; Edghill, E L; Damhuis, A; Shepherd, M H; Paisey, R; Hattersley, A T; Ellard, S
2012-01-01
The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.
-
Characterization of gamma rays existing in the NMIJ standard neutron field.
Harano, H; Matsumoto, T; Ito, Y; Uritani, A; Kudo, K
2004-01-01
Our laboratory provides national standards on fast neutron fluence. Neutron fields are always accompanied by gamma rays produced in neutron sources and surroundings. We have characterised these gamma rays in the 5.0 MeV standard neutron field. Gamma ray measurement was performed using an NE213 liquid scintillator. Pulse shape discrimination was incorporated to separate the events induced by gamma rays from those by neutrons. The measured gamma ray spectra were unfolded with the HEPRO program package to obtain the spectral fluences using the response matrix prepared with the EGS4 code. Corrections were made for the gamma rays produced by neutrons in the detector assembly using the MCNP4C code. The effective dose equivalents were estimated to be of the order of 25 microSv at the neutron fluence of 10(7) neutrons cm(-2).
-
Coers, Jörn; Bernstein-Hanley, Isaac; Grotsky, David; Parvanova, Iana; Howard, Jonathan C; Taylor, Gregory A; Dietrich, William F; Starnbach, Michael N
2008-05-01
Chlamydiae are obligate intracellular bacterial pathogens that exhibit a broad range of host tropism. Differences in host tropism between Chlamydia species have been linked to host variations in IFN-gamma-mediated immune responses. In mouse cells, IFN-gamma can effectively restrict growth of the human pathogen Chlamydia trachomatis but fails to control growth of the closely related mouse pathogen Chlamydia muridarum. The ability of mouse cells to resist C. trachomatis replication is largely dependent on the induction of a family of IFN-gamma-inducible GTPases called immunity-related GTPases or IRGs. In this study we demonstrate that C. muridarum can specifically evade IRG-mediated host resistance. It has previously been suggested that C. muridarum inactivates the IRG protein Irga6 (Iigp1) to dampen the murine immune response. However, we show that Irga6 is dispensable for the control of C. trachomatis replication. Instead, an effective IFN-gamma response to C. trachomatis requires the IRG proteins Irgm1 (Lrg47), Irgm3 (Igtp), and Irgb10. Ectopic expression of Irgb10 in the absence of IFN-gamma is sufficient to reduce intracellular growth of C. trachomatis but fails to restrict growth of C. muridarum, indicating that C. muridarum can specifically evade Irgb10-driven host responses. Importantly, we find that Irgb10 protein intimately associates with inclusions harboring C. trachomatis but is absent from inclusions formed by C. muridarum. These data suggest that C. muridarum has evolved a mechanism to escape the murine IFN-gamma response by restricting access of Irgb10 and possibly other IRG proteins to the inclusion.
-
ERIC Educational Resources Information Center
Blum, Sonja; Dash, Pramod K.
2004-01-01
Growth factor-mediated signaling has emerged as an essential component of memory formation. In this study, we used a phospholipase C gamma 1 (PLC[gamma]1) binding, cell-penetrating peptide to sequester PLC[gamma]1 away from its target, the phosphotyrosine residues within the activated growth factor receptor. Peptides appear to transduce neurons…
-
Increased TeV gamma-ray activity from Mrk 421 on January 1-4
NASA Astrophysics Data System (ADS)
Wood, J.; Martinez, I.; Lauer, R.
2017-01-01
The HAWC Observatory measured increased gamma-ray fluxes from the direction of BL Lac Markarian 421 (z=0.031) over four successive nights starting on January 1, 2017: Transit Starting 07:40:55 UTC on Jan 1, 2017 (MJD 57754.32): Flux = (4.8 +/- 1.1) x10^-11 photons/cm2/s [2.5 Crab Units] Transit Starting 07:36:59 UTC on Jan 2, 2017 (MJD 57755.32): Flux = (3.6 +/- 1.0) x10^-11 photons/cm2/s [1.9 Crab Units] Transit Starting 07:33:04 UTC on Jan 3, 2017 (MJD 57756.31): Flux = (4.0 +/- 1.0) x10^-11 photons/cm2/s [2.1 Crab Units] Transit Starting 07:29:08 UTC on Jan 4, 2017 (MJD 57757.31): Flux = (4.1 +/- 1.0) x10^-11 photons/cm2/s [2.2 Crab Units] All fluxes reported here are the integral flux above 1 TeV averaged over the 6 hour source transit obtained from a maximum likelihood fit under the assumption of a fixed spectral shape with power law index of 2.2 and exponential cut-off at 5 TeV. This shape is the current best fit for HAWC data from Markarian 421. The highest flux occurred on Jan 1, 2017.
-
ICF Gamma-Ray measurements on the NIF
NASA Astrophysics Data System (ADS)
Herrmann, Hans; Kim, Y.; Hoffman, N. M.; Batha, S. H.; Stoeffl, W.; Church, J. A.; Sayre, D. B.; Liebman, J. A.; Cerjan, C. J.; Carpenter, A. C.; Grafil, E. M.; Khater, H. Y.; Horsfield, C. J.; Rubery, M.
2013-10-01
The primary objective of the NIF Gamma Reaction History (GRH) diagnostic is to provide bang time and burn width information in order to constrain implosion simulation parameters such as shell velocity and confinement time. This is accomplished by measuring DT fusion gamma-rays with energy-thresholded Gas Cherenkov detectors that convert MeV gamma-rays into UV/visible photons for high-bandwidth optical detection. Burn-weighted CH ablator areal density is also inferred based on measurement of the 12C(n,n') gammas emitted at 4.44 MeV from DT neutrons inelastically scattering off carbon nuclei as they pass through the plastic ablator. This requires that the four independent GRH gas cells be set to differing Cherenkov thresholds (e.g., 2.9, 4.5, 8 & 10 MeV) in order to be able to unfold the primary spectral components predicted to be in the gamma ray energy spectrum (i.e., DT γ 27Al & 28Si (n,n') γ from the thermo-mechanical package (TMP); and 12C(n,n' γ from the ablator). The GRH response to 12C(n,n') γ is calibrated in-situ by placing a known areal density of carbon in the form of a puck placed ~6 cm from a DT exploding pusher implosion. Comparisons between inferred gamma fluences and simulations based on the nuclear cross sections databases will be presented. Supported by US DOE NNSA.
-
NASA Astrophysics Data System (ADS)
Yastrebinskii, R. N.
2018-04-01
The investigations on estimating the attenuation of capture gamma radiation by a composite neutron-shielding material based on modified titanium hydride and Portland cement with a varied amount of boron carbide are performed. The results of calculations demonstrate that an introduction of boron into this material enables significantly decreasing the thermal neutron flux density and hence the levels of capture gamma radiation. In particular, after introducing 1- 5 wt.% boron carbide into the material, the thermal neutron flux density on a 10 cm-thick layer is reduced by 11 to 176 factors, and the capture gamma dose rate - from 4 to 9 times, respectively. The difference in the degree of reduction in these functionals is attributed to the presence of capture gamma radiation in the epithermal region of the neutron spectrum.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Mukhamedzhanov, A. M.; Gagliardi, C. A.; Goldberg, V. Z.
2008-07-15
The {sup 15}N(p,{gamma}){sup 16}O reaction provides a path from the CN cycle to the CNO bi-cycle and CNO tri-cycle. The measured astrophysical factor for this reaction is dominated by resonant capture through two strong J{sup {pi}}=1{sup -} resonances at E{sub R}=312 and 962 keV and direct capture to the ground state. Asymptotic normalization coefficients (ANCs) for the ground and seven excited states in {sup 16}O were extracted from the comparison of experimental differential cross sections for the {sup 15}N({sup 3}He,d){sup 16}O reaction with distorted-wave Born approximation calculations. Using these ANCs and proton and {alpha} resonance widths determined from an R-matrixmore » fit to the data from the {sup 15}N(p,{alpha}){sup 12}C reaction, we carried out an R-matrix calculation to obtain the astrophysical factor for the {sup 15}N(p,{gamma}){sup 16}O reaction. The results indicate that the direct capture contribution was previously overestimated. We find the astrophysical factor to be S(0)=36.0{+-}6.0 keV b, which is about a factor of 2 lower than the presently accepted value. We conclude that for every 2200{+-}300 cycles of the main CN cycle one CN catalyst is lost due to this reaction.« less
-
Minc, Daniel; Machado, Sergio; Bastos, Victor Hugo; Machado, Dionis; Cunha, Marlo; Cagy, Mauricio; Budde, Henning; Basile, Luis; Piedade, Roberto; Ribeiro, Pedro
2010-01-18
The goal of the present study was to explore the dynamics of the gamma band using the coherence of the quantitative electroencephalography (qEEG) in a sensorimotor integration task and the influence of the neuromodulator bromazepam on the band behavior. Our hypothesis is that the needs of the typewriting task will demand the coupling of different brain areas, and that the gamma band will promote the binding of information. It is also expected that the neuromodulator will modify this coupling. The sample was composed of 39 healthy subjects. We used a randomized double-blind design and divided subjects into three groups: placebo (n=13), bromazepam 3mg (n=13) and bromazepam 6 mg (n=13). The two-way ANOVA analysis demonstrated a main effect for the factors condition (i.e., C4-CZ electrode pair) and moment (i.e., C3-CZ, C3-C4 and C4-CZ pairs of electrodes). We propose that the gamma band plays an important role in the binding among several brain areas in complex motor tasks and that each hemisphere is influenced in a different manner by the neuromodulator. (c) 2009 Elsevier Ireland Ltd. All rights reserved.
-
Monte Carlo simulations of the gamma-ray exposure rates of common rocks
DOE Office of Scientific and Technical Information (OSTI.GOV)
Haber, Daniel A.; Malchow, Russell L.; Burnley, Pamela C.
Monte Carlo simulations have been performed to model the gamma ray emission and attenuation properties of common rocks. In geologic materials, 40K, 238U, and 232Th are responsible for most gamma ray production. If the concentration of these radioelements and attenuation factors such as degree of water saturation are known, an estimate of the gamma-ray exposure rate can be made. The results show that there are no significant differences in gamma-ray screening between major rock types. If the total number of radionuclide atoms are held constant then the major controlling factor is density of the rock. Finally, the thickness of regolithmore » or soil overlying rock can be estimated by modeling the exposure rate if the radionuclide contents of both materials are known.« less
-
Monte Carlo simulations of the gamma-ray exposure rates of common rocks
Haber, Daniel A.; Malchow, Russell L.; Burnley, Pamela C.
2016-11-24
Monte Carlo simulations have been performed to model the gamma ray emission and attenuation properties of common rocks. In geologic materials, 40K, 238U, and 232Th are responsible for most gamma ray production. If the concentration of these radioelements and attenuation factors such as degree of water saturation are known, an estimate of the gamma-ray exposure rate can be made. The results show that there are no significant differences in gamma-ray screening between major rock types. If the total number of radionuclide atoms are held constant then the major controlling factor is density of the rock. Lastly, the thickness of regolithmore » or soil overlying rock can be estimated by modeling the exposure rate if the radionuclide contents of both materials are known.« less
-
Monte Carlo simulations of the gamma-ray exposure rates of common rocks
DOE Office of Scientific and Technical Information (OSTI.GOV)
Haber, Daniel A.; Malchow, Russell L.; Burnley, Pamela C.
Monte Carlo simulations have been performed to model the gamma ray emission and attenuation properties of common rocks. In geologic materials, 40K, 238U, and 232Th are responsible for most gamma ray production. If the concentration of these radioelements and attenuation factors such as degree of water saturation are known, an estimate of the gamma-ray exposure rate can be made. The results show that there are no significant differences in gamma-ray screening between major rock types. If the total number of radionuclide atoms are held constant then the major controlling factor is density of the rock. Lastly, the thickness of regolithmore » or soil overlying rock can be estimated by modeling the exposure rate if the radionuclide contents of both materials are known.« less
-
Laban-Guceva, Nevenka; Antova, Magdalena; Bogoev, Milco
2007-11-01
TED is a severe eye disease leading in rare cases to decrease of sight, optic nerve compression and blindness. Recently, significant progresses in understanding the disease have been done. Nevertheless, the treatment of the disease, especially in its severe form remains challenging. Glucocorticoids (GC) have been the basis of the treatment for a long time. Orbital irradiation (OI) and optical decompression (OD) are also used in managing the severe forms of TED. Somatostatin, intravenous immunoglobulin have been also used, with conflicting results. Regarding the potential for the treatment of TED with cytokine antagonists, controlled clinical studies are not available. Since cytokines play an important role in the pathogenesis of the TED, they seemed to be logical choice for modern TED treatment. It has been shown that both Th1 (interleukin-2, tumor necrosis factor gamma, interleukin gamma) and Th2 (interleukin -4, -5, -10) profile T cells are activated in the TED. We therefore measured interleukin-gamma, IF-gamma and interleukin -10 (IL-10)(Th1 and Th2 pattern) to assess its relationship to the course of the disease. This paper shows that both Th1 (IL-2) and Th2 (IF-gamma) pathways represented by those two cytokines are not involved (IL-10 before 2.29+/-5.23 and after treatment 3.77+/-8.44; IF gamma before 0.50+/-0.24 and after treatment 0.35+/-0.19). No relationship to the response to treatment was found. GC resulted in positive response in 8/22 patients, OI (12 patients) given after CS therapy, resulted in a response in all patients. Increase in proptosis, loss of visual acuity is spite of CS treatment prompted OD in two patients, who both recovered visual acuity and proptosis fell under 25 mm Hertel.
-
Lewis type 1 antigen synthase (beta3Gal-T5) is transcriptionally regulated by homeoproteins.
Isshiki, Soichiro; Kudo, Takashi; Nishihara, Shoko; Ikehara, Yuzuru; Togayachi, Akira; Furuya, Akiko; Shitara, Kenya; Kubota, Tetsuro; Watanabe, Masahiko; Kitajima, Masaki; Narimatsu, Hisashi
2003-09-19
The type 1 carbohydrate chain, Galbeta1-3GlcNAc, is synthesized by UDP-galactose:beta-N-acetylglucosamine beta1,3-galactosyltransferase (beta3Gal-T). Among six beta3Gal-Ts cloned to date, beta3Gal-T5 is an essential enzyme for the synthesis of type 1 chain in epithelium of digestive tracts or pancreatic tissue. It forms the type 1 structure on glycoproteins produced from such tissues. In the present study, we found that the transcriptional regulation of the beta3Gal-T5 gene is controlled by homeoproteins, i.e. members of caudal-related homeobox protein (Cdx) and hepatocyte nuclear factor (HNF) families. We found an important region (-151 to -121 from the transcription initiation site), named the beta3Gal-T5 control element (GCE), for the promoter activity. GCE contained the consensus sequences for members of the Cdx and HNF families. Mutations introduced into this sequence abolished the transcriptional activity. Four factors, Cdx1, Cdx2, HNF1alpha, and HNF1beta, could bind to GCE and transcriptionally activate the beta3Gal-T5 gene. Transcriptional regulation of the beta3Gal-T5 gene was consistent with that of members of the Cdx and HNF1 families in two in vivo systems. 1) During in vitro differentiation of Caco-2 cells, transcriptional up-regulation of beta3Gal-T5 was observed in correlation with the increase in transcripts for Cdx2 and HNF1alpha. 2) Both transcript and protein levels of beta3Gal-T5 were determined to be significantly reduced in colon cancer. This down-regulation was correlated with the decrease of Cdx1 and HNF1beta expression in cancer tissue. This is the first finding that a glycosyltransferase gene is transcriptionally regulated under the control of homeoproteins in a tissue-specific manner. beta3Gal-T5, controlled by the intestinal homeoproteins, may play an important role in the specific function of intestinal cells by modifying the carbohydrate structure of glycoproteins.
-
Impaired theta-gamma coupling during working memory performance in schizophrenia.
Barr, Mera S; Rajji, Tarek K; Zomorrodi, Reza; Radhu, Natasha; George, Tony P; Blumberger, Daniel M; Daskalakis, Zafiris J
2017-11-01
Working memory deficits represent a core feature of schizophrenia. These deficits have been associated with dysfunctional dorsolateral prefrontal cortex (DLPFC) cortical oscillations. Theta-gamma coupling describes the modulation of gamma oscillations by theta phasic activity that has been directly associated with the ordering of information during working memory performance. Evaluating theta-gamma coupling may provide greater insight into the neural mechanisms mediating working memory deficits in this disorder. Thirty-eight patients diagnosed with schizophrenia or schizoaffective disorder and 38 healthy controls performed the verbal N-Back task administered at 4 levels, while EEG was recorded. Theta (4-7Hz)-gamma (30-50Hz) coupling was calculated for target and non-target correct trials for each working memory load. The relationship between theta-gamma coupling and accuracy was determined. Theta-gamma coupling was significantly and selectively impaired during correct responses to target letters among schizophrenia patients compared to healthy controls. A significant and positive relationship was found between theta-gamma coupling and 3-Back accuracy in controls, while this relationship was not observed in patients. These findings suggest that impaired theta-gamma coupling contribute to working memory dysfunction in schizophrenia. Future work is needed to evaluate the predictive utility of theta-gamma coupling as a neurophysiological marker for functional outcomes in this disorder. Copyright © 2017. Published by Elsevier B.V.
-
Effect of gamma irradiation on Korean traditional multicolored paintwork
NASA Astrophysics Data System (ADS)
Yoon, Minchul; Kim, Dae-Woon; Choi, Jong-il; Chung, Yong-Jae; Kang, Dai-Ill; Hoon Kim, Gwang; Son, Kwang-Tae; Park, Hae-Jun; Lee, Ju-Woon
2015-10-01
Gamma irradiation can destroy fungi and insects involved in the bio-deterioration of organic cultural heritages. However, this irradiation procedure can alter optical and structural properties of historical pigments used in wooden cultural heritage paintings. The crystal structure and color centers of these paintings must be maintained after application of the irradiation procedure. In this study, we investigated the effects of gamma irradiation on Korean traditional multicolored paintwork (Dancheong) for the preservation of wooden cultural heritages. The main pigments in Korean traditional wooden cultural heritages, Sukganju (Hematite; Fe2O3), Jangdan (Minium; Pb3O4), Whangyun (Crocoite; PbCrO4), and Jidang (Rutile; TiO2), were irradiated by gamma radiation at doses of 1, 5, and 20 kGy. After irradiation, changes in Commision Internationale d'Eclairage (CIE) color values (L*, a*, b*) were measured using the color difference meter, and their structural changes were analyzed using X-ray diffraction (XRD) analysis. The slightly change in less than 1 dE* unit by gamma irradiation was observed, and structural changes in the Dancheong were stable after exposure to 20 kGy gamma irradiation. In addition, gamma irradiation could be applied to painted wooden cultural properties from the Korean Temple. Based on the color values, gamma irradiation of 20 kGy did not affect the Dancheong and stability was maintained for five months. In addition, the fungicidal and insecticidal effect by less than 5 kGy gamma irradiation was conformed. Therefore, the optical and structural properties of Dancheong were maintained after gamma irradiation, which suggested that gamma irradiation can be used for the preservation of wooden cultural heritages painted with Dancheong.
-
Gamma radiation field intensity meter
Thacker, L.H.
1995-10-17
A gamma radiation intensity meter measures dose rate of a radiation field. The gamma radiation intensity meter includes a tritium battery emitting beta rays generating a current which is essentially constant. Dose rate is correlated to an amount of movement of an electroscope element charged by the tritium battery. Ionizing radiation decreases the voltage at the element and causes movement. A bleed resistor is coupled between the electroscope support element or electrode and the ionization chamber wall electrode. 4 figs.
-
Gamma radiation field intensity meter
Thacker, L.H.
1994-08-16
A gamma radiation intensity meter measures dose rate of a radiation field. The gamma radiation intensity meter includes a tritium battery emitting beta rays generating a current which is essentially constant. Dose rate is correlated to an amount of movement of an electroscope element charged by the tritium battery. Ionizing radiation decreases the voltage at the element and causes movement. A bleed resistor is coupled between the electroscope support element or electrode and the ionization chamber wall electrode. 4 figs.
-
NEAR Gamma Ray Spectrometer Characterization and Repair
NASA Technical Reports Server (NTRS)
Groves, Joel Lee; Vajda, Stefan
1998-01-01
This report covers the work completed in the third year of the contract. The principle activities during this period were (1) the characterization of the NEAR 2 Gamma Ray Spectrometer using a neutron generator to generate complex gamma ray spectra and a large Ge Detecter to identify all the major peaks in the spectra; (2) the evaluation and repair of the Engineering Model Unit of the Gamma Ray Spectrometer for the NEAR mission; (3) the investigation of polycapillary x-ray optics for x-ray detection; and (4) technology transfer from NASA to forensic science.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Inestrosa, Nibaldo C.; Godoy, Juan A.; MIFAB, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago
2005-03-10
The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-{beta}-peptide (A{beta}), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPAR{gamma} is present in rat hippocampal neurons in culture. (2) Activation of PPAR{gamma} by troglitazone and rosiglitazone protects rat hippocampal neurons against A{beta}-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPAR{gamma} agonists, includingmore » troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic A{beta}-induced rise in bulk-free Ca{sup 2+}. (4) PPAR{gamma} activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3{beta} (GSK-3{beta}) and an increase of the cytoplasmic and nuclear {beta}-catenin levels. We conclude that the activation of PPAR{gamma} prevents A{beta}-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR{gamma} and the Wnt signaling pathway. More important, the fact that the activation of PPAR{gamma} attenuated A{beta}-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.« less
-
Foppoli, Marco; Ferreri, Andrés J M
2015-03-01
Gamma-delta T-cell lymphomas are aggressive and rare diseases originating from gamma-delta lymphocytes. These cells, which naturally play a role in the innate, non-specific immune response, develop from thymic precursor in the bone marrow, lack the major histocompatibility complex restrictions and can be divided into two subpopulations: Vdelta1, mostly represented in the intestine, and Vdelta2, prevalently located in the skin, tonsils and lymph nodes. Chronic immunosuppression such as in solid organ transplanted subjects and prolonged antigenic exposure are probably the strongest risk factors for the triggering of lymphomagenesis. Two entities are recognised by the 2008 WHO Classification: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). The former is more common among young males, presenting with B symptoms, splenomegaly and thrombocytopenia, usually with the absence of nodal involvement. Natural behaviour of HSGDTL is characterised by low response rates, poor treatment tolerability, common early progression of disease and disappointing survival figures. PCGDTL accounts for <1% of all primary cutaneous lymphomas, occurring in adults with relevant comorbidities. Cutaneous lesions may vary, but its clinical behaviour is usually aggressive and long-term survival is anecdotal. Available literature on gamma-delta T-cell lymphomas is fractioned, mostly consisting of case reports or small cumulative series. Therefore, clinical suspicion and diagnosis are usually delayed, and therapeutic management remains to be established. This review critically analyses available evidence on diagnosis, staging and behaviour of gamma-delta T-cell lymphomas, provides recommendations for therapeutic management in routine practice and discusses relevant unmet clinical needs for future studies. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
-
Gharesi-Fard, Behrouz; Zolghadri, Jaleh; Kamali-Sarvestani, Eskandar
2008-03-01
Considering the deleterious role of T helper1 (Th1) cells in pregnancy outcome, a successful treatment for recurrent spontaneous abortion (RSA) should be able to make a significant shift away from Th1 responses. Although paternal leukocyte immunization has been used for treatment of RSA for years, because of methodological differences there is no consensus on the mechanism of action and effectiveness of this method. Twenty-five Iranian non-pregnant women with RSA and 16 non-pregnant control women with at least two successful pregnancies were included in this study. All cases were followed up after leukocyte therapy for pregnancy outcome. Mononuclear cells from women were co-cultured with the husband's mononuclear cells before and after immunotherapy. The levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were checked on culture supernatant by enzyme-linked immunosorbent assay method. The mean concentration of TNF-alpha was significantly higher in patients compared with that in normal controls (P=0.0001). After immunotherapy, the TNF-alpha level was only significantly decreased in women with successful outcome (P=0.0001). Immunotherapy also induced a significant reduction in the IFN-gamma level (P=0.009). The results of this investigation confirm the role of TNF-alpha in RSA and propose the assessment of TNF-alpha production as a valuable prognostic parameter for the prediction of abortion after leukocyte therapy.
-
Nishida, K; Ohta, Y; Ishiguro, I
1998-02-20
We examined the effect of gamma-glutamylcysteinylethyl ester (gamma-GCE), which is readily transported into hepatocytes and increases hepatocellular reduced glutathione (GSH) levels, on the progression of carbon tetrachloride (CCl4)-induced liver injury in mice in comparison with that of GSH. Administration of more than 160 micromol/kg of gamma-GCE, but not GSH, to mice at 3 h after intraperitoneal injection of CCl4 (1 ml/kg) significantly attenuated increases in serum aspartate aminotransferase and alanine aminotransferase activities at 24 h after the CCl4 injection. Increases in hepatic lipid peroxide (LPO) concentrations and decreases in hepatic GSH concentrations after the CCl4 injection were significantly diminished by the gamma-GCE (160 micromol/kg) administration, but not by the same dose of GSH. Gamma-GCE, gamma-glutamylcysteine, and cysteine acted as substrates for glutathione peroxidases much less efficiently than GSH in the post-mitochondrial fraction of normal mouse liver cells. These results indicate that gamma-GCE attenuates the progression of CCl4-induced acute liver injury in mice through the maintenance of hepatic GSH levels, leading to inhibition of hepatic LPO formation, which could be due to an efficient utilization of GSH converted from gamma-GCE in the liver cells.
-
[Interleukin 8 and interferon gamma in ocular toxoplasmosis].
Czepiel, Jacek; Biesiada, Grazyna; Sobczyk-Krupiarz, Iwona; Miklasszewska, Grazyna; Fedak, Danuta; Solnica, Bogdan; Mach, Tomasz; Garlicki, Aleksander
2011-01-01
Toxoplasmosis is one of the most common parasitic infections in the world, it is caused by Toxoplasma gondii. The infection is typically asymptomatic or the symptoms are very mild. Approximately 10% patients have limphadenopathy, involvement of the others organs, like eyes, nervous system, liver, heart, are observed more rarely. The aim of our study was to assess the level of selected cytokines in blood among patients with ocular toxoplasmosis. We have enrolled in the study 30 patients, 19-42 years old, treated for ocular toxoplasmosis, and 20 healthy volunteers, 20-48 years old, to the control group. Tests for blood morphology, C-reactive protein, the level of IL-8 and IFN-gamma were performed in all patients. The blood parameters in toxoplasmosis group were performed before antiparasitic treatment was given. The level of IFN-gamma in blood was lower among patients with ocular toxoplasmosis comparing with control group (1.52 vs. 4.18 pg/ml; p = 0.002). The level of IL-8 in blood was lower among patients with ocular toxoplasmosis comparing with control group (22.96 vs. 94.3 pg/ml; p = 0,007). There were no correlations between analyzed cytokines and blood morphology or CRP. The low level of IFN-gamma and IL-8 in blood is important factor leading to reactivation of the ocular toxoplasmosis.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kon, D; Kameda Medical Centre, Chiba, JP; Nakano, M
2015-06-15
Purpose The purpose of this study is to investigate dominant factors for doses to extracranial sites in treatment with Leksell Gamma Knife (LGK). Methods Monte Carlo simulation was implemented using EGS5 version 1.4.401. The simulation was divided into two major steps for the purpose of efficiency. As the first step, phase-space files were obtained at a scoring plane located just below patient-side surface of the collimator helmet of LGK. Scored particles were classified into three groups, primary, leakage and scatter, using their history information until their arrival to the scoring plane. Then classification was used at the following second stepmore » simulation to investigate which type of particle is dominant in the deposited energy at extra-cranial sites. In the second stage, a cylindrical phantom with a semisphere shaped head was modeled such that the geometrical center of the phantom’s head corresponds to the unit center point (UCP) of LGK. Scoring regions were arranged at 10 cm intervals from the UCP to 70 cm away on the central axis of the phantom. Energy deposition from each type of particles and location of interaction were recorded. Results The dominant factor of deposited energy depended on the collimator size. In the case of smaller collimator size, leakage was dominant. However, contribution of leakage was relatively small in the case of larger collimator size. The contribution of internal scatter varied with the distance from the UCP. In the proximal areas, internal scatter was dominant, whereas in the distal areas, particles interacting with machine components became dominant factor. Conclusion The Result of this study indicates that the dominant factor to dose to an extracranial site can vary with the distance from UCP and with collimator size. This means that the variation of this contribution must be considered for modeling of the extracranial dose especially in the distal area. This work was partly supported by the JSPS Core
-
Kim, H; You, S; Foster, L K; Farris, J; Choi, Y J; Foster, D N
2001-01-01
We have used differential display PCR to study altered gene expression in immortalized chicken embryo fibroblasts (CEFs) that have been established in our laboratory. This technique resulted in the cloning of a novel counterpart of the previously cloned chicken dimerization cofactor of hepatocyte nuclear factor (HNF)-1 (cDcoH), which was identified as cDcoHalpha. The steady-state mRNA levels of cDcoHalpha were up-regulated in all immortal CEFs tested compared with primary CEF cells. cDcoH and cDcoHalpha showed opposite patterns of mRNA expression due to differential regulation of transcription rates, but not mRNA half-lives, in primary and immortal CEFs. Expression of cDcoHalpha increased in the late G1 and early S phases of the cell cycle, while cDcoH mRNA increased in the late S and G2/M phases. In contrast with consistent expression of both genes in primary quiescent cells, cDcoH mRNA, but not cDcoHalpha mRNA, was dramatically decreased in primary senescent cells. The highest levels of cDcoHalpha mRNA were found in the kidney, liver, heart and ovarian follicles, while the major tissues expressing cDcoH were hypothalamus, kidney and liver. cDcoH and cDcoHalpha probes did not cross-hybridize to human hepatocyte mRNA. When transfected into human HepG2 cells, both cDcoH and cDcoHalpha showed similar functional activity as measured by increased expression of a reporter gene, as well as alpha-fetoprotein and albumin genes that both contain HNF-1 binding elements in their promoters. Our results suggest that the novel chicken DcoHalpha might function as a transcriptional cofactor for HNF-1 in specific cellular-environmental states. PMID:11237869
-
Effects of aberrant gamma frequency oscillations on prepulse inhibition.
Jones, Nigel C; Anderson, Paul; Rind, Gil; Sullivan, Caley; van den Buuse, Maarten; O'Brien, Terence J
2014-10-01
Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.
-
Ouyang, Jingfeng; Huang, Wei; Yu, Wanwan; Xiong, Wei; Mula, Ramanjaneya V R; Zou, Hongbin; Yu, Yongping
2014-02-05
Type 1 diabetes mellitus (T1DM), a multisystem disease with both biochemical and anatomical/structural consequences, is a major health concern worldwide. Pancreatic islet transplantation provides a promising treatment for T1DM. However, the limited availability of islet tissue or new sources of insulin producing cells (IPCs) that are responsive to glucose hinder this promising approach. Though slow, the development of pancreatic beta-cell lines from rodent or human origin has been steadily progressing. Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent, culture-expanded, non-hematopoietic cells that are currently being investigated as a novel cellular therapy. The in vitro differentiation potential of IPCs has raised hopes for a treatment of clinical diseases associated with autoimmunity. We screened for small molecules that induce pancreatic differentiation of IPCs. There are some compounds which showed positive effects on the DTZ staining. The aminopyrrole derivative compound XW4.4 which shows the best activity among them was found to induce pancreatic differentiation of rat MSCs (rMSCs). The in vitro studies indicated that treatment of rMSCs with compound XW4.4 resulted in differentiated cells with characteristics of IPCs including islet-like clusters, spherical, grape-like morphology, insulin secretion, positive for dithizone, glucose stimulation and expression of pancreatic endocrine cell marker genes. The data has also suggested that hepatocyte nuclear factor 3β (HNF 3β) may be involved in pancreatic differentiation of rMSCs when treated with XW4.4. Results indicate that XW4.4 induced rMSCs support the efforts to derive functional IPCs and serve as a means to alleviate limitations surrounding islet cell transplantation in the treatment of T1DM. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
-
Chung, K S; Madar, D A; Goldsmith, J C; Kingdon, H S; Roberts, H R
1978-01-01
Human Factor IX (Christmas factor) was isolated from the plasma of a patient with mild hemophilia B. The patient's plasma contained 5% Factor IX clotting activity but 100% Factor IX antigenic activity as determined by immunological assays, which included inhibitor neutralization and a radioimmunoassay for Factor IX. This abnormal Factor IX is called Factor IX Chapel Hill (Factor IXCH). Both normal Factor IX and Factor IXCH have tyrosine as the NH2-terminal amino acid. The two proteins have a similar molecular weight, a similar amino acid analysis, the same number of gamma-carboxyglutamic acid residues (10 gamma-carboxyglutamic acid residues), and a similar carbohydrate content. Both exist as a single-chain glycoprotein in plasma. The major difference between normal Factor IX and Factor IXCH is that the latter exhibits delayed activation to Factor IXa in the presence of Factor XIa and Ca2+. Thus, Factor IXCH differs from other previously described abnormal Factor IX molecules. Images PMID:711853
-
Liu, Long; Fan, Yanfeng; Zhang, Zhenhe; Yang, Chan; Geng, Tuoyu; Gong, Daoqing; Hou, Zhuocheng; Ning, Zhonghua
2017-01-01
The reproductive system of a female bird is responsible for egg production. The genes highly expressed in oviduct are potentially important. From RNA-seq analysis, C2H9orf152 (an orthologous gene of human C9orf152) was identified as highly expressed in chicken uterus. To infer its function, we obtained and characterized its complete cDNA sequence, determined its spatiotemporal expression, and probed its transcription factor(s) through pharmaceutical approach. Data showed that the complete cDNA sequence was 1468bp long with a 789bp of open reading frame. Compared to other tested tissues, this gene was highly expressed in the oviduct and liver tissues, especially uterus. Its expression in uterus was gradually increased during developmental and reproductive periods, which verified its involvement in the growth and maturity of reproductive system. In contrast, its expression was not significant different between active and quiescent uterus, suggesting the role of C2H9orf152 in reproduction is likely due to its long-term effect. Moreover, based on its 5'-flanking sequence, Foxd3 and Hnf4a were predicted as transcription factors of C2H9orf152. Using berberine or retinoic acid (which can regulate the activities of Hnf4a and Foxd3, respectively), we demonstrated suppression of C2H9orf152 by the chemicals in chicken primary hepatocytes. As retinoic acid regulates calcium metabolism, and Hnf4a is a key nuclear factor to liver, these findings suggest that C2H9orf152 is involved in liver function and calcium metabolism of reproductive system. In conclusion, C2H9orf152 may have a long-term effect on chicken reproductive system by regulating calcium metabolism, suggesting this gene has an important implication in the improvement of egg production and eggshell quality. Copyright © 2016 Elsevier B.V. All rights reserved.
-
CONSTRAINTS ON THE SYNCHROTRON EMISSION MECHANISM IN GAMMA-RAY BURSTS
DOE Office of Scientific and Technical Information (OSTI.GOV)
Beniamini, Paz; Piran, Tsvi, E-mail: paz.beniamini@mail.huji.ac.il, E-mail: tsvi.piran@mail.huji.ac.il
2013-05-20
We reexamine the general synchrotron model for gamma-ray bursts' (GRBs') prompt emission and determine the regime in the parameter phase space in which it is viable. We characterize a typical GRB pulse in terms of its peak energy, peak flux, and duration and use the latest Fermi observations to constrain the high-energy part of the spectrum. We solve for the intrinsic parameters at the emission region and find the possible parameter phase space for synchrotron emission. Our approach is general and it does not depend on a specific energy dissipation mechanism. Reasonable synchrotron solutions are found with energy ratios ofmore » 10{sup -4} < {epsilon}{sub B}/{epsilon}{sub e} < 10, bulk Lorentz factor values of 300 < {Gamma} < 3000, typical electrons' Lorentz factor values of 3 Multiplication-Sign 10{sup 3} < {gamma}{sub e} < 10{sup 5}, and emission radii of the order 10{sup 15} cm < R < 10{sup 17} cm. Most remarkable among those are the rather large values of the emission radius and the electron's Lorentz factor. We find that soft (with peak energy less than 100 keV) but luminous (isotropic luminosity of 1.5 Multiplication-Sign 10{sup 53}) pulses are inefficient. This may explain the lack of strong soft bursts. In cases when most of the energy is carried out by the kinetic energy of the flow, such as in the internal shocks, the synchrotron solution requires that only a small fraction of the electrons are accelerated to relativistic velocities by the shocks. We show that future observations of very high energy photons from GRBs by CTA could possibly determine all parameters of the synchrotron model or rule it out altogether.« less
-
Gamma-Terpinene Modulates Acute Inflammatory Response in Mice.
Ramalho, Theresa Raquel de Oliveira; Oliveira, Maria Talita Pacheco de; Lima, Ana Luisa de Araujo; Bezerra-Santos, Claudio Roberto; Piuvezam, Marcia Regina
2015-09-01
The monoterpene gamma-terpinene is a natural compound present in essential oils of a wide variety of plants, including the Eucalyptus genus, which has been reported to possess anti-inflammatory activity. The goal of this study was to evaluate the effect of gamma-terpinene on several in vivo experimental models of acute inflammation. Swiss mice were pretreated with gamma-terpinene and subjected to protocols of paw edema with different phlogistic agents such as carrageenan, prostaglandin-E2, histamine, or bradykinin. The microvascular permeability was measured by intraperitoneal injection of acetic acid and measuring the amount of protein extravasation. Carrageenan-induced peritonitis was used to analyze the effect of gamma-terpinene on inflammatory cell migration and cytokine production. We also developed an acute lung injury protocol to define the anti-inflammatory effect of gamma-terpinene. Mice pretreated with gamma-terpinene displayed reduced paw edema induced by carrageenan from 1-24 h after challenge. A similar reduction was observed when gamma-terpinene was administered after stimulation with PGE2, bradykinin, and histamine. Treatment with gamma-terpinene also inhibited fluid extravasation in the acetic acid model of microvascular permeability. In a carrageenan-induced peritonitis model, gamma-terpinene treatment reduced neutrophil migration as well as the production of interleukin-1β and tumor necrosis factor-α when compared to nontreated animals, and in the acute lung injury protocol, gamma-terpinene diminished the neutrophil migration into lung tissue independently of the total protein extravasation in the lung. These data demonstrate that, in different models of inflammation, treatment with gamma-terpinene alleviated inflammatory parameters such as edema and pro-inflammatory cytokine production, as well as cell migration into the inflamed site, and that this monoterpene has anti-inflammatory properties. Georg Thieme Verlag KG Stuttgart · New York.
-
NASA Astrophysics Data System (ADS)
Beauchamp, S.; Lacroix, M.
2012-08-01
The effect of gamma and UV-C irradiation on the production of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4 PPs) in DNA was investigated to compare the natural resistance of the genome of a Gram-positive bacterium and a Gram-negative bacterium against irradiation. Solution of pure DNA and bacterial strains Listeria monocytogenes and Escherichia coli were irradiated using gamma and UV-C rays. Extracted DNA from bacteria and pure DNA samples were then analysed by ELISA using anti-CPDs and anti-6-4 PPs monoclonal antibodies. The results show that gamma rays, as well as UV-C rays, induce the formation of CPDs and 6-4 PPs in DNA. During UV-C irradiation, the three samples showed a difference in their sensitivity against formation of CPDs (P≤0.05). Pure DNA was the most sensitive while the genome of L. monocytogenes was the most resistant. Also during UV-C irradiation, the genome of L. monocytogenes was the only one to show a significant resistance against formation of 6-4 PPs (P≤0.05). During gamma irradiation, for both types of lesion, pure DNA and the genome of E. coli did not show significant difference in their sensitivity (P>0.05) while the genome of L. monocytogenes showed a resistance against formation of CPDs and 6-4 PPs.
-
Benchmark gamma-ray skyshine experiment
DOE Office of Scientific and Technical Information (OSTI.GOV)
Nason, R.R.; Shultis, J.K.; Faw, R.E.
1982-01-01
A benchmark gamma-ray skyshine experiment is descibed in which /sup 60/Co sources were either collimated into an upward 150-deg conical beam or shielded vertically by two different thicknesses of concrete. A NaI(Tl) spectrometer and a high pressure ion chamber were used to measure, respectively, the energy spectrum and the 4..pi..-exposure rate of the air-reflected gamma photons up to 700 m from the source. Analyses of the data and comparison to DOT discrete ordinates calculations are presented.
-
López, Tatiana; García, Diego; Angel, Bárbara; Carrasco, Elena; Codner, Ethel; Ugarte, Francisca; Pérez-Bravo, Francisco
2008-02-02
In order to assess whether Fok I vitamin D receptor gene (VDR) polymorphism is involved in the genetic susceptibility of type 1 diabetes, a case-control study was conducted and VDR genotypes were related to serum concentrations of 25(OH) vitamin D and cytokines transforming growth factor beta1 (TGF-beta1) and interferon gamma (INF-gamma). 151 incident cases of type 1 diabetes and 182 non related healthy controls from Santiago were studied for VDR polymorphisms in peripheral blood DNA. Exon 2 (Fok I) segments were amplified by polimerase chain reaction and analyzed by means of restriction fragment length polymorphism to determine each corresponding genotype. Differences for allele, genotype and serological markers as 25(OH) vitamin D, TGF-beta1 and INF-gamma levels distribution between patients and controls were analyzed. Fok I polymorphism distribution analysis showed no differences between patients and controls. Among diabetics, higher levels of TGF-beta1 (median, 282.6 pg/ml; range, 131.8-3,031.4) were observed compared with healthy children (median, 232.2 pg/ml; range, 135.7-506.5) (p < 0.0038). Similar results were observed for INF-gamma concentrations (median, 121.1 pg/ml, and range, 5.3-228.8, in cases, and median, 89.6 pg/ml, and range, 10.9-117.2 in controls) (p < 0.0004). The diabetic carriers of the ff genotype showed low levels of 25(OH) vitamin D compared with the carriers of the F allele: mean (standard deviation), 23.1 (5.9) versus 27.9 (10.3) ng/ml (p < 0.03). A similar result was observed for TGF-beta1 concentrations in diabetic carriers of ff genotype and patients carriers of the F allele (298.5 versus 276.6; p < 0.05). Fok I polymorphism of VDR could have a marginal role in the immunologic disturbance in type 1 diabetes.
-
Discoveries by the Fermi Gamma Ray Space Telescope
NASA Technical Reports Server (NTRS)
Gehrels, Neil
2011-01-01
Fermi is a large space gamma-ray mission developed by NASA and the DOE with major contributions from France, Germany, Italy, Japan and Sweden. It was launched in June 2008 and has been performing flawlessly since then. The main instrument is the Large Area Telescope (LAT) operating in the 20 MeV to 300 GeV range and a smaller monitor instrument is the Gamma-ray Burst Monitor (GBM) operating in the 8 keV to 40 MeV range. New findings are occurring every week. Some of the key discoveries are: 1) Discovery of many new gamma-ray pulsars, including gamma-ray only and millisecond pulsars. 2) Detection of high energy gamma-ray emission from globular clusters, most likely due to summed emission from msec pulsars. 3) Discovery of delayed and extended high energy gamma-ray emission from short and long gamma-ray busts. 4) Detection of approximately 250 gamma-ray bursts per year with the GBM instrument. 5) Most accurate measurement of the cosmic ray electron spectrum between 30 GeV and 1 TeV, showing some excess above the conventional diffusion model. The talk will present the new discoveries and their implications.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Moskalenko, Igor V.; Porter, Troy A.
2007-06-14
We use the GEANT4 Monte Carlo framework to calculate the gamma-ray albedo of the Moon due to interactions of cosmic ray (CR) nuclei with moon rock. Our calculation of the albedo spectrum agrees with the EGRET data. We show that the spectrum of gamma-rays from the Moon is very steep with an effective cutoff around 3 GeV (600 MeV for the inner part of the Moon disc). Since it is the only (almost) black spot in the gamma-ray sky, it provides a unique opportunity for calibration of gamma-ray telescopes, such as the forthcoming Gamma Ray Large Area Space Telescope (GLAST).more » The albedo flux depends on the incident CR spectrum which changes over the solar cycle. Therefore, it is possible to monitor the CR spectrum using the albedo gamma-ray flux. Simultaneous measurements of CR proton and helium spectra by the Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics (PAMELA), and observations of the albedo -rays by the GLAST Large Area Telescope (LAT), can be used to test the model predictions and will enable the GLAST LAT to monitor the CR spectrum near the Earth beyond the lifetime of PAMELA.« less
-
A Monte Carlo modeling alternative for the API Gamma Ray Calibration Facility.
Galford, J E
2017-04-01
The gamma ray pit at the API Calibration Facility, located on the University of Houston campus, defines the API unit for natural gamma ray logs used throughout the petroleum logging industry. Future use of the facility is uncertain. An alternative method is proposed to preserve the gamma ray API unit definition as an industry standard by using Monte Carlo modeling to obtain accurate counting rate-to-API unit conversion factors for gross-counting and spectral gamma ray tool designs. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
A New Limit on Planck Scale Lorentz Violation from Gamma-ray Burst Polarization
NASA Technical Reports Server (NTRS)
Stecker, Floyd W.
2011-01-01
Constraints on possible Lorentz invariance violation (UV) to first order in E/M(sub Plank) for photons in the framework of effective field theory (EFT) are discussed, taking cosmological factors into account. Then. using the reported detection of polarized soft gamma-ray emission from the gamma-ray burst GRB041219a that is indicative' of an absence of vacuum birefringence, together with a very recent improved method for estimating the redshift of the burst, we derive constraints on the dimension 5 Lorentz violating modification to the Lagrangian of an effective local QFT for QED. Our new constraints are more than five orders of magnitude better than recent constraints from observations of the Crab Nebula.. We obtain the upper limit on the Lorentz violating dimension 5 EFT parameter absolute value of zeta of 2.4 x 10(exp -15), corresponding to a constraint on the dimension 5 standard model extension parameter. Kappa (sup 5) (sub (v)oo) much less than 4.2 X 10(exp -3)4 / GeV.
-
HESS J1844-030: A New Gamma-Ray Binary?
NASA Astrophysics Data System (ADS)
McCall, Hannah; Errando, Manel
2018-01-01
Gamma-ray binaries are comprised of a massive, main-sequence star orbiting a neutron star or black hole that generates bright gamma-ray emission. Only six of these systems have been discovered. Here we report on a candidate stellar-binary system associated with the unidentified gamma-ray source HESS J1844-030, whose detection was revealed in the H.E.S.S. galactic plane survey. Analysis of 60 ks of archival Chandra data and over 100 ks of XMM-Newton data reveal a spatially associated X-ray counterpart to this TeV-emitting source (E>1012 eV), CXO J1845-031. The X-ray spectra derived from these exposures yields column density absorption in the range nH = (0.4 - 0.7) x 1022 cm-2, which is below the total galactic value for that part of the sky, indicating that the source is galactic. The flux from CXO J1845-031 increases with a factor of up to 2.5 in a 60 day timescale, providing solid evidence for flux variability at a confidence level exceeding 7 standard deviations. The point-like nature of the source, the flux variability of the nearby X-ray counterpart, and the low column density absorption are all indicative of a binary system. Once confirmed, HESS J1844-030 would represent only the seventh known gamma-ray binary, providing valuable data to advance our understanding of the physics of pulsars and stellar winds and testing high-energy astrophysical processes at timescales not present in other classes of objects.
-
NASA Astrophysics Data System (ADS)
Mukherjee, Bhaskar; Makowski, Dariusz; Simrock, Stefan
2005-06-01
The neutron and gamma doses are crucial to interpreting the radiation effects in microelectronic devices operating in a high-energy accelerator environment. This report highlights a method for an accurate estimation of photoneutron and the accompanying bremsstrahlung (gamma) doses produced by a 450 MeV electron linear accelerator (linac) operating in pulsed mode. The principle is based on the analysis of thermoluminescence glow-curves of TLD-500 (Aluminium Oxide) and TLD-700 (Lithium Fluoride) dosimeter pairs. The gamma and fast neutron response of the TLD-500 and TLD-700 dosimeter pairs were calibrated with a 60Co (gamma) and a 241Am-Be (α, n) neutron standard-source, respectively. The Kinetic Energy Released in Materials (kerma) conversion factor for photoneutrons was evaluated by folding the neutron kerma (dose) distribution in 7LiF (the main component of the TLD-700 dosimeter) with the energy spectra of the 241Am-Be (α, n) neutrons and electron accelerator produced photoneutrons. The neutron kerma conversion factors for 241Am-Be neutrons and photoneutrons were calculated to be 2.52×10 -3 and 1.37×10 -3 μGy/a.u. respectively. The bremsstrahlung (gamma) dose conversion factor was evaluated to be 7.32×10 -4 μGy/a.u. The above method has been successfully utilised to assess the photoneutron and bremsstrahlung doses from a 450 MeV electron linac operating at DESY Research Centre in Hamburg, Germany.
-
Gamma-sky.net: Portal to the gamma-ray sky
NASA Astrophysics Data System (ADS)
Voruganti, Arjun; Deil, Christoph; Donath, Axel; King, Johannes
2017-01-01
http://gamma-sky.net is a novel interactive website designed for exploring the gamma-ray sky. The Map View portion of the site is powered by the Aladin Lite sky atlas, providing a scalable survey image tesselated onto a three-dimensional sphere. The map allows for interactive pan and zoom navigation as well as search queries by sky position or object name. The default image overlay shows the gamma-ray sky observed by the Fermi-LAT gamma-ray space telescope. Other survey images (e.g. Planck microwave images in low/high frequency bands, ROSAT X-ray image) are available for comparison with the gamma-ray data. Sources from major gamma-ray source catalogs of interest (Fermi-LAT 2FHL, 3FGL and a TeV source catalog) are overlaid over the sky map as markers. Clicking on a given source shows basic information in a popup, and detailed pages for every source are available via the Catalog View component of the website, including information such as source classification, spectrum and light-curve plots, and literature references. We intend for gamma-sky.net to be applicable for both professional astronomers as well as the general public. The website started in early June 2016 and is being developed as an open-source, open data project on GitHub (https://github.com/gammapy/gamma-sky). We plan to extend it to display more gamma-ray and multi-wavelength data. Feedback and contributions are very welcome!
-
NASA Technical Reports Server (NTRS)
Crannell, C. J.; Crannell, H.; Ramaty, R.
1978-01-01
Processes which lead to the production of gamma rays with energy greater than 8 MeV in solar flares are reviewed and evaluated. Excited states produced by inelastic scattering, charge exchange, and spallation reactions in the abundant nuclear species are considered in order to identify nuclear lines which may contribute to the Gamma ray spectrum of solar flares. The flux of 15.11 MeV Gamma rays relative to the flux of 4.44 MeV Gamma rays from the de-excitation of the corresponding states in C12 is calculated for a number of assumed distributions of exciting particles. This flux ratio is a sensitive diagnostic of accelerated particle spectra. Other high energy nuclear levels are not so isolated as the 15.11 MeV state and are not expected to be so strong. The spectrum of Gamma rays from the decay of Pi dey is sensitive to the energy distribution of particles accelerated to energies greater than 100 MeV.
-
Gamma-Ray Imaging for Explosives Detection
NASA Technical Reports Server (NTRS)
deNolfo, G. A.; Hunter, S. D.; Barbier, L. M.; Link, J. T.; Son, S.; Floyd, S. R.; Guardala, N.; Skopec, M.; Stark, B.
2008-01-01
We describe a gamma-ray imaging camera (GIC) for active interrogation of explosives being developed by NASA/GSFC and NSWCICarderock. The GIC is based on the Three-dimensional Track Imager (3-DTI) technology developed at GSFC for gamma-ray astrophysics. The 3-DTI, a large volume time-projection chamber, provides accurate, approx.0.4 mm resolution, 3-D tracking of charged particles. The incident direction of gamma rays, E, > 6 MeV, are reconstructed from the momenta and energies of the electron-positron pair resulting from interactions in the 3-DTI volume. The optimization of the 3-DTI technology for this specific application and the performance of the GIC from laboratory tests is presented.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Singal, J.; Ko, A.; Petrosian, V., E-mail: jsingal@richmond.edu
We present the redshift evolutions and distributions of the gamma-ray luminosity and photon spectral index of flat spectrum radio quasar (FSRQ) type blazars, using non-parametric methods to obtain the evolutions and distributions directly from the data. The sample we use for analysis consists of almost all FSRQs observed with a greater than approximately 7σ detection threshold in the first-year catalog of the Fermi Gamma-ray Space Telescope's Large Area Telescope, with redshifts as determined from optical spectroscopy by Shaw et al. We find that FSQRs undergo rapid gamma-ray luminosity evolution, but negligible photon index evolution, with redshift. With these evolutions accountedmore » for we determine the density evolution and luminosity function of FSRQs and calculate their total contribution to the extragalactic gamma-ray background radiation, resolved and unresolved, which is found to be 16(+10/–4)%, in agreement with previous studies.« less
-
Gamma-ray burst constraints on the galactic frequency of extrasolar Oort Clouds
NASA Technical Reports Server (NTRS)
Shull, J. Michael; Stern, S. Alan
1995-01-01
With the strong Compton Gamma-Ray Observatory/Burst and Transient Source Experiment (CGRO/BATSE) evidence that most gamma-ray bursts do not come from galactic neutron stars, models involving the accretion of a comet onto a neutron star (NS) no longer appear to be strong contenders for explaining the majority of bursts. If this is the case, then it is worth asking whether the lack of an observed galactic gamma-ray burst population provides a useful constraint on the number of comets and comet clouds in the galaxy. Owing to the previously unrecognized structural weakness of cometary nuclei, we find the capture cross sections for comet-NS events to be much higher than previously published estimates, with tidal breakup at distances R(sub b) approx. equals 4 x 10(exp 10) cm from the NS. As a result, impacts of comets onto field NSs penetrating the Oort Clouds of other stars are found to dominate all other galactic NS-comet capture rates by a factor of 100. This in turn predicts that if comet clouds are common, there should be a significant population of repeater sources with (1) a galactic distribution, (2) space-correlated repetition, and (3) a wide range of peak luminosities and luminosity time histories. If all main sequence stars have Oort Clouds like our own, we predict approximately 4000 such repeater sources in the Milky Way at any time, each repeating on time scales of months to years. Based on estimates of the sensitivity of the CGRO/BATSE instrument and assuming isotropic gamma-ray beaming from such events, we estimate that a population of approximately 20-200 of these galactic NS-Oort Cloud gamma-ray repeater sources should be detectable by CGRO. In addition, if giant planet formation is common in the galaxy, we estimate that the accretion of isolated comets injected to the interstellar medium by giant planet formation should produce an additional source of galactic, nonrepeating, events. Comparing these estimates to the 3-4 soft gamma-ray repeater sources
-
Multiwavelength Observations of the Blazar BL Lacertae: A New Fast TeV Gamma-Ray Flare
NASA Astrophysics Data System (ADS)
Abeysekara, A. U.; Benbow, W.; Bird, R.; Brantseg, T.; Brose, R.; Buchovecky, M.; Buckley, J. H.; Bugaev, V.; Connolly, M. P.; Cui, W.; Daniel, M. K.; Falcone, A.; Feng, Q.; Finley, J. P.; Fortson, L.; Furniss, A.; Gillanders, G. H.; Gunawardhana, I.; Hütten, M.; Hanna, D.; Hervet, O.; Holder, J.; Hughes, G.; Humensky, T. B.; Johnson, C. A.; Kaaret, P.; Kar, P.; Kertzman, M.; Krennrich, F.; Lang, M. J.; Lin, T. T. Y.; McArthur, S.; Moriarty, P.; Mukherjee, R.; O’Brien, S.; Ong, R. A.; Otte, A. N.; Park, N.; Petrashyk, A.; Pohl, M.; Pueschel, E.; Quinn, J.; Ragan, K.; Reynolds, P. T.; Richards, G. T.; Roache, E.; Rulten, C.; Sadeh, I.; Santander, M.; Sembroski, G. H.; Shahinyan, K.; Wakely, S. P.; Weinstein, A.; Wells, R. M.; Wilcox, P.; Williams, D. A.; Zitzer, B.; The VERITAS Collaboration; Jorstad, S. G.; Marscher, A. P.; Lister, M. L.; Kovalev, Y. Y.; Pushkarev, A. B.; Savolainen, T.; Agudo, I.; Molina, S. N.; Gómez, J. L.; Larionov, V. M.; Borman, G. A.; Mokrushina, A. A.; Tornikoski, M.; Lähteenmäki, A.; Chamani, W.; Enestam, S.; Kiehlmann, S.; Hovatta, T.; Smith, P. S.; Pontrelli, P.
2018-04-01
Combined with measurements made by very-long-baseline interferometry, the observations of fast TeV gamma-ray flares probe the structure and emission mechanism of blazar jets. However, only a handful of such flares have been detected to date, and only within the last few years have these flares been observed from lower-frequency-peaked BL Lac objects and flat-spectrum radio quasars. We report on a fast TeV gamma-ray flare from the blazar BL Lacertae observed by the Very Energetic Radiation Imaging Telescope Array System (VERITAS). with a rise time of ∼2.3 hr and a decay time of ∼36 min. The peak flux above 200 GeV is (4.2 ± 0.6) × 10‑6 photon m‑2 s‑1 measured with a 4-minute-binned light curve, corresponding to ∼180% of the flux that is observed from the Crab Nebula above the same energy threshold. Variability contemporaneous with the TeV gamma-ray flare was observed in GeV gamma-ray, X-ray, and optical flux, as well as in optical and radio polarization. Additionally, a possible moving emission feature with superluminal apparent velocity was identified in Very Long Baseline Array observations at 43 GHz, potentially passing the radio core of the jet around the time of the gamma-ray flare. We discuss the constraints on the size, Lorentz factor, and location of the emitting region of the flare, and the interpretations with several theoretical models that invoke relativistic plasma passing stationary shocks.
-
Glycine facilitates gamma-glutamylcysteinylethyl ester-mediated increase in liver glutathione level.
Nishida, K; Ohta, Y; Ishiguro, I
1997-08-27
gamma-Glutamylcysteinylethyl ester (gamma-GCE) increases reduced glutathione (GSH) levels in GSH-depleted rat hepatocytes. Because glycine, a constituent of GSH, exists at 0.3 to 0.4 mM in rat plasma, we examined the influence of glycine added to the medium on the action of gamma-GCE to increase GSH levels in the rat hepatocytes. Glycine (0.2-0.8 mM) dose-dependently enhanced gamma-GCE-mediated increase in intracellular GSH levels with an increase in intracellular gamma-GCE levels. These results indicate that exogenous glycine facilitates gamma-GCE-mediated increase in intracellular GSH levels in rat hepatocytes possibly by enhancing the uptake of gamma-GCE into the cells.
-
Anık, Ahmet; Çatlı, Gönül; Abacı, Ayhan; Sarı, Erkan; Yeşilkaya, Ediz; Korkmaz, Hüseyin Anıl; Demir, Korcan; Altıncık, Ayça; Tuhan, Hale Ünver; Kızıldağ, Sefa; Özkan, Behzat; Ceylaner, Serdar; Böber, Ece
2015-11-01
To perform molecular analysis of pediatric maturity onset diabetes of the young (MODY) patients by next-generation sequencing, which enables simultaneous analysis of multiple genes in a single test, to determine the genetic etiology of a group of Turkish children clinically diagnosed as MODY, and to assess genotype-phenotype relationship. Forty-two children diagnosed with MODY and their parents were enrolled in the study. Clinical and laboratory characteristics of the patients at the time of diagnosis were obtained from hospital records. Molecular analyses of GCK, HNF1A, HNF4A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, and BLK genes were performed on genomic DNA by using next-generation sequencing. Pathogenicity for novel mutations was assessed by bioinformatics prediction software programs and segregation analyses. A mutation in MODY genes was identified in 12 (29%) of the cases. GCK mutations were detected in eight cases, and HNF1B, HNF1A, PDX1, and BLK mutations in the others. We identified five novel missense mutations - three in GCK (p.Val338Met, p.Cys252Ser, and p.Val86Ala), one in HNF1A (p.Cys241Ter), and one in PDX1 (p.Gly55Asp), which we believe to be pathogenic. The results of this study showed that mutations in the GCK gene are the leading cause of MODY in our population. Moreover, genetic diagnosis could be made in 29% of Turkish patients, and five novel mutations were identified.
-
NASA Technical Reports Server (NTRS)
Sagdeev, Roald
1995-01-01
The main scientific objectives of the project were: (1) Calculation of average time history for different subsets of BATSE gamma-ray bursts; (2) Comparison of averaged parameters and averaged time history for different Burst And Transient Source Experiments (BASTE) Gamma Ray Bursts (GRB's) sets; (3) Comparison of results obtained with BATSE data with those obtained with APEX experiment at PHOBOS mission; and (4) Use the results of (1)-(3) to compare current models of gamma-ray bursts sources.
-
Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2
DOE Office of Scientific and Technical Information (OSTI.GOV)
Mitterberger, Maria C.; Kim, Geumsoo; Rostek, Ursula
2012-05-01
Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation inmore » CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.« less
-
1989-12-29
1.1.2. General Performance Criteria for Gamma Ray Spectrometers 4 1.1.3. Special Criteria for Space-Based Spectrometer Systems 7 1.1.4. Prior Approaches...calculations were performed for selected incident gamma ray energies and were used to generate tabular and graphical listings of gamma scattering results. The... generated . These output presentations were studied to identify behavior patterns of "good" and "bad" event sequences. For the specific gamma energy
-
Noiseless coding for the Gamma Ray spectrometer
NASA Technical Reports Server (NTRS)
Rice, R.; Lee, J. J.
1985-01-01
The payload of several future unmanned space missions will include a sophisticated gamma ray spectrometer. Severely constrained data rates during certain portions of these missions could limit the possible science return from this instrument. This report investigates the application of universal noiseless coding techniques to represent gamma ray spectrometer data more efficiently without any loss in data integrity. Performance results demonstrate compression factors from 2.5:1 to 20:1 in comparison to a standard representation. Feasibility was also demonstrated by implementing a microprocessor breadboard coder/decoder using an Intel 8086 processor.
-
Yorifuji, Tohru; Higuchi, Shinji; Kawakita, Rie; Hosokawa, Yuki; Aoyama, Takane; Murakami, Akiko; Kawae, Yoshiko; Hatake, Kazue; Nagasaka, Hironori; Tamagawa, Nobuyoshi
2018-06-21
Causative mutations cannot be identified in the majority of Asian patients with suspected maturity-onset diabetes of the young (MODY). To elucidate the genetic basis of Japanese patients with MODY-like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. 263 Japanese patients with early-onset, nonobese, MODY-like diabetes mellitus referred to Osaka City General Hospital for diagnosis. Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation-positive and mutation-negative patients were further analyzed for clinical features. Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation-positive patients did not have affected parents and 8.2% were in the overweight range (BMI >85 th percentile). HOMA-IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation-positive patients. Compared with mutation-positive patients, mutation-negative patients were significantly older (p = 0.003), and had higher BMI percentile at diagnosis (p = 0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation-negative patients (p = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation-negative patients with paternal inheritance (p = 0.0106). Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin-resistance are common in Japanese patients with mutation-positive MODY. A significant fraction of mutation-negative patients had features of early-onset type 2 diabetes common in Japanese, and non-Mendelian inheritance needs to be considered for these patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
-
Thermal-neutron capture gamma-rays. Volume 1
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tuli, J.K.
1997-05-01
The energy and photon intensity of gamma rays as seen in thermal-neutron capture are presented in ascending order of gamma energy. All those gamma-rays with intensity of {ge} 2% of the strongest transition are included. The two strongest transitions seen for the target nuclide are indicated in each case. Where the target nuclide mass number is indicated as nat the natural target was used. The gamma energies given are in keV. The gamma intensities given are relative to 100 for the strongest transition. All data for A > 44 are taken from Evaluated Nuclear Structure Data File (4/97), a computermore » file of evaluated nuclear structure data maintained by the National Nuclear Data Center, Brookhaven National Laboratory, on behalf of the Nuclear Structure and Decay and Decay Data network, coordinated by the International Atomic Energy Agency, Vienna. These data are published in Nuclear Data Sheets, Academic Press, San Diego, CA. The data for A {le} 44 is taken from ``Prompt Gamma Rays from Thermal-Neutron Capture,`` M.A. Lone, R.A. Leavitt, D.A. Harrison, Atomic Data and Nuclear Data Tables 26, 511 (1981).« less
-
Resonance production in. gamma gamma. collisions
DOE Office of Scientific and Technical Information (OSTI.GOV)
Renard, F.M.
1983-04-01
The processes ..gamma gamma.. ..-->.. hadrons can be depicted as follows. One photon creates a q anti q pair which starts to evolve; the other photon can either (A) make its own q anti q pair and the (q anti q q anti q) system continue to evolve or (B) interact with the quarks of the first pair and lead to a modified (q anti q) system in interaction with C = +1 quantum numbers. A review of the recent theoretical activity concerning resonance production and related problems is given under the following headings: hadronic C = +1 spectroscopy (qmore » anti q, qq anti q anti q, q anti q g, gg, ggg bound states and mixing effects); exclusive ..gamma gamma.. processes (generalities, unitarized Born method, VDM and QCD); total cross section (soft and hard contributions); q/sup 2/ dependence of soft processes (soft/hard separation, 1/sup +- +/ resonances); and polarization effects. (WHK)« less
-
Tao, Jing; Bukanova, Elena N; Akhtar, Shamsuddin
2018-01-01
Although factor Xa inhibitors have become a popular choice for chronic oral anticoagulation, effective drug reversal remains difficult due to a lack of specific antidote. Currently, 4-factor prothrombin complex concentrate (4F-PCC) is considered the treatment of choice for factor Xa inhibitor-related major bleeding. However, safety of 4F-PCC and its risk of thrombosis when used for this off-label purpose remain unclear. The purpose of this retrospective study is to determine the rate of thromboembolism when 4F-PCC is used for the emergent reversal of factor Xa inhibitors. We conducted a single-center retrospective review of medical records between 2013 and 2017. Patients were included if they received 4F-PCC to reverse rivaroxaban, apixaban, or edoxaban for emergent invasive procedures or during episodes of major bleeding defined as bleeding with hemodynamic instability, fall in hemoglobin of 2 g/dL, or bleeding requiring blood transfusion. Thrombotic events including myocardial infarction, pulmonary embolism, deep vein thrombosis, cerebral vascular accident, and arterial thrombosis of the limb or mesentery were recorded if they occurred within 14 days of 4F-PCC administration. Data was analyzed using point and interval estimation to approximate the rate and confidence interval of thromboembolic events. Forty-three patients were identified in our review. Doses of 4F-PCC were determined by the treating physician and mainly ranged from 25 to 50 IU/kg. Twenty-two patients (51.2%) received both sequential compression devices (SCDs) and subcutaneous heparin for DVT prophylaxis. Twenty-one patients (48.8%) were placed on SCDs only. Three patients received concomitant FFP. Thrombotic events within 14 days of 4F-PCC administration occurred in 1 out of 43 patients (2.1%, 95% CI [0.1-12.3]). This thrombotic event was an upper extremity DVT which occurred 1 day after the patient received 1325 IU (25 IU/kg) of 4F-PCC to reverse rivaroxaban for traumatic intracranial
-
Jeong, Woorim; Kim, June Sic; Chung, Chun Kee
2013-01-01
We aimed to evaluate the clinical value of gamma oscillations in MEG for intractable neocortical epilepsy patients with cortical dysplasia by comparing gamma and interictal spike events. A retrospective analysis of MEG recordings of 30 adult neocortical epilepsy patients was performed. Gamma (30–70 Hz) and interictal spike events were independently identified, their independent or concurrent presence determined, and their source localization rates compared. Of 30 patients, gamma activities were detected in 28 patients and interictal spikes in 24 patients. Gamma events alone appeared in 5 patients, interictal spikes alone in 1 patient, and no events in 1 patient. Gamma co-occurred with interictal spikes in 20.1 ± 22.1% and interictal spikes co-occurred with gamma in 15.0 ± 19.2%. Rates of event localization within the resection cavity were significantly different (p = 0.042) between gamma (63.3 ± 32.6%) and interictal spike (47.0 ± 41.3%) events. In 4 of the 5 gamma-only patients the mean localization rate was 42.5%. Compared with the interictal spike localization rate, 4 of 9 seizure-free patients had higher gamma localization rates, 4 had the same rate, and 1 had a lower rate. Individual gamma events can be detected independently from interictal spike presence. Gamma can be localized to the resection cavity at least comparably to or more frequently than that from interictal spikes. Even when interictal spikes were undetected, gamma sources were localized to the resection cavity. Gamma oscillations may be a useful indicator of epileptogenic focus. PMID:24273733
-
Energy dependence of polarization across broad deexcitation gamma-ray line profiles
NASA Astrophysics Data System (ADS)
Werntz, Carl; Lang, F. L.
1998-04-01
The energy profiles of deexcitation gamma-ray lines from recoiling inelastically scattered nuclei exhibit detailed structure. MeV-wide gamma-ray lines from the direction of the Orion nebula have been detected (H. Bloemen, et al., Astr. and Astrophys. L5, 281 (1994).) by COMPTEL whose source is postulated to be cosmic ray carbon and oxygen nuclei shock accelerated near supernova remnants colliding with ambient hydrogen and helium. Even when the heavy ion velocity distributions are isotropic, structure characteristic of the multipolarity of the gamma transition remains (A. M. Bykov et al, Astr. and Astrophys. 607, L37 (1996); B. Kozlovsky et al, Astrophys. J. 484, (1997).). In experiments in which the energy dependent structure of the deexcitation gamma-ray profiles is not resolved, the gammas display a high degree of linear polarization that rapidly changes with gamma-beam angle. We calculate the polarization, both linear and circular, as a function of gamma-ray energy across the laboratory line profiles of C12*(4.44) and O16*(6.13) inelastically excited by protons and alphas. We then investigate the polarization in the surviving structures for isotropic energetic ions colliding with ^1H and ^4He.
-
VizieR Online Data Catalog: Flaring gamma-ray sources; LAT 7.4yr (2FAV) (Abdollahi+, 2017)
NASA Astrophysics Data System (ADS)
Abdollahi, S.; Ackermann, M.; Ajello, M.; Albert, A.; Baldini, L.; Ballet, J.; Barbiellini, G.; Bastieri, D.; Becerra Gonzalez, J.; Bellazzini, R.; Bissaldi, E.; Blandford, R. D.; Bloom, E. D.; Bonino, R.; Bottacini, E.; Bregeon, J.; Bruel, P.; Buehler, R.; Buson, S.; Cameron, R. A.; Caragiulo, M.; Caraveo, P. A.; Cavazzuti, E.; Cecchi, C.; Chekhtman, A.; Cheung, C. C.; Chiaro, G.; Ciprini, S.; Conrad, J.; Costantin, D.; Costanza, F.; Cutini, S.; D'Ammando, F.; de Palma, F.; Desai, A.; Desiante, R.; Digel, S. W.; di Lalla, N.; di Mauro, M.; di Venere, L.; Donaggio, B.; Drell, P. S.; Favuzzi, C.; Fegan, S. J.; Ferrara, E. C.; Focke, W. B.; Franckowiak, A.; Fukazawa, Y.; Funk, S.; Fusco, P.; Gargano, F.; Gasparrini, D.; Giglietto, N.; Giomi, M.; Giordano, F.; Giroletti, M.; Glanzman, T.; Green, D.; Grenier, I. A.; Grove, J. E.; Guillemot, L.; Guiriec, S.; Hays, E.; Horan, D.; Jogler, T.; Johannesson, G.; Johnson, A. S.; Kocevski, D.; Kuss, M.; La Mura, G.; Larsson, S.; Latronico, L.; Li, J.; Longo, F.; Loparco, F.; Lovellette, M. N.; Lubrano, P.; Magill, J. D.; Mal! Dera, S.; Manfreda, A.; Mayer, M.; Mazziotta, M. N.; Michelson, P. F.; Mitthumsiri, W.; Mizuno, T.; Monzani, M. E.; Morselli, A.; Moskalenko, I. V.; Negro, M.; Nuss, E.; Ohsugi, T.; Omodei, N.; Orienti, M.; Orlando, E.; Paliya, V. S.; Paneque, D.; Perkins, J. S.; Persic, M.; Pesce-Rollins, M.; Petrosian, V.; Piron, F.; Porter, T. A.; Principe, G.; Raino, S.; Rando, R.; Razzano, M.; Razzaque, S.; Reimer, A.; Reimer, O.; Sgro, C.; Simone, D.; Siskind, E. J.; Spada, F.; Spandre, G.; Spinelli, P.; Stawarz, L.; Suson, D. J.; Takahashi, M.; Tanaka, K.; Thayer, J. B.; Thompson, D. J.; Torres, D. F.; Torresi, E.; Tosti, G.; Troja, E.; Vianello, G.; Wood, K. S.
2018-04-01
To build the second catalog of flaring gamma-ray sources (2FAV) catalog, we apply the Fermi All-sky Variability Analysis (FAVA; Ackermann+ 2013, J/ApJ/771/57) to the first 387 weeks of Fermi observations, from Mission Elapsed Time (MET) 239557418 to 473615018, or Modified Julian Date (MJD) from 54682 (2008 August 4) to 57391 (2016 January 4). In this time range, a total of 7106 seed flares were found, roughly 18 per week. As for the previous catalog, FAVA uses weekly time bins. Two independent energy bands are used, 0.1-0.8GeV and 0.8-300GeV, to enhance the sensitivity to spectrally soft and hard flares, respectively. (2 data files).
-
Short-term variability of gamma radiation at the ARM Eastern North Atlantic facility (Azores).
Barbosa, S M; Miranda, P; Azevedo, E B
2017-06-01
This work addresses the short-term variability of gamma radiation measured continuously at the Eastern North Atlantic (ENA) facility located in the Graciosa island (Azores, 39N; 28W), a fixed site of the Atmospheric Radiation Measurement programme (ARM). The temporal variability of gamma radiation is characterized by occasional anomalies over a slowly-varying signal. Sharp peaks lasting typically 2-4 h are coincident with heavy precipitation and result from the scavenging effect of precipitation bringing radon progeny from the upper levels to the ground surface. However the connection between gamma variability and precipitation is not straightforward as a result of the complex interplay of factors such as the precipitation intensity, the PBL height, the cloud's base height and thickness, or the air mass origin and atmospheric concentration of sub-micron aerosols, which influence the scavenging processes and therefore the concentration of radon progeny. Convective precipitation associated with cumuliform clouds forming under conditions of warming of the ground relative to the air does not produce enhancements in gamma radiation, since the drop growing process is dominated by the fast accretion of liquid water, resulting in the reduction of the concentration of radionuclides by dilution. Events of convective precipitation further contribute to a reduction in gamma counts by inhibiting radon release from the soil surface and by attenuating gamma rays from all gamma-emitting elements on the ground. Anomalies occurring in the absence of precipitation are found to be associated with a diurnal cycle of maximum gamma counts before sunrise decreasing to a minimum in the evening, which are observed in conditions of thermal stability and very weak winds enabling the build-up of near surface radon progeny during the night. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
Dou, Lin; Wang, Shuyue; Sun, Libo; Huang, Xiuqing; Zhang, Yang; Shen, Tao; Guo, Jun; Man, Yong; Tang, Weiqing; Li, Jian
2017-01-01
Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. © 2017 The Author(s). Published by S. Karger AG, Basel.