Major Histocompatibility Class Ⅱ HLA-DRα Gene Expression in Thyrocytes : Counter Regulation by the Class Ⅱ Transactivator and the Thyroid Y Box Protein

MONTANI, VALERIA,TANIGUCHI, SHIN-ICHI,SHONG, MINHO,SUZUKI, KOICHI,OHMORI, MASAYUKI,GIULIANI, CESIDIO,NAPOLITANO, GIORGIO,SAJI, MOTOYASU,FIORENTINO, BRUNO,REIMOLD, ANDREAS M.,TING, JENNY P.-Y,KOHN, LEO 충남대학교 생물공학연구소 1999 생물공학연구지 Vol.7 No.-

Aberrant expression of major histocompatibility complex(MHC) classⅡ proteins on thyrocytes, which is associated with autoimmune thyroid disease, is mimicked by γ-interferon (γ-IFN). To define elements and factors that regulate classⅡ gene expression in thyrocytes and that might be involved in aberrant expression, we have studied γ-IFN-induced HLA-DRα gene expression in rat FRTL-5 thyroid cells. The present report shows that classⅡ expression in FRTL-5 thyrocytes is positively regulated by the classⅡ transactivator (CIITA), and that CIITA mimics the action of γ-IFN. Thus as is the case for γ-IFN, several distinct and highly conserved elements on the 5'-flanking region of the HLA-DRα gene, the S, X_1, X_2, and Y boxes between -137 to -65 bp, are required for classⅡ gene expression induced by pCIITA transfection in FRTL-5 thyroid cells. CIITA and γ-IFN do not cause additive increases in HLA-DRα gene expression in FRTL-5 cells, consistent with the possibility that CIITA is an intermediate factor in the γ-IFN pathway to increased classⅡ gene expression. Additionally, γ-IFN treatment of FRTL-5 cells induces an endogenous CIITA transcript; pCIITA transfection mimics the ability of γ-IFN treatment of FRTL-5 thyroid cells to increase the formation of a specific and novel protein/DNA complex containing CBP, a coactivator of CRE binding proteins important for cAMP-induced gene expression; and the action of both γ-IFN and CIITA to increase classⅡ gene expression and increase complex formation is reduced by cotransfection of a thyroid Y box protein, which suppresses MHC classⅠ gene expression in FRTL-5 thyroid cells and is a homolog of human YB-1, which suppresses MHC classⅡ expression in human glioma cells. we conclude that CIITA and TSH receptor suppressor element binding protein-1 are components of the γ-IFN-regulated transduction system which, respectively, increase or decrease classⅡ gene expression in thyrocytes and may, therefore, be involved in aberrant classⅡ expression associated with autoimmune thyroid disease. (Endocrinology 139: 280-289, 1998)

Regulation of Major Histocompatibility Class Ⅱ Gene Expressino in FRTL-5 Thyrocytes : Opposite Effects of Interferon and Methimazole

MONTANI, VALERIA,SHONG, MINHO,TANIGUCHI, SHIN-ICHI,SUZUKI, KOICHI,GIULIANI, CESIDIO,NAPOLITANO, GIORGIO,SAITO, JUN,SAJI, MOTOYASU,FIORENTINO, BRUNO,REIMOLD, ANDREAS M.,SINGER, DINAH S.,KOHN, LEONARD D 충남대학교 생물공학연구소 1999 생물공학연구지 Vol.7 No.-

Aberrant expression of major histocompatibility complex (MHC) classⅡ antigens is associated with autoimmune thyroid disease; aberrant expression duplicating the autoimmune state can be induced by interferon-γ (IFNγ). We have studied IFNγ-induced human leukocyte antigen (HLA)-DRα gene expression in rat FRTL-5 thyroid cells to identify the elements and factors important for aberrant expression. Using an HLA-DRα 5'-flanking region construct from-176 to +45 bp coupled to the chloramphenicol acetyltransferase reporter gene, we show that there is no basal classⅡ gene expression in FRTL-5 thyroid cells, that IFNγ can induce expression, and, as is the case for antigen-presenting cells from the immune system, that IFNγ-induced expression requires several highly conserved elements on the 5'-flanking region, which, from 5' to 3', are the S, X_1, X_2, and Y boxes. Methimazole (MMI), a drug used to treat patients with Graves' disease and experimental thyroiditis in rats or mice, can suppress the IFNγ-induced increase in HLA-DRα gene expression as a function of time and concentration; MMI simultaneously decreases IFNγ-induced endogenous antigen presentation by the cell. Using gel shift assays and the HLA-DRα 5'-flanking region from -176 or -137 to +45 bp as radiolabeled probes, we observed the formation of a major protein-DNA complex with extracts from FRTL-5 cells untreated with IFNγ, termed the basal or constitutive complex, and formation of an additional complex with a slightly faster mobility in extracts from cells treated with IFNγ. MMI treatment of cells prevents IFNγ from increasing the formation of this faster migrating complex. Formation of both complexes is specific, as evidenced in competition studies with unlabeled fragments between -137 and -38 bp from the start of transcription; nevertheless, they can be distinguished in such studies. Thus, high concentrations of double stranded oligonucleotides containing the sequence of the Y box, but not S, X_1, or X_2 box sequences, can prevent formation of the IFNγ-increased faster migrating complex, but not the basal complex. Both complexes involve multiple proteins and can be distinguished by differences in their protein composition. Thus, using specific antisera, we show that two cAMP response element-binding proteins, activating transcription factor-1 and/or -2, are dominant proteins in the upper or basal complex. The upper or basal complex also includes c-Fos, Fra-2, Ets-2, and Oct-1. A dominant protein that distinguishes the IFNγ-increased lower complex is CREB-binding protein (CBP), a coactivator of cAMP response element-binding proteins. We, therefore, show that aberrant expression of MHC classⅡ in thyrocytes, induced by IFNγ, is associated with the induction or increased formation of a novel portein-DNA complex and that its formation as well as aberrant classⅡ expression are suppressed by MMI, a drug used to treat human and experimental autoimmune thyroid disease. Its component proteins differ from those in a major, basal, or constitutive protein-DNA complex formed with the classⅡ 5'-flanking region in cells that are not treated with IFNγ and that do not express the classⅡ gene. (Endocrinology 139: 290-302, 1998)

Hydroxychloroquine, Interleukin-6 Receptor Antagonists and Corticoid Treatments of Acute COVID-19 Infection: Psychiatric Symptoms and Mental Disorders 4 Months Later

Matthieu Gasnier(Matthieu Gasnier ),Walid Choucha(Walid Choucha ),David Montani(David Montani ),Nicolas Noël(Nicolas Noël ),Céline Verstuyft(Céline Verstuyft ),Francois Radiguer(Francois Radiguer ),Xa 대한정신약물학회 2022 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.20 No.4

Objective: Psychiatric symptoms and mental disorders are common after Coronavirus Disease-19 (COVID-19). Some drugs used to treat acute COVID-19 have psychiatric side effects. We assessed the psychiatric symptoms and mental disorders of patients treated for acute COVID-19 with hydroxychloroquine (HCQ), interleukin-6 receptor antagonists (anti-IL-6), and corticoids (CTC). Methods: We evaluated 177 patients in a day hospital 4 months after acute infection. Results: In a multivariate analysis, HCQ was associated with significant anxiety symptoms (odds ratio [OR] = 5.9, 95% confidence interval [95% CI] = 1.8−20.0, p = 0.003) and mental disorders (OR = 4.1, 95% CI = 1.2−13.9, p = 0.02). In a bivariate analysis with propensity matched cohorts, HCQ was associated with significant anxiety symptoms (9 patients [50.0%] with significant symptoms in the HCQ group versus 15 [20.1%] in the control group, OR = 3.8, 95% CI = 1.3−11.3, p = 0.01). Anti-IL-6 and CTC were not associated with significant psychiatric symptoms or mental disorders. Conclusion: We recommend monitoring psychiatric symptoms, especially anxiety, in patients treated with HCQ during COVID-19 infection. Further studies with larger samples and prospective assessments are needed to confirm our results.

Riemannian and Non-riemannian Extensions of Geometrodynamics Versus Einsteinian Gravity

Orchidea Maria Lecian,Giovanni Montani 한국물리학회 2010 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.56 No.5

We analyze some extensions of General Relativity. Within the framework of modified gravity,the Newtonian limit of a class of gravitational actions is discussed on the basis of the corresponding scalar-tensor model. For a generalized asymmetric metric, autoparallel trajectories are defined under suitable conditions at first-order approximation.

The Mixmaster Model as a Cosmological Framework and Aspects of its Quantum Dynamics

Giovanni Imponente,Giovanni Montani 한국물리학회 2003 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.42 No.III

This paper provides a review of some recent issues on the Mixmaster dynamics concerning the features of its stochasticity. After a description of the geometrical structure characterizing the homogeneous cosmological models in the Bianchi classification and the Belinsky-Khalatnikov-Lifshitz piecewise representation of the types VIII and IX oscillatory regime, we face the question regarding the time covariance of the resulting chaos as viewed in terms of continuous Misner-Chitr\'e like variables. Finally, we show how in the statistical mechanics framework the Mixmaster chaos raises as semiclassical limit of the quantum dynamics in the Planckian era.

Plasma Levels of K18 Fragments Do Not Correlate with Alcoholic Liver Fibrosis

Viola Schlossberger,Mathias Worni,Christina Kihm,Matteo Montani,Christian Datz,Jochen Hampe,Felix Stickel 거트앤리버 소화기연관학회협의회 2019 Gut and Liver Vol.13 No.1

Background/Aims: Noninvasive markers of liver fibrosis in alcoholic liver disease (ALD) are crucial to establish early intervention. Previous studies have suggested that plasma levels of cleaved keratin-18 (K18; M30) fragments can predict the severity of liver disease. The aim of this study was to correlate plasma M30 levels with stages of liver fibrosis in ALD. Methods: Patients with ALD (n=139, 79.1% males) and liver histology were included, and plasma samples were collected to quantify plasma M30 levels. Patients were stratified into five groups by fibrosis stage (F0=14; F1=15; F2=35; F3=17; and F4=58) according to the Kleiner score. Differences between groups were evaluated using the chi-square test or analysis of variance. Trends by fibrosis stage were calculated by logistic regression analysis, and sensitivity, specificity and positive and negative predictive values were determined. Results: There were no significant differences in M30 levels among fibrosis stages. The correlation between plasma M30 levels and fibrosis was poor (Pearson’s correlation coefficient= 0.13, Spearman rho=0.20 [p=0.02]), and M30 levels did not correlate with alcohol-specific histological features. However, significant correlations of M30 levels with aspartate aminotransferase (Spearman rho=0.653, p<0.001) and alanine aminotransferase (Spearman rho=0.432, p<0.001) were found. M30 levels of >200 U/L reveal a sensitivity for predicting cirrhosis of 84.5% with a negative predictive value of 73.5%. Conclusions: Plasma M30 levels are often elevated in ALD and correlate with serum transaminases but do not reflect fibrosis. The usefulness as a prognostic marker awaits evaluation in prospective studies.

Particles and Fields within a Unification Scheme

Francesco Cianfrani,Valentino Lacquaniti,Giovanni Montani 한국물리학회 2010 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.56 No.5

We discuss the properties of particles and fields in a multi-dimensional space-time, where the geometrization of gauge interactions can be performed. For instance, in a 5-dimensional Kaluza-Klein manifold, we argue that the motion of charged spinning bodies is obtained in a Papapetrou-like formulation. As far as spinors are concerned, we outline how the gauge coupling can be recognized by using a proper dependence on extra-coordinates and by using the dimensional reduction procedure.

Iodide Suppression of Major Histocompatibility Class I Gene Expression in Thyroid Cells Involves Enhancer A and the Transcription Factor NF-kB

Taniguchi, Shin-Ichi,Shong, Minho,Giuliani, Cesidio,Napolitano, Giorgio,Saji, Motoyasu,Montani, Valeria,Suzuki, Koichi,Singer, Dinah S.,Kohn, Leonard D. 충남대학교 생물공학연구소 1999 생물공학연구지 Vol.7 No.-

Increased MHC class I expression on thyrodytes is evident in ATD (4, 21) and has been suggested to be an important causal factor in the development or perpetuation of disease expression (3). The hypothesis has been offered that the elevations result in abnormal presentation of thyroid antigens to immune cells, thereby breaking tolerance, and that this elicits the clonal expansion of autoreactive T cells associated with disease expression (3).

Regulation of Major Histocompatibility (MHC) Class Ⅱ Human Leukocyte Antigen-DRα Gene Expression in Thyrocytes by Single Strand Binding Protein-1, a Transcription Factor That Also Regulates Thyrotropin Receptor and MHC Class I Gene Expression

BALDUCCI-SILANO, PINA L.,SUZUKI, KOICHI,OHTA, MASANORI,SAITO, JUN,OHMORI, MASAYUKI,MONTANI, VALERIA,NAPOLITANO, GIORGIO,SHONG, MINHO,TANIGUCHI, SHIN-ICHI,PIETRARELLI, MICHELE,LAVARONI, STEFANO,MORI, A 충남대학교 생물공학연구소 1999 생물공학연구지 Vol.7 No.-

The single strand binding protein (SSBP-1) is a positive regulator of TSH receptor gene expression and binds to an element with a GXXXXG motif. The S box of the mouse major histocompatibility classⅡ gene has multiple GXXXXG motifs and can also bind SSBP-1. The S box is one of four highly conserved elements on the 5'-flanking region of classⅡ genes that are necessary for interferon-γ (IFNγ) to overcome the normally suppressed state of the gene and induce aberrant classⅡ expression. In this report we show that SSBP-1, when overexpressed in FRTL-5 thyroid cells, is a positive regulator of human leukocyte antigen (HLA)-DRα classⅡ gene expression, as is IFNγ or the classⅡ trans-activator (CIITA). This is evidenced by increased exogenous promoter activity, increased endogenous RNA levels, and increased endogenous antigen expression after transfecting full-length SSBP-1 complementary DNA together with a HLA-DRα promoter-reporter gene chimera into TSH-treated FRTL-5 thyroid cells whose endogenous SSBP-1 levels are low. IFNγ reverses the ability of TSH to decrease endogenous SSBP-1 RNA levels. Also, whereas SSBP-1 transfection does not cause any increase in IFNγ-induced exogenous promoter activity, transfection of SSBP-1 and CIITA additively increases endogenous classⅡ RNA levels to levels measured in cells treated with IFNγ. Further, competition studies show that SSBP-1 binding is necessary for formation of the double strand protein/DNA complexes that are seen in electrophoretic mobility shift assays when the classⅡ 5'-flanking region is incubated with extracts from IFNγ-treated FRTL-5 cells and that have been previously associated with IFNγ-induced aberrant classⅡ expression. These data suggest that SSBP-1 is involved in the action of IFNγ to overcome the normally suppressed state of the classⅡ gene; it functions together with CIITA, whose expression is independently increased by IFNγ. The effect of SSBP-1 as a positive regulator of classⅡ promoter activity is lost in cells maintained without TSH, in which endogenous SSBP-1 RNA levels are already high in the absence of aberrant classⅡ gene expression. These data suggest that high levels of endogenous SSBP-1 are insufficient to cause aberrant classⅡ expression, but, rather, TSH or IFNγ treatment additionally modulates the cell, albeit differently, such that transfected or endogenous SSBP-1, respectively, can express its positive regulatory activity. The effect of TSH is consistent with reports indicating that TSH enhances the ability of IFNγ to increase classⅡ gene expression despite the fact IFNγ increases endogenous SSBP-1 to only the same levels as in cells untreated with TSH. Finally, the effect of SSBP-1 as a positive regulator is lost when GXXXXG motifs, which exist on both the coding and noncoding strands of the S box, are mutated. Consistent with this, mutation and oligonucleotide competition studies show that GXXXXG motifs are necessary for either strand of the S box to bind protein/DNA complexes containing SSBP-1 in FRTL-5 cell extracts or to bind to recombinant SSBP-1. They also suggest that the SSBP-1-binding sites on either strand of the HLA-DRα S box are functionally distinct. We conclude from these data that the positive regulatory action of SSBP-1 on classⅡ gene expression involves GXXXXG motifs on each strand of the highly conserved S box of the classⅡ 5'-flanking region. As SSBP-1 is modulated by IFNγ and is involved in classⅠ and TSH receptor as well as classⅡ gene expression in FRTL-5 cells, the sum of the data supports the hypotheses that common transcription factors regulate all three genes, and their altered activities may contribute to the development of autoimmunity. (Endocrinology 139: 2300-2313, 1998)

Does Leaders' Health (and Work-Related Experiences) Affect their Evaluation of Followers' Stress?

Gabriele Giorgi,Serena Mancuso,Francisco Javier Fiz Perez,Francesco Montani,Francois Courcy,Giulio Arcangeli 한국산업안전보건공단 산업안전보건연구원 2015 Safety and health at work Vol.6 No.3

Background: Stressed workers suffer from severe health problems which appear to have increased. Poor leadership is especially considered a source of stress. Indeed, supervisors might perceive their subordinates to be similar to them as far as stress is concerned and this might more widespread in organizations than previously thought. Methods: The present research investigates the relationships between leaders’ health, in terms of workrelated stress, mental health, and workplace bullying and their evaluation of subordinates’ stress. Five regression models were formulated to test our hypothesis. This is a cross-sectional study among 261 Italian leaders, using supervisor self-assessment and leaders’ assessments of their subordinates. Results: Leaders’ health was related to their evaluation of staff stress. Job demand, lack of job control, and lack of support by colleagues and supervisors evaluated in their subordinates were particularly associated with the leaders’ own health. Conclusion: Implications for developing healthy leaders are finally discussed.