Quantum Analysis of Jackiw and Teitelboim's Model for 1+1 D Gravity and Topological Gauge Theory

We study the BRST quantization of the 1+1 dimensional gravity model proposed by Jackiw and Teitelboim and also the topological gauge model which is equivalent to the gravity model at least classically. The gravity model quantized in the light-cone gauge is found to be a free theory with a nilpotent BRST charge. We show also that there exist twisted N=2 superconformal algebras in the Jackiw-Teitelboim's model as well as in the topological gauge model. We discuss the quantum equivalence between the gravity theory and the topological gauge theory. It is shown that these theories are indeed equivalent to each other in the light-cone gauge.Comment: 31 page

CP, Charge Fractionalizations and Low Energy Effective Actions in the SU(2) Seiberg-Witten Theories with Quarks

Several dynamical aspects of the SU(2) Seiberg-Witten models with N_f quark hypermultiplets are explored. We first clarify the meaning of the number of the singularities of the space of vacua. CP invariance of the theories are then studied and periodicities of theories in \theta with and without bare quark masses are obtained ((4-N_f)\pi and \pi, respectively). CP noninvariance at a generic point of QMS manifests itself as the electric and quark-number charge fractionalizations for the dyons; we show that the exact Seiberg-Witten solution contains such effects correctly, in agreement with the semiclassical analysis recently made by F.Ferrari. Upon N=1 perturbation the low energy effective theories at the singularities display confinement, and in most cases chiral symmetry breaking as a consequence. In one of the vacua for N_f=3 confinement is not accompanied by chiral symmetry breaking: we interpret it as an example of oblique confinement of 't Hooft. We discuss further the consistency of the physical picture found here by studying the effects of soft supersymmetry breaking as well as the behavior of the theory in the N=1 limit.Comment: 38 pages, LaTex file with 3 PostScript figure

G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding Through Angiotensin II Type-1 Receptor

A G protein-coupled receptor agonist, angiotensin II (AngII), induces epidermal growth factor (EGF) receptor (EGFR) transactivation possibly through metalloprotease- dependent, heparin-binding EGF (HB-EGF) shedding. Here, we have investigated signal transduction of this process by using COS7 cells expressing an AngII receptor, AT1. In these cells AngII-induced EGFR transactivation was completely inhibited by pretreatment with a selective HB-EGF inhibitor, or with a metalloprotease inhibitor. We also developed a COS7 cell line permanently expressing a HB-EGF construct tagged with alkaline phosphatase, which enabled us to measure HB-EGF shedding quantitatively. In the COS7 cell line AngII stimulated release of HB-EGF. This effect was mimicked by treatment either with a phospholipase C activator, a Ca2 ionophore, a metalloprotease activator, or H2O2. Conversely, pretreatment with an intracellular Ca2 antagonist or an antioxidant blocked AngII-induced HB-EGF shedding. Moreover, infection of an adenovirus encoding an inhibitor of Gq markedly reduced EGFR transactivation and HB-EGF shedding through AT1. In this regard, AngII-stimulated HB-EGF shedding was abolished in an AT1 mutant that lacks Gq protein coupling. However, in cells expressing AT1 mutants that retain Gq protein coupling, AngII is still able to induce HB-EGF shedding. Finally, the AngII-induced EGFR transactivation was attenuated in COS7 cells overexpressing a catalytically inactive mutant of ADAM17. From these data we conclude that AngII stimulates a metalloprotease ADAM17-dependent HB-EGF shedding through AT1/Gq/phospholipase C-mediated elevation of intracellular Ca2 and reactive oxygen species production, representing a key mechanism indispensable for EGFR transactivation

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Central Role of Gq in the Hypertrophic Signal Transduction of Angiotensin II in Vascular Smooth Muscle Cells

The angiotensin II (AngII) type 1 receptor (AT1) plays a critical role in hypertrophy of vascular smooth muscle cells (VSMCs). Although it is well known that Gq is the major G protein activated by the AT1 receptor, the requirement of Gq for AngII-induced VSMC hypertrophy remains unclear. By using cultured VSMCs, this study examined the requirement of Gq for the epidermal growth factor receptor (EGFR) pathway, the Rho-kinase (ROCK) pathway, and subsequent hypertrophy. AngII-induced intracellular Ca2+ elevation was completely inhibited by a pharmacological Gq inhibitor as well as by adenovirus encoding a Gq inhibitory minigene. AngII (100nm)-induced EGFR transactivation was almost completely inhibited by these inhibitors, whereas these inhibitors only partially inhibited AngII (100nm)-induced phosphorylation of a ROCK substrate, myosin phosphatase target subunit-1. Stimulation of VSMCs with AngII resulted in an increase of cellular protein and cell volume but not in cell number. The Gq inhibitors completely blocked these hypertrophic responses, whereas a G protein-independent AT1 agonist did not stimulate these hypertrophic responses. In conclusion, Gq appears to play a major role in the EGFR pathway, leading to vascular hypertrophy induced by AngII. Vascular Gq seems to be a critical target of intervention against cardiovascular diseases associated with the enhanced renin-angiotensin system

Cu,Zn-SOD deficiency induces the accumulation of hepatic collagen

<p>Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis.</p