High temperature expansion in supersymmetric matrix quantum mechanics

We formulate the high temperature expansion in supersymmetric matrix quantum mechanics with 4, 8 and 16 supercharges. The models can be obtained by dimensionally reducing N=1 U(N) super Yang-Mills theory in D=4,6,10 to 1 dimension, respectively. While the non-zero frequency modes become weakly coupled at high temperature, the zero modes remain strongly coupled. We find, however, that the integration over the zero modes that remains after integrating out all the non-zero modes perturbatively, reduces to the evaluation of connected Green's functions in the bosonic IKKT model. We perform Monte Carlo simulation to compute these Green's functions, which are then used to obtain the coefficients of the high temperature expansion for various quantities up to the next-leading order. Our results nicely reproduce the asymptotic behaviors of the recent simulation results at finite temperature. In particular, the fermionic matrices, which decouple at the leading order, give rise to substantial effects at the next-leading order, reflecting finite temperature behaviors qualitatively different from the corresponding models without fermions.Comment: 17 pages, 13 figures, (v2) some typos correcte

Monte Carlo approach to nonperturbative strings -- demonstration in noncritical string theory

We show how Monte Carlo approach can be used to study the double scaling limit in matrix models. As an example, we study a solvable hermitian one-matrix model with the double-well potential, which has been identified recently as a dual description of noncritical string theory with worldsheet supersymmetry. This identification utilizes the nonperturbatively stable vacuum unlike its bosonic counterparts, and therefore it provides a complete constructive formulation of string theory. Our data with the matrix size ranging from 8 to 512 show a clear scaling behavior, which enables us to extract the double scaling limit accurately. The ``specific heat'' obtained in this way agrees nicely with the known result obtained by solving the Painleve-II equation with appropriate boundary conditions.Comment: 15 pages, 10 figures, LaTeX, JHEP3.cls; references added, typos correcte

Methylation of the KEAP1 gene promoter region in human colorectal cancer

<p>Abstract</p> <p>Background</p> <p>The Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated.</p> <p>Methods</p> <p>We used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the <it>KEAP1 </it>promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, <it>NQO-1 </it>and <it>AKR1C1</it>.</p> <p>Results</p> <p>DNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the <it>KEAP1 </it>promoter region. HT29 cells with a hypermethylated <it>KEAP1 </it>promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased <it>KEAP1 </it>mRNA expression. These result suggested that methylation of the <it>KEAP1 </it>promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of <it>NQO-1 </it>and <it>AKR1C1 </it>mRNA than Colo320DM cells. Aberrant promoter methylation of <it>KEAP1 </it>was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the <it>KEAP1 </it>promoter region, conferring a protective effect against cytotoxic anticancer drugs.</p> <p>Conclusion</p> <p>Hypermethylation of the <it>KEAP1 </it>promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.</p

Identification of Carnitine Transporter CT1 Binding Protein Lin-7 in Nervous System

_L-Carnitine is an essential component of mitochondrial fatty acid b-oxidation in the muscle and may control the acetyl moiety levels in the brain for acetylcholine synthesis. Carnitine transporter 1(CT1)is the high affinity _L-carnitine transporter whose localization was observed in the kidney, testis, liver, skeletal muscle and brain. To clarify the molecular mechanism of carnitine transport, we sought to find the interacting protein that may be related to the transport function of CT1. Using the intracellular C-terminal region of rat CT1 containing PDZ(PSD95/DLG/ZO-1)motif as bait, we performed the yeast two-hybrid screening against rat brain cDNA library. Thirty two positive clones were obtained from the 2.7×10^7 clones screened. One of them was PDZ domain-containing protein Lin-7. We found that Lin-7 interacts specifically with C-termini of CT1:deletion and mutation of the CT1 C-terminal PDZ-motif abolished the interaction with Lin-7 in the yeast two-hybrid assay. In addition, a PDZ domain within Lin-7 associates with the CT1 C-terminal. The association of CT1 with Lin-7 enhanced _L-carnitine transport activities in HEK293 cells although there is no statistical significance. Coexpression of Lin-7 and CT1 is identified in motor neurons of the spinal cord ventral horn together with Lin-2, a binding partner of Lin-7 known to assemble proteins involved in synaptic vesicle exocytosis and synaptic junctions. Therefore, Lin-7 interacts with CT1 and may regulate their subcellular distribution or function in central nervous system

ヒト ジンゾウ ニョウサン トランス ポーター URAT 1 ト スイヨウ セイ ヨード ケイ ゾウエイザイ IODIPAMIDE ノ ソウゴ サヨウ

降圧薬などいくつかの薬剤は本来の薬理作用とは別に尿酸降下作用を持つものがあり,水溶性ヨード系造影剤もその一つでiodipamideやdiatrizoateでの尿酸排泄亢進が報告されていた.長らく不明のままであった腎尿酸輸送機構の分子実体は2002年の腎尿細管尿酸トランスポーターURAT1(Urate Transporter 1)の分子同定によりその理解が飛躍的に進んだ.本研究ではURAT1と水溶性造影剤のiodipamideおよびdiatrizoateの相互作用を検討することで,その尿酸排泄促進作用の分子機序の解明を目的とする.URAT1の尿酸輸送活性の測定にはURAT1安定発現HEK293細胞(HEK-URAT1)細胞を用いた.IodipamideはHEK-URAT1細胞でのRI標識尿酸取込みを著明に阻害した(IC_:1.19±0.08?μM)のに対し,diatrizoateは1?mMまでの範囲では50%以上の阻害作用を示さなかった.1?mMまでのiodipamideはHEK-URAT1細胞の生存率に影響を与えなかった.IodipamideによるURAT1媒介尿酸輸送への阻害作用のキネティクス解析の結果,その阻害は競合阻害であり,阻害定数Ki値は11.03?μMであった.以上より,iodipamideは尿酸トランスポーターURAT1と相互作用をすることを初めて確認できた.このことからiodipamideは細胞外からURAT1の尿酸結合部位に結合し,競合して阻害を行うことで,腎尿細管の経上皮性尿酸再吸収を抑制し,ひいては血清尿酸値を低下させるものと考えられた.Drug-induced hypouricemia has been found in several drugs such as probenecid, benzbromarone and angiotensin II receptor blocker(ARB)losartan. Xray contrast agents such as iodipamide and diatrizoate, used for the intravenous cholangiography and excretory urography, were reported to have uricosuric effct beside their original action. After the molecular identification of renal apical urate transporter URAT1 as an entrance of urate into the epithelial cells of proximal tubules, this protein is thought to be major determinant for renal reabsorption of urate that affect the blood urate levels in human. The purpose of this study is to examine whether iodipamide and diatrizoate act on URAT 1 . In URAT 1 -stably expressing HEK293(HEK-URAT1)cells, iodipamide inhibited [^C] urate uptake dose-dependently(IC_ , 1.19±0.08 μM), while diatrizoate did not. Up to the concentration of 1 mM, iodipamide incubation for 24 hr did not affect the viability of HEK293-URAT1 cells. Lineweaver-Burk plot of the kinetic analysis by URAT1-mediated urate uptake with or without iodipamide indicated that its interaction occurs in a competitive manner(Ki:11.03 μM). These results suggest that uricosuric effect of iodipamide can be explained by the interaction of iodipamide with urate-binding site of URAT1, and the inhibition of urate reabsorption from extracellular side by iodipamide causes uricosuria leading to induce hypouricemia

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Variations in Rectal Volumes and Dosimetry Values Including NTCP due to Interfractional Variability When Administering 2D-Based IG-IMRT for Prostate Cancer

We estimated variations in rectal volumes and dosimetry values including NTCP with interfractional motion during prostate IG-IMRT. Rectal volumes, DVH parameters, and NTCPs of 20 patients were analyzed. For this patient population, the median (range) volume on the initial plan for the rectum was 45.6 cc (31.3–82.0), showing on-treatment spread around the initial prediction based on the initial plan. DVH parameters of on-treatment CBCT analyses showed systematic regularity shift from the prediction based on the initial plan. Using the Lyman-Kutcher-Burman model, NTCPs of predicted late rectal bleeding toxicity of rectal grade ≥ 2 (RTOG) and the QUANTEC update rectal toxicity for the prediction based on the initial plan were 0.09% (0.02–0.24) and 0.02% (0.00–0.07), respectively, with NTCPs from on-treatment CBCT analyses being 0.35% (0.01–6.16) and 0.12% (0.00–4.11), respectively. Using the relative seriality model, for grade ≥ 2 bleeding rectal toxicity, NTCP of the prediction based on the initial plan was 0.64% (0.15–1.22) versus 1.48% (0.18–7.66) for on-treatment CBCT analysis. Interfraction variations in rectal volumes occur in all patients due to physiological changes. Thus, rectal assessment during 2D-based IG-IMRT using NTCP models has the potential to provide useful and practical dosimetric verification