Extensively Hydrated but Folded: A Novel State of Globular Proteins Stabilized at High Pressure and Low Temperature

AbstractWe studied conformational fluctuations of the transcription factor c-Myb R2 subdomain (52 residues with three Trp) at high pressure and low temperature (5°C) using two different spectroscopic methods, Trp fluorescence and 1H NMR, on its chemically stable mutant C130I (pseudo-wild-type (WTS)), which has a large internal cavity. As pressure was increased from 3 to 300 MPa, the Trp fluorescence λmax of WTS shifted from 342 to ∼355 nm, clearly showing that the three Trp rings become fully exposed to the polar environment, which usually is taken to indicate that the protein underwent unfolding. In contrast, as pressure was increased from 3 to 300 MPa, the high-field-shifted 1H NMR signals characteristic of the folded state showed a still higher-field shift, but no significant changes in their intensity. The last result unequivocally shows that the protein remains largely folded at 300 MPa. The apparent discrepancy between the two predictions would only be solved if one were to postulate the existence of an extensively hydrated but folded state in WTS. Intriguingly, such a state was not found in a cavity-filling mutant of WTS, C130I/V103L, suggesting that this state is mediated by cavity hydration. The generality and significance of this state in proteins are discussed

Long interspersed nuclear element 1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer

金沢大学がん研究所Purpose: Global hypomethylation and the hypermethylation of gene promoter regions are common events in tumor DNA. The aim of this study was to evaluate the prognostic significance of both global hypomethylation and gene promoter hypermethylation in DNA from non-small cell lung cancer (NSCLC). Experimental Design: Genomic DNA was obtained from the tumor tissue of 379 NSCLC patients who underwent surgery. Methylation levels were measured by real-time PCR following bisulfite modification of DNA and were correlated with clinicopathologic parameters and patient prognosis. Methylation of long interspersed nuclear element 1 (LINE-1) was used as a surrogate marker for global methylation. Hypermethylation of the APC, CDH13, and RASSF1 promoter regions was also evaluated. Results: Tumor tissue showed significantly higher CDH13 and RASSF1 methylation levels compared with normal lung tissue, but lower LINE-1 methylation levels. APC, RASSF1, and LINE-1 methylation levels were significant prognostic factors in univariate analysis of an initial cohort of 234 cases. APC and LINE-1 methylation remained significant prognostic factors in multivariate analysis that included age, gender, smoking history, histologic type, and pathologic stage. LINE-1 methylation showed marginally significant prognostic value in stage IA and IB disease. Expansion of the study cohort to 364 cases revealed that LINE-1 methylation had significant prognostic value for stage IA NSCLC patients in multivariate analysis. Conclusions: LINE-1 hypomethylation was an independent marker of poor prognosis in stage IA NSCLC. Validation of this finding in additional tumor cohorts could have clinical relevance for the management of early-stage NSCLC. ©2010 AACR

Strong exciton‐photon coupling and its polarization dependence in a metal‐mirror microcavity with oriented PIC J‐aggregates

We present a study of strong exciton-photon coupling and its dependence on incident light polarization in a metal-metal mirror microcavity containing PIC J-aggregates. Rabi-splitting energies between upper and lower polariton branches are estimated as 94 meV and 69 meV for s- and p-polarized incident light, respectively. These large values are due to large oscillator strength of Frenkel excitons in the PIC J-aggregates and strong confinement of light attributed to the metallic microcavity as well. As for the effective thickness of the active layer for s-polarized light, a good agreement is obtained between Lfiteff = 201 nm deduced from the experimental data and Lcalceff = 207 nm calculated from the summation of the measured thickness of active layer with the estimated penetration depths into silver mirrors. We also discuss the difference in the polarization dependences of Rabi-splitting energy, quantitatively. It is concluded that the polarization dependence is mainly due to an alignment of the J-aggregates in the active layer and is not affected so much by anisotropy of the penetration depths into the silver mirrors

Optimal liver drainage rate for survival in patients with unresectable malignant hilar biliary obstruction using 3D-image volume analyzer

Background: Drainage exceeding 50% of total liver volume is a beneficial prognostic factor in patients with unresectable malignant hilar biliary obstruction (UMHBO). However, it is unclear what threshold percentage of total liver volume drained ('liver drainage rate') significantly improves survival in patients with UMHBO who received systemic chemotherapy. Objectives: We aimed to assess the optimal liver drainage rate that improves survival in patients with UMHBO receiving chemotherapy using a three-dimensional (3D)-image volume analyzer. Design: This study was a single-center retrospective cohort study. Methods: Data from 90 patients with UMHBO who received chemotherapy after endoscopic biliary drainage using metal stents at Okayama University Hospital from January 2003 to December 2020 were reviewed. The liver drainage rate was calculated by dividing the drained liver volume by the total liver volume using a 3D-image volume analyzer. The primary endpoint was overall survival by liver drainage rate. The secondary endpoints were time to recurrent biliary obstruction (TRBO) and prognostic factors. Results: The median total liver volume was 1172 (range: 673-2032) mL, and the median liver drainage rate was 83% (range: 50-100). Overall survival was 376 (95% CI: 271-450) days, and patients with >80% drainage (n = 67) had significantly longer survival than those with 80% liver drainage [hazard ratio (HR): 0.35, 95% CI: 0.20-0.62, p = 0.0003] and hilar cholangiocarcinoma (HR: 0.30, 95% CI: 0.17-0.50, p Conclusion: In patients with UMHBO scheduled for chemotherapy, >80% drainage is associated with improved survival. Further prospective multicenter studies are needed to verify the results of this study

MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway

Gemcitabine is an effective chemotherapeutic agent for biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA). However, few other effective agents are currently available, particularly for GEM-refractory BTCs. We previously identified microRNA-451a (miR-451a) as a potential therapeutic target in GBC. To elucidate the antineoplastic effects of miR-451a and its underlying mechanisms, we transfected miR-451a into GBC, gemcitabine-resistant GBC (GR-GBC), and gemcitabine-resistant CCA (GR-CCA) cell lines. Furthermore, mimicking in vivo conditions, tumorigenic GBC organoids and three-dimensional (3D) cell culture systems were employed to investigate the anti-proliferative effects of miR-451a on BTCs, and its effect on stem cell properties. We found that miR-451a significantly inhibited cell proliferation, induced apoptosis, and reduced chemoresistant phenotypes, such as epithelial-mesenchymal transition, in both GBC and GR-GBC. The principal mechanism is probably the negative regulation of the phosphatidylinositol 3-kinase/AKT pathway, partially accomplished by directly downregulating macrophage migration inhibitory factor. The Gene Expression Omnibus database revealed that miR-451a was the most significantly downregulated microRNA in CCA tissues. The introduction of miR-451a resulted in similar antineoplastic effects in GR-CCA. Furthermore, miR-451a reduced cell viability in 3D spheroid models and tumorigenic GBC organoids. These findings suggest that the supplementation of miR-451a is a potential treatment strategy for GEM-refractory BTCs

Peer-to-Peer Energy Trading Meets Blockchain: Consensus via Score-Based Bid Assignment

The demand for peer-to-peer energy trading (P2PET) grows alongside the advancement of smart grids. A P2PET system enables its peers to trade energy as in a double-sided auction market by issuing auction bids to buy or sell energy. A robust public ledger, that satisfies the standard properties of persistence and liveness, is necessary for the system to record trading agreements, i.e., combinations between buy and sell bids which would form a \emph{transaction}. The Bitcoin based blockchain satisfies such properties as proven in the backbone protocol (EuroCrypt\u2715). However, existing blockchain-based P2PET approaches rely on general-purpose blockchains with smart contract capabilities, unavoidably incurring in high operational costs. Therefore, this work intends to design a dedicated blockchain for the ledger of P2PET. We first revisit the blockchain data structure to support auction bids. Then, we abstract the process of forming transactions, i.e., matching bids, with a score-based many-to-many Bid Assignment Problem (BAP). Leveraging our proposed BAP in addition to the corresponding scoring function, we propose a ``proof-of\u27\u27 scheme, namely Proof-of-Bid-Assignment (PoBA), and design the corresponding blockchain aided protocol. The key difference from any previous work, we are aware of, is that our protocol selects blocks according to the score of their content, i.e., bids and transactions. Hence, a higher-scored block would be preferable to the underlying P2PET system regardless of whether the block\u27s generator is honest, since, intuitively, it would increase the number of trading agreements. Finally, by modeling PoBA with a universal sampler (AsiaCrypt\u2716) and analyzing honest users\u27 local chain dynamics, we prove the security of our design with respect to the standard ledger properties

Malignant pleural mesothelioma with long-term tumor disappearance of a local relapse after surgery: a case report

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Spacetime Superalgebra in AdS_4 \times S^7 via Supermembrane Probe

The spacetime superalgebra via the supermembrane probe in the background of AdS_4 \times S^7 is discussed to the lowest order in the spinor coordinate \t. To obtain the correct spacetime superalgebras, all \t^2 order corrections for supervielbein and super 3-form gauge potential have to be included. The central extension of the superalgebra OSp(8|4) of the super isometries for AdS_4 \times S^7 is found.Comment: 8 pages, Latex, minor corrections, final version to appear in Phys. Rev.

Different histological types of non-small cell lung cancer have distinct folate and DNA methylation levels

金沢大学がん研究所分子標的がん医療研究開発センターAberrant DNA methylation is a commonly observed epigenetic change in lung cancer. Folate has been suggested to play a role in the homeostasis of DNA methylation and has also been implicated in cancer chemotherapy. We investigated a possible role for folate in DNA methylation by measuring folate concentrations in tumors and adjacent normal tissues from 72 non-small cell lung cancer (NSCLC) patients. These were compared to DNA methylation levels and to clinicopathological features. Folate concentrations were determined as the sum of 5,10-methylenetetrahydrofolate and tetrahydrofolate. The MethyLight assay was used to quantitate methylation in promoter regions of P16(CDKN2A), APC, CDH13, RARB, RASSF1, RUNX3, and MYOD1. Methylation of LINE-1 repeats was used as a surrogate for global methylation. Folate levels in tumors correlated positively with LINE-1, CDH13, and RUNX3 methylation. Folate concentrations and methylation of LINE-1, RASSF1, and RUNX3 were significantly higher in adenocarcinoma compared to squamous cell carcinoma (SCC). Two sets of array-based data retrieved from the Gene Expression Omnibus consistently showed that expression of FOLR1, a folate transport enzyme, and GGH, an enzyme that prevents folate retention, were higher and lower, respectively, in adenocarcinomas compared to SCC. This was independently validated by quantitative RT-PCR in 26 adenocarcinomas and 13 SCC. Our results suggest that folate metabolism plays a role in aberrant DNA methylation in NSCLC. The histological subtype differences in folate concentration and DNA methylation observed here were associated with distinct expression patterns for folate metabolizing enzymes. These findings may have clinical applications for histology-directed chemotherapy with fluoropyrimidine and anti-folates in NSCLC. © 2009 Japanese Cancer Association

Abrupt rotation of the rashba spin to the direction perpendicular to the surface

金沢大学理工研究域数物科学系The polarization vector of the Rashba spin, which must be parallel to the two-dimensional (2D) plane in an ideal system, is found to change abruptly and definitely to the direction perpendicular to the surface at the K̄ point of the Brillouin zone of a real hexagonal system, the Tl/Si(111)-(1×1) surface. This finding obtained experimentally by angle-resolved and spin-resolved photoemission measurements is fully confirmed by a first-principles theoretical calculation. We found that the abrupt rotation of the Rashba spin is simply understood by the 2D symmetry of the hexagonal structure. © 2009 The American Physical Society