Doxorubicin (DOX) is a widely used classical broad-spectrum anticancer drug. The major mechanism of DOX-mediated anticancer activity at clinically relevant concentrations is believed to be via DNA ...double-strand breaks due to topoisomerase IIα. However, other mechanisms by which DOX causes cytotoxicity have been proposed, including formaldehyde-dependent virtual interstrand cross-linking (ICL) formation. In this study, a method was established whereby cytotoxicity caused by virtual ICL derived from DOX is turned on and off using a cell culture system. Using this strategy, DOX-mediated cytotoxicity in Fanconi anemia group gene (
)/breast cancer susceptibility gene (
)-deficient cells increased up to 70-fold compared to that in cells proficient in DNA repair pathways by increasing intracellular formaldehyde (FA) concentration. This approach also demonstrated that cytotoxicity introduced by DOX-mediated FA-dependent virtual ICL is completely independent of the toxicity induced by topoisomerase II inhibition at the cellular level. The potential of dual-targeting by DOX treatment was verified using an acid-specific FA donor. Overall, anticancer therapy targeting tumors deficient in the FANC/BRCA pathway may be possible by minimizing DOX-induced toxicity in normal cells.
Covalent binding between proteins and a DNA strand produces DNA-protein crosslinks (DPC). DPC are one of the most deleterious types of DNA damage, leading to the blockage of DNA replication and ...transcription. Both DNA lesions and endogenous products with carbonyl functional groups can produce DPC in genomic DNA under normal physiological conditions. For example, formaldehyde, the most abundant endogenous human carcinogen, and apurinic/apyrimidinic (AP) sites, the most common type of endogenous DNA lesions, has been shown to crosslink proteins and/or DNA through their carbonyl functional groups. Unfortunately, compared to other types of DNA damage, DPC have been less studied and understood. However, a recent advancement has allowed researchers to determine accurate yields of various DNA lesions including formaldehyde-derived DPC with high sensitivity and specificity, paving the way for new developments in this field of research. Here, we review the current literature and remaining unanswered questions on DPC formation by endogenous formaldehyde and various aldehydic 2-deoxyribose lesions.
We review long-term changes in “zombie firms” in Japan over this half-century using listed firm data with a framework in which the concept of “zombie firms” includes possible efficient bailouts. The ...first wave of zombie firms occurred during the period of main banks (hereinafter MBs). MBs were able to actively choose which firms would receive bailouts at the time. However, commonly held beliefs about MBs’ monitoring power and the special role of corporate groups and long-term credit banks for bailouts are not supported. In the largest wave of the lost decade, we find the zombie firm problem in the manufacturing sector was just as serious as the non-manufacturing in terms of firm count. Moreover, the pathological phenomena such as unwilling concentration of loans to MBs were also rather typical in the manufacturing. Soft budget constraints have continued in the manufacturing even after the resolution of banks’ non-performing loans since the bubble burst came to an end, leading to the manufacturing-centered third wave of zombie firms following the Global Financial Crisis.
The Japanese economy experienced prolonged recessions during the 1990s. Previous studies suggest that evergreen lending to troubled firms known as ‘zombie firms’ distorted market discipline in terms ...of stabilising the economy and caused significant delays in its recovery. However, the eventual bankruptcy of zombies was rare. The purpose of this study is to investigate why zombie firms recovered in Japan. We first extend the method of Caballero et al. (2008) and identify zombies from among the listed firms. Subsequently, we investigate the nature of corporate restructuring that was effective in reviving zombie firms. Our multinomial logistic regressions suggest that reducing the employee strength of zombie firms and selling its fixed assets were beneficial in facilitating their recovery. However, corporate restructuring without accounting transparency or by discouraging incentives for managers was ineffective. In addition, corporate restructuring lacked effectiveness in the absence of favourable macroeconomic environment as well as substantial external financial support.
Activated carbon (AC)-containing porous cellulose beads (ACPBs) with a three-dimensionally interconnected porous structure and high impact strength were prepared in a single step from cellulose ...acetate and AC via a non-solvent-induced phase separation process at room temperature. The adsorption behavior of the ACPBs was evaluated using toluidine blue (TB) dye as a model adsorbate. The effects of initial dye concentration and contact time on the adsorption kinetics and isotherms of ACPBs were studied. The adsorption of TB by the ACPBs followed pseudo-second-order kinetics and could be expressed by the Langmuir adsorption isotherm model. ACPB adsorbed 119.1 mg/g of TB at an initial TB concentration of 101.0 mg/L and the Langmuir equation predicted that the maximum adsorption capacity of ACPBs for TB was 123.5 mg/g. ACPBs could retain original shape and around 85% of their adsorption capacity after three times recycle. Furthermore, ACPBs efficiently removed malodorous gases from gas mixtures, indicating potential for environmental applications including toxic dye and gas elimination.
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•Activated carbon and a porous cellulose matrix were combined to form an adsorbent.•The adsorbent showed a maximum toluidine blue dye removal capacity of 123.5 mg/g.•The kinetics and equilibrium of dye adsorption by the adsorbent are assessed.•The adsorbent exhibited efficient removal of malodorous gases from gas mixtures.
In 2011, while investigating fundamental groups of wild spaces, K.Eda
7
showed that the fundamental group of the Hawaiian earring (the Hawaiian earring group, in short)
has the property that for ...any homomorphism h from it to a free product A*B, there exists a natural number N such that
is contained in a conjugate subgroup to A or B. In the present article, we prove a corresponding property for certain HNN extensions and amalgamated free products. This allows us to show that some one-relator groups, including Baumslag-Solitar groups, are n-slender.
Although graphitic materials were thought to be hydrophobic, recent experimental results based on contact angle measurements show that the hydrophobicity of graphitic surfaces stems from airborne ...contamination of hydrocarbons. This leads us to question whether a pristine graphitic surface is indeed hydrophobic. To investigate the water wettability of graphitic surfaces, we use molecular dynamics simulations of water molecules on the surface of a single graphene layer at room temperature. The results indicate that a water droplet spreads over the entire surface and that a double-layer structure of water molecules forms on the surface, which means that wetting of graphitic surfaces is possible, but only by two layers of water molecules. No further water layers can cohere to the double-layer structure, but the formation of three-dimensional clusters of liquid water is confirmed. The surface of the double-layer structure acts as a hydrophobic surface. Such peculiar behavior of water molecules can be reasonably explained by the formation of hydrogen bonds: The hydrogen bonds of the interfacial water molecules form between the first two layers and also within each layer. This hydrogen-bond network is confined within the double layer, which means that no “dangling hydrogen bonds” appear on the surface of the double-layer structure. This formation of hydrogen bonds stabilizes the double-layer structure and makes its surface hydrophobic. Thus, the numerical simulations indicate that a graphene surface is perfectly wettable on the atomic scale and becomes hydrophobic once it is covered by this double layer of water molecules.
Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and ...autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
Objective In an extremely aging society, it is beneficial to reconsider the value of medical treatment for extremely elderly patients. We therefore focused on the efficacy of statin therapy in ...extremely elderly patients. This study investigated the efficacy of statins for secondary prevention in patients over 75 years old. Methods This prospective multicenter registry included 1,676 consecutive extremely elderly patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). The patients were followed up clinically for up to three years or until the occurrence of major adverse cardiac events (MACEs), defined as a composite of all-cause death and non-fatal myocardial infarction. Using propensity score methodology to eliminate selection bias, in a 1:1 matching ratio, we selected 466 pairs of patients for the analysis. Results During the median follow-up period of 25 months, MACEs occurred in 176 patients. The Kaplan-Meier analysis showed that statin treatment correlated with a lower probability of initial MACE occurrences within 30 days compared with no statin treatment (log-rank test, p<0.001). According to a landmark analysis at day 30, statin treatment still showed consistent effectiveness for reducing MACE occurrence during the follow up period (p=0.04). A multivariable Cox hazard analysis showed that statin therapy significantly reduced MACE occurrence (hazard ratio 0.55 0.40-0.75, p<0.001). In the stratification analysis, statin therapy was especially beneficial in patients without symptomatic heart failure. Conclusion Statins were effective in preventing MACEs in extremely elderly patients after PCI.
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