Highlights d Discovery of JH-RE-06, a compound disrupting REV1-POL zmediated mutagenic TLS d JH-RE-06 induces REV1 dimerization to block the REV1-REV7 interaction d JH-RE-06 sensitizes tumors to cisplatin and reduces mutagenesis in vitro d JH-RE-06 suppresses tumor progression in mice and prolongs animal survival

Abstract. We report a 40-year history of SF6 atmospheric mole fractions measured at the Advanced Global Atmospheric Gases Experiment (AGAGE) monitoring sites, combined with archived air samples, to determine emission estimates from 1978 to 2018. Previously we reported a global emission rate of 7.3±0.6 Gg yr−1 in 2008 and over the past decade emissions have continued to increase by about 24 % to 9.04±0.35 Gg yr−1 in 2018. We show that changing patterns in SF6 consumption from developed (Kyoto Protocol Annex-1) to developing countries (non-Annex-1) and the rapid global expansion of the electric power industry, mainly in Asia, have increased the demand for SF6-insulated switchgear, circuit breakers, and transformers. The large bank of SF6 sequestered in this electrical equipment provides a substantial source of emissions from maintenance, replacement, and continuous leakage. Other emissive sources of SF6 occur from the magnesium, aluminium, and electronics industries as well as more minor industrial applications. More recently, reported emissions, including those from electrical equipment and metal industries, primarily in the Annex-1 countries, have declined steadily through substitution of alternative blanketing gases and technological improvements in less emissive equipment and more efficient industrial practices. Nevertheless, there are still demands for SF6 in Annex-1 countries due to economic growth, as well as continuing emissions from older equipment and additional emissions from newly installed SF6-insulated electrical equipment, although at low emission rates. In addition, in the non-Annex-1 countries, SF6 emissions have increased due to an expansion in the growth of the electrical power, metal, and electronics industries to support their continuing development. There is an annual difference of 2.5–5 Gg yr−1 (1990–2018) between our modelled top-down emissions and the UNFCCC-reported bottom-up emissions (United Nations Framework Convention on Climate Change), which we attempt to reconcile through analysis of the potential contribution of emissions from the various industrial applications which use SF6. We also investigate regional emissions in East Asia (China, S. Korea) and western Europe and their respective contributions to the global atmospheric SF6 inventory. On an average annual basis, our estimated emissions from the whole of China are approximately 10 times greater than emissions from western Europe. In 2018, our modelled Chinese and western European emissions accounted for ∼36 % and 3.1 %, respectively, of our global SF6 emissions estimate.

Following the Montreal Protocol, emissions of ozone-depleting substances, including trichlorofluoromethane (CFC-11, CCl3F), decreased substantially since the mid-1980s, leading to initial stratospheric ozone recovery and substantial climate change mitigation 1,2 . However, CFC-11 emissions began rising again in 2013, three years after the global production phase-out 3 . Atmospheric observations from eastern Asia attributed much of the global rise to emissions from eastern China 4 . Here, we show that in 2019, emissions from eastern China returned to pre-2013 levels (5.0 ± 1.0 Gg yr -1

Divergent thinking (DT) tests are often used for creativity assessment. They differ from many other tests in that they are open-ended. A great deal of research has examined the influence of test instructions on the number and nature of responses to DT tests. Most instructions explicitly emphasize quantity (e.g., "give as many ideas as you can"). Others target additional features, such as creativity, originality, or idea quality. Do such alternative explicit instructions make any difference? The present meta-analysis examined studies that compared the explicit instructions emphasizing creativity, originality, and quality to quantity instructions. Using a 3-level multilevel approach, analyses with all 204 effect sizes from 31 studies indicated that creativity and quality instructions increased performance on DT when added to quantity instructions (gs ϭ .243 and .271, respectively), more than quantity instructions alone. However, the originality instructions did not change DT performance (g ϭ Ϫ.159). Thus, explicit instructions may increase or decrease DT performance, depending on which alternative explicit instructions are used and how they are presented. Practical implications of the findings are discussed, as are limitations of this research.

In this study, as a bioisosteric alternative scaffold of the antiviral aryl diketoacids (ADKs), we used 5-hydroxychromone on which two arylmethyloxy substituents were installed. The 5-hydroxychromones (5b-5g) thus prepared showed anti-HCV activity and, depending on the aromatic substituents on the 2-arylmethyloxy moiety, some of the derivatives (5b-5f) were also active against SCV. In addition, unlike the ADKs which showed selective inhibition against the helicase activity of the SCV NTPase/helicase, the 5-hydroxychromones (5b-5f) were active against both NTPase and helicase activities of the target enzyme. Among those, 3-iodobenzyloxy-substituted derivative 5e showed the most potent activity against HCV (EC(50) = 4 μM) as well as SCV (IC(50) = 4 μM for ATPase activity, 11 μM for helicase activity) and this might be used as a platform structure for future development of the multi-target or broad-spectrum antivirals.

Clostridium difficile toxin A causes acute colitis associated with intense infiltration of neutrophils. Although C. difficile toxin A is known to induce nuclear factor-kappaB-mediated chemokine expression in intestinal epithelial cells, little is known about its effect on the regulation of activator protein-1 (AP-1) by mitogen-activated protein kinase (MAPK). In the present study, we investigated whether the MAPK and AP-1 signaling pathway is involved in interleukin (IL)-8 expression and enteric inflammation in response to stimulation with toxin A. Toxin A activated MAPK and AP-1 composed of c-Jun/c-Fos heterodimers in primary intestinal epithelial cells and HT-29 cell lines. Transfection with mutant genes for Ras, c-Jun, p38, or c-Jun N-terminal kinase (JNK) significantly inhibited C. difficile toxin A-induced activation of AP-1 and expression of IL-8 in HT-29 cell lines. Furthermore, the p38 inhibitor SB203580 attenuated toxin A-induced inflammation in vivo in the mouse ileum, evidenced by a significant decrease in neutrophil infiltration, villous destruction, and mucosal congestion. Our results suggest that the Ras/MAPK cascade acts as the upstream signaling for AP-1 activation and IL-8 expression in toxin A-stimulated intestinal epithelial cells and may be involved in the development of enteritis after infection with toxin A-producing C. difficile.

In order to increase stability of quercetin, its metabolically and chemically susceptible hydroxyl groups 7-OH and 3-OH respectively were transiently blocked with a pivaloxymethyl (POM) promoiety to provide two novel quercetin conjugates [7-O-POM-Q, 3-O-POM-Q]. In the absence of stabilizer (ascorbic acid), the synthesized conjugates showed significantly increased stability in cell culture media [t(½) = 4 h, 52 h] compared with quercetin (t(½) < 30 min) and quercetin prodrug 1 (t(½) = 0.8 h). In addition, the quercetin conjugate 2 underwent efficient cellular uptake and intracellular levels of its hydrolysis product, quercetin, were maintained up to 12 h. Stability and intracellular accumulation of were demonstrated by its stabilizer-independent cytostatic effect and induction of apoptotic cell death. Even though was more stable than, it failed to penetrate cell membranes. However, the remarkable stability of warrants further investigation of quercetin conjugates with various promoieties at the 3-OH position.

Objective. Interleukin-10 (IL-10) is a pleiotropic immunoregulatory cytokine with a chondroprotective effect that is elevated in cartilage and synovium in patients with osteoarthritis. However, the role of IL-10 during endochondral bone formation and its mechanism of action have not been elucidated.Methods. IL-10 -/-mice and IL-10-treated tibial organ cultures were used to study loss and gain of IL-10 functions, respectively, during endochondral bone formation. Primary chondrocytes from the long bones of mouse embryos were cultured with and without IL-10. To assess the role of IL-10 in chondrogenic differentiation, we conducted mesenchymal cell micromass cultures.Results The main pathologic feature of osteoarthritis (OA) is gradual loss of cartilage from exposure to repetitive loading. The initial response of chondrocytes to external mechanical loading is adaptation; that is, they become metabolically active and proliferative (1). However, repetitive stress induces hypertrophic differentiation and, eventually, chondrocyte apoptosis. During this process, the balance between anabolic and catabolic signaling pathways in which SOX9 and RUNX-2, respectively, function as major regulatory transcription factors is critical in determining the fate of chondrocytes (2,3). Several cytokines can affect the expression of SOX9 and RUNX-2 via complex autocrine and paracrine loops and, as a consequence, have an effect on the progression of OA (4,5).The physiologic and pathologic roles of the main catabolic cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣ (TNF␣), have been well established in chondrocyte biology (4).