Global quieting of high-frequency seismic noise due to COVID-19 pandemic lockdown measures.

Human activity causes vibrations that propagate into the ground as high-frequency seismic waves. Measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic caused widespread changes in human activity, leading to a months-long reduction in seismic noise of up to 50%. The 2020 seismic noise quiet period is the longest and most prominent global anthropogenic seismic noise reduction on record. Although the reduction is strongest at surface seismometers in populated areas, this seismic quiescence extends for many kilometers radially and hundreds of meters in depth. This quiet period provides an opportunity to detect subtle signals from subsurface seismic sources that would have been concealed in noisier times and to benchmark sources of anthropogenic noise. A strong correlation between seismic noise and independent measurements of human mobility suggests that seismology provides an absolute, real-time estimate of human activities.

Extensive marine-terminating ice sheets in Europe from 2.5 million years ago.

Geometries of Early Pleistocene [2.58 to 0.78 million years (Ma) ago] ice sheets in northwest Europe are poorly constrained but are required to improve our understanding of past ocean-atmosphere-cryosphere coupling. Ice sheets are believed to have changed in their response to orbital forcing, becoming, from about 1.2 Ma ago, volumetrically larger and longer-lived. We present a multiproxy data set for the North Sea, extending to over a kilometer below the present-day seafloor, which demonstrates spatially extensive glaciation of the basin from the earliest Pleistocene. Ice sheets repeatedly entered the North Sea, south of 60°N, in water depths of up to ~250 m from 2.53 Ma ago and subsequently grounded in the center of the basin, in deeper water, from 1.87 Ma ago. Despite lower global ice volumes, these ice sheets were near comparable in spatial extent to those of the Middle and Late Pleistocene but possibly thinner and moving over slippery (low basal resistance) beds.

Nutritional benefit of olive oil: the biological effects of hydroxytyrosol and its arylating quinone adducts.

Olive oil is the essential component of the Mediterranean diet, a nutritional regimen gaining ever-increasing renown for its beneficial effects on inflammation, cardiovascular disease, and cancer. A unique characteristic of olive oil is its enrichment in oleuropein, a member of the secoiridoid family, which hydrolyzes to the catechol hydroxytyrosol and functions as a hydrophilic phenolic antioxidant that is oxidized to its catechol quinone during redox cycling. Little effort has been spent on exploring the biological properties of the catechol hydroxytyrosol quinone, a strong arylating electrophile that forms Michael adducts with thiol nucleophiles in glutathione and proteins. This study compares the chemical and biological characteristics of hydroxytyrosol with those of the tocopherol family in which Michael adducts of arylating desmethyltocopherol quinones have been identified and correlated with biologic properties including cytotoxicity and induction of endoplasmic reticulum stress. It is noted that hydroxytyrosol and desmethyltocopherols share many similarities, suggesting that Michael adduct formation by an arylating quinone electrophile may contribute to the biological properties of both families, including the unique nutritional benefit of olive oil.

Studies in vitamin E: biochemistry and molecular biology of tocopherol quinones.

Tocopherols and tocotrienols, parent congeners in the vitamin E family, function as phenolic antioxidants. However, there has been little interest in their quinone electrophiles formed as a consequence of oxidation reactions, even though unique biological properties were suggested by early studies conducted immediately after the discovery of vitamin E. Oxidation of tocopherols and tocotrienols produces para- and ortho-quinones, and quinone methides, while oxidation of their carboxyethyl hydroxychroman derivatives produces quinone lactones. These quinone electrophiles are grouped in two subclasses, the nonarylating fully methylated alpha-family and the arylating desmethyl beta-, gamma-, and delta-family. Arylating quinone electrophiles form Michael adducts with thiol nucleophiles, provided by cysteinyl proteins or peptides, which can be identified and quantified by tetramethylammonium hydroxide thermochemolysis. They have striking biological properties which differ significantly from their nonarylating congeners. They are highly cytotoxic, inducing characteristic apoptotic changes in cultured cells. Cytotoxicity is intimately associated with the induction of endoplasmic reticulum stress and a consequent unfolded protein response involving the pancreatic ER kinase (PERK) signaling pathway that commits overstressed cells to apoptosis. The step-function difference between arylating and nonarylating tocopherol quinones is conceivably the basis for distinct biological properties of parent tocopherols, including the epigenetic modification of a histone thiol, the ceramide pathway, natriuresis, and the activity of COX-2, NF-kappaB, PPARgamma, and cyclin. The role of alpha-tocopherol in the origin and evolution of the western hominin diet, the so-called "Mediterranean" diet, and the prominence of alpha-tocopherol in colostrum, mother's milk, and infant nutrition are considered. Finally, the discordance introduced into the diet by arylating tocopherol quinone precursors through the wide use of vegetable oils in deep-frying is recognized.

Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress.

Quinones permeate our biotic environment, contributing to both homeostasis and cytotoxicity. All quinones generate reactive oxygen species through redox cycling, while partially substituted quinones also undergo arylation (Michael adduct formation) yielding covalent bonds with nucleophiles such as cysteinyl thiols. In contrast to reactive oxygen species, the role of arylation in quinone cytotoxicity is not well understood. We found that the arylating quinones, including unsubstituted 1,4-benzoquinone (1,4-BzQ) and partially substituted vitamin E congener gamma-tocopherol quinone (gamma-TQ), were cytotoxic, with gamma-TQ > 1,4-BzQ, whereas the fully substituted nonarylating vitamin E congener alpha-tocopherol quinone was not. In vitro, both arylating quinones formed Michael adducts with the thiol nucleophile N-acetylcysteine (NAC) at rates where 1,4-BzQ > gamma-TQ. In cultured cells, concurrent addition of NAC eliminated 1,4-BzQ caused toxicity, but preincubation was required for the same NAC detoxification effect on gamma-TQ. These data clearly established the role of arylation in quinone toxicity and revealed that arylating quinone structure affects cytotoxicity by governing detoxification through the rate of adduct formation. Furthermore, arylating quinones induced endoplasmic reticulum (ER) stress by activating the pancreatic ER kinase (PERK) signaling pathway including elF2alpha, ATF4, and C/EBP homologous protein (CHOP). Detoxification by NAC greatly attenuates CHOP induction in arylating quinone-treated cells, suggesting that ER stress is a cellular mechanism for arylating quinone cytotoxicity.

Tocopherol metabolism using thermochemolysis: chemical and biological properties of gamma-tocopherol, gamma-carboxyethyl-hydroxychroman, and their quinones.

Identification and quantitative estimation of quinone metabolites of gamma-tocopherol (gamma-T) and its derivative gamma-carboxyethyl hydroxychroman (gamma-CEHC) are complicated by their functions as arylating electrophiles. We hypothesize that their biological properties are expressed through arylating quinone electrophile addition (Michael reaction) with thiol nucleophiles in cells and tissues. Glutathione (GSH) reacted with gamma-tocopheryl quinone (gamma-TQ) to form the hydroquinone adduct, which was identified by electrospray time-of-flight MS (ESI-TOF-MS). Tetramethylammonium hydroxide (TMAH) thermochemolysis reduced and methylated quinones and cleaved and methylated thioether adducts. These relatively nonpolar derivatives were readily separated by GC and identified by MS fragmentation patterns. gamma-CEHC was synthesized and oxidized to a product identified as the quinone lactone (gamma-CEHC-QL). TMAH methylated both gamma-CEHC-QL and its GSH adduct without opening the lactone ring, and these products were separated by GC and identified by MS fragmentation patterns. gamma-CEHC-QL reacted with both the cysteinyl enzyme papain and fetal bovine serum, and TMAH thermochemolysis showed that each product mixture contained unreacted precursor and thioether adduct. Cytotoxicities of phenolic precursors, gamma-T and gamma-CEHC, and their quinones, gamma-TQ and gamma-CEHC-QL, respectively, were compared in COS1, NT2, 3T3, and N2a cell lines. Phenolic precursor gamma-T had a small effect only with NT2 and 3T3 cells while gamma-CEHC had no effect in any cell line. Arylating quinones were highly cytotoxic in all cell lines with gamma-TQ showing a significantly greater cytotoxicity than gamma-CEHC-QL. These data are consistent with our arylating electrophile hypothesis as an explanation for some biological activities of Ts through their quinone metabolites.

Electrophile tocopheryl quinones in apoptosis and mutagenesis: thermochemolysis of thiol adducts with proteins and in cells.

Electrophile tocopheryl quinones from the phenolic antioxidants gamma-tocopherol and delta-tocopherol form Michael adducts with the thiol nucleophile glutathione. These tocopheryl quinones are involved in cytotoxicity, apoptosis, and mutagenesis, and their biologic properties are associated with the depletion of intracellular thiols. We now show that both proteins and tissues treated with the electrophile gamma-tocopheryl quinone (gamma-TQ) form thiol adducts. The monoglutathion-S-yl derivative of gamma-TQ was subjected to thermochemolysis with the strong methylating base tetramethylammonium hydroxide. GC/MS showed four signature peaks and a fragmentation pattern characteristic of the thiol adduct. Similarly, pure monoglutathion-S-yl and diglutathion-S-yl derivatives of delta-TQ were subjected to thermochemolysis, and GC/MS showed characteristic fragmentation patterns for thiol adducts. The four signature peaks were identified when pure proteins with accessible thiol groups (hemoglobin and histone), FBS, and tissue culture medium and cell preparations were treated with gamma-TQ. Signature peaks in both complete medium and washed cells showed the presence of both soluble and insoluble thiol adducts. The effective or free arylating electrophile concentration in complete medium should always be evaluated in tissue culture studies. gamma-TQ is a mutagen but not a genotoxin; therefore, the histone adduct may be a previously unrecognized histone modification involved in chromatin dynamics leading to mutagenesis.

gamma-Tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release.

Recently, it was suggested the potential role of gamma-tocopheryl quinone (gamma-TQ), an oxidative metabolite of gamma-tocopherol, as a powerful chemotherapeutic agent, since it was shown that this molecule exerts powerful cytotoxic effects, induces apoptosis and escapes drug resistance in human acute lymphoblastic leukemia and promyelocytic leukemia cells. We have studied the apoptogenic potential of gamma-TQ in cultured human leukemia HL-60 and colon adenocarcinoma WiDr cells, and in murine thymoma cells growing in vivo in ascites form. The cells were treated with gamma-TQ and apoptosis was evaluated morphologically by acridine-orange staining and cytofluorimetrically by Annexin V binding assay. gamma-TQ-induced apoptosis in a dose- and time-dependent manner in all the cell types tested, although HL-60 and thymoma cells were much more sensitive than WiDr cells. In HL-60 cells apoptosis was mediated by the activation of the caspase-3 cascade. In particular, we observed a time- and dose-dependent increase in the activities of the upstream caspase-9 and caspase-8 and of the downstream caspase-3. The activation of caspase-9 preceded that of caspase-8 and its specific inhibition completely prevented apoptosis. These findings and data showing the precocious release of cytochrome c from mitochondria, a decrease in Bcl-2, and a change in mitochondrial transmembrane potential (Delta psi(m)), all suggest that the intrinsic mitochondrial pathway is primarily involved in the development of gamma-TQ-induced apoptosis. The late activation of caspase-8 and data showing the partial cleavage of pro-apoptotic protein BID suggest that the initial activation of caspase-9 may be potentiated by a feedback amplification loop involving the caspase-8/BID pathway.

Mutagenicity of tocopheryl quinones: evolutionary advantage of selective accumulation of dietary alpha-tocopherol.

We have shown that phenolic antioxidant tocopherols are oxidized to nonarylating alpha-tocopheryl quinone (alpha-TQ) and arylating gamma- and delta-TQ electrophiles. The arylating quinones stimulate apoptosis and are highly cytotoxic in mammalian cells. Some xenobiotic phenolic antioxidants are mutagens, and it has been suggested that their arylating quinone metabolites are the active agents in mutagenesis related to carcinogenesis. We found that neither alpha- nor gamma-TQ was directly genotoxic in supercoiled-to-nicked circular DNA conversions, but these agents interacted with the cytomegalovirus reporter-driven plasmid and enhanced luciferase transfection, with gamma-TQ > alpha-TQ. The Ames test, using gamma-TQ and a number of Salmonella strains, showed no evidence of bacterial mutagenesis. gamma-TQ was highly cytotoxic and alpha-TQ slightly cytotoxic in eukaryocyte AS52 cells. A guanosine phosphoribosyltransferase gene assay showed that gamma-TQ was highly mutagenic and alpha-TQ slightly mutagenic in AS52 cells. A review of the literature identified associations where a decrease in dietary gamma-tocopherol (gamma-T) diminishes and an increase in dietary gamma-T and its quinone enhances carcinogenicity. Humans and other omnivores selectively accumulate alpha-tocopherol, even though gamma-T is their principal dietary tocopherol. We suggest that this selectivity confers an evolutionary advantage by limiting tissue gamma-T, a putative precursor of the mutagen gamma-TQ.

Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells.

Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.