In this review, we summarize the multiple functions of NQO1, its established roles in redox processes and potential roles in redox control that are currently emerging. NQO1 has attracted interest due ...to its roles in cell defense and marked inducibility during cellular stress. Exogenous substrates for NQO1 include many xenobiotic quinones. Since NQO1 is highly expressed in many solid tumors, including via upregulation of Nrf2, the design of compounds activated by NQO1 and NQO1-targeted drug delivery have been active areas of research. Endogenous substrates have also been proposed and of relevance to redox stress are ubiquinone and vitamin E quinone, components of the plasma membrane redox system. Established roles for NQO1 include a superoxide reductase activity, NAD+ generation, interaction with proteins and their stabilization against proteasomal degradation, binding and regulation of mRNA translation and binding to microtubules including the mitotic spindles. We also summarize potential roles for NQO1 in regulation of glucose and insulin metabolism with relevance to diabetes and the metabolic syndrome, in Alzheimer's disease and in aging. The conformation and molecular interactions of NQO1 can be modulated by changes in the pyridine nucleotide redox balance suggesting that NQO1 may function as a redox-dependent molecular switch.
The ocean's ability to sequester carbon away from the atmosphere exerts an important control on global climate. The biological pump drives carbon storage in the deep ocean and is thought to function ...via gravitational settling of organic particles from surface waters. However, the settling flux alone is often insufficient to balance mesopelagic carbon budgets or to meet the demands of subsurface biota. Here we review additional biological and physical mechanisms that inject suspended and sinking particles to depth. We propose that these 'particle injection pumps' probably sequester as much carbon as the gravitational pump, helping to close the carbon budget and motivating further investigation into their environmental control.
The ocean's biological carbon pump transfers carbon from the surface ocean to the deep ocean by several distinct pathways, including gravitational settling of organic particles, mixing and advection ...of suspended organic carbon, and active transport by vertically migrating metazoans. Carbon exported by these pathways can be sequestered as respired CO2 in the deep ocean for years to centuries. However, the contribution of each pathway to carbon export and sequestration remains highly uncertain. Here, satellite and in situ ocean biogeochemical observations are assimilated in an ensemble numerical model of the biological pump to quantify global and regional carbon export and sequestration. The ensemble mean global carbon export is 10.2 Pg C yr−1 and the total amount of carbon sequestered via the biological pump is 1,300 Pg C. The gravitational pump is responsible for 70% of the total global carbon export, 85% of which is zooplankton fecal pellets and 15% is sinking phytoplankton aggregates, while migrating zooplankton account for 10% of total export and physical mixing is responsible for the remaining 20%. These pathways have different sequestration times, with an average of 140 years for the gravitational pump, 150 years for the migrant pump, and only 50 years for the mixing pump. Regionally, the largest sequestration inventories and longest sequestration times are found in the northern high latitudes, while the shortest sequestration times are found in the subtropical gyres. These results suggest that ocean carbon storage will weaken as the oceans stratify and the subtropical gyres expand due to anthropogenic climate change.
Plain Language Summary
Tiny organisms called phytoplankton help to reduce atmospheric CO2 levels by absorbing large amounts of carbon in the surface ocean during photosynthesis. Various biological and physical processes, or pathways, then work together to transfer some of this carbon to the deep ocean where it can be stored for potentially hundreds of years. In this study, we examined these pathways using computer models that are consistent with data from satellite‐based sensors and ocean observations. Our model shows that the most important pathways for carbon storage are transport by sinking particles and swimming zooplankton, while transport by ocean currents is the least important pathway. The North Atlantic and North Pacific oceans have the greatest carbon storage power, while the subtropical oceans have the least. These results imply that ocean carbon storage may decrease in the future, because subtropical regions will expand in a warming climate.
Key Points
Carbon export and sequestration pathways are quantified with a data‐assimilated global ocean ecosystem and biogeochemistry model
Gravitational and migrant pumps are the most important biological pump pathways for carbon storage and mixing pump is the least important
Longest sequestration times in the subarctic and shortest in the subtropics, implying a future weakening of biological carbon sequestration
NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in ...an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction. Other documented roles of NQO1 include its ability to function as a component of the plasma membrane redox system generating antioxidant forms of ubiquinone and vitamin E and at high levels, as a direct superoxide reductase. Emerging roles of NQO1 include its function as an efficient intracellular generator of NAD
+
for enzymes including PARP and sirtuins which has gained particular attention with respect to metabolic syndrome. NQO1 interacts with a growing list of proteins, including intrinsically disordered proteins, protecting them from 20S proteasomal degradation. The interactions of NQO1 also extend to mRNA. Recent identification of NQO1 as a mRNA binding protein have been investigated in more detail using SERPIN1A1 (which encodes the serine protease inhibitor α-1-antitrypsin) as a target mRNA and indicate a role of NQO1 in control of translation of α-1-antitrypsin, an important modulator of COPD and obesity related metabolic syndrome. NQO1 undergoes structural changes and alterations in its ability to bind other proteins as a result of the cellular reduced/oxidized pyridine nucleotide ratio. This suggests NQO1 may act as a cellular redox switch potentially altering its interactions with other proteins and mRNA as a result of the prevailing redox environment.
Despite growing attention to the role of social context in determining political participation, the effect of the structure of social networks remains little examined. This article introduces a model ...of interdependent decision making within social networks, in which individuals have heterogeneous motivations to participate, and networks are defined via a qualitative typology mirroring common empirical contexts. The analysis finds that some metrics for networks' influence-size, the prevalence of weak ties, the presence of elites-have a more complex interaction with network structure and individual motivations than has been previously acknowledged. For example, in some contexts additional network ties decrease participation. This presents the potential for selection bias in empirical studies. The model offers a fuller characterization of the role of network structure and predicts expected levels of participation across network types and distributions of motivations as a function of network size, weak and strong ties, and elite influence.
Reversible covalent chemistry (RCC) adds another dimension to commonly used sample preparation techniques like solid-phase extraction (SPE), solid-phase microextraction (SPME), molecular imprinted ...polymers (MIPs) or immuno-affinity cleanup (IAC): chemical selectivity. By selecting analytes according to their covalent reactivity, sample complexity can be reduced significantly, resulting in enhanced analytical performance for low-abundance target analytes. This review gives a comprehensive overview of the applications of RCC in analytical sample preparation. The major reactions covered include reversible boronic ester formation, thiol-disulfide exchange and reversible hydrazone formation, targeting analyte groups like diols (sugars, glycoproteins and glycopeptides, catechols), thiols (cysteinyl-proteins and cysteinyl-peptides) and carbonyls (carbonylated proteins, mycotoxins). Their applications range from low abundance proteomics to reversible protein/peptide labelling to antibody chromatography to quantitative and qualitative food analysis. In discussing the potential of RCC, a special focus is on the conditions and restrictions of the utilized reaction chemistry.
To evaluate the maximum-tolerated dose (MTD), safety, and efficacy of elotuzumab in combination with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma (MM).
Elotuzumab ...(2.5, 5.0, 10, or 20 mg/kg intravenously IV) and bortezomib (1.3 mg/m(2) IV) were administered on days 1 and 11 and days 1, 4, 8, and 11, respectively, in 21-day cycles by using a 3 + 3 dose-escalation design. Patients with stable disease or better after four cycles could continue treatment until disease progression or unexpected toxicity. Responses were assessed during each cycle by using European Group for Blood and Marrow Transplantation (EBMT) criteria.
Twenty-eight patients with a median of two prior therapies were enrolled; three patients each received 2.5, 5.0, and 10 mg/kg of elotuzumab and 19 received 20 mg/kg (six during dose escalation and 13 during an expansion phase). No dose-limiting toxicities were observed during cycle 1 of the dose-escalation phase, and the MTD was not reached up to the maximum planned dose of 20 mg/kg. The most frequent grade 3 to 4 adverse events (AEs) were lymphopenia (25%) and fatigue (14%). Two elotuzumab-related serious AEs of chest pain and gastroenteritis occurred in one patient. An objective response (a partial response or better) was observed in 13 (48%) of 27 evaluable patients and in two (67%) of three patients refractory to bortezomib. Median time to progression was 9.46 months.
The combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/refractory MM.
Chromophoric dissolved organic matter (CDOM) is a ubiquitous component of the open ocean dissolved matter pool, and is important owing to its influence on the optical properties of the water column, ...its role in photochemistry and photobiology, and its utility as a tracer of deep ocean biogeochemical processes and circulation. In this review, we discuss the global distribution and dynamics of CDOM in the ocean, concentrating on developments in the past 10 years and restricting our discussion to open ocean and deep ocean (below the main thermocline) environments. CDOM has been demonstrated to exert primary control on ocean color by its absorption of light energy, which matches or exceeds that of phytoplankton pigments in most cases. This has important implications for assessing the ocean biosphere via ocean color-based remote sensing and the evaluation of ocean photochemical and photobiological processes. The general distribution of CDOM in the global ocean is controlled by a balance between production (primarily microbial remineralization of organic matter) and photolysis, with vertical ventilation circulation playing an important role in transporting CDOM to and from intermediate water masses. Significant decadal-scale fluctuations in the abundance of global surface ocean CDOM have been observed using remote sensing, indicating a potentially important role for CDOM in ocean-climate connections through its impact on photochemistry and photobiology.
The ocean's biological carbon pump (BCP) affects the Earth's climate by sequestering CO2 away from the atmosphere for decades to millennia. One primary control on the amount of carbon sequestered by ...the biological pump is air‐sea CO2 disequilibrium, which is controlled by the rate of air‐sea CO2 exchange and the residence time of CO2 in surface waters. Here, we use a data‐assimilated model of the soft tissue BCP to quantify carbon sequestration inventories and time scales from remineralization in the water column to equilibration with the atmosphere. We find that air‐sea CO2 disequilibrium enhances the global biogenic carbon inventory by ∼35% and its sequestration time by ∼70 years compared to identical calculations made assuming instantaneous air‐sea CO2 exchange. Locally, the greatest enhancement occurs in the subpolar Southern Ocean, where air‐sea disequilibrium increases sequestration times by up to 600 years and the biogenic dissolved inorganic carbon inventory by >100% in the upper ocean. Contrastingly, in deep‐water formation regions of the North Atlantic and Antarctic margins, where biological production creates undersaturated surface waters which are subducted before fully equilibrating with the atmosphere, air‐sea CO2 disequilibrium decreases the depth‐integrated sequestration inventory by up to ∼150%. The global enhancement of carbon sequestration by air‐sea disequilibrium is particularly important for carbon respired in deep waters that upwell in the Southern Ocean. These results highlight the importance of accounting for air‐sea CO2 disequilibrium when evaluating carbon sequestration by the biological pump and for assessing the efficacy of ocean‐based CO2 removal methods.
Plain Language Summary
In the surface ocean, tiny organisms called phytoplankton convert CO2 to organic matter, a portion of which is transferred to the deep ocean where it then releases CO2. This regenerated CO2 can be stored for hundreds to thousands of years before it is brought back to the surface ocean and reenters the atmosphere. Through this transfer of carbon from the surface to the depth, the “biological carbon pump” helps the ocean take up more CO2 from the atmosphere. In this study, we used computer models to determine how the rate of CO2 exchange between the ocean and the atmosphere impacts the amount of time CO2 can be stored in the ocean. Since the air‐sea exchange of CO2 is slow, the amount of carbon stored by the biological pump is about 35% greater than it would be if the exchange happened instantly. The slow air‐sea exchange rate also increases the length of time this carbon will be stored in the ocean. It is important to take this effect into account when assessing methods for deliberately storing CO2 in the ocean.
Key Points
Impact of air‐sea CO2 disequilibrium on biogenic carbon inventories and sequestration times is quantified using an ocean biogeochemical model
Air‐sea CO2 disequilibrium enhances global sequestration time by ∼70 years and biogenic dissolved inorganic carbon inventory by ∼35%
Disequilibrium effect is the strongest in the Southern Ocean and North Atlantic and weakest in the Pacific Ocean
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