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This article is linked to Malham et al papers. To view these articles, visit https://doi.org/10.1111/apt.17994 and https://doi.org/10.1111/apt.18026.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying ...anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.
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IJS, KILJ, NUK, PNG, UL, UM
Northern lakes are a source of greenhouse gases to the atmosphere and contribute substantially to the global carbon budget. However, the sources of methane (CH₄) to northern lakes are poorly ...constrained limiting our ability to the assess impacts of future Arctic change. Here we present measurements of the natural groundwater tracer, radon, and CH₄ in a shallow lake on the Yukon-Kuskokwim Delta, AK and quantify groundwater discharge rates and fluxes of groundwater-derived CH₄. We found that groundwater was significantly enriched (2000%) in radon and CH₄ relative to lake water. Using a mass balance approach, we calculated average groundwater fluxes of 1.2 ± 0.6 and 4.3 ± 2.0 cm day-1, respectively as conservative and upper limit estimates. Groundwater CH 4 fluxes were 7—24 mmol m⁻² -day⁻¹ and significantly exceeded diffusive air–water CH₄ fluxes (1.3–2.3 mmol m⁻² day⁻¹) from the lake to the atmosphere, suggesting that groundwater is an important source of CH 4 to Arctic lakes and may drive observed CH₄ emissions. Isotopic signatures of CH₄ were depleted in groundwaters, consistent with microbial production. Higher methane concentrations in groundwater compared to other high latitude lakes were likely the source of the comparatively higher CH₄ diffusive fluxes, as compared to those reported previously in high latitude lakes. These findings indicate that deltaic lakes across warmer permafrost regions may act as important hotspots for CH₄ release across Arctic landscapes.
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BFBNIB, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NMLJ, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Actinium-227 is a powerful tool to study vertical mixing in the ocean, and was more recently proposed as a tracer of hydrothermal plumes. However, because 227Ac activities are especially low in the ...ocean, relatively few studies have been conducted to date, and none has been done on the large scale, as is reported in the present study. Here, we report a section of dissolved 227Ac in the North Atlantic Ocean between Portugal-Greenland-Canada based on nine full-depth profiles obtained in the framework of the international GEOTRACES program (GA01 section - GEOVIDE cruise, May–July 2014). The simultaneous determination of 231Pa, the parent nuclide of 227Ac, along the section allowed us to report a section of excess 227Ac activities (227Acex).
Actinium-227 activities were especially low along the section (<0.4 dpm m−3) compared to other ocean basins. In most cases, 227Ac activities reached secular equilibrium with 231Pa in the water column 500 m above the seafloor. Secular equilibrium is considered reached after ∼five half-lives of the daughter. Secular equilibrium therefore suggests no external input over the last ∼100 years. The highest 227Ac activities were often found close to the seafloor, indicating that 227Ac diffuses out of the sediments. However, two different patterns question the traditional one-dimensional vertical mixing model typically applied to 227Ac released by deep-sea sediments: first, significant 227Acex were found in the upper 500 m of the water column at several stations located near the Iberian margin. In the upper 500 m, the high 227Acex activities could indicate lateral advection of waters that interacted with the margins. Second, mid-water peaks of 227Acex were occasionally observed along the transect. At station 44 in the Irminger Basin, a peak of 227Acex activity at 2500 m that was co-located with high dissolved Fe concentrations could be interpreted as the signature of a hydrothermal plume. Near the seafloor, we often observed bottom nepheloid layers and we cannot exclude that these layers impact the 227Ac distributions.
•Actinium-227 activities were especially low along the section (<0.4 dpm m-3) compared to other ocean basins.•In most cases, 227Ac activities reached secular equilibrium with 231Pa (suggesting no external input over the last ∼100 years) in the water column 500 m above the seafloor.•The highest 227Ac activities were often found close to the seafloor, indicating that 227Ac diffuses out of the sediments.•In the upper 500 m, high 227Acex activities could indicate lateral advection of waters that interacted with the margins.•Near the seafloor, we often observed bottom nepheloid layers and we cannot exclude that these layers impact the 227Ac distributions, since manganese oxides were shown to be present in these layers and may thus scavenge 227Ac among other radionuclides.+
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
River discharge has an important influence on the chemistry of Arctic shelf seas and surface waters. In this study, we examined the changes in nutrient, trace metal, dissolved organic matter, ...dissolved inorganic carbon, alkalinity, and radium isotope distributions across the Mackenzie River delta and estuary in June 2016, and estimated trace element and isotopes fluxes from the Mackenzie River to the Western Arctic Ocean. While inorganic nutrient, dissolved inorganic carbon, alkalinity, trace metal, and radium levels remained fairly constant through the delta, dissolved organic matter concentrations were 2–3.5 times higher at the mouth of the river, reflecting inputs from the delta. In the estuarine mixing zone, radium isotope ratios indicated that both desorption from suspended sediments and benthic inputs affected solute concentrations. Similarly, most of the measured trace metals (Ba, Co, Cu, Mn, Ni) exhibited non-conservative addition in the freshwater-saltwater transition zone, while Pb was removed and U was mixed conservatively. Inorganic nutrients were affected by both addition and removal processes in the estuary. Dissolved inorganic carbon and alkalinity exhibited net removal, likely due to a combination of biological uptake, gas exchange, CaCO₃ precipitation, and surface ion exchange processes. Approximately 45% and 60% of dissolved organic carbon and nitrogen, respectively, were removed rapidly at low salinities, in contrast with previous studies suggesting conservative mixing through Arctic estuaries. This study highlights the need to take deltaic and estuarine processes into account when determining the flux of riverine solutes to the coastal ocean.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a ...patient’s life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn’s disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.
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•Reanalysis of GWAS data identifies a SNP associated with outcome in Crohn’s disease•This SNP modulates inflammatory responses in monocytes via a FOXO3-driven pathway•The mild disease-associated allele reduces TNFα and increases IL-10 production•Prognosis in RA and malaria (also TNFα-related diseases) is also linked to this SNP
An analysis of GWAS data of patients with Crohn’s disease distinguishes SNPs associated with disease risk from those associated with outcome. Functional studies indicate that a noncoding SNP associated with FOXO3A influences a cytokine inflammatory pathway that impacts outcome, not only in Crohn’s but also other diseases such as rheumatoid arthritis and malaria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We establish, under both theoretical conditions and empirical application, the separate roles of (1) market asset class exposure through index funds; (2) style factor exposure, such as exposure to ...value, momentum, and quality, which have traditionally delivered higher and differentiated returns than market index exposure; and (3) pure alpha-seeking sources of return in excess of index and factor returns. A new methodology determines optimal allocations of index, factors, and alpha-seeking funds by imposing priors on the information ratios of factors and alpha strategies. We expect in many cases, prior standard deviations for factor funds will be smaller than those for alpha strategies, whereas prior means for alpha strategies may be larger than those for factor funds.
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BFBNIB, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
Inflammatory bowel disease IBD is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used ...to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. The etiology involves a ...combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), and autophagy plays a key role in relieving ER stress and restoring homeostasis. This review summarizes the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options.
We report detailed sections of radium-226 (226Ra, T1/2= 1602 years) activities and barium (Ba) concentrations determined in the North Atlantic (Portugal–Greenland–Canada) in the framework of the ...international GEOTRACES program (GA01 section – GEOVIDE project, May–July 2014). Dissolved 226Ra and Ba are strongly correlated along the section, a pattern that may reflect their similar chemical behavior. Because 226Ra and Ba have been widely used as tracers of water masses and ocean mixing, we investigated their behavior more thoroughly in this crucial region for thermohaline circulation, taking advantage of the contrasting biogeochemical patterns existing along the GA01 section. We used an optimum multiparameter (OMP) analysis to distinguish the relative importance of physical transport (water mass mixing) from nonconservative processes (sedimentary, river or hydrothermal inputs, uptake by particles and dissolved–particulate dynamics) on the 226Ra and Ba distributions in the North Atlantic. Results show that the measured 226Ra and Ba concentrations can be explained by conservative mixing for 58 and 65 % of the samples, respectively, notably at intermediate depth, away from the ocean interfaces. 226Ra and Ba can thus be considered conservative tracers of water mass transport in the ocean interior on the space scales considered here, namely, on the order of a few thousand kilometers. However, regions in which226Ra and Ba displayed nonconservative behavior and in some cases decoupled behaviors were also identified, mostly at the ocean boundaries (seafloor, continental margins and surface waters). Elevated 226Ra and Ba concentrations found in deepwater in the West European Basin suggest that lower Northeast Atlantic Deep Water (NEADWl) accumulates 226Ra and Ba from sediment diffusion and/or particle dissolution during transport. In the upper 1500 m of the West European Basin, deficiencies in 226Ra and Ba are likely explained by their incorporation in planktonic calcareous and siliceous shells, or in barite (BaSO4) by substitution or adsorption mechanisms. Finally, because Ba and 226Ra display different source terms (mostly deep-sea sediments for 226Ra and rivers for Ba), strong decoupling between 226Ra and Ba were observed at the land–ocean boundaries. This is especially true in the shallow stations near the coasts of Greenland and Newfoundland where high 226Ra / Ba ratios at depth reflect the diffusion of 226Ra from sediment and low 226Ra / Ba ratios in the upper water column reflect the input of Ba associated with meteoric waters.
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