Global fine-scale changes in ambient NO2 during COVID-19 lockdowns.

Nitrogen dioxide (NO2) is an important contributor to air pollution and can adversely affect human health1-9. A decrease in NO2 concentrations has been reported as a result of lockdown measures to reduce the spread of COVID-1910-20. Questions remain, however, regarding the relationship of satellite-derived atmospheric column NO2 data with health-relevant ambient ground-level concentrations, and the representativeness of limited ground-based monitoring data for global assessment. Here we derive spatially resolved, global ground-level NO2 concentrations from NO2 column densities observed by the TROPOMI satellite instrument at sufficiently fine resolution (approximately one kilometre) to allow assessment of individual cities during COVID-19 lockdowns in 2020 compared to 2019. We apply these estimates to quantify NO2 changes in more than 200 cities, including 65 cities without available ground monitoring, largely in lower-income regions. Mean country-level population-weighted NO2 concentrations are 29% ± 3% lower in countries with strict lockdown conditions than in those without. Relative to long-term trends, NO2 decreases during COVID-19 lockdowns exceed recent Ozone Monitoring Instrument (OMI)-derived year-to-year decreases from emission controls, comparable to 15 ± 4 years of reductions globally. Our case studies indicate that the sensitivity of NO2 to lockdowns varies by country and emissions sector, demonstrating the critical need for spatially resolved observational information provided by these satellite-derived surface concentration estimates.

Reconstructing Middle and Upper Paleolithic human mobility in Portuguese Estremadura through laser ablation strontium isotope analysis.

Understanding mobility and landscape use is important in reconstructing subsistence behavior, range, and group size, and it may contribute to our understanding of phenomena such as the dynamics of biological and cultural interactions between distinct populations of Upper Pleistocene humans. However, studies using traditional strontium isotope analysis are generally limited to identifying locations of childhood residence or nonlocal individuals and lack the sampling resolution to detect movement over short timescales. Here, using an optimized methodology, we present highly spatially resolved 87Sr/86Sr measurements made by laser ablation multicollector inductively coupled plasma mass spectrometry along the growth axis of the enamel of two marine isotope stage 5b, Middle Paleolithic Neanderthal teeth (Gruta da Oliveira), a Tardiglacial, Late Magdalenian human tooth (Galeria da Cisterna), and associated contemporaneous fauna from the Almonda karst system, Torres Novas, Portugal. Strontium isotope mapping of the region shows extreme variation in 87Sr/86Sr, with values ranging from 0.7080 to 0.7160 over a distance of c. 50 km, allowing short-distance (and arguably short-duration) movement to be detected. We find that the early Middle Paleolithic individuals roamed across a subsistence territory of approximately 600 km2, while the Late Magdalenian individual parsimoniously fits a pattern of limited, probably seasonal movement along the right bank of the 20-km-long Almonda River valley, between mouth and spring, exploiting a smaller territory of approximately 300 km2. We argue that the differences in territory size are due to an increase in population density during the Late Upper Paleolithic.

Bioaccumulation of mercury in Lake Michigan painted turtles (Chrysemys picta).

Mercury (Hg) contamination of aquatic environments can lead to bioaccumulation in organisms, but most previous work has focused on fish and not on semi-aquatic reptiles such as turtles that traverse both terrestrial and aquatic habitats. Here, we analyzed total Hg (THg) concentrations in 30 painted turtles (Chrysemys picta) collected from Lake Michigan (USA) coastal wetlands in 2013 to determine if (1) turtles bioaccumulated THg from the environment, (2) concentrations differed between turtle liver and muscle tissue, and (3) tissue concentrations were related to environmental concentrations (e.g., sediment THg). All individual turtles had detectable THg concentrations in both liver and muscle tissue. On average, THg concentrations were over three times higher in liver tissue compared to muscle tissue. We found a positive linear relationship between muscle THg concentrations and turtle body mass, a proxy for age, suggesting bioaccumulation in this species. Neither liver nor muscle THg concentrations followed the sediment contaminant gradient in the wetlands. Despite this, location was a strong predictor of tissue concentration in a linear model suggesting that other site-specific characteristics may be important. Overall, our results demonstrate that painted turtles accumulate mercury in liver and muscle tissues at different rates, which may be constrained by local conditions. Further research is needed to better understand the relationship between environmental mercury concentrations and body burdens in animals like turtles that traverse habitats. In addition, long-lived turtles could be incorporated into pollution monitoring programs to provide a more holistic picture of food web contamination and ecosystem health.

Leveraging a Landscape-Level Monitoring and Assessment Program for Developing Resilient Shorelines throughout the Laurentian Great Lakes.

Traditionally, ecosystem monitoring, conservation, and restoration have been conducted in a piecemeal manner at the local scale without regional landscape context. However, scientifically driven conservation and restoration decisions benefit greatly when they are based on regionally determined benchmarks and goals. Unfortunately, required data sets rarely exist for regionally important ecosystems. Because of early recognition of the extreme ecological importance of Laurentian Great Lakes coastal wetlands, and the extensive degradation that had already occurred, significant investments in coastal wetland research, protection, and restoration have been made in recent decades and continue today. Continued and refined assessment of wetland condition and trends, and the evaluation of restoration practices are all essential to ensuring the success of these investments. To provide wetland managers and decision makers throughout the Laurentian Great Lakes basin with the optimal tools and data needed to make scientifically-based decisions, our regional team of Great Lakes wetland scientists developed standardized methods and indicators used for assessing wetland condition. From a landscape perspective, at the Laurentian Great Lakes ecosystem scale, we established a stratified random-site-selection process to monitor birds, anurans, fish, macroinvertebrates, vegetation, and physicochemical conditions of coastal wetlands in the US and Canada. Monitoring of approximately 200 wetlands per year began in 2011 as the Great Lakes Coastal Wetland Monitoring Program. In this paper, we describe the development, delivery, and expected results of this ongoing international, multi-disciplinary, multi-stakeholder, landscape-scale monitoring program as a case example of successful application of landscape conservation design.

Relative contributions of nearshore and wetland habitats to coastal food webs in the Great Lakes.

Hydrologic linkages among coastal wetland and nearshore areas allow coastal fish to move among the habitats, which has led to a variety of habitat use patterns. We determined nutritional support of coastal fishes from 12 wetland-nearshore habitat pairs using stable isotope analyses, which revealed differences among species and systems in multi-habitat use. Substantial (proportions > 0.30) nutrition often came from the habitat other than that in which fish were captured. Nearshore subsidies to coastal wetlands indicate wetlands are not exclusively exporters of energy and materials; rather, there is reciprocity in the mutual energetic support of nearshore and wetland food webs. Coastal wetland hydrogeomorphology influenced the amount of multi-habitat use by coastal fishes. Fishes from systems with relatively open interfaces between wetland and nearshore habitats exhibited less nutritional reliance on the habitat in which they were captured, and higher use of resources from the adjacent habitat. Comparisons of stable isotope analyses of nutrition with otolith analyses of occupancy indicated nutritional sources often corresponded with habitat occupancy; however, disparities among place of capture, otolith analyses, and nutritional analyses indicated differences in the types of support those analyses inform. Disparities between occupancy information and nutritional information can stem from movements for support functions other than foraging. Together, occupancy information from otolith microchemistry and nutritional information from stable isotope analyses provide complementary measures of the use of multiple habitats by mobile consumers. This work underscores the importance of protecting or restoring a diversity of coastal habitats and the hydrologic linkages among them.

An expanded fish-based index of biotic integrity for Great Lakes coastal wetlands.

Biotic indicators are useful for assessing ecosystem health because the structure of resident communities generally reflects abiotic conditions integrated over time. We used fish data collected over 5 years for 470 Great Lakes coastal wetlands to develop multi-metric indices of biotic integrity (IBI). Sampling and IBI development were stratified by vegetation type within each wetland to account for differences in physical habitat. Metrics were evaluated against numerous indices of anthropogenic disturbance derived from water quality and surrounding land-cover variables. Separate datasets were used for IBI development and testing. IBIs were composed of 10-11 metrics for each of four vegetation types (bulrush, cattail, water lily, and submersed aquatic vegetation). Scores of all IBIs correlated well with disturbance indices using the development data, and the accuracy of our IBIs was validated using the testing data. Our fish IBIs can be used to prioritize wetland protection and restoration efforts across the Great Lakes basin. The IBIs will also be useful in monitoring programs mandated by the Agreement between Canada and the United States of America on Great Lakes Water Quality, such as for assessing Beneficial Use Impairments (BUIs) in Great Lakes Areas of Concern, and in other ecosystem management programs in Canada and the USA.

Body burdens of heavy metals in Lake Michigan wetland turtles.

Tissue heavy metal concentrations in painted (Chrysemys picta) and snapping (Chelydra serpentina) turtles from Lake Michigan coastal wetlands were analyzed to determine (1) whether turtles accumulated heavy metals, (2) if tissue metal concentrations were related to environmental metal concentrations, and (3) the potential for non-lethal sampling techniques to be used for monitoring heavy metal body burdens in freshwater turtles. Muscle, liver, shell, and claw samples were collected from painted and snapping turtles and analyzed for cadmium, chromium, copper, iron, lead, magnesium, manganese, and zinc. Turtle tissues had measurable quantities of all eight metals analyzed. Statistically significant correlations between tissue metal concentrations and sediment metal concentrations were found for a subset of metals. Metals were generally found in higher concentrations in the larger snapping turtles than in painted turtles. In addition, non-lethal samples of shell and claw were found to be possible alternatives to lethal liver and muscle samples for some metals. Human consumption of snapping turtles presents potential health risks if turtles are harvested from contaminated areas. Overall, our results suggest that turtles could be a valuable component of contaminant monitoring programs for wetland ecosystems.

Physicochemical characterization of airborne particulate matter at a mainline underground railway station.

Underground railway stations are known to have elevated particulate matter (PM) loads compared to ambient air. As these particles are derived from metal-rich sources and transition metals may pose a risk to health by virtue of their ability to catalyze generation of reactive oxygen species (ROS), their potential enrichment in underground environments is a source of concern. Compared to coarse (PM10) and fine (PM2.5) particulate fractions of underground railway airborne PM, little is known about the chemistry of the ultrafine (PM0.1) fraction that may contribute significantly to particulate number and surface area concentrations. This study uses inductively coupled plasma mass spectrometry and ion chromatography to compare the elemental composition of size-fractionated underground PM with woodstove, roadwear generator, and road tunnel PM. Underground PM is notably rich in Fe, accounting for greater than 40% by mass of each fraction, and several other transition metals (Cu, Cr, Mn, and Zn) compared to PM from other sources. Importantly, ultrafine underground PM shows similar metal-rich concentrations as the coarse and fine fractions. Scanning electron microscopy revealed that a component of the coarse fraction of underground PM has a morphology indicative of generation by abrasion, absent for fine and ultrafine particulates, which may be derived from high-temperature processes. Furthermore, underground PM generated ROS in a concentration- and size-dependent manner. This study suggests that the potential health effects of exposure to the ultrafine fraction of underground PM warrant further investigation as a consequence of its greater surface area/volume ratio and high metal content.

Disparities in Air Pollutants Across Racial, Ethnic, and Poverty Groups at US Public Schools.

We investigate socioeconomic disparities in air quality at public schools in the contiguous US using high resolution estimates of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) concentrations. We find that schools with higher proportions of people of color (POC) and students eligible for the federal free or reduced lunch program, a proxy for poverty level, are associated with higher pollutant concentrations. For example, we find that the median annual NO2 concentration for White students, nationally, was 7.7 ppbv, compared to 9.2 ppbv for Black and African American students. Statewide and regional disparities in pollutant concentrations across racial, ethnic, and poverty groups are consistent with nationwide results, where elevated NO2 concentrations were associated with schools with higher proportions of POC and higher levels of poverty. Similar, though smaller, differences were found in PM2.5 across racial and ethnic groups in most states. Racial, ethnic, and economic segregation across the rural-urban divide is likely an important factor in pollution disparities at US public schools. We identify distinct regional patterns of disparities, highlighting differences between California, New York, and Florida. Finally, we highlight that disparities exist not only across urban and non-urban lines but also within urban environments.

Sediment contamination and faunal communities in two subwatersheds of Mona Lake, Michigan.

Urbanization of watersheds can impose multiple stressors on stream, wetland, and lake ecosystems. Sediment contamination, alterations to the natural hydrologic regime, and nutrient loading are examples of these stressors which often occur simultaneously. As a consequence, restoration is challenged by the multi-stressor reality of most urban watersheds. The goal of this study was to compare two watersheds in western Michigan, both with substantial urban development, but with different levels of sediment contamination resulting from historic industrial activities, to determine the effects of contamination on invertebrate and fish community structure. The study included multiple sites on both streams, two wetlands adjacent to each stream, and the embayments where each stream emptied into Mona Lake. We compared a suite of abiotic parameters including sediment contamination, sediment toxicity, and water column chemical/physical conditions as well as fish and invertebrate community structure. Sediment contaminants, including heavy metals and polycyclic aromatic hydrocarbons, were found in higher concentrations and survival of test organisms in toxicity bioassays was reduced in the more industrialized watershed. Fewer insect taxa, especially the sensitive Ephemeroptera, Plecoptera, and Trichoptera, were found in the more industrialized system. Fish taxa richness and catch per unit effort were reduced in the wetlands of the more industrialized watershed as well and both invertebrate and fish index of biotic integrity scores were also lower in the more industrialized system. Our study demonstrates that contamination due to historic industrial activities can have substantial and lasting effects on biotic communities of multiple habitat types well downstream of where the activities occurred.

The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis.

Cellular cholesterol levels alter the processing of the amyloid precursor protein (APP) to produce Abeta. Activation of liver X receptors (LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter Abeta levels in vitro and in vivo. To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist (TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 (ADAM-10) and ADAM-17, two APP alpha-secretases. We found that TIMP-3 inhibited alpha-secretase cleavage of APP and an apolipoprotein E (apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP beta-C-terminal fragment and Abeta production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and alpha-secretase cleavage and encourages endocytosis and beta-secretase cleavage. In vivo, TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease (AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of Abeta.

The Origin of Carbonate Veins Within the Sedimentary Cover and Igneous Rocks of the Cocos Ridge: Results From IODP Hole U1414A.

Carbonate veins in the igneous basement and in the lithified sedimentary cover of the Cocos Ridge at International Ocean Discovery Program (IODP) Hole 344-U1414A reveal the hydrologic system and fluid-rock interactions. IODP Hole 344-U1414A was drilled on the northern flank of the Cocos Ridge and is situated 1 km seaward from the Middle America Trench offshore Costa Rica. Isotopic and elemental compositions were analyzed to constrain the fluid source of the carbonate veins and to reveal the thermal history of Hole 344-U1414A. The formation temperatures (oxygen isotope thermometer) of the carbonate veins in the lithified sedimentary rocks range from 70 to 92 °C and in the basalt from 32 to 82 °C. 87Sr/86Sr ratios of the veins in the altered Cocos Ridge basalt range between 0.707307 and 0.708729. The higher ratios are similar to seawater strontium ratios in the Neogene. 87Sr/86Sr ratios lower 0.7084 indicate exchange of Sr with the igneous host rock. The calcite veins hosted by the sedimentary rocks are showing more primitive 87Sr/86Sr ratios <0.706396. The isotopic compositions indicate seawater, modified into a hydrothermal fluid by subsequent heating, as the main fluid source. Low-temperature alteration and the presence of a high-temperature fluid resulted in different carbonate precipitates forming up to several cm thick veins. The geochemical data combined with age data of the sedimentary rocks suggest intraplate seamount volcanism in the area between the Galapagos hot spot and the Cocos Island as an additional heating source, after the formation of the Cocos Ridge at the Galapagos hot spot.

Assessing snow extent data sets over North America to inform and improve trace gas retrievals from solar backscatter.

Accurate representation of surface reflectivity is essential to tropospheric trace gas retrievals from solar backscatter observations. Surface snow cover presents a significant challenge due to its variability and thus snow-covered scenes are often omitted from retrieval data sets; however, the high reflectance of snow is potentially advantageous for trace gas retrievals. We first examine the implications of surface snow on retrievals from the upcoming TEMPO geostationary instrument for North America. We use a radiative transfer model to examine how an increase in surface reflectivity due to snow cover changes the sensitivity of satellite retrievals to NO2 in the lower troposphere. We find that a substantial fraction (>50%) of the TEMPO field of regard can be snow covered in January, and that the average sensitivity to the tropospheric NO2 column substantially increases (doubles) when the surface is snow covered. We then evaluate seven existing satellite-derived or reanalysis snow extent products against ground station observations over North America to assess their capability of informing surface conditions for TEMPO retrievals. The Interactive Multisensor Snow and Ice Mapping System (IMS) had the best agreement with ground observations (accuracy of 93%, precision of 87%, recall of 83%). Multiangle Implementation of Atmospheric Correction (MAIAC) retrievals of MODIS-observed radiances had high precision (90% for Aqua and Terra), but underestimated the presence of snow (recall of 74% for Aqua, 75% for Terra). MAIAC generally outperforms the standard MODIS products (precision of 51%, recall of 43% for Aqua; precision of 69%, recall of 45% for Terra). The Near-real-time Ice and Snow Extent (NISE) product had good precision (83%) but missed a significant number of snow-covered pixels (recall of 45%). The Canadian Meteorological Centre (CMC) Daily Snow Depth Analysis Data set had strong performance metrics (accuracy of 91%, precision of 79%, recall of 82%). We use the F score, which balances precision and recall, to determine overall product performance (F = 85%, 82(82)%, 81%, 58%, 46(54)% for IMS, MAIAC Aqua(Terra), CMC, NISE, MODIS Aqua(Terra) respectively) for providing snow cover information for TEMPO retrievals from solar backscatter observations. We find that using IMS to identify snow cover and enable inclusion of snow-covered scenes in clear-sky conditions across North America in January can increase both the number of observations by a factor of 2.1 and the average sensitivity to the tropospheric NO2 column by a factor of 2.7.

Microbial subnetworks related to short-term diel O2 fluxes within geochemically distinct freshwater wetlands.

Oxygen (O2) concentrations often fluctuate over diel timescales within wetlands, driven by temperature, sunlight, photosynthesis and respiration. These daily fluxes have been shown to impact biogeochemical transformations (e.g. denitrification), which are mediated by the residing microbial community. However, little is known about how resident microbial communities respond to diel physical and chemical fluxes in freshwater wetland ecosystems. In this study, total microbial (bacterial and archaeal) community structure was significantly related to diel time points in just one out of four distinct freshwater wetlands sampled. This suggests that daily environmental shifts may influence wetlands differentially based upon the resident microbial community and specific physical and chemical conditions of a freshwater wetland. When exploring the microbial communities within each wetland at finer resolutions, subcommunities of taxa within two wetlands were found to correspond to fluctuating O2 levels. Microbial taxa that were found to be susceptible to fluctuating O2 levels within these subnetworks may have intimate ties to metabolism and/or diel redox cycles. This study highlights that freshwater wetland microbial communities are often stable in community structure when confronted with short-term O2 fluxes; however, specialist taxa may be sensitive to these same fluxes.

Damage mechanisms at the cement-implant interface of polished cemented femoral stems.

The occurrence of damage on polished femoral stems has been widely reported in the literature, and bone cement has been implicated in a tribocorrosive failure process. However, the mechanisms of cement-mediated damage and the impact of cement formulation on this process are not well understood. In this study, 13 Zimmer CPT polished femoral stems, and the corresponding cement specimens were retrieved at revision surgery and analyzed using high-resolution imaging techniques. Surface damage attributed to tribocorrosion was observed on all stems. Corrosion product, in the form of black flaky surface debris, was observed on the surface of cement specimens; both energy-dispersive X-ray spectroscopy and inductively coupled plasma mass spectrometry(ICP-MS) confirmed the presence of cobalt and chromium, with the ICP-MS showing much higher levels of Cr compared to Co when compared to the original stem material. Agglomerates of ZrO2 radiopacifier were also identified on the cement surface and, in some cases, showed evidence of abrasive wear; the size of these particles correlated well with elliptical pitting evident on the surfaces of the corresponding stems. This evidence supports the hypothesis that agglomerates of hard radiopacifier particles within the cement may induce a wear-dominated tribocorrosive interaction at the stem-cement interface that damages the surface of polished CoCr femoral stems. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2027-2033, 2017.

The effects on bronchial epithelial mucociliary cultures of coarse, fine, and ultrafine particulate matter from an underground railway station.

We have previously shown that underground railway particulate matter (PM) is rich in iron and other transition metals across coarse (PM10-2.5), fine (PM2.5), and quasi-ultrafine (PM0.18) fractions and is able to generate reactive oxygen species (ROS). However, there is little knowledge of whether the metal-rich nature of such particles exerts toxic effects in mucus-covered airway epithelial cell cultures or whether there is an increased risk posed by the ultrafine fraction. Monolayer and mucociliary air-liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) were exposed to size-fractionated underground railway PM (1.1-11.1 µg/cm(2)) and release of lactate dehydrogenase and IL-8 was assayed. ROS generation was measured, and the mechanism of generation studied using desferrioxamine (DFX) and N-acetylcysteine (NAC). Expression of heme oxygenase-1 (HO-1) was determined by RT-qPCR. Particle uptake was studied by transmission electron microscopy. Underground PM increased IL-8 release from PBECs, but this was diminished in mucus-secreting ALI cultures. Fine and ultrafine PM generated a greater level of ROS than coarse PM. ROS generation by ultrafine PM was ameliorated by DFX and NAC, suggesting an iron-dependent mechanism. Despite the presence of mucus, ALI cultures displayed increased HO-1 expression. Intracellular PM was observed within vesicles, mitochondria, and free in the cytosol. The results indicate that, although the mucous layer appears to confer some protection against underground PM, ALI PBECs nonetheless detect PM and mount an antioxidant response. The combination of increased ROS-generating ability of the metal-rich ultrafine fraction and ability of PM to penetrate the mucous layer merits further research.

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era.

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country's late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g(-1)), than black males (ME = 3.80 µg·g(-1)) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead.

Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia.

Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in an imatinib-resistant (MYL-R) and -sensitive (MYL) cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCß, NEK9) or decreased (Abl, Kit, JNK, ATM, Yes) abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942). MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244). Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition.

Reconstructing past seawater Mg/Ca and Sr/Ca from mid-ocean ridge flank calcium carbonate veins.

Proxies for past seawater chemistry, such as Mg/Ca and Sr/Ca ratios, provide a record of the dynamic exchanges of elements between the solid Earth, the atmosphere, and the hydrosphere and the evolving influence of life. We estimated past oceanic Mg/Ca and Sr/Ca ratios from suites of 1.6- to 170-million-year-old calcium carbonate veins that had precipitated from seawater-derived fluids in ocean ridge flank basalts. Our data indicate that before the Neogene, oceanic Mg/Ca and Sr/Ca ratios were lower than in the modern ocean. Decreased ocean spreading since the Cretaceous and the resulting slow reduction in ocean crustal hydrothermal exchange throughout the early Tertiary may explain the recent rise in these ratios.