•The newly devised PAMMS method couples accelerator mass spectrometry with LC-ESI-MS (84).•PAMMS is high-throughput and collects AMS, UV, and molecular MS data in a single run (85).•Characterization ...was performed by detecting radiolabeled amino acids and metabolites (85).
Accelerator mass spectrometry (AMS) is the method of choice for quantitation of low amounts of 14C-labeled biomolecules. Despite exquisite sensitivity, an important limitation of AMS is its inability to provide structural information about the analyte. This limitation is not critical when the labeled compounds are well-characterized prior to AMS analysis. However, analyte identity is important in other experiments where, for example, a compound is metabolized and the structures of its metabolites are not known. We previously described a moving wire interface that enables direct AMS measurement of liquid sample in the form of discrete drops or HPLC eluent without the need for individual fraction collection, termed liquid sample-AMS (LS-AMS). We now report the coupling of LS-AMS with a molecular mass spectrometer, providing parallel accelerator and molecular mass spectrometry (PAMMS) detection of analytes separated by liquid chromatography. The repeatability of the method was examined by performing repeated injections of 14C-labeled tryptophan, and relative standard deviations of the 14C peak areas were ≤10.57% after applying a normalization factor based on a standard. Five 14C-labeled amino acids were separated and detected to provide simultaneous quantitative AMS and structural MS data, and AMS results were compared with solid sample-AMS (SS-AMS) data using Bland-Altman plots. To demonstrate the utility of the workflow, yeast cells were grown in a medium with 14C-labeled tryptophan. The cell extracts were analyzed by PAMMS, and 14C was detected in tryptophan and its metabolite kynurenine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A cavity ring-down spectroscopy (CRDS) instrument was developed using mature, robust hardware for the measurement of carbon-14 in biological studies. The system was characterized using carbon-14 ...elevated glucose samples and returned a linear response up to 387 times contemporary carbon-14 concentrations. Carbon-14 free and contemporary carbon-14 samples with varying carbon-13 concentrations were used to assess the method detection limit of approximately one-third contemporary carbon-14 levels. Sources of inaccuracies are presented and discussed, and the capability to measure carbon-14 in biological samples is demonstrated by comparing pharmacokinetics from carbon-14 dosed guinea pigs analyzed by both CRDS and accelerator mass spectrometry. The CRDS approach presented affords easy access to powerful carbon-14 tracer techniques that can characterize complex biochemical systems.
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IJS, KILJ, NUK, PNG, UL, UM
Abstract
Impregnating military uniforms and outdoor clothing with the insecticide permethrin is an approach to reduce exposure to insect borne diseases and to repel pests and disease vectors such as ...mosquitos and sandflies, but the practice exposes wearers to prolonged dermal exposure to the pesticide. Key metabolite(s) from a low dose dermal exposure of permethrin were identified using accelerator mass spectrometry. Metabolite standards were synthesized and a high performance liquide chromatography (HPLC) elution protocol to separate individual metabolites in urine was developed. Six human subjects were exposed dermally on the forearm to 25 mg of permethrin containing 1.0 µCi of 14C for 8 h. Blood, saliva and urine samples were taken for 7d. Absorption/elimination rates and metabolite concentrations varied by individual. Average absorption was 0.2% of the dose. Serum concentrations rose until 12–24 h postdermal application then rapidly declined reaching predose levels by 72 h. Maximum saliva excretion occurred 6 h postdosing. The maximum urinary excretion rate occurred during 12–24 h; average elimination half-life was 56 h. 3-Phenoxybenzyl alcohol glucuronide was the most abundant metabolite identified when analyzing elution fractions, but most of the radioactivity was in still more polar fractions suggesting extensive degradative metabolism and for which there were no standards. Analyses of archived urine samples with the ultra performance liquid chromatography-accelerator mass spectrometry-mass spectrometry (UPLC-AMS-MS) system isolated a distinct polar metabolite but it was much diminished from the previous analyses a decade earlier.
Human-induced climate change significantly alters the spatiotemporal characteristics of climate zones, which drives agricultural land use and ecosystem change. However, the detectability of shifting ...climate zones and the rate and time of the changes has yet to be adequately addressed at the regional-to-local scale. We mapped and analyzed changes to temperature and precipitation across Kenya during the past four decades, and linked those changes to shifts in the geographic distribution and arrangement of climate zones at regional scales. We observed an approximate 1 °C increase in average annual temperature over the 40-year period. A total of 76,346 km
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shifted from cooler to hotter zones, while 1298 km
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shifted from hotter to cooler zones. Tropical climate regions expanded from 91 to 93%, with over 13,000 km
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shifting from alpine and temperate to tropical regions. Average annual precipitation demonstrated little or no trend, but substantial spatial changes were observed. A total of 136,129 km
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shifted from wetter to drier zones, while 23,317 km
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shifted from drier to wetter zones. Arid climate regions expanded from 72 to 81%, a roughly 50,000 km
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shift from humid and semi-humid-to-semi-arid to arid regions. Overall, there was a 207,557 km
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shift in temperature and precipitation zones. As the climate zones predominately shift toward hotter and drier conditions, climatic diversity will decline, and in turn, ecosystem diversity and the ecosystem goods and services to society will decline. The changes also have broader global implications in terms of their contribution to global drylands as well as influencing earth system cycles. Overall, such information can better inform the Kenyan National Climate Change Response Strategy and be used to reach the UN Sustainable Development Goals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding ...pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol.
This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines.
A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7–14 d before biopsy, with the last dose 14C-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively.
14C-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total 14C-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake.
Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate. This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Barriers in access to pediatric surgical care are common in low- and middle-income countries (LMICs), but also exist in high-income countries, particularly in urban and rural areas.
This article ...describes “Disparities in Access to Care”—held within the Social Injustice Symposium at the 2020 American Pediatric Surgical Association (APSA) Annual Meeting.
This symposium outlined disparities in access to care, illustrated by examples from pediatric trauma and neonatal surgery in U.S. urban, U.S. rural, and non-U.S. global locations (LMICs). Geographic and financial challenges were common to families from the rural U.S. and LMICs. In contrast, families in U.S. urban settings generally do not face geographic barriers, but are often economically and racially diverse and many face complex societal factors leading to poor outcomes. Systemic processes must be changed to improve pediatric surgical health outcomes.
A comprehensive health system with an equal emphasis on supportive care and surgery is required in all settings. Global collaboration and partnerships can provide an avenue for advocacy and strategic innovation to improve quality of care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Indigenous community land tenure in many locations worldwide is shifting towards individually parcelized and privatized systems. Among the drivers of this shifting land tenure are distant ...political‐economic forces and commodity markets, from local to global. Accompanying the observed land tenure changes are shifts in livelihoods, away from subsistence‐based and toward market‐oriented activities. These changes can ultimately impact land use, land cover, and biodiversity conservation. We investigated a global‐to‐local causal pathway, from agriculture, livestock, and forestry production for distant markets, extending through shifting land tenure and livelihoods, to impacts on forest cover within ejidos (a type of community landholding) across Yucatán, México, where Maya people are the primary land managers. To reveal this causal pathway, we conducted exploratory data analysis, using ordinary least squares regression, mapped variables, and variographic analyses to assess spatial patterns and correlations. We further explored relationships among variables using spatially explicit simultaneous autoregressive models. We found that commodity production for distant markets is strongly related to parcelized ejido lands, which in turn are often deforested. Conversely, community‐managed lands, which traditionally involve subsistence‐based agroforestry, are much more likely to be densely forested. Overall, we conclude that recent deforestation of ejido lands across the State is, at least partly, the result of shifting land tenure and livelihoods due to the increasing presence of commodity markets. Moreover, we conclude that community‐managed lands and associated subsistence livelihoods can attenuate deforestation and potentially advance forest and biodiversity conservation across México and elsewhere.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Lawrence Livermore National Laboratory – Center for Accelerator Mass Spectrometry (LLNL/CAMS) 1 MV AMS system was converted from a biomedical AMS instrument to a natural abundance 14C ...spectrometer. The system is equipped with a gas-accepting hybrid ion source capable of measuring both solid (graphite) and gaseous (CO2) samples. Here we describe a series of experiments intended to establish and optimize 14CO2 measurement capabilities at natural abundance levels. A maximum instantaneous ionization efficiency of 8 % was achieved with 3 % CO2 in helium at a flow rate of approximately 220 µL/min (3.5 µg C/min). For modern materials (e.g., OX I) we measured an average of 240 ± 50 14C counts/µg C, equivalent to a total system efficiency of approximately 3 %. Experimental CO2 samples with F14C values ranging from 0.20 to 1.05 measured as both graphite and directly as CO2 gas produced equivalent values with an average offset of < 2σ.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Climate and agricultural land-use change has increased the likelihood of infectious disease emergence and transmissions, but these drivers are often examined separately as combined effects ...are ignored. Further, seldom are the influence of climate and agricultural land use on emerging infectious diseases examined in a spatially explicit way at regional scales. Our objective in this study was to spatially examine the climate, agriculture, and socio-demographic factors related to agro-pastoralism, and especially the combined effects of these variables that can influence the prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels across northern Kenya. Our research questions focused on: (1) How MERS-CoV in dromedary camels has varied across geographic regions of northern Kenya, and (2) what climate, agriculture, and socio-demographic factors of agro-pastoralism were spatially related to the geographic variation of MERS-CoV cases in dromedary camels. To answer our questions, we analyzed the spatial distribution of historical cases based on serological evidence of MERS-CoV at the county level and applied spatial statistical analysis to examine the spatial relationships of the MERS-CoV cases between 2016 and 2018 to climate, agriculture, and socio-demographic factors of agro-pastoralism. Regional differences in MERS-CoV cases were spatially correlated with both social and environmental factors, and particularly ethno-religious camel practices, which highlight the complexity in the distribution of MERS-CoV in dromedary camels across Kenya.
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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
Dibenzodef,pchrysene (DBC) is an environmental polycyclic aromatic hydrocarbon (PAH) that causes tumors in mice and has been classified as a probable human carcinogen by the International Agency for ...Research on Cancer. Animal toxicity studies often utilize higher doses than are found in relevant human exposures. Additionally, like many PAHs, DBC requires metabolic bioactivation to form the ultimate toxicant, and species differences in DBC and DBC metabolite metabolism have been observed. To understand the implications of dose and species differences, a physiologically based pharmacokinetic model (PBPK) for DBC and major metabolites was developed in mice and humans. Metabolism parameters used in the model were obtained from experimental in vitro metabolism assays using mice and human hepatic microsomes. PBPK model simulations were evaluated against mice dosed with 15 mg/kg DBC by oral gavage and human volunteers orally microdosed with 29 ng of DBC. DBC and its primary metabolite DBC-11,12-diol were measured in blood of mice and humans, while in urine, the majority of DBC metabolites were obeserved as conjugated DBC-11,12-diol, conjugated DBC tetrols, and unconjugated DBC tetrols. The PBPK model was able to predict the time course concentrations of DBC, DBC-11,12-diol, and other DBC metabolites in blood and urine of human volunteers and mice with reasonable accuracy. Agreement between model simulations and measured pharmacokinetic data in mice and human studies demonstrate the success and versatility of our model for interspecies extrapolation and applicability for different doses. Furthermore, our simulations show that internal dose metrics used for risk assessment do not necessarily scale allometrically, and that PBPK modeling provides a reliable approach to appropriately account for interspecies differences in metabolism and physiology.
•We developed a physiologically based pharmacokinetic model (PBPK) for dibenzodef,pchrysene (DBC) in mice and humans.•PBPK model accurately predicts concentrations of DBC and metabolites in blood and urine of mice and humans.•Model simulations suggest DBC dose metrics used for risk assessments do not scale allometrically between mice and humans.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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