Multiple Chemical Groups Research Articles

Cyclic dipeptide-based small molecules modulate zinc-mediated liquid-liquid phase separation of tau.

Liquid-liquid phase separation (LLPS) is a complex physicochemical phenomenon mediated by multivalent transient weak interactions among macromolecules like polymers, proteins, and nucleic acids. It has implications in cellular physiology and disease conditions like cancer and neurodegenerative disorders. Many proteins associated with neurodegenerative disorders like RNA binding protein FUS (FUsed in Sarcoma), alpha-synuclein (α-Syn), TAR DNA binding protein 43 (TDP-43), and tau are shown to undergo LLPS. Recently, the tau protein responsible for Alzheimer's disease (AD) and other tauopathies is shown to phase separate into condensates in vitro and in vivo. The diverse noncovalent interactions among the biomolecules dictate the complex LLPS phenomenon. There are limited chemical tools to modulate protein LLPS which has therapeutic potential for neurodegenerative disorders. We have rationally designed cyclic dipeptide (CDP)-based small-molecule modulators (SMMs) by integrating multiple chemical groups that offer diverse chemical interactions to modulate tau LLPS. Among them, compound 1c effectively inhibits and dissolves Zn-mediated tau LLPS condensates. The SMM also inhibits tau condensate-to-fibril transition (tau aggregation through LLPS). This approach of designing SMMs of LLPS establishes a novel platform that has potential implication for the development of therapeutics for neurodegenerative disorders.

Demographic differences in chemical mixture exposure and associated determinants among Swedish adolescents

Background and aim: Few population-based studies of adolescents have investigated the relation between socio-demographic factors and the wider chemical exposome. Adolescents are likely going through a sensitive developmental window were negative exposure-induced health effects can manifest into adulthood. We aim to identify associations of social demographic factors with the chemical exposome of Swedish adolescents as well as to identify demographic groups more at risk of higher exposure to specific substances. Methods: Using the Riksmaten Adolescents 2016-17 cohort (RMU) we analysed several social-demographic factors: gender, participant/maternal (P/M) birth country income level, parental education levels, and geographic location (longitude/latitude), and their relation to blood/serum/urine concentrations of a large range of toxic substances (N=64) across multiple chemical groups (heavy metals, chlorinated pesticides, PCBs, BFRs, PFASs, phthalates, phenols, pesticides, PAHs). Association analysis was conducted using ordinal regression models due to its robustness to handle highly skewed data. Results: P/M birth country was the most frequent determinant of toxic substance concentrations, being significantly associated with concentrations of 45 substances, followed by gender (N=41), and longitude (N=37). P/M birth country also showed the largest fold-differences in concentrations, with subjects born in high-income countries having several-fold higher estimated adjusted mean (EAM) concentrations of PCBs, BFRs and PFASs than those born in low-income countries. In contrast, adolescents born in low-income countries had higher EAM levels of heavy metals, chlorinated pesticides, and phthalates. Substances belonging to the same chemical group tended to have the same determinants. Interesting north to south or west to east gradients of substance concentrations were identified in Sweden, suggesting geographical inequalities of exposure. Conclusions: P/M birth country is an important confounder and should be included in future toxicology population-based studies. Exposure associations with latitude/longitude should be further investigated. Keywords: Adolescents, RMU, ordinal regression, exposome, metals, PCB, BFR, PFAS, pesticides, phthalates, phenols, epidemiology, birth country income

Link between Polycyclic Aromatic Hydrocarbon Size and Aqueous Alteration in Carbonaceous Chondrites Revealed by Laser Mass Spectrometry

The organic inventories of carbonaceous chondrites (CCs) provide insights into the physicochemical environments involved in the Solar System’s formation and the postaccretionary evolution of meteorite parent bodies. Studying changes in these inventories across samples that have experienced varying degrees of aqueous/hydrothermal alteration untangles one aspect of such complex records. Here, the polycyclic aromatic hydrocarbon (PAH) and heterocyclic aromatic compound (HAC) contents of 15 CCs representing CI1, CM1, CM2, C2u, C3u, and CO3 classes were probed with two-step laser mass spectrometry (L2MS) and subjected to a comparative principal component analysis (PCA), a multivariate analysis method. PAHs with mass-to-charge ratios (m/z) of 128 to >300 were detected, with large PAHs (4–7 rings) dominating the spectra of the most aqueously altered samples like Ivuna (CI1) and NWA 12328 (CM1), while a larger relative fraction of smaller PAHs (3–4 rings) was observed in less altered samples like Chwichiya 002 (C3.00u). The same trend was observed across CM2 samples with varying degrees of aqueous alteration with the exception of Jbilet Winselwan (CM2.3-2.5), which has experienced impact shock. Alkylated homologues of C14H10 and C16H10 were detected in all samples, with the latter showing a stronger correlation with aqueous alteration. Additionally, oxygen-containing PAHs and thiophenes were detected. These experiments demonstrate that aqueous alteration induces aromatic condensation in CCs of multiple chemical groups, and many of the 4–7-ring PAHs (>215 m/z) in CCs may be products of aqueous alteration. Thus, PAH size distributions are an additional parameter to consider when evaluating a meteorite’s alteration history.

A simplified index to quantify the irritation/corrosion potential of chemicals – Part II: Eye

Eye irritation is a key human health endpoint assessed by in vitro and in vivo methods. One of the commonly used scoring methods to quantify the eye irritation potential of chemicals is the Modified Maximum Average Score (MMAS). It is dependent on the eye irritation effects (e.g. corneal opacity) originally proposed by Draize and then partially adopted by the OECD TG 405. These scores are not always fully reported in regulatory dossiers and lead to several drawbacks, 1) the difficulty to translate MMAS into a classification within the existing EU CLP/UN GHS criteria, 2) the absence of corrosion (serious eye damage), and 3) the dependency on input parameters which are usually not required under the OECD TGs (e.g. eye surface area). This study determined if classification can be driven by a maximum of two observed effects thereby simplifying the scoring calculation. The Simplified Irritation Index (SIIEYE), based only on corneal opacity and conjunctival redness, was developed using validated studies representing multiple chemical groups. A correlation was observed between the MMAS and the SIIEYE allowing harmonisation of the classification for the existing data. This index proved to be useful in the development of in silico model.

A simplified index to quantify the irritation/corrosion potential of chemicals – Part I: Skin

Skin irritation is a key human health endpoint assessed by in vitro and in vivo methods. The OECD TG 404 guideline (in vivo) is based on erythema and oedema translated semi-quantitatively into Draize scores, providing hazard statements for substance classification following EUCLP/UNGHS criteria. Draize scores require quantitation from subjective in vivo observations, to obtain a scoring index, the Primary Irritation Index (PII). However, it is not recognised under REACH due to translating difficulties, notably the cut-off limit for classification and non-inclusion of corrosive effects. The aim of this study was to determine if classification can be driven by just one of the observed effects, erythema only, to create a Simplified Irritation Index (SIISKIN). This simplifies the scoring calculation and reduces subjectivity. A quantitative approach with cut-off limits is thus proposed for classification. Substances can be classified as non-irritant, potentially irritant, irritant, or corrosive. The Simplifed Irritation Index (SIISKIN) is based on validated studies, representing multiple chemical groups. A significant correlation between SIISKIN and the harmonised classification was observed, and a proportionate relationship between the SIISKIN and the corresponding PII. The index proved to be useful in the development of an in silico model.

Assessment of Grouped Weighted Quantile Sum Regression for Modeling Chemical Mixtures and Cancer Risk.

Individuals are exposed to a large number of diverse environmental chemicals simultaneously and the evaluation of multiple chemical exposures is important for identifying cancer risk factors. The measurement of a large number of chemicals (the exposome) in epidemiologic studies is allowing for a more comprehensive assessment of cancer risk factors than was done in earlier studies that focused on only a few chemicals. Empirical evidence from epidemiologic studies shows that chemicals from different chemical classes have different magnitudes and directions of association with cancers. Given increasing data availability, there is a need for the development and assessment of statistical methods to model environmental cancer risk that considers a large number of diverse chemicals with different effects for different chemical classes. The method of grouped weighted quantile sum (GWQS) regression allows for multiple groups of chemicals to be considered in the model such that different magnitudes and directions of associations are possible for each group of chemicals. In this paper, we assessed the ability of GWQS regression to estimate exposure effects for multiple chemical groups and correctly identify important chemicals in each group using a simulation study. We compared the performance of GWQS regression with WQS regression, the least absolute shrinkage and selection operator (lasso), and the group lasso in estimating exposure effects and identifying important chemicals. The simulation study results demonstrate that GWQS is an effective method for modeling exposure to multiple groups of chemicals and compares favorably with other methods used in mixture analysis. As an application, we used GWQS regression in the California Childhood Leukemia Study (CCLS), a population-based case-control study of childhood leukemia in California to estimate exposure effects for many chemical classes while also adjusting for demographic factors. The CCLS analysis found evidence of a positive association between exposure to the herbicide dacthal and an increased risk of childhood leukemia.

Fungicide Resistance in Powdery Mildew Fungi.

Powdery mildew fungi (Erysiphales) are among the most common and important plant fungal pathogens. These fungi are obligate biotrophic parasites that attack nearly 10,000 species of angiosperms, including major crops, such as cereals and grapes. Although cultural and biological practices may reduce the risk of infection by powdery mildew, they do not provide sufficient protection. Therefore, in practice, chemical control, including the use of fungicides from multiple chemical groups, is the most effective tool for managing powdery mildew. Unfortunately, the risk of resistance development is high because typical spray programs include multiple applications per season. In addition, some of the most economically destructive species of powdery mildew fungi are considered to be high-risk pathogens and are able to develop resistance to several chemical classes within a few years. This situation has decreased the efficacy of the major fungicide classes, such as sterol demethylation inhibitors, quinone outside inhibitors and succinate dehydrogenase inhibitors, that are employed against powdery mildews. In this review, we present cases of reduction in sensitivity, development of resistance and failure of control by fungicides that have been or are being used to manage powdery mildew. In addition, the molecular mechanisms underlying resistance to fungicides are also outlined. Finally, a number of recommendations are provided to decrease the probability of resistance development when fungicides are employed.

Impacts of surface chemistry of functional carbon nanodots on the plant growth

Functional carbon nanodots (FCNs) with multiple chemical groups have great impact on the growth regulation of plants. To understand the role of the chemical groups, FCNs were reduced from the raw material by pyrolysis method and hydrolysis method. The chemical structure of these materials were characterized by using TGA, TEM, FT-IR, XPS, Raman and elementary analysis. The raw and reduced FCNs were used as plants growth regulators in culture medium of Arabidopsis thaliana. Our results indicate there is a strong correlation between the physiological responses of plants and the surface chemistries (especially carboxyl group and ester group) of the nanomaterials. The quantum-sized FCNs with multiple carboxyl groups and ester groups show better aqueous dispersity and can induce various positive physiological responses in Arabidopsis thaliana seedlings compared with the FCNs decorated without carboxyl and ester as well as aggregated FCNs. The raw FCNs present higher promotion capacity in plants biomass and roots length, and the quantum-sized FCNs are easier to be absorbed by plants and generate more positive effects on plants.

Mussel-inspired polydopamine-directed crystal growth of core-shell n-Al@PDA@CuO metastable intermixed composites

Over past few years, there has been increased interest in the development of metastable intermixed composites (MICs). As typical high energetic materials, MICs find important applications in aerospace and pyrotechnics. Newly developed methods based on the bioinspired surface modification enables advanced MICs with improved stability, higher energy content, and tunable performances. In this paper, the dopamine has been used to coat nano-sized Al (n-Al), forming a polydopamine (PDA) interfacial binding layer by in-situ polymerization. This interfacial binding layer makes it possible to prevent n-Al from further oxidation, and more importantly, functionalized n-Al with multiple chemical groups. Multiple oxidants could be synthesized on the coated n-Al surface under the direction of PDA on the heterogeneous nucleation and growth of crystals, affording exclusively the core-shell MICs. Typically, core-shell n-Al@PDA@CuO MICs have been fabricated. In comparison to the traditional n-Al/CuO MICs, the resulted n-Al@PDA@CuO showed an improved initial reaction temperature (528.4 °C), enhanced energy release (2934.8 J g−1) and lower combustion temperature (1606 °C). The infrared thermograph results also reveal that the n-Al@PDA@CuO has higher combustion efficiency since the n-Al core and CuO shell are better contacted at a nanoscale.

The Importance of Selecting Appropriate Rotation and Tank-Mix Partners for Novel SDHIs to Enhance Botrytis Fruit Rot Control in Strawberry.

Botrytis fruit rot (BFR), caused by the necrotrophic fungus Botrytis cinerea, is the most important disease of strawberry and is mainly controlled by applications of fungicides from multiple chemical groups. To develop more effective and sustainable BFR management programs, field trials were conducted to evaluate the efficacy of fluopyram and penthiopyrad, two newly registered succinate dehydrogenase inhibitors (SDHIs), rotated or tank mixed with the multisites thiram and captan or the single-sites fludioxonil and fenhexamid. The treatments were applied at two different strawberry fields during the 2013-14 and 2014-15 seasons. Overall, tank mixtures of fluopyram and penthiopyrad increased yield and reduced BFR better than rotations with the same fungicides. The multisite thiram tank mixed with fluopyram reduced BFR incidence by 63 to 86% versus 56 to 84% when the two fungicides were rotated. Thiram tank mixed with penthiopyrad reduced BFR incidence by 55 to 72% versus 42 to 66% when rotated. Captan rotated or tank mixed with fluopyram had a positive effect on yield and BFR incidence, whereas the combination of captan with penthiopyrad had negative impacts. Similarly, the single-site fenhexamid had significant positive impacts when rotated or tank mixed with fluopyram but resulted in poor BFR control when combined with penthiopyrad. The rotation of fludioxonil with both SDHIs had a significant positive effect, although its combination with fluopyram was more effective. The multirotation consisting of both SDHIs and different multi- and single-site fungicides did not provide a greater efficacy than the dual rotation or tank-mixture programs. Our findings suggest more scrutiny is needed when recommending tank-mixture or rotation partners for new fungicides to ensure compatibility and enhanced BFR management. Future recommendations should emphasize the importance of such selections at an early stage for delaying fungicide resistance development and extending the lifespan of at-risk fungicides.

A High-Throughput Method (ASE-GC/MS/MS/MRM) for Quantification of Multiple Hydrocarbon Compounds in Marine Environmental Samples

AbstractA high-throughput method was applied in small and complex environmental samples for targeting multiple organic fractions (polar, nonpolar). The analytical method consists of a single-step lipid extraction and purification procedure (accelerated solvent extraction [ASE] system) coupled with a single-run step using gas chromatography with tandem mass spectrometry, operated in multiple reaction monitoring mode (GC/MS/MS/MRM). Successful application of this method is summarized for multiple chemical groups (aliphatics, terpanes, steranes, triaromatic steroids, polycyclic aromatic hydrocarbons, and oxidation products).

Susceptibility of Australian Myzus persicae (Hemiptera: Aphididae) to Three Recently Registered Insecticides: Spirotetramat, Cyantraniliprole, and Sulfoxaflor

The green peach aphid, Myzus persicae (Sulzer), is a significant agricultural pest that has developed resistance to a large number of insecticides globally. Within Australia, resistance has previously been confirmed for multiple chemical groups, including pyrethroids, carbamates, organophosphates, and neonicotinoids. In this study, we use leaf-dip and topical bioassays to investigate susceptibility and potential cross-resistance of 12 field-collected populations of Australian M. persicae to three recently registered insecticides: sulfoxaflor, spirotetramat, and cyantraniliprole. Despite all 12 populations carrying known resistance mechanisms to carbamates, organophosphates, and pyrethroids, and two populations also exhibiting low-level metabolic resistance to neonicotinoids, we found little evidence of variation in susceptibility to sulfoxafor, spirotetramat, or cyantraniliprole. This provides further evidence that cross-resistance to spirotetramat, cyantraniliprole, and sulfoxaflor in M. persicae is not conferred by the commonly occurring resistance mechanisms MACE, super-kdr, amplification of the E4 esterase gene, or enhanced expression and copy number of the P450 gene, CYP6CY3. Importantly, this study also established toxicity baseline data that will be important for future monitoring of insecticide responses of M. persicae from both broadacre and horticultural crops.

Discovery of metabolic resistance to neonicotinoids in green peach aphids (Myzus persicae) in Australia.

Myzus persicae is a serious pest that attacks a broad range of agricultural crops. This species has developed chemical resistance to many insecticides globally, and within Australia resistance to multiple chemical groups has been identified. Resistance to neonicotinoid insecticides has been discovered in several countries, but has not previously been confirmed in Australia. We use biomolecular assays and bioassays on field-collected populations to investigate neonicotinoid resistance in M. persicae within Australia. Several geographically and genetically distinct populations showed evidence for resistance in bioassays. Genetic markers identified that the mechanism of neonicotinoid resistance in Australia is metabolic resistance through the enhanced expression of a cytochrome P450 gene, CYP6CY3. M. persicae populations in parts of Australia are now resistant to four different insecticide chemical groups, raising concerns about the long-term management of this pest. While higher copy numbers of CYP6CY3 were seen in all resistant populations, the number of gene copies was not strongly correlated with the level of resistance as determined by LD50 values generated through bioassays. This finding sheds further light on the complexity of the P450 genes in regulating neonicotinoid resistance. © 2016 Society of Chemical Industry.

Uses of NHANES Biomarker Data for Chemical Risk Assessment: Trends, Challenges, and Opportunities.

BackgroundEach year, the U.S. NHANES measures hundreds of chemical biomarkers in samples from thousands of study participants. These biomarker measurements are used to establish population reference ranges, track exposure trends, identify population subsets with elevated exposures, and prioritize research needs. There is now interest in further utilizing the NHANES data to inform chemical risk assessments.ObjectivesThis article highlights a) the extent to which U.S. NHANES chemical biomarker data have been evaluated, b) groups of chemicals that have been studied, c) data analysis approaches and challenges, and d) opportunities for using these data to inform risk assessments.MethodsA literature search (1999–2013) was performed to identify publications in which U.S. NHANES data were reported. Manual curation identified only the subset of publications that clearly utilized chemical biomarker data. This subset was evaluated for chemical groupings, data analysis approaches, and overall trends.ResultsA small percentage of the sampled NHANES-related publications reported on chemical biomarkers (8% yearly average). Of 11 chemical groups, metals/metalloids were most frequently evaluated (49%), followed by pesticides (9%) and environmental phenols (7%). Studies of multiple chemical groups were also common (8%). Publications linking chemical biomarkers to health metrics have increased dramatically in recent years. New studies are addressing challenges related to NHANES data interpretation in health risk contexts.ConclusionsThis article demonstrates growing use of NHANES chemical biomarker data in studies that can impact risk assessments. Best practices for analysis and interpretation must be defined and adopted to allow the full potential of NHANES to be realized.CitationSobus JR, DeWoskin RS, Tan YM, Pleil JD, Phillips MB, George BJ, Christensen K, Schreinemachers DM, Williams MA, Cohen Hubal EA, Edwards SW. 2015. Uses of NHANES biomarker data for chemical risk assessment: trends, challenges, and opportunities. Environ Health Perspect 123:919–927; http://dx.doi.org/10.1289/ehp.1409177

Evaluating the accuracy of density functional theory for calculating 1H and 13C NMR chemical shifts in drug molecules

The accuracy of different DFT methodologies for calculating 1H and 13C NMR chemical shifts in (R)-ispinesib, a complex drug molecule with multiple chemical groups and one stereocentre, has been evaluated. The accuracy of 6 basis sets and 16 different XC functionals was tested. In addition, we present a detailed study on the role of geometry optimisation (in gas and solution phase using a chloroform polarisable continuum model) on the accuracy of the calculated NMR spectra. NMR calculations using the double-ζ basis sets DGDZVP and 6-31++G(d,p) were found to be more accurate (and computationally more efficient) than those using larger triple-ζ basis sets. The O3LYP/DGDZVP methodology in solution phase using a geometry optimised at the same level of theory was found to be the most accurate method with mean absolute errors (MAEs) for 1H and 13C chemical shifts of 0.174ppm and 3.972ppm, respectively. Irrespective of the choice of XC or basis set used, complete geometry optimisation in either gas or solvent phase was found to be essential for attaining the highest accuracy in both 1H and 13C calculated chemical shifts. Finally, the role of molecular conformation was examined by calculating the Boltzmann-weighted 1H and 13C chemical shifts. Overall, we demonstrate that DFT shows exceptional promise for use in calculating the NMR chemical shifts in complex drug molecules. In the future, DFT calculations of NMR parameters are set to play an increasingly important role in drug discovery and chemical optimisation.

Total and cardiovascular mortality rates in relation to discharges from toxics release inventory sites in the United States

BackgroundThis study analyzed Toxics Release Inventory (TRI) discharges in association with covariate-adjusted total and cardiovascular mortality rates for males and females in US counties. MethodsAverage annual county-level reported releases from TRI facilities measured in pounds per square mile which were calculated for the years1990–1999, and tested for associations with age-adjusted mortality rates for 2006–2010. Chemicals were grouped into four categories: 1) carcinogens, 2) metals, 3) hazardous air pollutants, and 4) chemicals in the Comprehensive Environmental Response, Compensation and Liability Act. For each of these chemical groups the reported total, water, and air emissions were measured. Age-adjusted mortality rates were found separately for males and females from the Centers for Disease Control and Prevention for total and cardiovascular disease. Covariates included rates of smoking, obesity, high school and college education, race/ethnicity, poverty, unemployment, percent without health insurance, and urban–rural setting. Data were analyzed using multiple linear regression models. ResultsGreater average annual TRI releases in 1990–1999 in all four chemical categories were significantly associated with higher mortality rates in 2006–2010 for both total and cardiovascular mortality, and for both males and females, adjusted for covariates. Associations were stronger for air releases than for water releases. ConclusionsThis study provides the first evidence that greater amounts of TRI releases are related to higher population mortality rates for cardiovascular disease. In addition, the study showed that adverse TRI effects were broadly present for both males and females for multiple chemical groups. Further progress is needed to reduce the use and release of harmful chemicals from TRI facilities in the United States.

Evolution of an amino acid based prodrug approach: stay tuned.

Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P-X-C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance.

New Approaches to the Characterization of Obsidian from the Mediterranean Island Sources: Interpreting Chronological Change in Neolithic Sardinia and Corsica

ABSTRACTGeochemical fingerprinting of obsidian sources was first applied in the Mediterranean region nearly four decades ago. Since then, a number of analytical methods (e.g. INAA, XRF, SEM/Microprobe, ICP-MS) have proven successful in distinguishing the Mediterranean island sources of Giali, Lipari, Melos, Palmarola, Pantelleria, and Sardinia. Moreover, recent geoarchaeological surveys of the central Mediterranean sources have resulted in the more precise location and documentation of each obsidian flow or outcrop, and multiple chemical groups have been identified on at least three of the islands. The ability to specifically attribute artifacts to one of at least five obsidian flows in the Monte Arci region of Sardinia, for example, has enabled the study of specific patterns of source exploitation and the trade mechanisms which resulted in the distribution of obsidian hundreds of kilometers away during the Neolithic period (ca. 6000-3000 BC).Results are presented here from the chemical analysis of 186 artifacts from several sites in Sardinia and Corsica as part of the largest and most comprehensive study of obsidian sources and trade in the Mediterranean. Analyses of large numbers of artifacts demonstrate the differential use of island subsources, which may be attributed to factors such as access (e.g. topography, distance from coast), size and frequency of nodules, and mechanical and visual properties. The patterns of source exploitation revealed by this study specifically support a down-the-line model of obsidian trade during the neolithic period. In addition, the spatial and chronological patterns of obsidian distribution may be used to address such issues as the colonization of the islands; the introduction of neolithic economies; and the increasing social complexity of neolithic and bronze age societies in the central Mediterranean.