Application of clusterization algorithms for analysis of semivolatile pollutants in Arkhangelsk snow.

The best way to understand the environmental status of a certain region involves thorough non-target analysis, which will result in a list of pollutants under concern. Arkhangelsk (64° 32' N 40° 32' E, pop. ~ 344,000) is the largest city in the world to the north of the 60th parallel. Several industrial enterprises and the "cold finger" effect represent the major sources of air contamination in the city. Analysis of snow with comprehensive two-dimensional gas chromatography-high-resolution mass spectrometry allows detecting and quantifying the most hazardous volatile and semivolatile anthropogenic pollutants and estimating long-term air pollution. Target analysis, suspect screening, and non-target analysis of snow samples collected from ten sites within the city revealed the presence of several hundreds of organic compounds including 18 species from the US EPA list of priority pollutants. Fortunately, the levels of these compounds appeared to be much lower than the safe levels established in Russia. Phenol and dioctylphthalate could be considered as the pollutants of concern because their levels were about 20% of the safe thresholds. ChromaTOF® Tile, MetaboAnalyst software platform, and open-source software protocols were applied to process the obtained data. The obtained clusterization results of the samples were generally similar for various tools; however, each of them had certain peculiarities. Bis(2-ethylhexyl) hexanedioate, benzyl alcohol, phthalates, aniline, dinitrotoluenes, and fluoranthene showed the strongest influence on the clusterization of the studied samples. Possible sources of the major pollutants were proposed: car traffic and pulp and paper mills.

Influence of the Cultivation Conditions of the Glioblastoma Neurosphere on the Expression of MALAT1 and LINCROR Long Non-coding RNA Genes.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. One of the reasons for the resistance of GBM to treatment is the extreme heterogeneity of the tumor and, in particular, the presence of cancer stem cells (CSCs) in the population of glioblastoma cells. In this work, we investigated the effect of conditions that reduce the proportion of CSCs in the GBM cell population on the levels of long noncoding RNAs (lincROR and MALAT1) involved in the formation of the phenotype of glioblastoma cancer stem cells. We have shown that culturing under conditions that cause a decrease in cell stemness (when fetal bovine serum is added to the culture medium) affected the content of these transcripts: in the cells of most of the analyzed lines, a decrease in the level of the positive stemness regulator lincROR and an increase in the content of MALAT1 were noted.

Cyclization of N-arylcyclopropanecarboxamides into N-arylpyrrolidin-2-ones under electron ionization and in the condensed phase.

RATIONALE: Mass spectrometry is known as an excellent method to predict the behavior of organic compounds in solution. The behavior of organic compounds in the gas phase inside the ion source of a mass spectrometer allows their intrinsic properties to be defined, avoiding the influence of intermolecular interactions, counter ions and solvent effects. METHODS: Arylpyrrolidin-2-ones were obtained by condensed-phase synthesis from the corresponding N-arylcyclopropanecarboxamides. Electron ionization (EI) with accurate mass measurements by high-resolution time-of-flight mass-spectrometry and quantum chemical calculations were used to understand the behavior of the molecular radical cations of N-arylcyclopropanecarboxamides and N-arylpyrrolidin-2-ones in the ion source of a mass spectrometer. The geometries of the molecules, transition states, and intermediates were fully optimized using DFT-PBE calculations. RESULTS: Fragmentation schemes, ion structures, and possible mechanisms of primary isomerisation were proposed for isomeric N-arylcyclopropanecarboxamides and N-arylpyrrolidin-2-ones. Based on the fragmentation pattern of the N-arylcyclopropanecarboxamides, isomerisation of the original M+• ions into the M+• ions of the N-arylpyrrolidin-2-ones was shown to be only a minor process. In contrast, this cyclization proceeds easily in the condensed phase in the presence of Brønsted acids. CONCLUSIONS: Based on the experimental data and quantum chemical calculations the principal mechanism of decomposition of the molecular ions of N-arylcyclopropanecarboxamides involves their direct fragmentation without any rearrangements. An alternative mechanism is responsible for the isomerisation of a small portion of the higher energy molecular ions into the corresponding N-arylpyrrolidin-2-one ions. Copyright © 2016 John Wiley & Sons, Ltd.

N-dealkylation of amines during water disinfection - Revealing a new direction in the formation of disinfection by-products.

Among numerous disinfection by-products (DBP) forming during aqueous chlorination nitrogen containing species are of special concern due to their toxicological properties. Nevertheless, corresponding reaction products of these natural and anthropogenic compounds are not sufficiently studied so far. An interesting reaction involves dealkylation of the substituted amine moiety. Here we present the results of the comparative study of one-electron oxidation and aqueous chlorination of several aliphatic and aromatic amines. The reaction products were reliably identified with gas chromatography - high resolution mass spectrometry (GC-HRMS), high pressure liquid chromatography - electrospray ionization high resolution mass spectrometry HPLC-ESI/HRMS), and electrochemistry - electrospray ionization high resolution mass spectrometry (EC-ESI/HRMS). Certain similarities dealing with the formation of the corresponding aldehydes and substitution of alkyl groups at the nitrogen atom for hydrogen were shown for the studied processes. The mechanism of the substituted amines' aqueous chlorination involving one-electron oxidation is proposed and confirmed by the array of the observed reaction products. Alternative reactions taking place in conditions of aqueous chlorination, i.e. aromatic electrophilic substitution, may successfully compete with dealkylation and produce major products.

Halogen substitution reactions of halobenzenes during water disinfection.

Although being successfully applied all over the world for more than 100 years water disinfection by means of chlorination possesses certain drawbacks, first of all formation of hazardous disinfection by-products (DBP). Aromatic halogenated DBPs significantly contribute to the total organic halogen and developmental toxicity of chlorinated water. The present study deals with investigation of possible substitution of one halogen for another in aromatic substrates in conditions of aqueous chlorination/bromination. The reaction showed high yields especially in case of substrates with proper position of an activating group in the aromatic ring. Thus, ipso-substitution of iodine by chlorine is the main process of aqueous chlorination of para-iodoanisole. Oxidation of the eliminating I+ ions into non-reactive IO3- species facilitates the substitution. Oxidation of eliminating Br+ is not so easy while being highly reactive it attacks initial substrates forming polybrominated products. Substitution of iodine and bromine by chlorine may also involve migration of electrophilic species inside the aromatic ring resulting in larger number of isomeric DBPs. Substitution of chlorine by bromine in aromatic substrates during aqueous bromination is not so pronounced as substitution of bromine by chlorine in aqueous chlorination due to higher electronegativity of chlorine atom. However, formation of some chlorine-free polybrominated products proves possibility of that process.

GC-HRMS with Complementary Ionization Techniques for Target and Non-target Screening for Chemical Exposure: Expanding the Insights of the Air Pollution Markers in Moscow Snow.

Environmental exposure assessment is an important step in establishing a list of local priority pollutants and finding the sources of the threats for proposing appropriate protection measures. Exposome targeted and non-targeted analysis as well as suspect screening may be applied to reveal these pollutants. The non-targeted screening is a challenging task and requires the application of the most powerful analytical tools available, assuring wide analytical coverage, sensitivity, identification reliability, and quantitation. Moscow, Russia, is the largest and most rapidly growing European city. That rapid growth is causing changes in the environment which require periodic clarification of the real environmental situation regarding the presence of the classic pollutants and possible new contaminants. Gas chromatography - high resolution time-of-flight mass spectrometry (GC-HR-TOFMS) with electron ionization (EI), positive chemical ionization (PCI), and electron capture negative ionization (ECNI) ion sources were used for the analysis of Moscow snow samples collected in the early spring of 2018 in nine different locations. Collection of snow samples represents an efficient approach for the estimation of long-term air pollution, due to accumulation and preservation of environmental contaminants by snow during winter period. The high separation power of GC, complementary ionization methods, high mass accuracy, and wide mass range of TOFMS allowed for the identification of several hundred organic compounds belonging to the various classes of pollutants, exposure to which could represent a danger to the health of the population. Although quantitative analysis was not a primary aim of the study, targeted analysis revealed that some priority pollutants exceeded the established safe levels. Thus, dibutylphthalate concentration was over 10-fold higher than its safe level (0.001 mg/L), while benz[a]pyrene concentration exceeded Russian maximal permissible concentration value of 5 ng/L in three samples. The large amount of information generated during the combination of targeted and non-targeted analysis and screening samples for suspects makes it feasible to apply the big data analysis to observe the trends and tendencies in the pollution exposome across the city.

Inventory and phylogenomic distribution of meiotic genes in Nasonia vitripennis and among diverse arthropods.

The parasitoid jewel wasp Nasonia vitripennis reproduces by haplodiploidy (arrhenotokous parthenogenesis). In diploid females, meiosis occurs during oogenesis, but in haploid males spermatogenesis is ameiotic and involves a single equational division. Here we describe the phylogenomic distribution of meiotic genes in N. vitripennis and in 10 additional arthropods. Homologues for 39 meiosis-related genes (including seven meiosis-specific genes) were identified in N. vitripennis. The meiotic genes missing from N. vitripennis are also sporadically absent in other arthropods, suggesting that certain meiotic genes are dispensable for meiosis. Among an additional set of 15 genes thought to be specific for male meiosis in Drosophila, two genes (bol and crl) were identified in N. vitripennis and Apis mellifera (both for which canonical meiosis is absent in males) and in other arthropods. The distribution of meiotic genes across arthropods and the impact of gene duplications and reproductive modes on meiotic gene evolution are discussed.

Arctic snow pollution: A GC-HRMS case study of Franz Joseph Land archipelago.

Anthropogenic pollution of the Arctic atmosphere is of great interest due to the vulnerability of the Arctic ecosystems, as well as the processes of global transport and accumulation of atmospheric aerosols at high latitudes under conditions of cold climate. The present work throws light upon chemical composition of Arctic snow as a natural deposition matrix for atmospheric semi-volatile pollutants taken from the northernmost Arctic archipelago - Franz Josef Land, which is least affected by local sources of pollution and being a unique unstudied environmental object. The used methodology involved the liquid-liquid extraction of snow samples with dichloromethane and combination of targeted and non-targeted analyses of semi-volatile organic compounds with comprehensive two-dimensional gas chromatography - high-resolution mass spectrometry. While almost none of the known priority pollutants (except three dialkylphthalates) were identified in the studied samples, non-targeted screening revealed a specific class of biomass burning biomarkers - fatty amides with oleamide being the major component among them. Some peculiar organic pollutants (N,N-dimethylcyclohexylamine and N,N-dimethylbenzylamine) were identified in few samples. First results on the semi volatile pollutants in Franz Joseph Land snow were obtained using the most reliable GC × GC-HRMS non-target analysis.

Surface-stabilized nonferromagnetic ordering of a layered ferromagnetic manganite.

An outstanding question regarding the probing or possible device applications of correlated electronic materials (CEMs) with layered structure is the extent to which their bulk and surface properties differ or not. The broken translational symmetry at the surface can lead to distinct functionality due to the charge, lattice, orbital, and spin coupling. Here we report on the case of bilayered manganites with hole doping levels corresponding to bulk ferromagnetic order. We find that, although the hole doping level is measured to be the same as in the bulk, the surface layer is not ferromagnetic. Further, our low-energy electron diffraction and x-ray measurements show that there is a c-axis collapse in the outermost layer. Bulk theoretical calculations reveal that, even at fixed doping level, the relaxation of the Jahn-Teller distortion at the surface is consistent with the stabilization of an A-type antiferromagnetic state.

Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers.

OBJECTIVE: To assess bioequivalence between Equasym Retard and Medikinet retard containing 20 mg methylphenidate (MPH) hydrochloride in a fed state. MATERIALS: Equasym Retard 20 mg capsules (UCB, Monheim, Germany) and Medikinet retard 20 mg capsules (Medice, Iserlohn, Germany). METHODS: This was an open, single-center, randomized, 2-period, 2-sequence, balanced cross-over study with a wash-out period of 1 week between administrations in 14 healthy male and female volunteers, aged 18 - 45 years. Blood samples were collected over 24 hours and methylphenidate plasma concentration-time data were used to calculate pharmacokinetic metrics for both formulations. The main metrics were AUC0-t and Cmax. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was 80 - 125% (AUC0-t, Cmax). RESULTS: All dosed subjects finished both treatment periods and were included in pharmacokinetic and safety analyses. The adverse events observed, mainly nervous system disorders (headache), were all mild or moderate in intensity and resolved without any action taken. The adverse event profile was consistent with the currently applicable SmPCs (Summaries of Product Characteristics) for Equasym Retard and Medikinet retard. Geometric means +/- SD for AUC0-t and Cmax were 35.5 +/- 10.1 ng x h/ml and 4.05 +/- 0.96 ng/ml (Equasym Retard) and 39.2 +/- 13.8 ng x h/ml and 5.26 +/- 2.11 ng/ml (Medikinet retard). The 90% geometric confidence interval for AUC0-t (extent of absorption) was within limits accepted for bioequivalence. Bioequivalence could not be demonstrated for the rate of bioavailability (Cmax); both the lower confidence limit and the point estimate were below 80% of the reference. The study has shown that both formulations lead to a similar pattern of absorption and elimination following single dose administration in the fed state, although the test formulation shows a somewhat slimmer profile, where the first peak is less pronounced. No bioequivalence could be shown within the first 4 hours. The second peak of the test was also lower than the one of the reference (both lower confidence limit and point estimate below 80%). CONCLUSIONS: The two formulations are not bioequivalent, especially if the rate and values within the first four hours after administration are taken into account.

Regression algorithm for calculating second-dimension retention indices in comprehensive two-dimensional gas chromatography.

Gas chromatography-mass spectrometry (GC-MS) is one of the most accurate, well developed, and reliable analytical tools for the analysis of volatile and semivolatile compounds. The GC-MS data have been extensively improved by enhancing the separation capacity via comprehensive two-dimensional gas chromatography (GC × GC). The reliability of the identification of the analytes in GC × GC-MS can be notably improved by applying the second-dimension retention index (2I) as additional analytical parameter along with the commonly used first dimension retention index (1I) and mass spectrum. A novel approach for calculating second-dimension retention indices (2I) for semivolatile organic compounds is proposed. It is noteworthy that the standards used in calculations are the same compounds recommended as internal standards by US EPA 8270 Method for analysis of semivolatile organic compounds. The new algorithm takes into account the analyte retention time and its retention temperature at the secondary column, (2tR) and (2TR), respectively. The experimental data collected with different primary oven temperature ramp rates and carrier gas flow rates have shown that the calculated by the proposed approach 2I values remain the same for each evaluated compound, drifting in a very narrow range. The proposed approach was tested using 100 organic compounds from various chemical classes including alkanes, phenols, nitrobenzenes, chlorinated hydrocarbons, anilines, polycyclic aromatic hydrocarbons (PAHs), phthalates, etc. The important advantage of the proposed 2I values for compounds of the same chemical origin (reference standards and analytes) involves applicability of well-known Lee's indices for non-polar phases. Therefore, the proposed approach can be used in targeted and non-targeted analysis of a wide range of organic compounds. The reduced version of the second dimension retention indices provides a valuable mapping of the homologues series of organic compounds, making their detection and identification easy and reliable.

Detection of semi-volatile compounds in cloud waters by GC×GC-TOF-MS. Evidence of phenols and phthalates as priority pollutants.

Although organic species are transported and efficiently transformed in clouds, more than 60% of this organic matter remains unspeciated. Using GCxGC-HRMS technique we were able to detect and identify over 100 semi-volatile compounds in 3 cloud samples collected at the PUY station (puy de Dôme mountain, France) while they were present at low concentrations in a very small sample volume (<25 mL of cloud water). The vast majority (∼90%) of the detected compounds was oxygenated, while the absence of halogenated organic compounds should be specially mentioned. This could reflect both the oxidation processes in the atmosphere (gas and water phase) but also the need of the compounds to be soluble enough to be transferred and dissolved in the cloud droplets. Furans, esters, ketones, amides and pyridines represent the major classes of compounds demonstrating a large variety of potential pollutants. Beside these compounds, priority pollutants from the US EPA list were identified and quantified. We found phenols (phenol, benzyl alcohol, p-cresole, 4-ethylphenol, 3,4-dimethylphenol, 4-nitrophenol) and dialkylphthalates (dimethylphthalate, diethylphthalate, di-n-butylphthalate, bis-(2-ethylhexyl)-phthalate, butylbenzylphthalate, di-n-octyl phthalate). In general, the concentrations of phthalates (from 0.09 to 52 µg L-1) were much higher than those of phenols (from 0.03 to 0.74 µg L-1). To our knowledge phthalates in clouds are described here for the first time. We investigated the variability of phenols and phthalates concentrations with cloud air mass origins (marine vs continental) and seasons (winter vs summer). Although both factors seem to have an influence, it is difficult to deduce general trends; further work should be conducted on large series of cloud samples collected in different geographic areas and at different seasons.

Semi volatile organic compounds in the snow of Russian Arctic islands: Archipelago Novaya Zemlya.

Environmental contamination of the Arctic has widely been used as a worldwide pollution marker. Various classes of organic pollutants such as pesticides, personal care products, PAHs, flame retardants, biomass burning markers, and many others emerging contaminants have been regularly detected in Arctic samples. Although numerous papers have been published reporting data from the Canadian, Danish, and Norwegian Arctic regions, the environmental situation in Russian Arctic remains mostly underreported. Snow analysis is known to be used for monitoring air pollution in the regions with cold climate in both short-term and long-term studies. This paper presents the results of a nontargeted study on the semivolatile organic compounds detected and identified in snow samples collected at the Russian Artic Archipelago Novaya Zemlya in June 2016. Gas chromatography coupled to a high-resolution time-of-flight mass spectrometer enabled the simultaneous detection and quantification of a variety of pollutants including those from the US Environmental Protection Agency (EPA) priority pollutants list, emerging contaminants (plasticizers, flame retardants-only detection), as well as the identification of novel Arctic organic pollutants, (e.g., fatty acid amides and polyoxyalkanes). The possible sources of these novel pollutants are also discussed. GC-HRMS enabled the detection and identification of emerging contaminants and novel organic pollutants in the Arctic, e.g., fatty amides and polyoxyalkanes.

Molecular recognition of pseudodistamine isomeric precursors trans-3(4)-aminopiperidin-4(3)-ols by EI mass spectrometry.

Synthesis of drugs, biologically active compounds or their derivatives always requires precise and reliable method of their identification, including differentiation of the possible isomers. Pseudodistamines and their precursors became a matter of elevated attention due to their different enzymatic inhibition. This paper deals with one of the groups of the pseudodistamine precursors - trans-3(4)-aminopiperidin-4(3)-ols. Their synthesis brings to a mixture of 2 regioisomers, resulting in the necessity of their reliable recognition. NMR spectroscopy commonly used by organic chemists requires advance knowledge and experience to analyse the spectra of these regioisomers. Therefore, we herein proposed a simpler way to recognize trans-3(4)-aminopiperidin-4(3)-ols using mass spectrometry with electron ionization. Fragmentation of 4 pairs of aminopiperidinol regioisomers with variation of amine moiety was studied. The obtained results allowed defining a group of 3 ions ([M-18]+., [M-19]+, [M-43]+) related only to the structure of trans-4-aminopiperidin-3-ols and 1 ion (m/z 100) related to the structure of trans-3-aminopiperidin-4-ols. Besides, interrogation of intensity of ions common for spectra of both regioisomers allows making differentiation as well.

Identification and interconversion of isomeric 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles in conditions of electrospray ionization.

1,2,3-Triazoles and 1,2,3-thiadiazoles have been receiving permanent interest due to their exciting chemical reactivity and interesting biological properties including antibacterial, anticancer and antiviral activities. There are four compounds bearing 1H-1,2,3-triazole core in clinical studies which may appear in the market of drugs in nearest future. Definitely reliable methods of their identification and quantification should be developed by that time. Mass spectrometry showed itself as the most reliable method of analysis when dealing with trace levels of organic compounds in the mixtures and in the most complex matrices, including biological ones. In the present study tandem mass spectrometry was used to study fragmentation pathways of protonated and deprotonated molecules of isomeric 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles in conditions of electrospray ionization (ESI). A group of marker ions allowing differentiation between the targeted isomeric compounds was established. Besides, interconversion of these isomers into one another was studied in the gas phase in conditions mimicking these processes in solution.

Novel pollutants in the Moscow atmosphere in winter period: Gas chromatography-high resolution time-of-flight mass spectrometry study.

The most common mass spectrometry approach analyzing contamination of the environment deals with targeted analysis, i.e. detection and quantification of the selected (priority) pollutants. However non-targeted analysis is becoming more often the method of choice for environmental chemists. It involves implementation of modern analytical instrumentation allowing for comprehensive detection and identification of the wide variety of compounds of the environmental interest present in the sample, such as pharmaceuticals and their metabolites, musks, nanomaterials, perfluorinated compounds, hormones, disinfection by-products, flame retardants, personal care products, and many others emerging contaminants. The paper presents the results of detection and identification of previously unreported organic compounds in snow samples collected in Moscow in March 2016. The snow analysis allows evaluation of long-term air pollution in the winter period. Gas chromatography coupled to a high resolution time-of-flight mass spectrometer has enabled us with capability to detect and identify such novel analytes as iodinated compounds, polychlorinated anisoles and even Ni-containing organic complex, which are unexpected in environmental samples. Some considerations concerning the possible sources of origin of these compounds in the environment are discussed.

Relation of neuroleptic dose and tardive dyskinesia to attention, information-processing, and psychophysiology in medicated schizophrenics.

Relationships of neuroleptic dosage and tardive dyskinesia with measures of attentional, information-processing, and psychophysiological dysfunctions in medicated chronic schizophrenics were explored by correlational and stepwise multiple-regression analysis. High neuroleptic dosage was found to be associated with increased reaction time, reduced span of apprehension, low basal skin conductance level, and reduced skin conductance reactivity. Severe abnormal involuntary movements were associated with increased eye-tracking dysfunction, increased scanning eye-movement rate, increased reaction time, and reduced skin conductance reactivity. These findings led to the hypothesis that neuroleptic dosage and tardive dyskinesia may be sources of error variance in the measurement of attentional, information-processing, and psychophysiological functions in schizophrenics.

Usefulness of physical examination in detecting the presence or absence of anemia.

Previous studies addressing the usefulness of pallor in anemia are deficient because of observer or spectrum bias. Three internists made individual assessments of conjunctivae, face, nails, palms, and palmar creases in 98 male and 5 female hospitalized patients at a Veterans Administration Medical Center. The true-positive rates (sensitivities) were highest for pallor at any one of three sites (ie, the conjunctivae, face, or palms; 0.65) and for pallor of the palms (0.53). True-negative rates (specificities) were best for palmar creases (1.00), for pallor at conjunctivae, face, and palms (all three in combination; 0.95), and for the face (0.90). Receiver operator characteristic curve analysis revealed that the examination of the nailbeds is inferior to all other sites or combinations. Interobserver variability K scores were negative for palmar creases but ranged from .16 to .51 for other sites. We conclude that (1) the absence of pallor does not rule out anemia, and therefore this sign is not useful for screening an asymptomatic population; (2) pallor of the conjunctivae, face, and palms together is of benefit in confirming the presence of anemia; and (3) neither the nailbeds nor palmar creases are of value in assessing the presence or absence of anemia.

What should patients be told prior to a medical procedure? Ethical and legal perspectives on medical informed consent.

Ethicists and the medicolegal system agree that patients have rights to information prior to an elective medical procedure. Yet, it is far from clear whether there is at the present time an adequate framework for informing patients. Medicolegally, court cases as early as the 1900s strongly emphasized the preservation of individual rights to information in the patient-physician relationship. Most recently, an increasing number of states use the criterion of what a "reasonable man" would want as the basis for medical informed consent. Medical ethicists also have offered general principles for consideration by physicians: the importance of patient autonomy and preferences in decisions related to their own health care. This report examines the historical development of informed consent in the United States, legal and ethical perspectives in medical informed consent, and the pragmatic issues yet to be considered by physicians in keeping their duty to inform patients prior to a medical procedure.