Pairs Of Isomers Research Articles

Study on the Chemical Components and Anti-neuroinflammatory Activity of the Roots of Clausena excavate Burm. f.

The ethanol extract of the roots of Clausena excavata gave two previously undescribed coumarins, clauexcatin A (1) and clauexcatin B (2), as well as a pair of new isomers, trans/cis-clauexcatin C (3a, 3b), along with thirty known compounds. Among these, compound 33 was isolated from this genus for the first time. The structures of these compounds were elucidated based on their physicochemical properties and spectroscopic data. The anti-neuroinflammatory activities were assessed using LPS-activated BV-2 microglial cells. Compounds 6, 8, 17, 24, 29, and 30 exhibited significant inhibition of nitric oxide release in a dose-dependent manner, with their inhibitory effects being 1.2 to 10.9 times greater than that of the positive control (minocycline).

Systematic Characterisation of the Fragmentation of Flavonoids Using High-Resolution Accurate Mass Electrospray Tandem Mass Spectrometry

Flavonoids are a class of polyphenolic secondary metabolites found in plants. Due to their ubiquity in our daily dietary intake and their major anti-oxidative, anti-inflammatory and anti-mutagenic activities, they have been a major focus of wide-ranging research for the past two decades. Mass spectrometry combined with liquid chromatography is one of the most popular techniques for the analysis of flavonoids. In this study, high-resolution accurate mass electrospray tandem mass spectrometry was used to study 30 flavonoids in both positive and negative ionisation modes. From the data obtained, common losses were summarised and compiled. Dominating neutral losses were tabulated. The radical loss of CH3· was observed in flavonoids containing methoxy groups and three key diagnostic product ions were identified. These were m/z 153 (indicative of two OH groups on ring A) m/z 167 (indicative of one OH and one methoxy group on ring A) and m/z 151 (a flavanol, with no ketone oxygen but two OH groups on ring A). These will be useful in structural elucidation of unknown flavonoids and flavonoid metabolites. Energy breakdown graphs were utilised to distinguish between three pairs of structural isomers, and to help rationalise proposed fragmentation pathways. Lastly, a competition of loss of CH3· and methane was reported for rhamnetin and isorhamnetin in the negative ion mode for the first time. Proposed fragmentation pathways were given to rationalise the differences in peak intensities for this competitive process.

Cyclometalated Iridium(III) Complex with Substituted Benzimidazole: pH Directed Organelle-Specific Localization Within Lysosome.

We report the synthesis and pH dependent emission spectral behaviour of four emissive iridium(III) complexes (Ir1-Ir4) with two isomeric pairs of bis-trifluoromethyl appended benzimidazole ligands. The imidazolyl hydrogen(N-H) has been replaced by phenyl groups (N-Ph) in two ligands to understand the impact of hydrogen bonding on the photophysical properties of the complexes and it indeed plays interesting role in the charge-transfer dynamics. The pH dependent electronic spectral change is observed for two of the complexes. The enhancement of emission intensity is observed at different wavelength for pH<7 and pH>7 for Ir1 and Ir3. The emission sensing of biogenic amines with pka values ranging from 5.80-9.74 is reported along with cellular imaging. The complex Ir1 specifically localizes within lysosome (pH=4.5-5) and thus image this organelle with great precision. The detail electronic spectra and electrochemical behaviour were reported here along with TDDFT results.

Soluble polyimides with ultralow dielectric constant and dielectric loss and high colorless transparency based on spirobisindane-bis (aryl ester) diamines

With the emergence of 5G technology, the traditional polyimide with a relatively high dielectric constant (Dk) and dielectric loss (Df) are not suitable the requirements of ultra-high transmission and ultra-low loss. In particular, reducing the Df value of polyimide has become a significant difficulty in science and engineering. Herein, an elaborate design was proposed for the preparation of polyimide with both low Dk and low Df, based on a pair of diamine isomer containing two esters and a spiro-bis-indene structure (p-SBI2EA and m-SBI2EA), and their polymerization with 4,4′-(Hexafluoroisopropylidene)diphthalic anhydride (6FDA). The resultant polyimide films showed an exceptional dielectric property, with Dk values of 2.83 and 2.88, and Df values of 0.0043 and 0.0048 for p-SBI2EA-6FDA and m-SBI2EA-6FDA, respectively, at high frequencies (40 GHz). Interestingly, introducing the spirobisindane structure significantly displayed preeminent solubility in both high-boiling-point and low-boiling-point solvents. Furthermore, the PI films exhibited perfect optical performance, with cutoff wavelengths (λcut-off) of 315 and 321 nm, transmittance exceeding 86 % and 89 % at 450 nm, and yellowing indices (YI) as low as 1.72 and 1.63, respectively. The features of the PIs render them auspicious candidate materials for applications in 5G high frequency communication and optical fields.

Evolution of Chemistry in the envelope of HOt CorinoS (ECHOS). II. The puzzling chemistry of isomers as revealed by the HNCS/HSCN ratio

The observational detection of some metastable isomers in the interstellar medium with abundances comparable to those of the most stable isomer, or even when the stable isomer is not detected, highlights the importance of non-equilibrium chemistry. This challenges our understanding of the interstellar chemistry and shows the need to study isomeric forms of molecular species to constrain chemical processes occurring in the interstellar medium. Our goal is to study the chemistry of isomers through the sulphur isomer pair HNCS and HSCN, since HSCN has been observed in regions where its stable isomer has not been detected, and the observed HNCS/HSCN ratio seems to significantly vary from cold to warm regions. We used the Nautilus time-dependent gas-grain chemical code to model the formation and destruction paths of HNCS and HSCN in different astrochemical scenarios, as well as the time evolution of the HNCS/HSCN ratio. We also analysed the influence of the environmental conditions on their chemical abundances. We present an observational detection of the metastable isomer HSCN in the Class I object B1-a ($N$=(1.1pm 0.6)times 1012 cm$^ $), but not of the stable isomer HNCS, despite HNCS lying 3200 K lower in energy than HSCN. Our theoretical results show an HNCS/HSCN ratio sensitive to the gas temperature and the evolutionary time, with the highest values obtained at early stages ($t$lesssim 10$^4$ yr) and low ($T_ g $lesssim 20 K) temperatures. A more detailed analysis also shows that the main mechanism forming HNCS in young ($t$$&lt;$10$^5$ yr) and cold ($T_ g $$=$10 K) objects at moderate-low densities ($n$$_ H $leq 10$^5$ cm$^ $) is a grain surface reaction (the chemical desorption reaction N$_ solid $+HCS$_ solid $rightarrow HNCS), unlike previous predictions that suggest only gas-phase chemistry for its formation. However, for the formation of its metastable isomer HSCN, over the same time range and physical conditions, we find that both surface and gas-phase reactions (through the ion H$_2$NCS$^+$) play important roles. In warmer ($T_ g $geq 50 K) regions, the formation of this isomer pair is only dominated by gas-phase chemistry through the ions H$_2$NCS$^+$ (mainly at low densities) and HNCSH$^+$ (mainly at high densities). The results suggest a different efficiency of the isomerisation processes depending on the source temperature. The progressive decrease of HNCS/HSCN with gas temperature at early evolutionary times derived from our theoretical results indicates that this ratio may be used as a tracer of cold young objects. This work also demonstrates the key role of grain surface chemistry in the formation of the isomer pair HNCS and HSCN in cold regions, as well as the importance of the ions H$_2$NCS$^+$ and HNCSH$^+$ in warm/hot regions. Since most of the interstellar regions where HSCN is detected are cold regions (starless cores, Class 0/I objects), a larger sample including sources characterised by high temperatures (e.g. hot cores) are needed to corroborate the theoretical results.

Erinacenones A–L: Twelve New Isoindolinone Alkaloids from the Edible and Medicinal Mushroom Hericium erinaceus

A total of twelve previously unreported isoindolin-1-one compounds, erinacenones A–L (1–12), were isolated from liquid cultures of the medicinal fungus Hericium erinaceus. Their structures were elucidated based on spectroscopic data analysis. The absolute configuration of 12 was determined by comparing its optical rotations with values reported in the literature. The most distinctive feature of these compounds is that their nitrogen atoms are connected to different parts of the special structure moieties. Among them, compounds 3 and 4, as well as 10 and 11, are two pairs of isomers differing only by a small change in the position of one double bond. Compounds 4 and 5 were found to show cytotoxic activities, with IC50 values of 24.7 and 18.4 μM, respectively, against MCF-7 cell lines.

SOURCE APPORTIONMENT OF ATMOSPHERIC AND SEDIMENTARY PAHS FROM KOLKATA, INDIA USING COMPOUND-CLASS-SPECIFIC RADIOCARBON ANALYSIS (CCSRA)

ABSTRACT Polycyclic aromatic hydrocarbons (PAHs) are major air pollutants that are ubiquitously produced by the combustion of organic materials, and it is extremely important to identify their pollution sources. In this study, molecular fingerprinting and compound class-specific radiocarbon dating (CCSRA) were performed on PAHs from canal sediments and air samples collected in Kolkata, India’s third largest city (population approximately 16 million), where PAHs pollution has been a serious problem. Average PAH (Σ12-parent PAHs) concentrations in air samples were 65.1 ng m–3 in summer and 70.9 ng m–3 in winter and in canal sediments were 32.7 µg g–1, which are classified as “very high-level” pollution. Molecular fingerprinting using methyl-PAH/PAH (MPAHs/PAHs) ratios and isomer pair ratios with molecular weights of 178, 202, 228, and 276 suggested that wood and coal combustion were the dominant sources of PAHs in the sediment, and that atmospheric PAHs were influenced by oil combustion in addition to them. The fraction of contemporary carbon (ƒC) of sedimentary PAHs (0.056–0.100), together with the extremely low MPAHs/PAHs ratio results, lead to the conclusion that the major source of the high concentration of PAHs in the canals is from coal combustion. On the other hand, the ƒC of atmospheric PAHs (0.272–0.369) was close to the share of biomass fuels in India’s domestic fuel consumption in 2011 (about 35%). Furthermore, the observed ƒC-discrepancy between atmospheric and sedimentary PAHs in the same urban environment was interpreted to give an insight into the loading pathway of PAHs to canal sediments in Kolkata.

Utilizing ESI-MS/MS and ion mobility spectrometry for structural characterization and isomer differentiation of 1, 2-unsaturated (1-4) linked disaccharide derivatives and their 2-C-functionalized analogues.

The 1, 2-unsaturated derivatives of (1-4) linked disaccharides serve as versatile building blocks for synthesizing biologically active compounds. Distinguishing between four pairs of stereoisomers in mixtures presents a challenging task. In this study, disaccharide derivatives are analyzed as alkali metal adducts using electrospray ionization tandem mass spectrometry (ESI-MS/MS), both as individual compounds and in mixtures by ion mobility mass spectrometry (IMS). Electrospray ionization (ESI) in combination with tandem mass spectrometry (MS/MS) in positive mode was employed to differentiate lithium adduct ions of hexa-acetyl/hexa-benzyl-D-lactals, and hexa-acetyl/hexa-benzyl-D-maltals, along with their corresponding 2-C-branched malonates. The high resolving power of trapped ion mobility spectrometry (TIMS) with the imeX™ functionality rapidly identified different metal adducts (Li, Na, Cs) as individual isomers and separated mixtures of stereoisomers. The measured collisional cross section (CCS) values were analyzed in relation to predicted CCS values. MS/MS spectra of the [M + Li]+ ions of glycal disaccharide analogues exhibited typical cross-ring and glycosidic bond cleavages. Collision-induced dissociation (CID) spectra provided insights into their fragmentation behavior, allowing differentiation of (1-4) linked disaccharides. TIMS technology delivered adjustable ion mobility resolution for suitable separation of the four sets of stereo isomeric compounds. However, accurately predicting CCS values to differentiate between respective isomeric pairs using the SigmaCCS program for sodium adducts is only partially achievable. ESI CID spectra of [M + Li]+ adduct ions for individual glycal disaccharide analogues facilitate the discrimination between alpha and beta (1-4) linked unsaturated disaccharides and their 2-C-branched analogues. Through optimized experimental conditions, complete baseline ion mobility separation of stereoisomer pairs of the Cs adducts is achieved.

Comprehensive exploration of a traditional Chinese medicinal plant of Magnolia officinalis based on high-coverage mass spectrometry and multidimensional chemical-biological analysis

Magnolia bark is a traditional Chinese medicine used for hypoglycaemia. With the widespread use of Magnolia bark, its resources are facing a serious shortage. To address this issue, a strategy based on high-coverage mass spectrometry (HCMS) and multidimensional chemical-biological analysis (MCBA) was proposed for the comprehensive exploration of Magnolia officinalis which is the main source of Magnolia bark. The strategy is divided into three main steps. In the first step, the stem bark, stem xylem, root bark, root xylem, leaf and rootlet of Magnolia officinalis were comprehensively analyzed using high-coverage mass spectrometry. In the second step, multivariate statistical analysis was used to explore the heterogeneity of the six parts and detect differential chemical components. In the third step, a combination of experimental screening and molecular docking was used to explore α-glucosidase inhibitors from Magnolia officinalis. Multidimensional chemical-biological analysis (MCBA) of Magnolia officinalis was achieved by combining the last two steps. Finally, a total of 103 compounds were identified from the whole plant of Magnolia officinalis. Differential components of stem bark, stem xylem, leaf, root bark, root xylem and rootlet were systematically revealed. A pair of positional isomers, namely magnolol and honokiol, were found to be α-glucosidase inhibitors. The activity of their combination is superior to that of each single compound, indicating that magnolol and honokiol are in a synergistic relationship. This strategy contributes to comprehensive exploitation of functional plants and effective alleviation of resource shortage. This study also provides a research paradigm for other similar traditional Chinese medicinal plants.

Metabolic profiling and pharmacokinetic studies of alkamides, a pair of cis-trans isomers N-isobutyl-2E,4E,8Z,10E/Z-dodecatetraenamide, from Asari Radix et Rhizoma by UHPLC-Q/TOF-MS and UHPLC-MS/MS

Cis-trans isomers of N-isobutyl-2E,4E,8Z,10E-dodecatetraenamide (DDA-E) and N-isobutyl-2E,4E,8Z,10Z-dodecatetraenamide (DDA-Z) are representative alkamides with numbness of tongue, anti-inflammatory and analgesic activities of Asari Radix et Rhizoma. However, their respective metabolic pathways and pharmacokinetic behaviors are still unknown. This study aim to investigate the metabolism of the two alkamides in vitro and in vivo using ultra-high-performance liquid chromatography-quadruple-time-of-flight mass spectrometry. Furthermore, a rapid, sensitive, and selective ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to quantify DDA-E/Z in rat plasma. Results indicated that DDA-E and DDA-Z showed significant differences in metabolism and pharmacokinetics. Across all samples, 24 metabolites of DDA-E and 21 metabolites of DDA-Z were detected. A variety of pathways were involved in the production of these metabolites, mainly hydroxylation and oxidation. The linear range of DDA-E/Z was 1–2500 ng/mL (R2 = 0.9984), and the lowest quantification limit was 1 ng/mL. Precision, accuracy, extraction recovery, matrix effect, and stability of DDA-E/Z were within acceptable limits. Pharmacokinetic research was conducted using male Sprague-Dawley rats receiving intravenous (1 mg/kg) or intragastric (40 mg/kg) administration of DDA-E or DDA-Z solution. There was a calculated absolute bioavailability of 15.67 % for DDA-E and 4.83 % for DDA-Z when consumed orally. The apparent volume of distribution of intravenous and intragastric administrations were 4.44 ± 0.41 L/kg and 5.18 ± 0.67 L/kg for DDA-E, and 1.56 ± 1.66 L/kg and 2.35 ± 0.42 L/kg for DDA-Z. The maximal plasma concentrations of DDA-E and DDA-Z were 599.84 ± 149.92 nM and 422.09 ± 69.17 nM, and the time to maximum peak were 4.33 ± 3.51 h and 0.70 ± 1.12 h, respectively. In conclusion, in subsequent pharmacodynamics and safety evaluation studies, great attention should be paid to the metabolic characteristics and pharmacokinetic differences between DDA-E and DDA-Z.

Microscopic Aggregation and Film‐Forming Characteristics of Lubricant Additives on Oil–Water Interface: MD Simulation and Experiments on Water Separability

ABSTRACTThe anti‐emulsification property of lubricating oil is an important index to measure the quality of oil. In this paper, the behaviour of surfactants such as lubricating oil additives at the oil–water interface and the influence of the position of ethylene oxide (EO) and propylene oxide (PO) in the block polyether demulsifier on the demulsification effect were investigated by molecular simulation and experimental verification. The properties of seven lubricating oil additives with different functions and two pairs of isomers were investigated by molecular simulation, and their demulsification effects were verified by experiments. Some simulation results such as interface thickness and density distribution can accurately predict the experimental demulsification effect. Moreover, it was found that the position isomerism of surfactants affected the demulsification performance by changing the lipophilic balance and interface properties. The demulsification performance of sequenced copolymers is generally better than that of anti‐sequenced copolymers. The accurate prediction of molecular dynamics simulation makes the selection of lubricating oil demulsifier more extensive and has practical application value.

Isomer engineering of triptycene-fused multi-resonance TADF emitters: Implications for controlling blue electroluminescence performance

Concurrently achieving high efficiency, narrowband emission, and low efficiency roll-off remains a challenging task for realizing stable blue organic light-emitting diodes (OLEDs) with high color purity. To tackle this issue, herein, two isomeric pairs of B,N-doped multi-resonance thermally activated delayed fluorescence (MR-TADF) emitters, namely, 2,3-Tp-BuDABNA-R and 3,4-Tp-BuDABNA-R (R=H, 3,5-Xyl), featuring triptycene (Tp) moieties fused into the 2,3- and 3,4-positions of the B,N core, respectively, are presented. Both isomeric forms exhibit blue emissions with near-unity photoluminescence (PL) quantum yields in their doped host films. Notably, the 3,4-Tp-fused emitter shows 6-fold faster reverse intersystem crossing (RISC) compared to the 2,3-Tp-fused emitter, albeit with PL spectral broadening. Along with a smaller activation energy of RISC, the stronger spin–orbit coupling between the singlet (S1) and triplet (T2) excited states of the 3,4-Tp-fused emitter is suggested to facilitate the RISC process. Furthermore, a high-frequency vibration in the Tp-fused benzene ring, accompanied by a large reorganization energy, is found to mainly contribute to the spectral broadening of the 3,4-Tp-fused emitter. Blue TADF-OLEDs based on each isomeric emitter similarly achieve a high maximum external quantum efficiency of ∼ 26%. Remarkably, the devices with the 3,4-isomer exhibit significantly reduced efficiency roll-offs compared to the 2,3-isomer, demonstrating that isomer engineering of MR emitters can have a distinct impact on controlling device performance.

High-resolution 3D spatial distribution of complex microbial colonies revealed by mass spectrometry imaging

IntroductionBacterial living states and the distribution of microbial colony signaling molecules are widely studied using mass spectrometry imaging (MSI). However, current approaches often treat 3D colonies as flat 2D disks, inadvertently omitting valuable details. The challenge of achieving 3D MSI in biofilms persists due to the unique properties of microbial samples. ObjectivesThe study aimed to develop a new biofilm sample preparation method that can realize high-resolution 3D MSI of bacterial colonies to reveal the spatial organization of bacterial colonies. MethodsThis article introduces the moisture-assisted cryo-section (MACS) method, enabling embedding-free sectioning parallel to the growth plane. The MACS method secures intact sections by controlling ambient humidity and slice thickness, preventing molecular delocalization. ResultsCombined with matrix-assisted laser desorption ionization mass spectrometry (MALDI)-MSI, the MACS method provides high-resolution insights into endogenic and exogenous molecule distributions in Pseudomonas aeruginosa (P. aeruginosa) biofilms, including isomeric pairs. Moreover, analyzed colonies are revived into 3D models, vividly depicting molecular distribution from inner to outer layers. Additionally, we investigated metabolite spatiotemporal dynamics in multiple colonies, observing changes over time and distinct patterns in single versus merged colonies. These findings shed light on the repel-merge process for multi-colony formation. Furthermore, our study monitored chemical responses inside biofilms after antibiotic treatment, showing increased antibiotic levels in the outer biofilm layer over time while maintaining low levels in the inner region. Moreover, the MACS method demonstrated its universality and applicability to other bacterial strains. ConclusionThese results unveil complex cell activities within biofilm colonies, offering insights into microbe communities. The MACS method is universally applicable to loosely packed microorganism colonies, overcoming the limitations of previously reported MSI methods. It has great potential for studying bacterial-infected cancer tissues and artificial organs, making it a valuable tool in microbiological research.

High-throughput liquid chromatography-vacuum differential mobility spectrometry-mass spectrometry for the analysis of isomeric drugs of abuse in human urine.

The use of differential mobility spectrometry at low pressure coupled to liquid chromatography-mass spectrometry (LC-vDMS-MS) was investigated for the analysis of 13 drugs of abuse (DoA) including the following: cocaine, ecgonine methyl ester, cocaethylene, benzoylecgonine, norcocaine, tramadol, isomeric pairs of metabolites; O-desmethyl-cis-tramadol and N-desmethyl-cis-tramadol, and cannabinoids: Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabidiol, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-9carboxy-Δ9-tetrahydrocannabinol, and 11-nor-9carboxy-Δ9-tetrahydrocannabinol glucuronide. Different parameters were optimized for isomeric separation, such as LC mobile phase composition (20%-100% methanol acetonitrile and isopropanol, flow rate: 8-100 μL/min) and DMS separation voltage. Methanol and acetonitrile significantly affected the compensation voltage of the analytes and improved DMS separation. A short trap/elute LC-vDMS-SIM/MS screening method of 1min was developed to quantify 11 drugs of abuse (except THC/CBD), in addition to a 4-min LC-vDMS-SIM/MS method to identify and quantify five cannabinoids including the isomers THC/CBD and three THC metabolites. THC is the principal psychoactive constituent of cannabis and is a controlled substance in comparison to its isomeric counterpart CBD; this highlights the importance and challenges to resolve these isomeric pairs by analytical techniques. The signal responses were linear over a concentration range of 0.005-10μg/mL for the DoA and 1-1000 ng/mL for cannabinoids. The intraday and interday precision were better than 12.2% and accuracy better than 115%. Urine samples from subjects who tested positive for THC and/or cocaine during roadside drug testing were evaluated to assess the performance of the methods LC-vDMS-SIM/MS and LC-MRM/MS. Results show that the developed LC-vDMS-SIM/MS method presents similar performance to LC-MRM/MS with improved sample throughput.

Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer’s disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics

Dysregulated glycerophospholipid (GP) metabolism in the brain is associated with the progression of neurodegenerative diseases including Alzheimer’s disease (AD). Routine liquid chromatography-mass spectrometry (LC-MS)-based large-scale lipidomic methods often fail to elucidate subtle yet important structural features such as sn-position, hindering the precise interrogation of GP molecules. Leveraging high-resolution demultiplexing (HRdm) ion mobility spectrometry (IMS), we develop a four-dimensional (4D) lipidomic strategy to resolve GP sn-position isomers. We further construct a comprehensive experimental 4D GP database of 498 GPs identified from the mouse brain and an in-depth extended 4D library of 2500 GPs predicted by machine learning, enabling automated profiling of GPs with detailed acyl chain sn-position assignment. Analyzing three mouse brain regions (hippocampus, cerebellum, and cortex), we successfully identify a total of 592 GPs including 130 pairs of sn-position isomers. Further temporal GPs analysis in the three functional brain regions illustrates their metabolic alterations in AD progression.

Evaluation of modelled versus observed non-methane volatile organic compounds at European Monitoring and Evaluation Programme sites in Europe

Abstract. Atmospheric volatile organic compounds (VOCs) constitute a wide range of species, acting as precursors to ozone and aerosol formation. Atmospheric chemistry and transport models (CTMs) are crucial to understanding the emissions, distribution, and impacts of VOCs. Given the uncertainties in VOC emissions, lack of evaluation studies, and recent changes in emissions, this work adapts the European Monitoring and Evaluation Programme Meteorological Synthesizing Centre – West (EMEP MSC-W) CTM to evaluate emission inventories in Europe. Here we undertake the first intensive model–measurement comparison of VOCs in 2 decades. The modelled surface concentrations are evaluated both spatially and temporally, using measurements from the regular EMEP monitoring network in 2018 and 2019, as well as a 2022 campaign. To achieve this, we utilised the UK National Atmospheric Emissions Inventory to derive explicit emission profiles for individual species and employed a tracer method to produce pure concentrations that are directly comparable to observations. The degree to which the modelled and measured VOCs agree varies depending on the specific species. The model successfully captures the overall spatial and temporal variations of major alkanes (e.g. ethane, n-butane) and unsaturated species (e.g. ethene, benzene) but less so for propane, i-butane, and ethyne. This discrepancy underscores potential issues in the boundary conditions for the latter species and in their primary emissions from, in particular, the solvent and road transport sectors. Specifically, potential missing propane emissions and issues with its boundary conditions are highlighted by large model underestimations and smaller propane-to-ethane ratios compared to the measurement. Meanwhile, both the model and measurements show strong linear correlations among butane isomers and among pentane isomers, indicating common sources for these pairs of isomers. However, modelled ratios of i-butane to n-butane and i-pentane to n-pentane are approximately one-third of the measured ratios, which is largely driven by significant emissions of n-butane and n-pentane from the solvent sector. This suggests issues with the speciation profile of the solvent sector, underrepresented contributions from transport and fuel evaporation sectors in current inventories, or both. Furthermore, the modelled ethene-to-ethyne and benzene-to-ethyne ratios differ significantly from measured ratios. The different model performance strongly points to shortcomings in the spatial and temporal patterns and magnitudes of ethyne emissions, especially during winter. For OVOCs, the modelled and measured concentrations of methanal and methylglyoxal show a good agreement, despite a moderate underestimation by the model in summer. This discrepancy could be attributed to an underestimation of contributions from biogenic sources or possibly a model overestimation of their photolytic loss in summer. However, the insufficiency of suitable measurements limits the evaluation of other OVOCs. Finally, model simulations employing the CAMS inventory show slightly better agreements with measurements than those using the Centre on Emission Inventories and Projections (CEIP) inventory. This enhancement is likely due to the CAMS inventory's detailed segmentation of the road transport sector, including its associated sub-sector-specific emission profiles. Given this improvement, alongside the previously mentioned concerns about the model's biased estimations of various VOC ratios, future efforts should focus on a more detailed breakdown of dominant emission sectors (e.g. solvents) and the refinement of their speciation profiles to improve model accuracy.

Efficient Strategy for Characterization and Quantification of Polyunsaturated Lipids by Microwave-Assisted MMPP Epoxidation.

Lipids play integral roles in biological processes, with carbon-carbon double bonds (C═C) markedly influencing their structure and function. Precise characterization and quantification of unsaturated lipids are crucial for understanding lipid physiology and discovering disease biomarkers. However, using mass spectrometry for these purposes presents significant challenges. In this study, we developed a microwave-assisted magnesium monoperoxyphthalate hexahydrate (MMPP) epoxidation reaction, coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS), to analyze unsaturated lipids. Microwave irradiation expedited the MMPP epoxidation, achieving complete derivatization in 10 min without byproducts. A diagnostic ion pair, displaying a 16 Da mass difference, effectively identified the location of the C═C bond in mass spectra. Microwave irradiation also significantly facilitated the epoxidation reaction of polyunsaturated lipids, achieving yields greater than 85% and yielding a complete epoxidation product. This simplifies chromatographic separation and aids in accurate quantification. Additionally, a purification process was implemented to remove excess derivatization reagents, significantly reducing mass spectrometry response suppression and enhancing analytical reproducibility. The method's effectiveness was validated by analyzing unsaturated lipids in rat plasma from a type I diabetes model. We quantified nine unsaturated lipids and characterized 42 fatty acids and glycerophospholipids. The results indicated that unsaturated fatty acids increased in diabetic plasma while unsaturated glycerophospholipids decreased. Furthermore, the relative abundances of Δ9/Δ11 isomer pairs also exhibited a close association with diabetes. In conclusion, microwave-assisted MMPP epoxidation coupled with LC-MS/MS provides an effective strategy for characterization and quantification of polyunsaturated lipids, offering deeper insight into the physiological impact of unsaturated lipids in related diseases.

Cyclic Ion Mobility of Isomeric New Psychoactive Substances Employing Characteristic Arrival Time Distribution Profiles and Adduct Separation.

Analysis of new psychoactive substances (NPS), which is essential for toxicological and forensic reasons, can be made complicated by the presence of isomers. Ion mobility has been used as a standalone technique or coupled to mass spectrometry to detect and identify NPS. However, isomer separation has so far chiefly relied on chromatography. Here we report on the determination of isomeric ratios using cyclic ion mobility-mass spectrometry without any chromatographic separation. Isomers were distinguished by mobility separation of lithium adducts. Alternatively, we used arrival time distribution (ATD) profiles that were characteristic of individual isomers and were acquired for protonated molecules or fragment ions. Both approaches provided comparable results. Calculations were used to determine the structures and collision cross sections of both protonated and lithiated isomers that accurately characterized their ion mobility properties. The applicability of ATD profiles to isomer differentiation was demonstrated using direct infusion and flow injection analysis with electrospray of solutions, as well as desorption electrospray of solid samples. Data processing was performed by applying multiple linear regression to the ATD profiles. Using the proposed ATD profile-based approach, the relationships between the determined and given content of isomers showed good linearity with coefficients of determination typically greater than 0.99. Flow injection analysis using an autosampler allowed us to rapidly determine isomeric ratios in a sample containing two isomeric pairs with a minor isomer of 10% (determined 9.3% of 3-MMC and 11.0% of 3-FMC in a mixture with buphedrone and 4-FMC). The proposed approach is not only useful for NPS, but also may be applicable to small isomeric molecules analyzed by ion mobility when complete separation of isomers is not achieved.

Improved hydrophobic subtraction model of reversed-phase liquid chromatography selectivity based on a large dataset with a focus on isomer selectivity

Reversed-phase (RP) liquid chromatography is an important tool for the characterization of materials and products in the pharmaceutical industry. Method development is still challenging in this application space, particularly when dealing with closely-related compounds. Models of chromatographic selectivity are useful for predicting which columns out of the hundreds that are available are likely to have very similar, or different, selectivity for the application at hand. The hydrophobic subtraction model (HSM1) has been widely employed for this purpose; the column database for this model currently stands at 750 columns. In previous work we explored a refinement of the original HSM1 (HSM2) and found that increasing the size of the dataset used to train the model dramatically reduced the number of gross errors in predictions of selectivity made using the model. In this paper we describe further work in this direction (HSM3), this time based on a much larger solute set (1014 solute/stationary phase combinations) containing selectivities for compounds covering a broader range of physicochemical properties compared to HSM1. The molecular weight range was doubled, and the range of the logarithm of the octanol/water partition coefficients was increased slightly. The number of active pharmaceutical ingredients and related synthetic intermediates and impurities was increased from four to 28, and ten pairs of closely related structures (e.g., geometric and cis-/trans- isomers) were included. The HSM3 model is based on retention measurements for 75 compounds using 13 RP stationary phases and a mobile phase of 40/60 acetonitrile/25 mM ammonium formate buffer at pH 3.2. This data-driven model produced predictions of ln α (chromatographic selectivity using ethylbenzene as the reference compound) with average absolute errors of approximately 0.033, which corresponds to errors in α of about 3 %. In some cases, the prediction of the trans-/cis- selectivities for positional and geometric isomers was relatively accurate, and the driving forces for the observed selectivity could be inferred by examination of the relative magnitudes of the terms in the HSM3 model. For some geometric isomer pairs the interactions mainly responsible for the observed selectivities could not be rationalized due to large uncertainties for particular terms in the model. This suggests that more work is needed in the future to explore other HSM-type models and continue expanding the training dataset in order to continue improving the predictive accuracy of these models. Additionally, we release with this paper a much larger data set (43,329 total retention measurements) at multiple mobile phase compositions, to enable other researchers to pursue their own lines of inquiry related to RP selectivity.

Stereochemically-aware bioactivity descriptors for uncharacterized chemical compounds

Stereochemistry plays a fundamental role in pharmacology. Here, we systematically investigate the relationship between stereoisomerism and bioactivity on over 1 M compounds, finding that a very significant fraction (~ 40%) of spatial isomer pairs show, to some extent, distinct bioactivities. We then use the 3D representation of these molecules to train a collection of deep neural networks (Signaturizers3D) to generate bioactivity descriptors associated to small molecules, that capture their effects at increasing levels of biological complexity (i.e. from protein targets to clinical outcomes). Further, we assess the ability of the descriptors to distinguish between stereoisomers and to recapitulate their different target binding profiles. Overall, we show how these new stereochemically-aware descriptors provide an even more faithful description of complex small molecule bioactivity properties, capturing key differences in the activity of stereoisomers.Scientific contributionWe systematically assess the relationship between stereoisomerism and bioactivity on a large scale, focusing on compound-target binding events, and use our findings to train novel deep learning models to generate stereochemically-aware bioactivity signatures for any compound of interest.