Collision-induced dissociation of protonated uracil water clusters probed by molecular dynamics simulations.

Collision-induced dissociation experiments of hydrated molecular species can provide a wealth of important information. However, they often need a theoretical support to extract chemical information. In the present article, in order to provide a detailed description of recent experimental measurements [Braud et al., J. Chem. Phys., 2019, 150, 014303], collision simulations between low-energy protonated uracil water clusters (H2O)1-7,11,12UH+ and an Ar atom were performed using a quantum mechanics/molecular mechanics formalism based on the self-consistent-charge density-functional based tight-binding method. The theoretical proportion of formed neutral vs. protonated uracil containing clusters, total fragmentation cross sections as well as the mass spectra of charged fragments are consistent with the experimental data which highlights the accuracy of the present simulations. They allow to probe which fragments are formed on the short time scale and rationalize the location of the excess proton on these fragments. We demonstrate that this latter property is highly influenced by the nature of the aggregate undergoing the collision. Analyses of the time evolution of the fragments populations and of their relative abundances demonstrate that, up to 7 water molecules, a direct dissociation mechanism occurs after collision whereas for 11 and 12 water molecules a statistical mechanism is more likely to participate. Although scarce in the literature, the present simulations appear as a useful tool to complement collision-induced dissociation experiments of hydrated molecular species.

Threshold collision induced dissociation of pyrene cluster cations.

We report threshold collision induced dissociation experiments on cationic pyrene clusters, for sizes n = 2-6. Fragmentation cross sections are recorded as a function of the collision energy and analyzed with a statistical model. This model can account for the dissociation cascades and provides values for the dissociation energies. These values, of the order of 0.7 eV-1 eV, are in excellent agreement with those previously derived from thermal evaporation. They confirm the charge resonance stability enhancement predicted by theoretical calculations. In addition, remarkable agreement is obtained with theoretical predictions for the two smaller sizes n = 2 and 3. For the larger sizes, the agreement remains good, although the theoretical values obtained for the most stable structures are systematically higher by 0.2 eV. This offset could be attributed to approximations in the calculations. Still, there is an indication in the results of an incomplete description of the role of isomerization and/or direct dissociation upon collisions. Finally, by-product clusters containing dehydrogenated species are found to dissociate at energies comparable to the non-dehydrogenated ones, which shows no evidence for covalent bonds within the clusters.

Size-dependent proton localization in hydrated uracil clusters: A joint experimental and theoretical study.

A collision-induced dissociation study of hydrated protonated uracil (H2O)n=1-15UH+ clusters is reported. The mass-selected clusters collide with water molecules and rare gases at a controlled center of mass collision energy. From these measurements, absolute fragmentation cross sections and branching ratios are extracted as a function of the uracil hydration. For small clusters, up to n = 4, we observe that only neutral water molecules are evaporated upon collisions, whereas, for larger clusters, neutral uracil is also evaporated: this transition in the nature of the evaporation products is interpreted considering the lowest-energy isomers of each species that are obtained from a combination of density-functional based tight-binding and MP2 calculations. The simulations show that in (H2O)1-4UH+ the proton is located on the uracil molecule or on a water molecule strongly bound to uracil whereas, in larger clusters, the proton is bound to water molecules far from uracil. This correlation between the structure of the low-energy isomers and the experimental fragmentation channel suggests that dissociation may occur in a very short time after collisions so that energy has not enough time to be redistributed among all degrees of freedom and the ground-state geometry of the parent cluster partly determines the nature of the favored fragmentation channels. Of course, thermal dissociations originating from long lived, thus thermalized, collision complexes cannot be ruled out but they are not expected to play the major role since the experimental results can be satisfactorily accounted for by assuming that the fragmentation processes are mainly impulsive.

Inter-laboratory study for the certification of trace elements in seawater certified reference materials NASS-7 and CASS-6.

Certification of trace metals in seawater certified reference materials (CRMs) NASS-7 and CASS-6 is described. At the National Research Council Canada (NRC), column separation was performed to remove the seawater matrix prior to the determination of Cd, Cr, Cu, Fe, Pb, Mn, Mo, Ni, U, V, and Zn, whereas As was directly measured in 10-fold diluted seawater samples, and B was directly measured in 200-fold diluted seawater samples. High-resolution inductively coupled plasma mass spectrometry (HR-ICPMS) was used for elemental analyses, with double isotope dilution for the accurate determination of B, Cd, Cr, Cu, Fe, Pb, Mo, Ni, U, and Zn in seawater NASS-7 and CASS-6, and standard addition calibration for As, Co, Mn, and V. In addition, all analytes were measured using standard addition calibration with triple quadrupole (QQQ)-ICPMS to provide a second set of data at NRC. Expert laboratories worldwide were invited to contribute data to the certification of trace metals in NASS-7 and CASS-6. Various analytical methods were employed by participants including column separation, co-precipitation, and simple dilution coupled to ICPMS detection or flow injection analysis coupled to chemiluminescence detection, with use of double isotope dilution calibration, matrix matching external calibration, and standard addition calibration. Results presented in this study show that majority of laboratories have demonstrated their measurement capabilities for the accurate determination of trace metals in seawater. As a result of this comparison, certified/reference values and associated uncertainties were assigned for 14 elements in seawater CRMs NASS-7 and CASS-6, suitable for the validation of methods used for seawater analysis.

A DFT study on PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles for the formation of functionalized pyrrolidines: mechanisms, selectivities, and the role of catalysts.

The mechanisms and chemo- and stereo-selectivities of PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles leading to functionalized pyrrolidines (5-endo-trig cyclization, Mechanism A) and their competing reaction leading to another kind of pyrrolidine (5-exo-trig cyclization, Mechanism B) have been investigated using density functional theory (DFT). Multiple possible reaction pathways associated with four different isomers (RR, SR, RS, and SS) for Mechanism A, and two isomers (R and S) for Mechanism B have been studied. The calculated results indicate that the Gibbs free energy barriers of Mechanism A are remarkably lower than those of Mechanism B, and the reaction pathway leading to the RS-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experiments. A C-H···π interaction has been identified to be responsible for the favorability of RS isomers by non-covalent interaction (NCI) analysis. Moreover, global reaction indexes (GRIs) and NBO analyses confirm that PBu3 acts as a Lewis base to strengthen the nucleophilicity of the reaction active site. The mechanistic insights gained in the present study should be valuable for the rational design of effective organocatalysts for this kind of reaction with high chemo- and stereo-selectivities.

Theoretical investigations of the reaction between 1,4-dithiane-2,5-diol and azomethine imines: mechanisms and diastereoselectivity.

In the present study, mechanistic insights into the domino reaction between 1,4-dithiane-2,5-diol and azomethine imines were derived from the computational study with B3LYP and M06-2X functionals. On the whole, the domino process comprises two consecutive reactions: cleavage of 1,4-dithiane-2,5-diol leading to mercaptoacetaldehyde and [3 + 3] cycloaddition of mercaptoacetaldehyde with azomethine imines. The cleavage of 1,4-dithiane-2,5-diol can take place via multiple possible pathways (1A-1E), and pathway 1E in which double-methanol molecules mediate the proton transfer process is the most energetically favorable, with an energy barrier of 19.9 kcal mol(-1). For the [3 + 3] cycloaddition, three possible pathways (2F-2H) were explored. The calculated energy profiles reveal that pathway 2H with activation energies ranging from 6.9 to 10.2 kcal mol(-1) is more energetically favorable than pathways 2F and 2G. Specifically, pathway 2H comprises three reaction steps: deprotonation of mercaptoacetaldehyde by DABCO allows for the formation of the thiol anion, which subsequently launches a nucleophilic attack on azomethine imines followed by intramolecular cyclization resulting in the final products. The calculated results are in agreement with the experimental observations that the reaction can proceed most efficiently in the presence of both DABCO and methanol. Furthermore, the hydrogen bonding interaction is identified to be the main factor determining the observed diastereoselectivity The current systematic theoretical study gives a full scenario of the reaction between 1,4-dithiane-2,5-diol and azomethine imines catalyzed by DABCO, and thus provides some valuable clues for further investigation and development of this kind of important reaction.

Overall and individual associations between per- and polyfluoroalkyl substances and liver function indices and the metabolic mechanism.

Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however, few studies have investigated the overall effect of PFAS mixtures. We aimed to investigate associations between exposure to PFAS mixtures and liver function indices and explore the relevant mechanisms. This study included 278 adult males from Guangzhou, China. Serum metabolite profiles were analyzed using untargeted metabolomics. We applied weighted quantile sum (WQS) regression as well as Bayesian kernel machine regression (BKMR) to analyze the association of nine PFAS mixtures with 14 liver function indices. PFAS mixtures were positively associated with apolipoprotein B (APOB) and gamma-glutamyltransferase (GGT) and negatively associated with direct bilirubin (DBIL) and total bilirubin (TBIL) in both the WQS and BKMR analyses. In addition, Spearman's correlation test showed individual PFAS correlated with APOB, GGT, TBIL, and DBIL, while there's little correlation between individual PFAS and other liver function indices. In linear regression analysis, PFHxS, PFOS, PFHpS, PFNA, PFDA, and PFUdA were associated with APOB; PFOA, PFDA, PFOS, PFNA, and PFUdA were associated with GGT. Subsequently, a metabolome-wide association study and mediation analysis were combined to explore metabolites that mediate these associations. The mechanisms linking PFAS to APOB and GGT are mainly related with amino acid and glycerophospholipid metabolism. High-dimensional mediation analysis showed that glycerophospholipids are the main markers of the association between PFAS and APOB, and that (R)-dihydromaleimide, Ile Leu, (R)-(+)-2-pyrrolidone-5-carboxylic acid, and L-glutamate are the main markers of the association between PFAS and GGT. In summary, overall associations between PFAS and specific indices of liver function were found using two statistical methods; the metabolic pathways and markers identified here may serve to prompt more detailed study in animal-based systems, as well as a similar detailed analysis in other populations.

Solid-phase extraction of palladium, platinum, and gold from water samples: comparison between a chelating resin and a chelating fiber with ethylenediamine groups.

Dissolved palladium (Pd), platinum (Pt), and gold (Au) form inert chloride complexes at low concentrations of pmol/kg in environmental water, thus rendering difficulty in the development of a precise analytical method for these metals. Herein, we report the preconcentration of Pd, Pt, and Au with a chelating fiber Vonnel-en and a chelating resin TYP-en with ethylenediamine (en) groups. Batch adsorption experiments reveal the adsorption capacity of Vonnel-en for Pd(II), Pt(IV), and Au(III) in 0.10 M HCl as 0.53, 0.22, and 0.27 mmol/g, respectively. The adsorption capacity of TYP-en for Pd(II), Pt(IV), and Au(III) in 0.10 M HCl is 0.31, 0.17, and 0.52 mmol/g, respectively. In column extraction experiments using small-volume samples containing Pd(II), Pt(II), Pt(IV), Au(I), or Au(III) at concentrations of µmol/kg, TYP-en is able to quantitatively recover Pd, Pt, and Au from 0.01 to 0.2 M HCl irrespective of their oxidation states. In contrast, Vonnel-en is unable to quantitatively recover Au(I). In column extraction experiments using large-volume samples containing Pd(II), Pt(IV), and Au(III) at concentrations of pmol/kg, the recovery of Pd(II), Pt(IV), and Au(III) by TYP-en from 0.07 M HCl is 100-105%. However, the recovery of Pd(II), Pt(IV), and Au(III) by Vonnel-en from 0.03 to 0.3 M HCl is 102-110, 7-15, and 20-52%, respectively. Thus, the chelating resin TYP-en has a high potential for the multielemental determination of Pd, Pt, and Au in environmental water.

Metabolome-wide association study of four groups of persistent organic pollutants and abnormal blood lipids.

Environmental exposure increases the risk of dyslipidemia, which affects human health. Research has shown that persistent organic pollutants (POPs), including per- and polyfluoroalkyl substances (PFASs), polychlorinated biphenyls, polybrominated diphenyl ethers, and phthalate metabolites, are associated with a higher risk of abnormal blood lipid levels in humans. However, the key molecules involved in dyslipidemia and the mechanisms are not fully understood. This study aims to investigate the biomarkers that mediate the relationships between blood lipids and four groups of POPs and revealed their potential mechanisms. Specifically, in 278 male blood samples, blood lipid and POPs levels were measured and metabolites were detected using untargeted metabolomics. Spearman's correlation analysis and binary logistic regression were employed to assess the relationship between POPs and lipid indexes. We observed that PFASs were associated with a higher risk of abnormal total cholesterol (TC) and low-density lipoprotein (LDL), while other POPs displayed little association with abnormal lipid indexes. Among all the PFASs, 6:2Cl-PFESA was associated with the fewest metabolites. A metabolome-wide association study combined with a meet-in-the-middle approach was used to identify potential biomarkers that mediate the association between POPs and abnormal blood lipids. The mediation analysis pointed to 105 significant mediators as potential biomarkers mediating the association between PFASs and TC, and 82 significant mediators were potential biomarkers that mediated the association between PFASs and LDL. 24-Hydroxycholesterol, 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al, PC(18:0/0:0), PC(22:5/0:0), GPCho(18:1/18:1), LysoPC(22:2(13Z,16Z)), LysoPC(16:0), 9(S)-HODE, 9,10-DHOME, l-glutamate, 4-hydroxybutyric acid, cytosine, PC(14:1(9Z)/18:0), sphinganine, and (S)-beta-aminoisobutyrate were identified as important biomarkers. The mechanism may mainly involves glycerophospholipid metabolism, primary bile acid biosynthesis, and linoleic acid metabolism. PPARγ likely plays a role in the associations between PFASs and abnormal cholesterol metabolism. Overall, our study provides clues for the early detection of PFAS-induced dyslipidemia and brings forth a theoretical framework for further research into this mechanism.

Acid-triggered, degradable and high strength-toughness copolyesters: Comprehensive experimental and theoretical study.

The popularization and widespread use of degradable polymers is hindered by their poor mechanical properties. It is of great importance to find a balance between degradation and mechanical properties. Herein, poly(butylene terephthalate) (PBT) modified by SPG diol from 10% to 40 mol% were synthesized through a two-step polycondensation reaction. Chemical structures, thermal properties, mechanical properties, viscoelastic behavior and degradation of poly(butylene terephthalate-co-spirocyclic terephthalate) (PBST) were investigated. The SPG could toughen the copolyesters and the elongation at break of PBST20 was up to 260%. Moreover, the introduction of SPG enables to provide an acid-triggered degradable unit in the main chain. PBSTs copolymers maintain stable structures in a neutral environment, and the degradation under acid conditions will be unlocked. As tailoring the content of SPG, the degradation rate of the chain scission in response to acid stimuli will be adjusted. The acid degradation was proved to be occurred at the SPG units in the amorphous phase by DSC, XRD, GPC and 1H NMR tests. After the acid degradation, the hydrolysis rate will also be accelerated, adapting to the requirements of different degradation schedules. The plausible hydrolytic pathways and mechanisms were proposed based on Fukui function analysis and density functional theory (DFT) calculation.

Major lithogenic contributions to the distribution and budget of iron in the North Pacific Ocean.

Recent studies have elucidated that iron (Fe) is a critical trace metal that influences the productivity of marine ecosystems and the biogeochemical cycles of other elements in the modern ocean. However, our understanding of the biogeochemistry of Fe remains incomplete. Herein, we report basin-scale and full-depth sectional distributions of total dissolvable iron (tdFe), dissolved iron (dFe), and labile particulate iron (lpFe = tdFe - dFe) in the North Pacific Ocean, as observed during three cruises of the GEOTRACES Japan program. We found that lpFe dominates tdFe and is significantly correlated with labile particulate aluminum (lpAl): lpFe [nmol kg-1] = (0.544 ± 0.005) lpAl [nmol kg-1] + 0.11 ± 0.04, r2 = 0.968, n = 432. The results indicate a major lithogenic contribution to the distribution of particulate Fe. For dFe, the unique distribution is attributed to the combined effects of biogeochemical cycling, manganese reduction, and lithogenic contribution. Based on concurrent observations of Fe, Al, and manganese (Mn), we infer that the width of the boundary scavenging zone is approximately 500 km off the Aleutian shelf. We estimate the inventory of tdFe in the North Pacific as 1.1 × 1012 mol, which is approximately four times that of dFe. Our results emphasize the potential importance of lpFe in the ocean's iron cycle.

Application of NOBIAS Chelate-PA 1 Resin to the Determination of Zirconium, Niobium, Hafnium, and Tantalum in Seawater.

Zirconium, niobium, hafnium, and tantalum are dissolved in seawater as hydroxide complexes at a concentration as low as 0.01 - 370 pmol kg-1 and are expected to be potential tracers for water masses in the ocean. Herein, we report a new analytical method for the multielemental determination of the four elements on the basis of column extraction, using a NOBIAS Chelate-PA 1 resin that contains ethylenediaminetriacetic acid groups. The elements were collected on the resin from seawater that had been added with 3.8 mM HF at pH 6.0, and were eluted with 5 M HF. After the evaporation of 5 M HF, the elements were dissolved in 0.5 M HNO3-6 mM H2SO4-1 mM HF and were determined by a high resolution ICP-MS, using a calibration curve method. We optimized the procedure to achieve quantitative recoveries and low backgrounds for the elements, although the complex formation between the metal ions and NOBIAS Chelate-PA 1 was decelerated by the seawater matrix. The method was tested by investigating the seawater samples of reference material and those collected from the depths at a station in the western North Pacific Ocean.

JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production.

Parthanatos is a form of PARP-1-dependent programmed cell death. The induction of parthanatos is emerging as a new strategy to kill gliomas which are the most common type of primary malignant brain tumor. Oxidative stress is thought to be a critical factor triggering parthanatos, but its underlying mechanism is poorly understood. In this study, we used glioma cell lines and H2O2 to investigate the role of JNK in glioma cell parthanatos induced by oxidative stress. We found that exposure to H2O2 not only induced intracellular accumulation of ROS but also resulted in glioma cell death in a concentration- and incubation time-dependent manner, which was accompanied with cytoplasmic formation of PAR polymer, expressional upregulation of PARP-1, mitochondrial depolarization, and AIF translocation to nucleus. Pharmacological inhibition of PARP-1 with 3AB or genetic knockdown of its level with siRNA rescued glioma cell death, as well as suppressed cytoplasmic accumulation of PAR polymer and nuclear translocation of AIF, which were consistent with the definition of parthanatos. Moreover, the phosphorylated level of JNK increased markedly with the extension of H2O2 exposure time. Either attenuation of intracellular ROS with antioxidant NAC or inhibition of JNK phosphorylation with SP600125 or JNK siRNA could significantly prevent H2O2-induced parthanatos in glioma cells. Additionally, inhibition of JNK with SP600125 alleviated intracellular accumulation of ROS and attenuated mitochondrial generation of superoxide. Thus, we demonstrated that JNK activation contributes to glioma cell parthanatos caused by oxidative stress via increase of intracellular ROS generation.

Insights into N-Heterocyclic Carbene-Catalyzed [4+2] Annulation Reaction of Enals with Nitroalkenes: Mechanisms, Origin of Chemo- and Stereoselectivity, and Role of Catalyst.

In this paper, density functional theory (DFT) calculations have been employed to investigate the detailed mechanisms, origin of chemo- and stereoselectivity, and role of catalyst for the reaction of enals with nitroalkenes catalyzed by N-heterocyclic carbenes (NHCs). The calculated results disclose that the reaction contains seven steps, that is, the nucleophilic attack on the α, ß-unsaturated aldehyde by NHC, the [1, 2]-proton transfer for the formation of Breslow intermediate, the ß-protonation for affording enolate intermediate, the nucleophilic addition on the Re/Si face of enolate by the nitroalkenes, the [1, 5] proton transfer, the ring-closure process, and the regeneration of NHC. The addition on the Re/Si face of enolate is identified to be the stereocontrolling step, in which the chiral centers including α-carbon of enals and ß-carbon of nitroalkenes are formed. Moreover, the reaction pathway leading to the RR-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experimental observation. Furthermore, the analyses of electrophilic and nucleophilic Parr functions and global reactivity indices (GRIs) have been performed to explore the origin of chemoselectivity and the role of catalyst. This theoretical work would provide valuable insights for the rational design of more effective organocatalyst for this kind of reactions with high stereoselectivities.

Pristimerin triggers AIF-dependent programmed necrosis in glioma cells via activation of JNK.

Programmed necrosis is established as a new form of programmed cell death and is emerging as a new strategy of treatment for cancers. Pristimerin is a natural chemical with anti-tumor effect despite the fact that its mechanism remains poorly understood. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the effect of pristimerin on glioma and its underlying mechanism. We found that pristimerin inhibited the viabilities of glioma cells in vitro and the growth of xenograft gliomas in vivo, which was accompanied by upregulation of JNK and phosphor-JNK, nuclear accumulation of AIF, and elevation in the ratio of Bax/Bcl-2. In vitro studies showed that pristimerin induced necrosis in glioma cells, as well as mitochondrial depolarization, overproduction of ROS and reduction of GSH. Ablation of AIF level with SiRNA mitigated pristimerin-induced nuclear accumulation of AIF and prevented necrosis in glioma cells. Moreover, pharmacological inhibition of JNK with SP600125 or knockdown of its level with SiRNA reversed mitochondrial depolarization attenuated the elevation of Bax/Bcl-2 and suppressed nuclear accumulation of AIF. Further, inhibition of ROS with NAC not only rescued glioma cell necrosis but also suppressed JNK activation, mitigated Bax/Bcl-2 ratio, maintained mitochondrial membrane potential, and inhibited AIF translocation into nucleus. Therefore, we demonstrated first in this study that pristimerin triggered AIF-dependent necroptosis in glioma cells via induction of mitochondrial dysfunction by activation of JNK through overproduction of ROS. These results suggest that pristimerin has potential therapeutic effects on glioma.

An off-line automated preconcentration system with ethylenediaminetriacetate chelating resin for the determination of trace metals in seawater by high-resolution inductively coupled plasma mass spectrometry.

A novel automated off-line preconcentration system for trace metals (Al, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb) in seawater was developed by improving a commercially available solid-phase extraction system SPE-100 (Hiranuma Sangyo). The utilized chelating resin was NOBIAS Chelate-PA1 (Hitachi High-Technologies) with ethylenediaminetriacetic acid and iminodiacetic acid functional groups. Parts of the 8-way valve made of alumina and zirconia in the original SPE-100 system were replaced with parts made of polychlorotrifluoroethylene in order to reduce contamination of trace metals. The eluent pass was altered for the back flush elution of trace metals. We optimized the cleaning procedures for the chelating resin column and flow lines of the preconcentration system, and developed a preconcentration procedure, which required less labor and led to a superior performance compared to manual preconcentration (Sohrin et al.). The nine trace metals were simultaneously and quantitatively preconcentrated from ∼120 g of seawater, eluted with ∼15 g of 1M HNO3, and determined by HR-ICP-MS using the calibration curve method. The single-step preconcentration removed more than 99.998% of Na, K, Mg, Ca, and Sr from seawater. The procedural blanks and detection limits were lower than the lowest concentrations in seawater for Mn, Ni, Cu, and Pb, while they were as low as the lowest concentrations in seawater for Al, Fe, Co, Zn, and Cd. The accuracy and precision of this method were confirmed by the analysis of reference seawater samples (CASS-5, NASS-5, GEOTRACES GS, and GD) and seawater samples for vertical distribution in the western North Pacific Ocean.

Highly emissive deoxyguanosine analogue capable of direct visualization of B-Z transition.

A 2-aminothieno[3,4-d]pyrimidine G-mimic deoxyribonucleoside, (th)dG, was synthesized and incorporated readily into oligonucleotides as a versatile fluorescent guanine analogue. We demonstrate that (th)dG enables the visual detection of Z-DNA successfully based on different π-stacking of B- and Z-DNA.