Novel MCP-Windowed EUV Light Source and Its Mass Spectrometric Application for Detecting Chlorinated Methanes.

Various vacuum ultraviolet (VUV) lamps are simple and convenient VUV light sources for mass spectrometry and other research fields. However, the strong absorption of high-energy photons by window materials limits the application of an extreme ultraviolet (EUV) light. In this study, a novel high-flux EUV light source is developed using a microchannel plate (MCP) window to transmit 73.6 nm (16.9 eV) EUV light generated via the radio frequency (RF) inductive discharge of neon. The MCP used is a 0.5 mm thick glass plate with a regular array of microtubes (12 µm i.d.). The photon fluxes of the EUV light source with the MCP window (12 mm i.d.) and an aperture (1.8 mm i.d.) are ∼1.31 × 1014 and ∼9.80 × 1012 photons s-1, respectively, while their corresponding leakage flow rates of the discharge gas are 0.062 and 0.046 cm3 atom s-1, according to the contrast experiments. The transmission efficiency of the MCP to the EUV light is 30.2%, with a 1.2% deviation. An EUV photoionization time-of-flight mass spectrometer (EUV-PI-TOFMS) is built to validate the practicality of the MCP-windowed EUV light source further. The detection sensitivities in 30 s measurements for methyl chloride (CH3Cl), methylene chloride (CH2Cl2), trichloromethane (CHCl3), and carbon tetrachloride (CCl4) in synthetic air are 4366, 4120, 5854, and 4095 counts ppbv-1, respectively. The corresponding 3σ limits of detection (LODs) are 42, 34, 24, and 15 pptv. This study develops a new feasible method for efficiently utilizing high-energy EUV light, with many application prospects in scientific research.

Sex difference in driving speed management: The mediation effect of impulse control.

Previous studies have shown that male drivers drive faster than female drivers, but there is no agreement on whether impulsivity could induce this sex difference, nor is there a cross-sectional comparison of the effects of different road environments. The purpose of this study was to verify whether impulsivity and impulse control could explain the sex differences in driving speed. A driving simulator study (study 1, N = 41) was performed to investigate whether there were sex differences in driving speeds in two road sections of different complexity, and a questionnaire survey (study 2, N = 163) was conducted to investigate the relationship between sex, impulsivity, impulse control and driving behavior of the participants. The results showed that male drivers drove faster on simple roads, but this difference did not show on complex roads. There were no sex differences in impulsivity traits, but male participants had significant lower levels of impulse control. The results also reveal a partial mediating role of impulse control in the relationship between sex and driving speed. These results suggest that impulse control can predict dangerous driving behaviors and is an important factor in explaining sex differences in driving speed.

A Simple High-Flux Switchable VUV Lamp Based on an Electrodeless Fluorescent Lamp for SPI/PAI Mass Spectrometry.

Single-photon ionization (SPI) is a unique soft ionization technique for organic analysis. A convenient high-flux vacuum ultraviolet (VUV) light source is a key precondition for wide application of SPI techniques. In this study, we present a novel VUV lamp by simply modifying an ordinary electrodeless fluorescent lamp. By replacing the glass bulb with a stainless steel bulb and introducing 5% Kr/He (v/v) as the excitation gas, an excellent VUV photon flux over 4.0 × 1014 photons s-1 was obtained. Due to its rapid glow characteristics, the VUV lamp can be switched on and off instantly as required by detection, ensuring the stability and service life of the lamp. To demonstrate the performance of the new lamp, the switchable VUV lamp was coupled with an SPI-mass spectrometer, which could be changed to photoinduced associative ionization (PAI) mode by doping gaseous CH2Cl2 to initiate an associative ionization reaction. Two types of volatile organic compounds sensitive to SPI and PAI, typically benzene series and oxygenated organics, respectively, were selected as samples. The instrument exhibited a high detection sensitivity for the tested compounds. With a measurement time of 11 s, the 3σ limits of detection ranged from 0.33 to 0.75 pptv in SPI mode and from 0.03 to 0.12 pptv in PAI mode. This study provides an extremely simple method to assemble a VUV lamp with many merits, e.g., portability, robustness, durability, low cost, and high flux. The VUV lamp may contribute to the development of SPI-related highly sensitive detection technologies.

Direct detection of acetonitrile at the pptv level with photoinduced associative ionization time-of-flight mass spectrometry.

Photoionization mass spectrometry (PI-MS) has become a versatile tool in the real-time analysis of volatile organic compounds (VOCs) from the atmosphere or exhaled breath. However, some key species, e.g., acetonitrile, are hard to measure due to their higher ionization energies than photon energy. In this study, the direct and sensitive detection of gaseous acetonitrile based on a photoinduced associative ionization (PAI) reaction was investigated with a laboratory-built PAI time-of-flight mass spectrometer (PAI-TOFMS). By doping CH2Cl2 in the photoionization ion source, the mass signal of acetonitrile that cannot be effectively obtained by photoionization appeared with an extremely high intensity through the PAI reaction between acetonitrile, CH2Cl2, and residual H2O in the system. Though the moisture in the sample gas has an evident impact on the detection efficiency of acetonitrile, with a relative signal intensity decreasing from 100% under dry conditions to 60% at saturated relative humidity, excellent detection sensitivity was still obtained for gaseous acetonitrile in different matrixes. The sensitivity calibration experiment showed that the detection sensitivities of acetonitrile in N2 buffer gas, exhaled gas, and outdoor air were 682.4 ± 5.2, 17.0 ± 0.7, and 23.9 ± 0.2 counts pptv-1, respectively, with an analysis time of 10 s. The corresponding 3σ LODs reached 0.22, 8.82, and 6.28 pptv, which are equivalent to 0.40, 16.0, and 11.4 ng m-3. The performance of the PAI-TOFMS was first demonstrated by analyzing exhaled acetonitrile from healthy non-smokers and smokers and continuous monitoring of acetonitrile in outdoor air. In summary, this study provides a new and highly sensitive method for the real-time detection of acetonitrile through mass spectrometry.

Association between fluoroquinolone exposure and children's growth and development: A multisite biomonitoring-based study in northern China.

BACKGROUND: Although animal experiments found that antibiotic exposure during early life increased adiposity, limited human epidemiological evidence is available for the effects of veterinary antibiotic exposure on children's growth and development. OBJECTIVE: This study was conducted to examine the body burden of fluoroquinolones in northern Chinese children and assess its association with growth and development. METHODS: After recruiting 233 children aged 0-15 years from 12 different sites in northern China in 2020, we measured urinary concentrations of 5 respective fluoroquinolones (fleroxacin, ofloxacin, norfloxacin, ciprofloxacin, and enrofloxacin) by high performance liquid chromatography. Categories of children's growth and development were identified based on the Z score of body mass index. The health risks of individual and combined antibiotic exposure were estimated by the hazard quotient (HQ) and hazard index (HI), respectively. The association between children's growth and development with antibiotic concentrations was evaluated via multiple logistic regression analysis. RESULTS: In total, 4 antibiotics, fleroxacin, ofloxacin, ciprofloxacin, and enrofloxacin, were found in urine samples of northern Chinese children at an overall frequency of 57.08%. Due to diet and economic differences, antibiotic concentrations in urine samples differed by study area, and the highest concentrations were found in Tianjin, Henan, and Beijing. The percentage of the participants with HQ > 1 caused by ciprofloxacin exposure was 20.61%, and the HI values in 23.18% of samples exceeded 1, suggesting potential health risks. The odds ratio (95% confidence interval) of overweight or obesity risk of tertile 2 of enrofloxacin was 3.01 (1.12, 8.11), indicating an increase in overweight or obesity risk for children with middle-concentration enrofloxacin exposure. CONCLUSION: This is the first study to show a positive association of enrofloxacin internal exposure with overweight or obesity risk in children, demonstrating that more attention should be given to the usage and disposal of fluoroquinolones to safeguard children's health.

Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl Rearrangement of 1,3-Diketones toward Bicyclic Lactams.

Although copper-nitrene has been extensively studied as a versatile active species in various transformations, asymmetric reactions involving copper-nitrene have been limited to the aziridination of olefins. Herein, we report the novel copper-nitrene-catalyzed desymmetric oxaziridination reaction of cyclic diketones with alkyl azides and the subsequent rearrangement of the resulting highly active intermediate, which produces a synthetically challenging chiral bicyclic lactam containing a quaternary carbon center. This procedure not only enriches the copper-nitrene-catalyzed asymmetric reactions, but also provides an alternative strategy to address the inherent challenges of catalytic asymmetric Schmidt reactions. This unique reaction could inspire the investigation of novel copper-nitrene-catalyzed asymmetric transformations and their reaction mechanisms.

Efficient degradation of tetracycline by CoFeLa-layered double hydroxides catalyzed peroxymonosulfate: Synergistic effect of radical and nonradical pathways.

Advanced oxidation technologies based on peroxymonosulfate (PMS) have attracted increasing attention because of their high reactivity and selectivity. Herein, we reported a novel CoFeLa-LDH catalyst, which exhibited excellent performance to activate PMS for tetracycline (TC) elimination. The influence of extra addition, simulation wastewater tests and the reusability experiments were investigated in detail. Remarkably, the quenching experiments and the results of EPR demonstrated the synergistic effect of radical and nonradical pathways in the TC degradation. Free radicals (SO4- and HO) played predominant roles in the first 1 min, and then both free and non-free radicals (1O2) interacted with TC. The possible TC degradation pathways were proposed on basis of the intermediates, which were analyzed by UPLC-QTOF-MS/MS. Finally, the reaction mechanisms of TC degradation in CoFeLa-LDH2/PMS system were proposed according to the comprehensive analysis.

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.

Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces degradation of low-density lipoprotein receptor (LDLR) in the liver. It is being pursued as a therapeutic target for LDL-cholesterol reduction. Earlier genome-wide gene expression studies showed that PCSK9 over-expression in HepG2 cells resulted in up-regulation of genes in cholesterol biosynthesis and down-regulation of genes in stress response pathways; however, it was not known whether these changes were directly regulated by PCSK9 or were secondary to PCSK9-induced changes to the intracellular environment. In order to further understand the biological function of PCSK9 we treated HepG2 cells with purified recombinant wild type (WT) and D374Y gain-of-function PCSK9 proteins for 8, 24, and 48 h, and used microarray analysis to identify genome-wide expression changes and pathways. These results were compared to the changes induced by culturing HepG2 cells in cholesterol-free medium, mimicking the intracellular environment of cholesterol starvation. We determined that PCSK9-induced up-regulation of cholesterol biosynthesis genes resulted from intracellular cholesterol starvation. In addition, we identified novel pathways that are presumably regulated by PCSK9 and are independent of its effects on cholesterol uptake. These pathways included "protein ubiquitination," "xenobiotic metabolism," "cell cycle," and "inflammation and stress response." Our results indicate that PCSK9 affects metabolic pathways beyond cholesterol metabolism in HepG2 cells.

PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) and induces its internalization and degradation. PCSK9 binding to LDLR is mediated through the LDLR epidermal growth factor-like repeat A (EGF-A) domain. We show for the first time that an EGF-A peptide inhibits PCSK9-mediated degradation of LDLR in HepG2 cells. In addition to LDLR, we show that PCSK9 also binds directly to ApoER2 and mouse VLDLR. Importantly, binding of PCSK9 to either LDLR or mouse VLDLR was effectively inhibited by EGF-A while binding to ApoER2 was less affected. In contrast, LDL receptor-associated protein (RAP), which interacts with LDL receptor repeat type A (LA) domains, inhibited PCSK9 binding to ApoER2 with greater efficacy than either LDLR or mVLDLR. These data demonstrate that while PCSK9 binds several receptors via its EGF-A binding domain, additional contacts with other receptor domains are also involved.

Cloning and characterization of murine neuromedin U receptors.

Neuromedin U (NmU) is a neuropeptide involved in various physiological functions such as feeding behavior, muscle contractile activity, and regulation of intestinal ion transport. Recently, two human G protein-coupled receptors have been identified as NmU-specific receptors, NmU-R1 and NmU-R2, which share 55% amino acid identity. It is unclear however, which of the two receptors mediates responses to NmU observed in rodent models. Attempts to define the pharmacological profile of the two receptors are confounded by overlapping expression of the two receptors and a lack of subtype-selective compounds. In order to establish a basis to further our understanding of the function of these receptors, we cloned and characterized the mouse homologues of the two human NmU receptors. Mouse NmU-R1 and mouse NmU-R2 are 79 and 81% identical to their respective human homologues. Expression of NmU-R1 was mainly observed in testis, gastrointestinal (GI) tract, and immune system, while NmU-R2 was primarily expressed in brain tissues. Each mouse receptor was independently expressed in HEK293 cells and demonstrated a dose-dependent calcium flux in response to NmU-8, NmU-23 and NmU-25. In an attempt to identify a synthetic NmU peptide that would exhibit selectivity at one of the two receptors, we examined the functional activity of eight alanine-substituted NmU-8 peptides. These experiments demonstrated that alanine substitution at positions 5 and 7 affects the functional activity of the peptide at both receptors. The arginine residue at position 7 is required for NmU-8 activity at either receptor while alanine substitution at position 5 selectively affects the potency and the efficacy at mNmU-R1. These experiments validate the use of rodent models to characterize NmU function relative to humans and suggest that substitution at Arginine-5 of NmU-8 may provide a receptor selective peptide.