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In this paper, an efficiency tunable reflective metasurface (MS) consisting of a dielectric substrate sandwiched between hollow Z-shaped (HZS) structure graphene and a metallic ground plane is proposed for single/dual-focusing effects based on Pancharatnam-Berry (PB) in terahertz (THz) region. Numerical simulations demonstrate that the designed HZS graphene can achieve a circular polarization (CP) conversion with efficiency of approximately 98 % at a Fermi energy level (EF) of 1.0 eV. Moreover, by adjusting the rotation angle of the HZS graphene, a full 0-2π phase coverage can be achieved. Of note, the simulation results also reveal that the reflective CP conversion efficiency is highly dependent on the value of the EF. By carefully designing the spatial phase distribution of the graphene MS, tunable reflective single/dual-focusing effects can be realized, with focusing efficiency controlled by the EF. It is anticipated that the proposed tunable graphene MS will have broad applications in communications, imaging, and others in THz domains.

The objective of this paper is to explore the transient behaviors of fiber reinforced composites with two embedded collinear cracks subject to a sudden thermal shock. The orthotropic composites with both the vertically oriented and horizontally aligned fibers are examined to present a systematic comparison. By means of the integral transform methodology and singular integral equations, the thermal and elastic governing equations are solved numerically to determine the transient thermal process and stress intensifications around the crack tips. Parametric investigations are carried out for fiber volume fractions and crack distances. The findings would be beneficial to a more thorough knowledge of fibrous composites’ fracture characteristics under thermal shocks, which helps material design and structural optimization of the composites with fiber reinforcements.

Abstract The combination of macrocyclic chemistry with co-crystal engineering has promoted the development of materials with vapochromic behaviors in supramolecular science. Herein, we develop a macrocycle co-crystal based on hybrid[4]arene and 1,2,4,5-tetracyanobenzene that is able to construct vapochromic materials. After the capture of benzene and toluene vapors, activated hybrid[4]arene-based co-crystal forms new structures, accompanied by color changes from brown to yellow. However, when hybrid[4]arene-based co-crystal captures cyclohexane and pyridine, neither structures nor colors change. Interestingly, hybrid[4]arene-based co-crystal can separate benzene from a benzene/cyclohexane equal-volume mixture and allow toluene to be removed from a toluene/ pyridine equal-volume mixture with purities reaching 100%. In addition, the process of adsorptive separation can be visually monitored. The selectivity of benzene from a benzene/cyclohexane equal-volume mixture and toluene from a toluene/ pyridine equal-volume mixture is attributed to the different changes in the charge-transfer interaction between hybrid[4]arene and 1,2,4,5-tetracyanobenzene when hybrid[4]arene-based co-crystal captures different vapors. Moreover, hybrid[4]arene-based co-crystal can be reused without losing selectivity and performance. This work constructs a vapochromic material for hydrocarbon separation.

Objective: The aim of this study was to elucidate the genetic pathways associated with Moyamoya disease (MMD) and Moyamoya syndrome (MMS), compare the functional activities, and validate relevant related genes in an independent dataset. Methods: We conducted a comprehensive search for genetic studies on MMD and MMS across multiple databases and identified related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments analyses were performed for these genes. Commonly shared genes were selected for further validation in the independent dataset, GSE189993. The Sangerbox platform was used to perform statistical analysis and visualize the results. P＜0.05 indicated a statistically significant result. Results: We included 52 MMD and 51 MMS-related publications and identified 126 and 51 relevant genes, respectively. GO analysis for MMD showed significant enrichment in cytokine activity, cell membrane receptors, enzyme binding, and immune activity. A broader range of terms was enriched for MMS. KEGG pathway analysis for MMD highlighted immune and cellular activities and pathways related to MMS prominently featured inflammation and metabolic disorders. Notably, nine overlapping genes were identified and validated. The expressions of RNF213, PTPN11, and MTHFR demonstrated significant differences in GSE189993. A combined receiver operating characteristic curve showed high diagnostic accuracy (AUC = 0.918). Conclusions: The findings indicate a close relationship of MMD with immune activity and MMS with inflammation, metabolic processes and other environmental factors in a given genetic background. Differentiating between MMD and MMS can enhance the understanding of their pathophysiology and inform the strategies for their diagnoses and treatment.

Polygonatum odoratum is widely recognized to conribute to various health benefits, primarily attributed to its polysaccharide (POP). Polysaccharides are not directly and readily absorbed by the gastrointestinal system, but can interact with the gut microbes. This study aims to clarify the mechanism of POP in mitigating and preventing OVA-induced allergic airway inflammation via the gut-lung axis. The results showed that POP improved the symptoms associated with allergic respiratory responses, and the efficacy of POP was impeded due to the disruption of gut microbiota caused by antibiotics. The POP altered gut microbiota effectively alleviated the type 2 inflammation, reduced the number of ILC2s in the lung and gut, and inhibited the movement of intestinal ILC2s towards the lung. Clostridia UCG-014 and Rikenellaceae RC9 were figured out as pathogenic bacteria inhibited by POP. This study provides a reference for therapeutic application of POP in managing allergic airway inflammation via the gut-lung axis.

This study employs artificial neural networks (ANNs) to predict the structural compliance of randomly generated irregular geometries derived from Finite Element (FE) calculations. By imposing volume constraints, the scope of the study is confined to applying ANNs for learning from structural data generated by considering either multiple random walks of a circle or a set of randomly placed circles with allowed overlaps. Numerical results indicate that the learning outcomes of the former approach are more satisfactory than those of the latter. This suggests that the effectiveness of employing ANNs for predicting the structural compliance of irregular geometries is contingent upon how the random geometries are generated and the material volume ratio. The learning outcomes of irregular structures generated by the former approach with a higher volume ratio exhibit greater satisfaction due to a higher degree of structural connectivity.

The raw and steamed products of ginseng exhibit different efficacy, and elucidation of the underlying chemical transformation is significant for their rational application and quality control. This work was designed to holistically depict the chemical variation of Panax ginseng (PG), P. quinquefolius (PQ), and P. notoginseng (PN) induced by the steaming, and to unveil the steaming-associated markers diagnostic for differentiating between the raw and processed products, following a three-step strategy: 1) systematic ginsenosides characterization by hybrid scan (namely HDDIDDA) available on the Vion™ ion mobility-quadrupole time-of-flight mass spectrometer coupled with reversed-phase ultra-high performance liquid chromatography; 2) holistic depiction of the chemical variation and discovery of potential markers by the pattern recognition untargeted metabolomics analysis; and 3) construction of steaming-induced transformation network combined with desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). Consequently, 542 ginsenosides were characterized from the raw and processed PG/PQ/PN. Steaming at 1–10 h could cause significant chemical variation, and separately 26, 28, and 18 potential markers were found for the steaming of PG, PQ, and PN. Steaming-induced transformation network mainly involved hydration of the malonyl group, hydrolysis of the glycosyl moiety, and dehydration at C-20. DESI-MSI further revealed spatial distribution of marker saponins in the cork layer, phloem, and xylem, and primarily confirmed the hydrolysis reactions occurring to ginseng steaming. Conclusively, the established strategy is practical to unveil the holistic ginsenosides variation of ginseng induced by the processing, which is useful in the quality control of both the herbal medicines and foods.

Abstract Background It has been reported that metformin use may reduce the risk of thyroid cancer, but existing studies have generated inconsistent results. The purpose of this study was to investigate such association between metformin use and the risk of thyroid cancer. Methods Studies of metformin use for the risk of thyroid cancer were searched in Web of Science, PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biomedical Database, Wanfang Data, and Chinese Scientific Journals Database (VIP) from the establishment date to December 2022. Newcastle–Ottawa scale is adopted for assessing the methodological quality of included studies, and the inter-study heterogeneity was assessed by using the I-squared statistic. Combined odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated through either fixed-effects or random-effects model according to the heterogeneity. Besides, subgroup analyses, sensitivity analyses and test for publication bias were conducted. Results Five studies involving 1,713,528 participants were enrolled in the qualitative and quantitative synthesis. The result of the meta-analyses showed that metformin use was associated with a statistically significant lower risk of thyroid cancer (pooled OR = 0.68, 95% CI = 0.50–0.91, P = 0.011). Moreover, in the subgroup analysis, we found that the use of metformin may also aid in the prevention of thyroid cancer in Eastern population (pooled OR = 0.55, 95% CI = 0.35–0.88, P = 0.012) rather than Western population (pooled OR = 0.89, 95% CI = 0.52–1.54, P = 0.685). Sensitivity analysis suggested the results of this meta-analyses were relatively stable. No publication bias was detected. Conclusion Metformin use is beneficial for reducing the risk of thyroid cancer. For further investigation, more well-designed studies are still needed to elucidate the association between metformin use and the risk of thyroid cancer.

Abstract Background Panax japonicus var. major (PJM) belongs to the well-known ginseng species used in west China for hundreds of years, which has the effects of lung tonifying and yin nourishing, and exerts the analgesic, antitussive, and hemostatic activities. Compared with the other Panax species, the chemical composition and the spatial tissue distribution of the bioactive ginsenosides in PJM have seldom been investigated. Methods Ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS) and desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) were integrated for the systematic characterization and spatial tissue distribution studies of ginsenosides in the rhizome of PJM. Considering the great difficulty in exposing the minor saponins, apart from the conventional Auto MS/MS (M1), two different precursor ions list-including data-dependent acquisition (PIL-DDA) approaches, involving the direct input of an in-house library containing 579 known ginsenosides (M2) and the inclusion of the target precursors screened from the MS1 data by mass defect filtering (M3), were developed. The in situ spatial distribution of various ginsenosides in PJM was profiled based on DESI-MSI with a mass range of m/z 100–1500 in the negative ion mode, with the imaging data processed by the High Definition Imaging (HDI) software. Results Under the optimized condition, 272 ginsenosides were identified or tentatively characterized, and 138 thereof were possibly not ever reported from the Panax genus. They were composed by 75 oleanolic acid type, 22 protopanaxadiol type, 52 protopanaxatriol type, 16 octillol type, 19 malonylated, 35 C-17 side-chain varied, and 53 others. In addition, the DESI-MSI experiment unveiled the differentiated distribution of saponins, but the main location in the cork layer and phloem of the rhizome. The abundance of the oleanolic acid ginsenosides was high in the rhizome slice of PJM, which was consistent with the results obtained by UHPLC/QTOF-MS. Conclusion Comprehensive characterization of the ginsenosides in the rhizome of PJM was achieved, with a large amount of unknown structures unveiled primarily. We, for the first time, reported the spatial tissue distribution of different subtypes of ginsenosides in the rhizome slice of PJM. These results can benefit the quality control and further development of PJM and the other ginseng species.

In recent years, there has been a growing awareness of the potential health benefits of the natural environment for human well-being. Given the fast-paced nature of contemporary lifestyles, research into the use of virtual environments as a means to provide various seasonal landscapes has gained increasing importance.ObjectiveThe aim of this study is to investigate the impact of different sensory modes on the preferences and therapeutic effects of virtual autumn landscapes on university campuses.MethodsIn this study, 320 participants, with an average age of 21.11 years (±1.21 years), were exposed to virtual environments featuring autumn color landscapes and bare tree landscapes using visual, auditory, and combined conditions. A control group was included for comparison. Differences in participants' physiological indicators (EEG, heart rate) and psychological measures (POMS, PANAS, SVS, ROS) were analyzed, with the use of the Holm correction (P < 0.05).Results(1) Autumn virtual landscapes with color had a superior therapeutic effect. (2) There were significant differences in the therapeutic effects of different sensory modes within the same season's landscape categories, suggesting that incorporating additional sensory dimensions may enhance therapeutic outcomes.ConclusionBased on the study's findings, we recommend that when designing therapeutic environments, attention should be given to seasonal variations and the integration of various sensory modes to optimize therapeutic results.

BackgroundRecurrent pregnancy loss is a distressing event during pregnancy, and understanding its causal factors is crucial. Follistatin, a glycoprotein involved in folliculogenesis and embryogenesis, has been implicated as a potential contributor to the risk of spontaneous abortion. However, establishing a causal relationship requires rigorous investigation using robust methods.MethodsIn this study, we utilized mendelian randomization (MR), a powerful genetic epidemiological approach, to examine the causal relationship between follistatin levels and spontaneous abortion. We obtained instrumental variables strongly associated with follistatin levels from large-scale genome-wide association from the IEU database. The inverse variance weighting (IVW) method was taken as gold standard. We also performed sensitivity test to evaluate the robustness of our result.ResultsMR analysis revealed a significant causal relationship between low follistatin levels and spontaneous abortion (p = 0.03). Sensitivity analyses, including pleiotropy test, heterogeneity test, and leave-one-out analysis, all supported the robustness of our findings.ConclusionOur study provides compelling evidence supporting the causal relationship between low follistatin levels and increased risk of spontaneous abortion. These findings underscore the importance of follistatin in the etiology of spontaneous abortion and suggest potential preventive interventions. Modulating follistatin levels or relevant pathways could hold promise for reducing the incidence of spontaneous abortion and improving reproductive outcomes. The utilization of MRs strengthens the validity of our results by mitigating confounding and reverse causality biases. Further research is needed to elucidate the underlying molecular mechanisms and explore therapeutic strategies targeting follistatin levels.

This study aimed to prepare an o/w mitiglinide microemulsion (MTGME) to improve the drug solubility and bioavailability. The formulation of o/w MTGME was optimized by the solubility study of drug, pseudo-ternary phase diagram and Box-Behnken design successively. MTGME was characterized by dynamic laser light scattering (DLS), zeta potential and transmission electron microscopy (TEM), moreover, the storage stability, pharmacodynamics and pharmacokinetics were investigated. The optimal prescription for MTGME consisted of Maisine 35–1 (oil), Cremophor EL (surfactant) and propylene glycol (PG, cosurfactant). MTGME with a spherical dimension of 58.1 ± 5.86 nm was stable when stored at 4 °C for 3 months. The blood glucose levers (BGL) of diabetic mice were uniformly and significantly decreased by intragastric (i.g.) administration of 1–4 mg/kg MTGME, in which BGL (i.g. 4 mg/kg MTGME) was reduced by 69% during 24 h. The pharmacokinetics study of MTGME (i.g., 20 mg/kg) in Wistar rats showed higher plasma drug concentration (Cmax, 2.9 folds), larger area under curve (AUC, 4.6 folds) and oral bioavailability than those of MTG suspensions. Generally, the MTGME (o/w) showed good effect on controlling hyperglycemia. Therefore, microemulsion can be used as an effective oral drug delivery system to improve the bioavailability of MTG.

Weichang'an pill (WCAP) is a traditional Chinese patent medicine, which is clinically used for the treatment of bowel syndrome and functional dyspepsia such as diarrhea, abdominal distension, and enteritis. So far, quality control studies of WCAP have mainly focused on the determination of chemical composition content, which has little relevance to biological activity and clinical effects. With the aim of identifying the multi-index ingredients with NF-κB inhibitory activities related to WCAP clinical effect, this present work described the chemical profile of WCAP by UHPLC-QE-MS, established the correlated relationship between chromatographic fingerprints and the NF-κB inhibitory activities based on multivariate statistical analysis, including hierarchical clustering analysis (HCA), Pearson correlation analysis, and Partial least squares regression analysis (PLSR). The spectrum-effect relationship analysis indicated 10 compounds, which were ferulic acid, naringin, narirutin, hesperidin, neohesperidin, aloe emodin, emodin, honokiol, magnolol, and physcion, might be the potential NF-κB inhibitory constituents in the pill. The NF-κB inhibitory effects of the ten compounds were verified by in vitro dual luciferase reporting detection system. Considering that the detection index should be representative of more medicinal materials, a rapid and efficient UPLC-DAD method was eventually developed to determine the content of the 13 components. Our findings will provide data support for WCAP quality control and advance the understanding of the quality assessment of traditional Chinese patent medicines.

For wild natural medicine, unanticipated biodiversity as species or varieties with similar morphological characteristics and sympatric distribution may co-exist in a single batch of medical materials, which affects the efficacy and safety of clinical medication. DNA barcoding as an effective species identification tool is limited by its low sample throughput nature. In this study, combining DNA mini-barcode, DNA metabarcoding and species delimitation method, a novel biological sources consistency evaluation strategy was proposed, and high level of interspecific and intraspecific variations were observed and validated among 5376 Amynthas samples from 19 sampling points regarded as “Guang Dilong” and 25 batches of proprietary Chinese medicines. Besides Amynthas aspergillum as the authentic source, 8 other Molecular Operational Taxonomic Units (MOTUs) were elucidated. Significantly, even the subgroups within A. aspergillum revealed here differ significantly on chemical compositions and biological activity. Fortunately, this biodiversity could be controlled when the collection was limited to designated areas, as proved by 2796 “decoction pieces” samples. This batch biological identification method should be introduced as a novel concept regarding natural medicine quality control, and to offer guidelines for in-situ conservation and breeding bases construction of wild natural medicine.

In terrestrial medicinal plants, polyacetylenoids have been isolated from almost 110 species belonging to 11 families including Compositae, Apiaceae, Araliaceae, Campanulaceae, Annonaceae, and Meliaceae. They are a class of natural products derived from fatty acids with carbon chain lengths of C8–19, C21, C23–25, C27, C29, and C33, possessing a pleiotropic profile of bioactivities such as anti-tumor, anti-inflammatory activities. Herein, this review aims at summarizing the inventory of polyacetylenoids occurring in terrestrial medicinal plants during the last two decades from 2000 to 2023, the NMR characteristics, and the progress on analytical methods and pharmacological investigation of the well-known plant polyacetylenoids.

Experimental evidence shows heat conduction in the porous media would be non-Fourier under specific circumstances. The novelty of this research lies in considerations of the non-Fourier effect and the interactions of two parallel thermally insulated cracks in the porous metal foam. The transient propagation characteristics are examined by utilizing the Dual-phase-lag model, which incorporates the certain time required to establish local thermal equilibrium between the solid framework and surrounding pores. Fourier transform and Laplace transform are employed to solve the mathematical model simulating a porous strip subjected to abrupt thermal shock. After reducing the problem to two groups of singular integral equations, the transient temperature distributions and heat flux intensity factors are determined with the help of numerical Laplace inversion. Numerical calculations are carried out to evaluate the impacts of crack positions, the relative density, phase lags, and two crack lengths on the thermal characteristics, which would contribute to a thorough understanding of the ultrafast process of porous materials operating in extreme conditions.

Objective To assess the efficacy of subthreshold micropulse laser photocoagulation (SMLP) therapy versus anti-vascular endothelial growth factor (anti-VEGF) therapy in patients with refractory macular edema (ME) secondary to non-ischemic branch retinal vein occlusion (BRVO). Methods This single-center, prospective, nonrandomized, case-control trial involved patients with refractory ME that responded poorly to three or more initial anti-VEGF injections. The patients were examined and divided into two groups according to their chosen treatment: the intravitreal ranibizumab (IVR) group and the SMLP group. Both groups were followed up monthly for 12 months. Therapeutic efficacy and safety were assessed throughout the follow-up period. Results The IVR group comprised 49 eyes, and the SMLP group comprised 45 eyes. The improvements in the optical coherence tomography findings and visual acuity were comparable between the two groups at the final follow-up. The total number of injections was significantly lower in the SMLP than IVR group. No serious adverse events occurred during the study period. Conclusions SMLP therapy is better for patients with central macular thickness (CMT) of ≤400 μm. For patients with CMT of >400 μm, we advise continuation of anti-VEGF agents to reduce ME followed by application of SMLP therapy when CMT has decreased to ≤400 μm.

Perilla frutescens was an annual herb considered as one of the “One Root of Medicine and Food”, and it was used widely for food and medical treatment. Its main active ingredients were volatile organic compounds (VOCs), but it was easily affected during drying and storage. The leaves, seeds and stems had shown differences in therapeutic effects, but the underlying reason remained unclear. In the present work, headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) and headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC–MS) were utilized to effectively and comprehensively analyze VOCs of fresh and dried P. frutescens between the leaves, stems and seeds. Meanwhile, chemometric analysis was applied to compare and identify characteristic volatile markers. As a result, 60 VOCs were identified by HS-GC-IMS and 115 VOCs were identified by HS-SPME-GC–MS from P. frutescen. 25 potential volatile markers were selected based on a combination model of orthogonal partial least squares discriminant analysis (OPLS-DA) and random forest (RF). The models could be used to analyze the variation between fresh and dried P. frutescens and distinguish the differences in different parts effectively and comprehensively. It was the first research regarding the method development of HS-GC-IMS and HS-SPME-GC–MS that comprehensively analyzes the VOCs characterization of fresh and dried P. frutescens in different parts and the findings obtained would evaluate the quality and provide a reference for further exploration of the edible and medicinal effects of P. frutescens.

Abstract Mantidis Ootheca (Sangpiaoxiao, mantis egg case) is a typical multi-origin Chinese medicinal material. The Chinese Pharmacopoeia stipulates that the Mantidis Ootheca originates from three species of Mantis: Tenodera sinensis, Statilia maculate, and Hierodula patellifera. However, Mantidis Ootheca mainly relies on field collection, which leads to confusion of its actual origin in the market. As the clinical use of Mantidis Ootheca with unknown original mantis species will pose potential risks to drug safety, it is necessary to survey the commercially available Mantidis Ootheca origin species. However, as the egg case of Mantis, the morphological characters of Mantidis Ootheca are limited and usually cannot serve as accurate identification tool. DNA barcoding, which is widely used in taxonomic studies of animals, is severely affected by the impact of storage pests and DNA degradation. Thus, this study collected a total of 4580 Mantidis Ootheca and pooled separately Mantidis Ootheca samples according to 18 different sources as DNA samples to analyze the origin diversity of Mantidis Ootheca individuals contaminated by common store pests collected in in the market using DNA metabarcoding, and to provide a basis for quality control of Mantidis Ootheca. 37 Mantis ASVs and 9 Mantis MOTUs were identified through species delimitation, and the high-level intraspecific diversity was depicted as haplotype network plot. Besides Tenodera sinensis and Hierodula patellifera as genuine original mantis species defined in the Chinese Pharmacopoeia, Tenodera angustipennis was also the origin species of these Mantidis Ootheca samples.

An integrative strategy of UHPLC/IM-QTOF-MS analysis, MS/MS molecular networking (MN), in-house library search, and a collision cross-section (CCS) simulation and comparison was developed for the rapid characterization of the chemical constituents in Chebulae Fructus (CF). A total of 122 Constituents were identified, and most were phenolcarboxylic and tannic compounds. Subsequently, 1,3,6-tri-O-galloyl-β-d-glucose, terflavin A, 1,2,6-tri-O-galloyl-β-d-glucose, punicalagin B, chebulinic acid, chebulagic acid, 1,2,3,4,6-penta-O-galloyl-β-d-glucose, and chebulic acid, among the 23 common constituents of CF, were screened out by UPLC-PDA fingerprinting and multivariate statistical analyses (HCA, PCA, and OPLS-DA). Then, Pearson’s correlation analysis and a grey relational analysis were performed for the spectrum-effect correlation between the UPLC fingerprints and the antioxidant capacity of CF, which was finally validated by an UPLC-DPPH• analysis for the main antioxidant constituents. Our study provides a global identification of CF constituents and contributes to the quality control and development of functional foods and preparations dedicated to CF.

Xuebijing (XBJ) Injection is a reputable patent Chinese medicine widely used to cure sepsis, among the Chinese ″Three Medicines and Three Prescriptions″ solution to fight against COVID-19. We were aimed to achieve the comprehensive multicomponent characterization from the single drugs to traditional Chinese medicine (TCM) formula, by integrating powerful data acquisition and the in-house MS2 spectral database searching. By ultra-high performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS), a hybrid scan approach (HDMSE-HDDDA) was developed, while the HDMSE data for five component drugs and 56 reference compounds were acquired and processed to establish an in-house MS2 spectral database of XBJ. Good resolution of the XBJ components was accomplished on a Zorbax Eclipse Plus C18 column within 24 min, while a fit-for-purpose HDMSE-HDDDA approach was elaborated in two ionization modes for enhanced MS2 data acquisition. XBJ MS2 spectral library was thus established on the UNIFITM platform involving rich structure-related information for the chemicals from five component drugs. We could identify or tentatively characterize 294 components from XBJ, involving 81 flavonoids, 51 terpenoids, 42 phthalides, 40 organic acids, 13 phenylpropanoids, seven phenanthrenequinones, six alkaloids, and 54 others. In contrast to the application of conventional MS1 library, this newly established strategy could demonstrate superiority in the accuracy of identification results and the characterization of isomers, due to the more restricted filtering/matching criteria. Conclusively, the integration of the HDMSE-HDDDA hybrid scan approach and the in-house MS2 spectral database can favor the efficient and more reliable multicomponent characterization from single drugs to the TCM formula.

This paper considers a new mean-variance model with strong mixing errors and describes a combination test for the mean shift and variance change. Under some stationarity and symmetry conditions, the important limiting distribution for a combination test is obtained, which can derive the limiting distributions for the mean change test and variance change test. As an application, an algorithm for a three-step method to detect the change-points is given. For example, the first step is to test whether there is at least a change-point. The second and third steps are to detect the mean change-point and the variance change-point, respectively. To illustrate our results, some simulations and real-world data analysis are discussed. The analysis shows that our tests not only have high powers, but can also determine the mean change-point or variance change-point. Compared to the existing methods of cpt.meanvar and mosum from the R package, the new method has the advantages of recognition capability and accuracy.

Precise delivery and responsive activation of therapeutic agents are critical for tumor precise therapy. Herein, inspired by intelligent express, a nanozyme-laden intelligent macrophage express was fabricated based on IR 820-macrophage loaded with GOx nanozymes for tumor-targeted photothermal-amplified starvation therapy with fluorescence imaging guidance. The nanozyme-laden intelligent macrophage express exerted precise delivery through cargo loading, conveying and unloading. For efficient cargo loading, H2O2-sensitive GOx nanozymes with blocked enzymatic activity were packaged on macrophage expresses with excellent phagocytic ability. Due to the inherent tumor tropism, the therapeutic agents-laden macrophage expresses naturally accumulated at tumor site with fluorescence navigation to track the conveying process. The spatiotemporal unpacking of the laden therapeutic agents at tumor site was triggered by the external laser for the macrophage express photothermal property. The released special tumor-microenvironment responsive GOx nanozymes were activated by H2O2 in tumor to start starvation therapy. Photothermal therapy generated mild hyperthermia and starvation therapy produced H2O2 further increased the nanozymes enzymatic activity, enhancing GOx-mediated starvation therapy. The nanozyme-laden intelligent macrophage express integrated laser-induce drug release and activation, tumor microenvironment-responsiveness, and circular amplification property, achieving the synergistic effects of PTT and starvation therapy in vitro and in vivo.

Dexmedetomidine (Dex) is a highly selective α2 adrenergic agonist used in clinical anesthesia. Studies have shown that Dex can act on the collecting duct and reduce the body’s water reabsorption, thereby increasing water discharge. However, the specific mechanism of Dex on water homeostasis remains unclear. The hypothalamus is the regulatory center of water and salt balance and secretes related neurochemical hormones, such as arginine vasopressin (AVP), to regulate the discharge of water and salt. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) in the hypothalamus are also considered to be the key targets of the thirst loop. They are responsible for the secretion of AVP. The suprachiasmatic nucleus (SCN) is also one of the brain regions where AVP neurons are densely distributed in the hypothalamus. This study used C57BL/6J mice for behavior, immunofluorescence, and blood analysis experiments. Our results showed that Dex could not only depress the expression of AVP in the PVN but also reduce serum AVP concentration. The animal water intake was decreased without impairing the difference in food consumption and the urine excretion was enhanced after the intraperitoneal injection of Dex, while AVP supplementation restored the water intake and inhibited the urine excretion of mice in the Dex group. In addition, the renin-angiotensin-aldosterone system is vital to maintaining serum sodium concentration and extracellular volume. We found that serum sodium, serum chloride, serum aldosterone (ALD) concentration, and plasma osmolality were decreased in the Dex group, which inhibited water reabsorption, and the plasma osmolarity of mice in the Dex group supplemented with AVP was significantly higher than that in Dex group. We also found that Dex significantly increased the concentration of blood urea nitrogen and decreased the concentration of creatinine within the normal range of clinical indicators, indicating that there was no substantive lesion in the renal parenchyma. These results showed that Dex could modulate the balance of water-electrolyte metabolism by depressing the expression of AVP in PVN without impairing renal function.

Severe interference from the endogenous substances is often encountered in characterizing the drug metabolites by liquid chromatography/mass spectrometry using data-dependent acquisition (DDA). To add a precursor ions list (PIL) by DDA or apply data-independent acquisition (DIA) coupled with post-acquisition data processing (such as mass defect filtering, MDF) may assist to target more metabolites from the complex biosamples. Dehydrocorynine (DHC) is a bioactive alkaloid compound rich in Corydalis yanhusuo. We integrated both PIL-DDA and DIA-MDF strategies to probe the metabolites of DHC simultaneously from the rat plasma, bile, urine, and feces. Chromatographic separation was performed on an HSS C18 SB column. The positive-mode collision-induced dissociation-MS2 data of DHC metabolites were recorded by PIL-DDA on both the QTrap 4500 and Vion IM-QTOF mass spectrometers, and by HDMSE on Vion IM-QTOF. Efficient workflows to process the high-definition DDA (HDDDA) and HDMSE data were elaborated. Totally 40 metabolites (orally administrated at the dose of 100 mg/kg) were identified or tentatively characterized, involving 30 from bile, 16 from feces, 7 from plasma, and 18 from urine. The methoxyls and C-5/C-6/C-8 were the main sites prone to be metabolized via demethylation and oxidation, and further glucuronic acid conjugation and sulfuric acid conjugation. Compared with literature, we can newly discover 17 metabolites in bile, and, for the first time, report the metabolites of DHC from rat urine and feces. Conclusively, the presented PIL-DDA and DIA-MDF strategies are powerful in elucidating the drug metabolites, which thus provides reference to characterizing the metabolic profiles of traditional Chinese medicine components.

The development of supramolecular chemistry has always been accompanied by the innovation of macrocyclic hosts. The synthesis of novel macrocycles with unique structures and functions will bring new development opportunities for supramolecular chemistry. As a new generation of macrocyclic hosts, biphenarenes have customizable cavity sizes and diverse backbones, overcoming the limitation that the cavities of traditionally popular macrocyclic hosts are generally smaller than 10 Å. These features undoubtedly endow biphenarenes with distinguished host–guest properties, which have attracted more and more attention. In this review, the structural characteristics and molecular recognition properties of biphenarenes are summarized. In addition, the applications of biphenarenes in adsorption and separation, drug delivery, fluorescence sensing and other fields are introduced. Hopefully, this review will provide a reference for the study of macrocyclic arenes, especially biphenarenes.

Ion mobility-mass spectrometry (IM-MS) is a powerful separation technique providing an additional dimension of separation to support the enhanced separation and characterization of complex components from the tissue metabolome and medicinal herbs. The integration of machine learning (ML) with IM-MS can overcome the barrier to the lack of reference standards, promoting the creation of a large number of proprietary collision cross section (CCS) databases, which help to achieve the rapid, comprehensive, and accurate characterization of the contained chemical components. In this review, advances in CCS prediction using ML in the past 2 decades are summarized. The advantages of ion mobility-mass spectrometers and the commercially available ion mobility technologies with different principles (e.g., time dispersive, confinement and selective release, and space dispersive) are introduced and compared. The general procedures involved in CCS prediction based on ML (acquisition and optimization of the independent and dependent variables, model construction and evaluation, etc.) are highlighted. In addition, quantum chemistry, molecular dynamics, and CCS theoretical calculations are also described. Finally, the applications of CCS prediction in metabolomics, natural products, foods, and the other research fields are reflected.

Abstract Background CssR, the product of the Corynebacterium glutamicum ncgl1578 gene cotranscribed with ncgl1579, is a TetR (tetracycline regulator) family repressor. Although many TetR-type regulators in C. glutamicum have been extensively described, members of the TetR family involved in the stress response remain unidentified. Results In this study, we found that CssR regulated the transcription of its own gene and the ncgl1576-ncgl1577 operon. The ncgl1576-ncgl1577 operon, which is located upstream of cssR in the orientation opposite that of the cssR operon, encodes an ATP-binding cassette (ABC), some of which are involved in the export of a wide range of antimicrobial compounds. The cssR-deletion (ΔcssR) mutant displayed increased resistance to various stresses. An imperfect palindromic motif (5′-TAA(G)TGN13CA(G)TTA-3′; 25 bp) located at the intergenic region between cssR and ncgl1577 was identified as the sole binding site for CssR. Expression of cssR and ncgl1577 was induced by antibiotics and heavy metals but not H2O2 or diamide, and the DNA-binding activity of CssR was impaired by antibiotics and heavy metals but not H2O2. Antibiotics and heavy metals caused CssR dissociation from target gene promoters, thus derepressing their transcription. Oxidant treatment neither altered the conformation of CssR nor modified its cysteine residues, indicating that the cysteine residues in CssR have no redox activity. In the ΔcssR mutant strain, genes involved in redox homeostasis also showed increased transcription levels, and the NADPH/NADP+ ratio was higher than that of the parental strain. Conclusion The stress response mechanism of CssR in C. glutamicum is realized via ligand-induced conformational changes of the protein, not via cysteine oxidation-based thiol modification. Moreover, the crucial role of CssR in the stress response was demonstrated by negatively controlling the expression of the ncgl1576-ncgl1577 operon, its structural gene, and/or redox homeostasis-related genes.

Precise identification and differentiation among those congeneric Traditional Chinese Medicines (TCMs) or derived from the same plant trend to be more challenging, particularly in the absence of appearance characteristics. Three TCMs, involving Gleditsiae Sinensis Fructus (GSF), Gleditsiae Fructus Abnormalis (GFA), and Gleditsiae Spina (GS), recorded in Chinese Pharmacopoeia (2020 edition) are derived from Gleditsia sinensis, but prescribed for different clinical uses. The documents aimed to compare their chemical differences are rare, to date. An untargeted metabolomics approach, based on ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS), was elaborated to unveil the potential chemical markers to differentiate among GSF, GFA, and GS. Good chromatographic separation of all the GSF/GFA/GS components was achieved within 33 min by utilizing a BEH C18 column, while data-independent MSE in the positive mode was selected for profiling the metabolic features. Notably, the high-mass saponins (1300–2500 Da) gave unique protonated precursors ([M + H]+) in the positive ESI mode, compared with those complicated ion species occurring in the negative mode. Pattern recognition chemometrics analysis of 45 batches of G. sinensis samples could unveil 70 significantly altered ions assigned as 46 potentially differential components. The positive/negative high-accuracy MS2 data analysis, phytochemical isolation/NMR analysis, and searching of an in-house library of G. sinensis, were utilized for structural elucidation. Three compounds (saikachinoside A, locustoside A, and locustoside B) rich in GSF could be the markers to differentiate from GFA/GS, while four components were characteristic for GS. These results obtained can greatly benefit the quality control of TCMs derived from G. sinensis.

Abstract A novel method for the preparation of antitumor drug vehicles has been optimized. Biological materials of chitosan oligosaccharide (CO) and γ‐polyglutamic acid (γ‐PGA) have previously been employed as modifiers to covalently modify graphene oxide (GO), which in turn loaded doxorubicin (DOX) to obtain a nano drug delivery systems of graphene oxide based composites (GO‐CO‐γ‐PGA‐DOX). The system was not equipped with the ability of initiative targeting, thus resulting into toxicity and side effects on normal tissues or organs. In order to further improve the targeting property of the system, the nucleic acid aptamer NH2‐AS1411 (APT) of targeted nucleolin (C23) was used to conjugate on GO‐CO‐γ‐PGA to yield the targeted nano drug delivery system APT‐GO‐CO‐γ‐PGA. The structure, composition, dispersion, particle size and morphology properties of the synthesized complex have been studied using multiple characterization methods. Drug loading and release profile data showed that APT‐GO‐CO‐γ‐PGA is provided with high drug loading capacity and is capable of controlled and sustained release of DOX. Cell experimental results indicated that since C23 was overexpressed on the surface of Hela cells but not on the surface of Beas‐2B cells, APT‐GO‐CO‐γ‐PGA‐DOX can target Hela cells and make increase toxicity to Hela cells than Beas‐2B cells, and the IC50 value of APT‐GO‐CO‐γ‐PGA‐DOX was 3.23±0.04 μg/mL. All results proved that APT‐GO‐CO‐γ‐PGA can deliver antitumor drugs in a targeted manner, and achieve the effect of reducing poison, which indicated that the targeted carrier exhibits a broad application prospect in the field of biomedicine.

Atherosclerosis is a chronic inflammatory disease associated with the development of plaques that can be converted into an acute clinical event by thrombosis or plaque rupture. Mesenchymal stem cells (MSCs) exhibit therapeutic effects for the treatment of various diseases, including atherosclerosis. In this study, we show that microRNA-145 (miR-145) is associated with atherosclerosis by microRNA sequencing and bioinformatics analysis. MSC-derived miR-145-rich exosomes could efficiently deliver miR-145 from MSCs to human umbilical vein endothelial cells (HUVECs). Treatment of miR-145-rich exosomes could downregulate JAM-A, inhibit migration in vitro, and reduce atherosclerotic plaque in vivo. Our study suggests that MSC-derived miR-145-rich exosomes have great potential for atherosclerosis prevention.

Summary Molecular analyses relying on RNA, as a direct way to unravel active microbes and their functional genes, have received increasing attention from environmental researchers recently. However, extracting sufficient and high‐quality total microbial RNA from seriously heavy metal‐contaminated soils is still a challenge. In this study, the guanidine thiocyanate‐high EDTA (GTHE) method was established and optimized for recovering high quantity and quality of RNA from long‐term heavy metal‐contaminated soils. Due to the low microbial biomass in the soils, we combined multiple strong denaturants and intense mechanical lysis to break cells for increasing RNA yields. To minimize RNAase and heavy metals interference on RNA integrity, the concentrations of guanidine thiocyanate and EDTA were increased from 0.5 to 0.625 ml g−1 soil and 10 to 100 mM, respectively. This optimized GTHE method was applied to seven severely contaminated soils, and the RNA recovery efficiencies were 2.80 ~ 59.41 μg g−1 soil. The total microbial RNA of non‐Cr(VI) (NT) and Cr(VI)‐treated (CT) samples was utilized for molecular analyses. The result of qRT‐PCR demonstrated that the expressions of two tested genes, chrA and yieF, were respectively upregulated 4.12‐ and 62.43‐fold after Cr(VI) treatment. The total microbial RNA extracted from NT and CT samples, respectively, reached to 26.70 μg and 30.75 μg, which were much higher than the required amount (5 μg) for metatranscriptomic library construction. Besides, ratios of mRNA read were more than 86%, which indicated the high‐quality libraries constructed for metatranscriptomic analysis. In summary, the GTHE method is useful to study microbes of contaminated habitats.

Objective: To explore the immune mechanism of syphilitic sero-fixation by measuring the expression levels of serum IL-17 and IL-21 in syphilis patients with positive serological test. Methods: Subjects included syphilitic sero-fixation, syphilis with Toluidine red unheated serum test (TRUST) negative, early syphilis, and normal healthy controls, 30 subjects per groups. Serum concentrations of IL-17 and IL-21 were measured by ELISA, while TRUST titers were measured with TRUST kit. The differences in serum IL-17 and IL-21 levels were compared among four groups. Pearson correlation analysis was used to analyze the correlation between TRUST titers and IL-17 and IL-21 levels. Results: The serum levels of IL-17 [(25.43±4.58) pg/mL]and IL-21[(36.14±6.54) pg/mL] in early syphilis group were significantly higher than that in the other three groups (P0.05). The serum levels of IL-17 and IL-21 were correlated positively with TRUST titers in the early syphilis patients (r=0.75, 0.62, respectively, both P0.05). Conclusions: Both IL-17 and IL-21 are involved in the syphilis immune process in early syphilis. The formation of syphilitic sero-fixation could be associated with decreased serum levels of IL-17 and IL-21, but not TRUST titers.

Untargeted metabolomics more suits the quality evaluation of TCM because of its holistic property. To assess the holistic quality difference of Saposhnikoviae Radix (the roots of Saposhnikovia divaricata), we integrate ultra-high-performance liquid chromatography coupled with ion mobility/quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS)-based untargeted metabolomics and quantitative assay. A BEH C18 column in the reversed-phase mode and a BEH Amide column in Hydrophilic Interaction Chromatography (HILIC) mode were utilized for metabolites profiling, which enabled high coverage of the non-polar to polar components in Saposhnikoviae Radix. Moreover, the application of major components knockout strategy enlarged the exposure of those minor components. Integrated use of high-definition MSE (HDMSE) and data-dependent acquisition (DDA) could enhance the metabolites characterization by providing reliable fragmentation information and collision cross section values. Computational in-house library-driven automated peak annotation of the HDMSE and DDA data assisted to characterize 104 components from Saposhnikoviae Radix. Chemometric analyses of the commercial Saposhnikoviae Radix samples (64 batches collected from 11 cultivars aging from 1 to 4 years), based on the positive MSE data, in general could indicate large discrimination between Guan-Fang-Feng (from Heilongjiang) and the others, but negligible difference among Saposhnikoviae Radix from the other ten provinces of China and with different ages. Quantitative assays of prim-O-glucosylcimifugin and 4′-O-β-D-glucosyl-5-O-methylvisamminol, by a rapid and fully validated UHPLC-UV method, could primarily deduce that Guan-Fang-Feng aging 2 and 3 years exhibited better quality. The methods established can holistically assess the quality of TCM with wide spans of plant metabolites covered.

Inherent complexity of plant metabolites necessitates the use of multi-dimensional information to accomplish comprehensive profiling and confirmative identification. A dimension-enhanced strategy, by offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (2D-LC/IM-QTOF-MS) enabling four-dimensional separations (2D-LC, IM, and MS), is proposed. In combination with in-house database-driven automated peak annotation, this strategy was utilized to characterize ginsenosides simultaneously from white ginseng (WG) and red ginseng (RG). An offline 2D-LC system configuring an Xbridge Amide column and an HSS T3 column showed orthogonality 0.76 in the resolution of ginsenosides. Ginsenoside analysis was performed by data-independent high-definition MSE (HDMSE) in the negative ESI mode on a Vion™ IMS-QTOF hybrid high-resolution mass spectrometer, which could better resolve ginsenosides than MSE and directly give the CCS information. An in-house ginsenoside database recording 504 known ginsenosides and 58 reference compounds, was established to assist the identification of ginsenosides. Streamlined workflows, by applying UNIFI™ to automatedly annotate the HDMSE data, were proposed. We could separate and characterize 323 ginsenosides (including 286 from WG and 306 from RG), and 125 thereof may have not been isolated from the Panax genus. The established 2D-LC/IM-QTOF-HDMSE approach could also act as a magnifier to probe differentiated components between WG and RG. Compared with conventional approaches, this dimension-enhanced strategy could better resolve coeluting herbal components and more efficiently, more reliably identify the multicomponents, which, we believe, offers more possibilities for the systematic exposure and confirmative identification of plant metabolites.

Despite Panax notoginseng (Sanchi: the root and rhizome) is globally popular serving as the source of food additives, health-care products, and traditional Chinese medicines (TCMs), the saponin difference between the root (PNR) and two aerial parts (leaf, PNL; flower bud, PNF) that can be vicariously used, remains unclear. Authentication of Sanchi, particular from the Chinese patent medicines (CPMs), poses great challenges. Ultra-high performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS)-based untargeted metabolomics and quantitative assay by UHPLC-UV were utilized to establish the “Identification Markers” for Sanchi. Targeted monitoring of multiple identification markers was performed for authenticating Sanchi simultaneously from 15 different CPMs. Dimension-enhanced profiling by UHPLC/IM-QTOF-MS in the negative high-definition MSE (HDMSE) mode and in-house library-driven peak annotation could characterize totally 328 ginsenosides (133 from PNR, 125 from PNL, and 161 from PNF). Multivariate statistical analysis of the PNR/PNL/PNF samples (45 batches) identified 27 potential markers. Five major markers (notoginsenoside R1, ginsenosides Rg1, -Rb1, -Rb2, and -Rb3) thereof were quantitatively assayed by a fully validated UHPLC-UV (detected at 203 nm) approach. The application of selective ion monitoring (SIM) of 12 differential saponins coupled with UHPLC separation could precisely identify Sanchi from 15 different CPMs (45 batches). Holistic difference in ginsenosides among three parts of P. notoginseng was unveiled, and the markers deduced may assist to identify the illicit substitution of leaf or flower as the root in the TCM compound formulae. Conclusively, the integration of untargeted metabolomics and quantitative analysis can provide reliable information enabling the precise authentication of TCM.

The flower bud of Panax notoginseng (PNF) consumed as a tonic shows potential in the prevention and treatment of cardiovascular diseases. To identify the contained multi-components and, in particular, to clarify which components can be absorbed and what metabolites are transformed, unveiling the effective substances of PNF is of vital significance. A unique ultrahigh-performance liquid chromatography/ion mobility quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS) profiling approach and efficient data processing by the UNIFITM bioinformatics platform were employed to comprehensively identify the multi-components of PNF and the related metabolites in the plasma of rats after oral administration (at a dose of 3.6 g/kg). Two MS2 data acquisition modes operating in the negative electrospray ionization mode, involving high-definition MSE (HDMSE) and data-dependent acquisition (DDA), were utilized aimed to extend the coverage and simultaneously ensure the quality of the MS2 spectra. As a result, 219 components from PNF were identified or tentatively characterized, and 40 thereof could be absorbed. Moreover, 11 metabolites were characterized from the rat plasma. The metabolic pathways mainly included the phase I (deglycosylation and oxidation). To the best of our knowledge, this is the first report that systematically studies the in vivo metabolites of PNF, which can assist in better understanding its tonifying effects and benefit its further development.

In this paper, we consider the mildly explosive autoregression yt=ρnyt−1+ut, 1≤t≤n, where ρn=1+c/nν, c>0, ν∈(0,1), and u1,…,un are arithmetically α-mixing errors. Under some weak conditions, such as Eu1=0, E|u1|4+δ<∞ for some δ>0 and mixing coefficients α(n)=O(n−(2+8/δ)), the Cauchy limiting distribution is established for the least squares (LS) estimator ρ^n of ρn, which extends the cases of independent errors and geometrically α-mixing errors. Some simulations for ρn, such as the empirical probability of the confidence interval and the empirical density, are presented to illustrate the Cauchy limiting distribution, which have good finite sample performances. In addition, we use the Cauchy limiting distribution of the LS estimator ρ^n to illustrate real data from the NASDAQ composite index from April 2011 to April 2021.

The pericarps of Zanthoxylum bungeanum (ZBP) and leaves of Zanthoxylum bungeanum (ZBL) are popular spices in China, and they have pharmacological activities as well. In this experiment, the volatile organic compounds (VOCs) of the pericarps of Zanthoxylum bungeanum in Sichuan (SJ) and its leaves (SJY) and the pericarps of Zanthoxylum bungeanum in Shaanxi (SHJ) and its leaves (SHJY) were analyzed by headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) and headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). The fingerprint of HS-GC-IMS and the heat maps of HS-SPME-GC-MS were established. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed. The results showed that a total of 95 components were identified, 62 components identified by HS-SPME-GC-MS and 40 components identified by HS-GC-IMS, of which 7 were the same. The analysis found that SJ and SHJ were obviously distinguished, while SJY and SHJY were not. There were considerably fewer VOCs in the leaves than in the pericarps. In the characterization of the VOCs of ZBL and ZBP, the flavor of ZBP was more acrid and stronger, while the flavor of ZBL was lighter and slightly acrid. Thirteen and eleven differential markers were identified by HS-GC-IMS and HS-SPME-GC-MS, respectively. This is helpful in distinguishing between SHJ and SJ, which contributes to their quality evaluation.

The co-elution, pervasive isomers, and frequently occurring in-source fragmentation definitely hinder the comprehensive characterization of the multiple components from traditional Chinese medicine (TCM) by liquid chromatography/mass spectrometry. Herein, a dimension-enhanced strategy, by utilizing an ion mobility quadrupole time-of-flight mass spectrometer coupled to ultra-high performance liquid chromatography (UHPLC/IM-QTOF-MS) with the ability of offering four-dimensional information (retention time, Rt; drift time or collision cross section, CCS; accurate mass of precursors; and accurate MS2 product ions), is presented. Shuanghe Decoction (SHD) is a classic tonifying formula composed of nine herbs, however, little is known to its chemical complexity, hitherto. Good chromatographic separation was achieved on an HSS T3 column, and by the Vion™ IMS-QTOF high-resolution mass spectrometer, data-independent MSE and High-Definition MSE (HDMSE) in both the negative and positive electrospray ionization modes were employed for acquiring the collision-induced dissociation-MS2 data. A self-built database, including 642 known compounds, was established, which assisted to perform the automated peak annotation by UNIFI™. By reference to 55 compounds, totally 236 components were identified or tentatively characterized from SHD with 4D data recorded. The combination of negative and positive modes could yield more information complementary to structural elucidation. Compared with the conventional MSE, HDMSE exhibit of merits in the provision of CCS, better separation and detection those easily co-eluting components, and reduction of the false positives in the identification results. Conclusively, the combination of HDMSE acquisition, in-house library, and UNIFI-facilitated automated peak annotation, renders a potent approach dedicated to deconvoluting the chemical composition of complex systems like TCM formulae.

The leaves of Panax species (e.g., Panax ginseng-PGL, P. quinquefolius-PQL, and P. notoginseng-PNL) can serve as a source for healthcare products. Comprehensive characterization and unveiling of the metabolomic difference among PGL, PQL, and PNL are critical to ensure their correct use. For this purpose, enhanced profiling and chemometrics were integrated to probe into the ginsenoside markers for PGL/PQL/PNL by ultra-high performance liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS). A hybrid scan approach (HDMSE-HDDDA) was established achieving the dimension-enhanced metabolic profiling, with 342 saponins identified or tentatively characterized from PGL/PQL/PNL. Multivariate statistical analysis (33 batches of leaf samples) could unveil 42 marker saponins, and the characteristic ginsenosides diagnostic for differentiating among PGL/PQL/PNL were primarily established. Compared with the single DDA or DIA, the HDMSE-HDDDA hybrid scan approach could balance between the metabolome coverage and spectral reliability, leading to high-definition MS spectra and the additional collision-cross section (CCS) useful to differentiate isomers.

Abstract Background Sperm motility parameters, which can be measured objectively and repeatedly by a computer-assisted sperm analysis (CASA) system, are important indicators of sperm quality. However, the sperm motility parameters assessed by a CASA system can be affected by various factors, including instrument components and settings, sperm preparation or analysis procedures. To date, no standardized protocol is available that would permit to assess sperm kinetic characteristics in passerine birds and this lack precludes any comparison of sperm swimming ability and sperm quality across species. Methods In this study, we chose the Tree Sparrow (Passer montanus) as the object to evaluate sperm motility parameters, including sperm motility, sperm velocity and sperm movement trajectory, at different analysis time, temperatures and pH using the WLJY-9000 CASA system. Results Sperm motility parameters remained statistically unchanged at 1‒9 min. Progressive motility was similar at 38 °C and 40 °C, but a greater percentage of slow progressive sperm was detected at 38 °C compared to 40 °C and 42 °C. Additionally, progressive motility was lower and immotility was higher at 42 °C than 38 °C and/or 40 °C (close to the body temperature of the Tree Sparrow). The percentages of rapid progressive sperm, progressive sperm and immotile sperm were statistically similar at pH 7.0, 7.5 and 8.0 with the exception of lower percentage of progressive sperm at pH 7.0 compared to pH 7.5. In addition, slower sperm velocity and worse sperm movement trajectory were found at pH 6.0 and 9.0 than those at pH 8.0, 7.5 or 7.0. Conclusions Our study indicates that the ideal conditions for sperm motility parameters assessment in Tree Sparrow are obtained between 1 and 9 min after dilution, an environment at body temperature (40 °C) and a pH around 7.5‒8.0. The results of this study provide a reference for the evaluation of sperm characteristics and sperm quality using a CASA system in passerine birds.

The degradation data have been widely applied in reliability analysis for deteriorating systems. However, the degradation data are usually contaminated by measurement errors that can severely affect the life estimation performance. This paper presents a degradation modeling and life estimation method using a Wiener degradation model by taking temporal uncertainty, measurement uncertainty, and unit-to-unit heterogeneity into account. The truncated normal distribution is employed to characterize the unit-to-unit heterogeneity in a population due to the fact that the degradation rates of many systems often manifest as positive values. The exact and explicit expressions of the life distribution are derived in the sense of the first hitting time by considering three kinds of uncertainties. The expectation maximization algorithm is used to estimate the model parameters because the resulting likelihood function includes hidden variables, which improves the estimation efficiency compared with the existing maximum likelihood estimation procedure. The effectiveness of the proposed approach is validated through a simulation example and a case study involving the degradation dataset of the LED.

Volatile organic compounds (VOCs) are the main chemical components of Schizonepetae Spica (SS), which have positive effects on the quality evaluation of SS. In this study, HS-SPME-GC-MS (headspace solid-phase microextraction-gas chromatography-mass spectrometry) and HS-GC-IMS (headspace-gas chromatography-ion mobility spectrometry) were performed to characterize the VOCs of SS from six different regions. A total of 82 VOCs were identified. In addition, this work compared the suitability of two instruments to distinguish SS from different habitats. The regional classification using orthogonal partial least squares discriminant analysis (OPLS-DA) shows that the HS-GC-IMS method can classify samples better than the HS-SPME-GC-MS. This study provided a reference method for identification of the SS from different origins.

Wenxin granule (WXG) is a popular traditional Chinese medicine (TCM) preparation for the treatment of arrhythmia disease. Potent analytical technologies are needed to elucidate its chemical composition and assess the quality differences among multibatch samples. In this work, both a multicomponent characterization and quantitative assay of WXG were conducted using two liquid chromatography–mass spectrometry (LC-MS) approaches. An ultra-high performance liquid chromatography–ion mobility quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS) approach combined with intelligent peak annotation workflows was developed to characterize the multicomponents of WXG. A hybrid scan approach enabling alternative data-independent and data-dependent acquisitions was established. We characterized 205 components, including 92 ginsenosides, 53 steroidal saponins, 14 alkaloids, and 46 others. Moreover, an optimized scheduled multiple reaction monitoring (sMRM) method was elaborated, targeting 24 compounds of WXG via ultra-high performance liquid chromatography–triple quadrupole linear ion trap mass spectrometry (UHPLC/QTrap-MS), which was validated based on its selectivity, precision, stability, repeatability, linearity, sensitivity, recovery, and matrix effect. By applying this method to 27 batches of WXG samples, the content variations of multiple markers from Notoginseng Radix et Rhizoma (21) and Codonopsis Radix (3) were depicted. Conclusively, we achieved the comprehensive multicomponent characterization and holistic quality assessment of WXG by targeting the non-volatile components.

To elucidate the chemical composition of a traditional Chinese medicine (TCM) formula necessitates the development of more potent analytical strategies, because of the complexity as a result of the superposition of multiple drugs. Fangji Huangqi Decoction (FHD) is a four-component TCM formula composed by complicated chemical constituents. By using the VionTM ion mobility quadrupole time-of-flight (IM-QTOF) mass spectrometer, we present a novel IM separation-enabled and precursor ions list (PIL)-included high-definition data-dependent acquisition (HDDDA) approach, and apply it to the multicomponent characterization of FHD by coupling to ultra-high performance liquid chromatography. Chromatographic separation was conducted on a CORTECS® UPLC® T3 column, while HDDDA was employed for MS2 data acquisition in both the negative and positive electrospray-ionization (ESI) modes. The PILs of FHD in two ESI modes were created based on the phytochemical knowledge of four component drugs and mass defect filtering, which ultimately could obtain 316 and 258 targeted masses, respectively, from the full-scan MS1 data. Interestingly, the additional inclusion of PILs in HDDDA could improve the coverage on the target components by 12% (ESI–) and 48% (ESI + ). Structural elucidation was performed by in-house database-driven automatic peak annotation using UNIFITM. We could identify or tentatively characterize 203 components from FHD, involving 25 alkaloids, 86 flavonoids, 48 triterpenoids (saponins), 16 lactones, and 28 others). It is the first report regarding the method development of HDDDA that targets the global TCM components characterization, and the findings obtained would benefit the quality control and the secondary development of FHD.

Panax ginseng C. A. Mey (PGCAM) is a herbaceous perennial belonging to the Araliaceae family, mainly including Mountain-Cultivated Ginseng (MCG) and Garden Ginseng (GG) on the market. We aimed to establish a rapid, accurate and effective method to distinguish 15-year-old MCG and GG using ultra-performance liquid chromatography-quadrupole time-of-flight-tandem mass spectrometry (UPLC-QTOF-MS/MS), and also explored the pharmacological mechanisms of the main components using the Integrative Pharmacology-based Network Computational Research Platform of Traditional Chinese Medicine (TCMIP V2.0; http://www.tcmip.cn/). Altogether, 23 potential quality markers were characterized to distinguish 15-year-old MCG and GG, including ginsenosides Ra2, Rg1, and Ra1, and malonyl-ginsenoside Ra3, etc. The contents of 19 constituents (mainly protopanaxadiol-type) were higher in MCG compared with that in GG, and four constituents (mainly carbohydrate compounds) were higher in GG. The 105 putative targets corresponding to 23 potential quality markers were mainly involved in 30 pathways, which could be divided into 10 models, such as immune regulation, systems (metabolic, nervous, cardiovascular, reproductive), blood-pressure regulation, as well as antitumor, antiaging, antibacterial and anti-inflammatory effects. Furthermore, the potential quality markers of MCG and GG could inhibit the proliferation of breast cancer by regulating the mRNA expression of PSA, S6K, MDM2, and P53 genes by acting on AR, MTOR, PI3K and other targets. The Integrative Pharmacology Strategy may provide an efficient way to identify chemical constituents and explore the pharmacological actions of TCM formulations.

Plant metabolites represent complex chemical system, which renders it difficult to clarify the chemical composition by conventional liquid chromatography/mass spectrometry (LC/MS) due to the limited selectivity and peak capacity. The rhizomes of Atractylodes macrocephala have been utilized as a traditional Chinese medicine Atractylodis Macrocephalae Rhizoma (Bai-Zhu), and have been reported containing multiple categories of plant metabolites. Targeting the multicomponents from A. macrocephala, an integral approach by offline two-dimensional liquid chromatography/ion mobility quadrupole time-of-flight mass spectrometry (2D-LC/IM-QTOF-MS) was established and validated. By configuring an XBridge Amide column of Hydrophilic Interaction Chromatography and an Atlantis Premier BEH C18AX column of mixed ion exchange and reversed-phase modes, the established 2D-LC/IM-QTOF-MS system showed high orthogonality up to 0.91. Dimension-enhanced, data-independent high-definition MSE (HDMSE) in the positive ESI mode was conducted on a Vion IM-QTOF mass spectrometer, and its hyphenation to offline 2D-LC could enable the four-dimensional separation (each dimension in 2D-LC, IM, and MS). Particularly, HDMSE facilitated the acquisition of high-definition MS1 and MS2 spectra. In-house library-driven computational peak annotation by the bioinformatics platform UNIFI could efficiently process and annotate the HDMSE data for the structural elucidation. By integrating reference compounds comparison, we could identify or tentatively characterize 251 components from A. macrocephala (including 115 sesquiterpenoids, 90 polyacetylenes, 11 flavonoids, 9 benzoquinones, 12 coumarins, and 14 others), which indicated large improvement in identifying those minor plant components, compared with the conventional LC/MS approach. Conclusively, offline 2D-LC/IM-QTOF-HDMSE in combination with computational data interpretation proves to be powerful facilitating the in-depth multicomponent characterization of herbal medicine.

Atherosclerosis is an inflammatory disease that can lead to cardiovascular disorders and stroke. In the atherosclerosis microenvironment, exosomes secreted from various cells, especially macrophage-derived exosomes, play an important role in cell–cell communication and cellular biological functions. In this article, we review previous studies on exosomal RNAs and discuss their potential value in atherosclerosis diagnosis and therapy. Based on our research, we concluded that macrophage exosomes have potential value in atherosclerosis diagnosis and therapy. However, there is a need for future studies to further investigate methods of exosome isolation and targeting.