Search

Abstract Background Early identification of the risk of early cancer-related death (within one year, ECRD) due to recurrence after liver resection for hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C is important for surgeons to make clinical decisions. Our study aimed to establish a nomogram to predict the ECRD due to recurrence for HCC patients with BCLC stage B/C. Methods A total of 672 HCC patients with BCLC stages B/C from four medical centers between January 2012 and December 2018 were included in our study. The patients were randomly divided into a training cohort (n = 404) and a validation cohort (n = 268) at a ratio of 6:4. The least absolute shrinkage and selection operator (LASSO) logistic regression model was used to establish a nomogram model. Results In our LASSO-logistic regression model, three variables were independently associated with the ECRD due to recurrence: the alpha-fetoprotein-tumor burden score (ATS score, Odd Ratio [OR]: 1.12, p = 0.001), BCLC stage (OR: 4.39, p

Abstract Gastric cancer (GC) is a prevalent malignancy with high mortality rates. Immunogenic cell death (ICD) is a unique form of programmed cell death that is closely linked to antitumor immunity and plays a critical role in modulating the tumor microenvironment (TME). Nevertheless, elucidating the precise effect of ICD on GC remains a challenging endeavour. ICD-related genes were identified in single-cell sequencing datasets and bulk transcriptome sequencing datasets via the AddModuleScore function, weighted gene co-expression network (WGCNA), and differential expression analysis. A robust signature associated with ICD was constructed using a machine learning computational framework incorporating 101 algorithms. Furthermore, multiomics analysis, including single-cell sequencing analysis, bulk transcriptomic analysis, and proteomics analysis, was conducted to verify the correlation of these hub genes with the immune microenvironment features of GC and with GC invasion and metastasis. We screened 59 genes associated with ICD and developed a robust ICD-related gene signature (ICDRS) via a machine learning computational framework that integrates 101 different algorithms. Furthermore, we identified five key hub genes (SMAP2, TNFAIP8, LBH, TXNIP, and PIK3IP1) from the ICDRS. Through single-cell analysis of GC tumor s, we confirmed the strong correlations of the hub genes with immune microenvironment features. Among these five genes, LBH exhibited the most significant associations with a poor prognosis and with the invasion and metastasis of GC. Finally, our findings were validated through immunohistochemical staining of a large clinical sample set, and the results further supported that LBH promotes GC cell invasion by activating the epithelial–mesenchymal transition (EMT) pathway.

Abstract Studies investigating the relationship between dietary vitamin B1 intake and risk of Hyperuricemia (HU) are scarce, the present study aimed to examine the association of dietary vitamin B1 intake and HU among adults. This cross-sectional study included 5750 adults whose data derived from National Health and Nutrition Examination Survey (NHANES) from March 2017 to March 2020. The dietary intake of vitamin B1 was assessed using 24-h dietary recall interviews. The characteristics of study participants were grouped into five levels according to the levels of vitamin B1 quintile. Multivariate logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of HU, according to the vitamin B1 intake quintile for male and female separately. The dose–response relationship was determined by the restricted cubic spline (RCS). Smoothed curve fitting was used to assess serum uric acid concentration versus dietary vitamin B1 intake in the study population. The prevalence of hyperuricemia was 18.90% (20.15% and 17.79% for males and females, respectively) in the United States from March 2017 to March 2020. Multiple logistic regression analyses showed that in the male population, the HU ratio (OR) of vitamin B1 intake in Q2 to Q5 compared with the lowest quintile (Q1) was 0.75 (95% CI 0.52, 1.09), 0.70 (95% CI 0.48, 1.02), 0.66 (95% CI 0.44, 0.99) and 0.55 (95% CI 0.34, 0.90). The P for trend was 0.028. In women, the ORs for vitamin B1 intake Q2 to Q5 were 0.87 (95% CI 0.64, 1.19), 0.97 (0.68–1.38), 1.05 (0.69–1.60) and 0.75 (0.42–1.34), respectively. The P for trend was 0.876. The RCS curve revealed a linear relationship between vitamin B1 intake and the risk of hyperuricemia in men (P nonlinear = 0.401). Smoothed curve fitting demonstrated a negative association between vitamin B1 intake and serum uric acid concentration in men, whereas there was no significant association between dietary vitamin B1 intake and the risk of hyperuricemia in women. In the US adult population, dietary vitamin B1 intake was negatively associated with hyperuricemia in males.

BackgroundParkinson’s disease (PD) is a prevalent disorder of the central nervous system, marked by the degeneration of dopamine (DA) neurons in the ventral midbrain. In the pathogenesis of PD, inflammation hypothesis has been concerned. This study aims to investigate clinical indicators of peripheral inflammation in PD patients and to explore the diagnostic value of neutrophil-to-lymphocyte ratio (NLR), albumin-to-fibrinogen ratio (AFR), and lymphocyte-to-monocyte ratio (LMR) in assessing PD risk.MethodsThis study included 186 patients with PD and 201 matched healthy controls (HC) with baseline data. Firstly, the differences of hematological indicators between PD group and healthy participants were compared and analyzed. Univariate and multivariate regression analyses were then conducted. Smooth curve fitting was applied to further validate the relationships between NLR, LMR, AFR, and PD. Subsequently, subgroup analysis was conducted in PD group according to different duration of disease and Hoehn and Yahr (H&Y) stage, comparing differences in clinical indicators. Finally, the receiver operating characteristic (ROC) curve was employed to assess the diagnostic value of NLR, LMR, and AFR in PD.ResultsCompared to the HC group, the PD group showed significantly higher levels of hypertension, diabetes, neutrophil count, monocyte count, CRP, homocysteine, fibrinogen, and NLR. Conversely, levels of LMR, AFR, lymphocyte count, HDL, LDL, TG, TC, uric acid, and albumin were significantly lower. The multivariate regression model indicated that NLR (OR = 1.79, 95% CI: 1.39–2.31, p

Abstract Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).

Skin is a vital barrier for the human body, protecting against external environmental influences and maintaining internal homeostasis. In addition, an imbalance of oxidative stress and antioxidant mechanisms can lead to skin-related diseases. Thus, for treating skin-related diseases, antioxidant therapy may be an important strategy to alleviate these symptoms. However, traditional drug therapies have limitations in treating these conditions, such as lack of lasting effect and insufficient skin permeability. Recently, nano-antioxidants, with their good permeability, sustained-release ability, multifunctionality, and other beneficial characteristics, have showed their advances in the exploration of skin-related diseases from research on safe therapies to clinical practice. Hereby, we review the latest research and advancements in nano-antioxidants for skin-related diseases. We categorize skin-related diseases into four main groups: skin inflammatory diseases, skin damage caused by ultraviolet rays, skin wound healing, and other skin-related conditions. Additionally, we summarize the prospects and potential future directions for nano-antioxidant drugs in treating skin-related diseases.

Cluster headache (CH) is a common primary headache that severely impacts patients’ quality of life, characterized by recurrent, severe, unilateral headaches often centered around the eyes, temples, or forehead. Distinguishing CH from other headache disorders is challenging, and its pathogenesis remains unclear. Notably, patients with CH often experience high levels of depression and suicidal tendencies, necessitating increased clinical attention. This comprehensive assessment combines various reports and the latest scientific literature to evaluate the current state of CH research. It covers epidemiology, population characteristics, predisposing factors, and treatment strategies. Additionally, we provide strategic insights into the holistic management of CH, which involves continuous, individualized care throughout the prevention, treatment, and rehabilitation stages. Recent advances in the field have revealed new insights into the pathophysiology of CH. While these findings are still evolving, they offer a more detailed understanding of the neurobiological mechanisms underlying this disorder. This growing body of knowledge, alongside ongoing research efforts, promises to lead to the development of more targeted and effective treatments in the future.

The screening and identification of drug metabolites in biological matrices is challenging, and ultra-high performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) has become a powerful technological tool for drug metabolites analysis due to its high sensitivity. However, the spectral information contained in existing chemical standards and databases is very limited, and the UHPLC-Q-Exactive Orbitrap MS technique alone cannot satisfy the identification of complex and diverse metabolites. Therefore, there is an urgent need for a new strategy to achieve comprehensive drug metabolic profile. Based on this, we have innovatively constructed a “recursive tree” analysis strategy and bridged it with network pharmacology for elucidating the pharmacological mechanisms of drugs. In this paper, we investigated the overall metabolic profile of formononetin as an example and utilized the primary branching metabolites of formononetin as effective ingredients for the study of the anti-NAFLD mechanism. The results showed that a total of 131 metabolites (prototype drug included) were detected and identified. Among them, 106 metabolites were found in rats and 31 metabolites were found in liver microsomes. Glucose conjugation, demethylation, sulfation, glucuronidation, and their complex reactions were the major processes of formononetin biotransformation. Network pharmacology results screened 104 potential targets and 20 major signaling pathways. Their mechanisms may be additive and/or synergistic effects. In addition, the therapeutic effects of formononetin against NAFLD were investigated based on palmitic acid / oleic acid-induced HepG2 cells. In summary, the recursive tree analysis strategy provides a convenient method for the identification of metabolites, and its seamless integration with network pharmacology lays the foundation for studying the pharmacological activities of natural products.

We present the case of a 33-year-old male referred across several hospitals because of suspected chronic thromboembolic pulmonary hypertension (CTEPH). Initially admitted in October 2022 for a recurrent, severe cough and diagnosed with CTEPH, he received anticoagulant therapy. However, his symptoms worsened, necessitating a transfer to another facility for thrombolysis treatment. Following an episode of syncope, an MRI scan revealed a metastatic brain tumor. Subsequently, he experienced a third transfer to our hospital, emergency surgery was performed to alleviate cerebral edema and excise a lesion in the left frontal lobe. Postoperative pathology was inconclusive, but a multidisciplinary team meeting, aided by experienced radiologists, eventually confirmed a diagnosis of pulmonary artery sarcoma (PAS) with systemic metastases. This case underscores the necessity of promptly ruling out PAS in patients presenting with significant emboli in the central pulmonary arteries and suggests early referral to specialized centers for suspected cases.

Delays in sowing have significant effects on the grain yield, yield components, and grain protein concentrations of winter wheat. However, little is known about how delayed sowing affects these characteristics at different positions in the wheat spikes. In this study, the effects of sowing date were investigated in a winter wheat cultivar, Shannong 30, which was sown in 2019 and 2020 on October 8 (normal sowing) and October 22 (late sowing) under field conditions. Delayed sowing increased the partitioning of 13C-assimilates to spikes, particularly to florets at the apical section of a spike and those occupying distal positions on the same spikelet. Consequently, the increase in grain number was the greatest for the apical sections, followed by the basal and central sections. No significant differences were observed between sowing dates in the superior grain number in the basal and central sections, while the number in apical sections was significantly different. The number of inferior grains in each section also increased substantially in response to delayed sowing. The average grain weights in all sections remained unchanged under delayed sowing because there were parallel increases in grain number and 13C-assimilate partitioning to grains at specific positions in the spikes. Increases in grain number m–2 resulted in reduced grain protein concentrations as the limited nitrogen supply was diluted into more grains. Delayed sowing caused the greatest reduction in grain protein concentration in the basal sections, followed by the central and apical sections. No significant differences in the reduction of the grain protein concentration were observed between the inferior and superior grains under delayed sowing. In conclusion, a 2-week delay in sowing improved grain yield through increased grain number per spike, which originated principally from an increased grain number in the apical sections of spikes and in distal positions on the same spikelet. However, grain protein concentrations declined in each section because of the increased grain number and reduced N uptake.

Remote sensing has been increasingly used for precision nitrogen management to assess the plant nitrogen status in a spatial and real-time manner. The nitrogen nutrition index (NNI) can quantitatively describe the nitrogen status of crops. Nevertheless, the NNI diagnosis for cotton with unmanned aerial vehicle (UAV) multispectral images has not been evaluated yet. This study aimed to evaluate the performance of three machine learning models, i.e., support vector machine (SVM), back propagation neural network (BPNN), and extreme gradient boosting (XGB) for predicting canopy nitrogen weight and NNI of cotton over the whole growing season from UAV images. The results indicated that the models performed better when the top 15 vegetation indices were used as input variables based on their correlation ranking with nitrogen weight and NNI. The XGB model performed the best among the three models in predicting nitrogen weight. The prediction accuracy of nitrogen weight at the upper half-leaf level (R2=0.89, RMSE=0.68 g m–2, RE=14.62% for calibration and R2=0.83, RMSE=1.08 g m–2, RE=19.71% for validation) was much better than that at the all-leaf level (R2=0.73, RMSE=2.20 g m–2, RE=26.70% for calibration and R2=0.70, RMSE=2.48 g m–2, RE=31.49% for validation) and at the plant level (R2=0.66, RMSE=4.46 g m–2, RE=30.96% for calibration and R2=0.63, RMSE=3.69 g m–2, RE=24.81% for validation). Similarly, the XGB model (R2=0.65, RMSE=0.09, RE=8.59% for calibration and R2=0.63, RMSE=0.09, RE=8.87% for validation) also outperformed the SVM model (R2=0.62, RMSE=0.10, RE=7.92% for calibration and R2=0.60, RMSE=0.09, RE=8.03% for validation) and BPNN model (R2=0.64, RMSE=0.09, RE=9.24% for calibration and R2=0.62, RMSE=0.09, RE=8.38% for validation) in predicting NNI. The NNI predictive map generated from the optimal XGB model can intuitively diagnose the spatial distribution and dynamics of nitrogen nutrition in cotton fields, which can help farmers implement precise cotton nitrogen management in a timely and accurate manner.

The accurate and rapid estimation of canopy nitrogen content (CNC) in crops is the key to optimizing in-season nitrogen fertilizer application in precision agriculture. However, the determination of CNC from field sampling data for leaf area index (LAI), canopy photosynthetic pigments (CPP; including chlorophyll a, chlorophyll b and carotenoids) and leaf nitrogen concentration (LNC) can be time-consuming and costly. Here we evaluated the use of high-precision unmanned aerial vehicle (UAV) multispectral imagery for estimating the LAI, CPP and CNC of winter wheat over the whole growth period. A total of 23 spectral features (SFs; five original spectrum bands, 17 vegetation indices and the gray scale of the RGB image) and eight texture features (TFs; contrast, entropy, variance, mean, homogeneity, dissimilarity, second moment, and correlation) were selected as inputs for the models. Six machine learning methods, i.e., multiple stepwise regression (MSR), support vector regression (SVR), gradient boosting decision tree (GBDT), Gaussian process regression (GPR), back propagation neural network (BPNN) and radial basis function neural network (RBFNN), were compared for the retrieval of winter wheat LAI, CPP and CNC values, and a double-layer model was proposed for estimating CNC based on LAI and CPP. The results showed that the inversion of winter wheat LAI, CPP and CNC by the combination of SFs+TFs greatly improved the estimation accuracy compared with that by using only the SFs. The RBFNN and BPNN models outperformed the other machine learning models in estimating winter wheat LAI, CPP and CNC. The proposed double-layer models (R2=0.67–0.89, RMSE=13.63–23.71 mg g–1, MAE=10.75–17.59 mg g–1) performed better than the direct inversion models (R2=0.61–0.80, RMSE=18.01–25.12 mg g–1, MAE=12.96–18.88 mg g–1) in estimating winter wheat CNC. The best winter wheat CNC accuracy was obtained by the double-layer RBFNN model with SFs+TFs as inputs (R2=0.89, RMSE=13.63 mg g–1, MAE=10.75 mg g–1). The results of this study can provide guidance for the accurate and rapid determination of winter wheat canopy nitrogen content in the field.

Abstract Background Colorectal cancer (CRC) is one of the most prevalent diagnosed malignancies and one of the leading causes of cancer-related deaths worldwide. 5-Fluorouracil (5-FU) and its combination regimen are commonly used as primary chemotherapeutic agents for advanced CRC. Intestinal mucositis is one of the most frequent side effects of 5-FU. Artesunate (Arte) is derived from the wormwood plant Artemisia annua. Arte is not only effective against malaria but also diabetes, atherosclerosis, inflammation, and other conditions. The mechanism by which 5-FU damages the intestinal tract is unclear, and there is no standard treatment for diarrhea caused by 5-FU. Therefore, it is critical to discover novel and promising therapeutic drugs for 5-FU side effect treatment. Methods The morphology and expression of genes and proteins associated with the aging of HUVECs, HIECs, and intestinal tissues were compared to the those of the control group. The cell lines and tissues were evaluated by SA-β-Gal staining, Western blotting, and RT‒qPCR. HIEC and HCT116 cell viability was assessed in vitro by a CCK-8 assay and in vivo by a subcutaneous tumor mouse assay. Tumor cell proliferation and apoptosis was evaluated by immunohistochemistry. Results Here, we report that Arte alleviates the adverse side effects caused by 5-FU in intestinal tissue, and that 5-FU-induced intestinal damage is associated with drug-induced chemical inflammation and an increase in the proportion of senescent cells. Arte decreases the ratio of SA-β-Gal-positive cells and downregulated the expression of aging-related proteins (p53, p16) and aging-related genes (p53, p21). Mechanistically, Arte relieves intestinal injury by inhibiting mTOR expression, which is associated with the regulation of aging. Moreover, Arte suppresses the p38MAPK and NF-κB signaling pathways, which are related to inflammation regulation. In addition, the combined therapy of Arte plus 5-FU significantly decreases cancer cell viability in vitro. Arte and 5-FU synergistically reduce the growth of colorectal cancer (CRC) xenografts in vivo. Conclusions Overall, our findings point to the crucial treatment effect of Arte on inflammation, intestinal cell senescence, and CRC cell proliferation and offer a new option for CRC treatment.

Background and aims: The increasing incidence of cardiovascular diseases has created an urgent need for safe and effective anti-thrombotic agents. Leech, as a traditional Chinese medicine, has the effect of promoting blood circulation and removing blood stasis, but its real material basis and mechanism of action for the treatment of diseases such as blood stasis and thrombosis have not been reported.Methods: In this study, Whitmania Pigra Whitman (WPW), Hirudo nipponica Whitman (HNW) and Whitmania acranutata Whitman (WAW) were hydrolyzed by biomimetic enzymatic hydrolysis to obtain the active peptides of WPW (APP), the active peptides of HNW (APH) and the active peptides of WAW (APA), respectively. Then their structures were characterized by sykam amino acid analyzer, fourier transform infrared spectrometer (FT-IR), circular dichroism (CD) spectrometer and LC-MS. Next, the anti-thrombotic activities of APP, APH and APA were determined by carrageenan-induced tail vein thrombosis model in mice, and the anti-thrombotic mechanisms of high-dose APP group (HAPP), high-dose APH group (HAPH) and high-dose APA group (HAPA) were explored based on UHPLC-Q-Exactive Orbitrap mass spectrometry.Results: The results showed that the amino acid composition of APP, APH and APA was consistent, and the proportion of each amino acid was few different. The results of FT-IR and CD showed that there were no significant differences in the proportion of secondary structures (such as β-sheet and random coil) and infrared absorption peaks between APP, APH and APA. Mass spectrometry data showed that there were 43 common peptides in APP, APH and APA, indicating that the three have common material basis. APP, APH and APA could significantly inhibit platelet aggregation, reduce black-tail length, whole blood viscosity (WBV), plasma viscosity (PV), and Fibrinogen (FIB), and prolong coagulation time, including activated partial thrombin time (APTT), prothrombin time (PT) and thrombin time (TT). In addition, 24 metabolites were identified as potential biomarkers associated with thrombosis development. Among these, 19, 23, and 20 metabolites were significantly normalized after administration of HAPP, HAPH, and HAPA in the mice, respectively. Furthermore, the intervention mechanism of HAPP, HAPH and HAPA on tail vein thrombosis mainly involved in linoleic acid metabolism, primary bile acid biosynthesis and ether lipid metabolism.Conclusion: Our findings suggest that APP, APH and APA can exert their anti-blood stasis and anti-thrombotic activities by interfering with disordered metabolic pathways in vivo, and there is no significant difference in their efficacies.

Delayed sowing mitigates lodging in wheat. However, the mechanism underlying the enhanced lodging resistance in wheat has yet to be fully elucidated. Field experiments were conducted to investigate the effects of sowing date on lignin and cellulose metabolism, stem morphological characteristics, lodging resistance, and grain yield. Seeds of Tainong 18, a winter wheat variety, were sown on October 8 (normal sowing) and October 22 (late sowing) during both of the 2015–2016 and 2016–2017 growing seasons. The results showed that late sowing enhanced the lodging resistance of wheat by improving the biosynthesis and accumulation of lignin and cellulose. Under late sowing, the expression levels of key genes (TaPAL, TaCCR, TaCOMT, TaCAD, and TaCesA1, 3, 4, 7, and 8) and enzyme activities (TaPAL and TaCAD) related to lignin and cellulose biosynthesis peaked 4–12 days earlier, and except for the TaPAL, TaCCR, and TaCesA1 genes and TaPAL, in most cases they were significantly higher than under normal sowing. As a result, lignin and cellulose accumulated quickly during the stem elongation stage. The mean and maximum accumulation rates of lignin and cellulose increased, the maximum accumulation contents of lignin and cellulose were higher, and the cellulose accumulation duration was prolonged. Consequently, the lignin/cellulose ratio and lignin content were increased from 0 day and the cellulose content was increased from 11 days after jointing onward. Our main finding is that the improved biosynthesis and accumulation of lignin and cellulose were responsible for increasing the stem-filling degree, breaking strength, and lodging resistance. The major functional genes enhancing lodging resistance in wheat that are induced by delayed sowing need to be determined.

Maize (Zea mays L.) is one of the three major food crops and an important source of carbohydrates for maintaining food security around the world. Plant height (H), stem diameter (SD), leaf area index (LAI) and dry matter (DM) are important growth parameters that influence maize production. However, the combined effect of temperature and light on maize growth is rarely considered in crop growth models. Ten maize growth models based on the modified logistic growth equation (Mlog) and the Mitscherlich growth equation (Mit) were proposed to simulate the H, SD, LAI and DM of maize under different mulching practices based on experimental data from 2015–2018. Either the accumulative growing degree-days (AGDD), helio thermal units (HTU), photothermal units (PTU) or photoperiod thermal units (PPTU, first proposed here) was used as a single driving factor in the models; or AGDD was combined with either accumulative actual solar hours (ASS), accumulative photoperiod response (APR, first proposed here) or accumulative maximum possible sunshine hours (ADL) as the dual driving factors in the models. The model performances were evaluated using seven statistical indicators and a global performance index. The results showed that the three mulching practices significantly increased the maize growth rates and the maximum values of the growth curves compared with non-mulching. Among the four single factor-driven models, the overall performance of the MlogPTU Model was the best, followed by the MlogAGDD Model. The MlogPPTU Model was better than the MlogAGDD Model in simulating SD and LAI. Among the 10 models, the overall performance of the MlogAGDD–APR Model was the best, followed by the MlogAGDD–ASS Model. Specifically, the MlogAGDD–APR Model performed the best in simulating H and LAI, while the MlogAGDD–ADL and MlogAGDD–ASS models performed the best in simulating SD and DM, respectively. In conclusion, the modified logistic growth equations with AGDD and either APR, ASS or ADL as the dual driving factors outperformed the commonly used modified logistic growth model with AGDD as a single driving factor in simulating maize growth.

Abstract Background Congenitally corrected transposition of the great arteries (ccTGA) is a rare cardiac anomaly and can lead to abnormal electrical activity of the heart. The implant of a pacemaker in such patients is more complicated than conventional operations. This case report of an adult with ccTGA who had a leadless pacemaker implant will provide a reference for diagnosing and treating such patients. Case presentation A 50-year-old male patient was admitted to hospital having experienced intermittent vision loss for a month. An electrocardiogram and Holter monitoring showed intermittent third-degree atrioventricular block, and echocardiography, cardiac computed tomography and cardiac magnetic resonance imaging confirmed a diagnosis of ccTGA. A leadless pacemaker was successfully implanted into the patient’s anatomical left ventricle, and the postoperative parameters were stable. Conclusion Implanting a leadless pacemaker into a patient with a rare anatomical and electrophysiological abnormality, such as ccTGA, is feasible and efficacious, but preoperative imaging evaluation is of considerable importance.

With the rapid development of natural language processing techniques, the use of language models in text classification and sentiment analysis has been increasing.However, language models are susceptible to piracy and redistribution by adversaries, posing a serious threat to the intellectual property of model owners.Therefore, researchers have been working on designing protection mechanisms to identify the copyright information of language models.However, existing watermarking of language models for text classification tasks cannot be associated with the owner’s identity, and they are not robust enough and cannot regenerate trigger sets.To solve these problems, a new model, namely black-box watermarking scheme for text classification tasks, was proposed.It was a scheme that can remotely and quickly verify model ownership.The copyright message and the key of the model owner were obtained through the Hash-based Message Authentication Code (HMAC), and the message digest obtained by HMAC can prevent forgery and had high security.A certain amount of text data was randomly selected from each category of the original training set and the digest was combined with the text data to construct the trigger set, then the watermark was embedded on the language model during the training process.To evaluate the performance of the proposed scheme, watermarks were embedded on three common language models on the IMDB’s movie reviews and CNews text classification datasets.The experimental results show that the accuracy of the proposed watermarking verification scheme can reach 100% without affecting the original model.Even under common attacks such as model fine-tuning and pruning, the proposed watermarking scheme shows strong robustness and resistance to forgery attacks.Meanwhile, the embedding of the watermark does not affect the convergence time of the model and has high embedding efficiency.

Background: Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (AD) is a tall perennial herb named Baizhi in Chinese Medical Works. Its medicinal use was first recorded in Shennong's Classic of Material Medical, the first herbal monograph in ancient China. Aim of the review: This review systematically summarises and evaluates traditional applications, botany, chemistry, and pharmacology of AD. This review aims to support the researchers who would like to explore its further potential as a medical agent. Materials and methods: The information was collected from Web of Science (https://www.webofscience.com), PubMed (https://pubmed.ncbi.nlm.nih.gov), CNKI (https://kns.cnki.net), Dissertations, Chinese Pharmacopoeia, and Government documents. The keyword used in the literature search was Angelica dahurica. The chemical structures of the compounds in AD were obtained from either research articles or PubChem. The historical origin and ethnopharmacology of AD were reviewed in detail. In addition, relevant information was obtained from regional and global unpublished sources. The plant's name and its classifications were confirmed using the Medicinal Plant Name Service (http://mpns.kew.org) and Plants of the World Online (https://powo.science.kew.org). Results: Over time, AD has been used extensively for its medicinal uses. The bioactive chemical compound present in it is imperatorin (IMP). It has anti-inflammatory, analgesic, and other therapeutic effects, and it is used as a marker for the quality evaluation of AD. The most studied part of the plant is the root. The root contains coumarins and volatile oil. Modern science has found that AD has the ability to treat skin wounds, analgesic, anti-inflammatory, anti-tumor, anti-depressant, and antioxidant effects, etc. Conclusions: This paper presents a detailed comparative analysis of available resources, confirming the origin, traditional applications, and therapeutic uses of AD. Most importantly, it is widely welcomed as a therapeutic drug. The results of several studies showed that the chemical components of AD were more deeply involved in the central nervous system and histopathological mechanisms. Moreover, AD not only has medical effects but also can be used as food condiments and food accessories.

Restrictive cardiomyopathy (RCM) is a rare childhood cardiomyopathy that is a challenging diagnostic problem for clinicians. We describe a case of an 8-year-old girl with a 2-year history of shortness of breath on exertion. Electrocardiogram and echocardiography showed biatrial enlargement, while cardiac magnetic resonance showed biatrial dilation and normal pericardial thickness. Left and right heart catheterization revealed a left ventricular (LV) end-diastolic pressure (EDP) of 20 mmHg, right ventricular (RV) EDP of 13 mmHg, and pulmonary arterial systolic pressure of 51 mmHg. LV and RV pressure traces showed that LV and RV pressures moved concordantly with respiration, and that the systolic area index was 0.98. Cardiac catheterization data were therefore supportive of RCM. Next-generation sequencing identified a heterozygous variant of the troponin I gene ( TNNI3 ; c.574C>T). Combining these findings led to a diagnosis of RCM. The patient’s parents chose conservative treatment, but at the 12-month follow-up she died of worsening heart failure and cerebral infarction. This case emphasizes the need for cardiac catheterization and genetic testing in RCM, and suggests that anticoagulants should be recommended to reduce the risk of thromboembolic events.

Abstract Objective To study the safety and electrical characteristics of various implanting sites of the Micra pacemaker. Method A total of 15 patients from Beijing Anzhen Hospital, Capital Medical University, were included, who were implanted with Micra leadless pacemakers and allocated to either the high ventricular septum group (eight patients) or the low ventricular septum group (seven patients) based on their individual patient factors and clinical conditions. The baseline of the patients, the implanting area, the electrocardiogram change after implantation, the implantation data, the threshold, R wave, impedance, and the date of the 1‐month follow‐up were then analyzed. With all of the data, the characteristics of different implantation sites of the Micra pacemaker were determined. Results Overall, the thresholds were low at implantation and remained stable over the 1‐, 3‐, 6‐month, 1‐, 2‐, 3‐, and 4‐year follow‐ups. On comparing the two groups, there was no difference in QRS duration at pacing (140.00 [40.00] ms vs. 179.00 [50.00] ms), threshold at implantation (0.38 [0.22] mV vs. 0.63 [1.00] mV), R wave at implantation ([10.85 ± 4.71] V vs. [7.26 ± 2.98] V), or impedance at implantation ([906.25 ± 162.39] Ω vs. [750.00 ± 173.40] Ω). While the difference in QRS duration between the two groups was not significant, the QRS duration of the high ventricular septum group exhibited a reduced tendency compared with that of the low ventricular group. The corrected QT interval during pacing exhibited a significant difference (440.00 [80.00] ms vs. 520.00 [100.00] ms; p .05). Conclusion High ventricular septum pacing appears to be a safe site for implantation of the Micra pacemaker. It could entail a shorter QRS duration at pacing and could be more physiological than low ventricular septum pacing.

Ophiopogonis Radix (OR) is a traditional Chinese medicine. In recent years, in order to achieve the purpose of drying, bleaching, sterilizing and being antiseptic, improving appearance, and easy storage, people often use sulfur fumigation for its processing. However, changes in the chemical composition of medicinal herbs caused by sulfur fumigation can lead to the transformation and loss of potent substances. Therefore, the development of methods to rapidly reveal the chemical transformation of medicinal herbs induced by sulfur fumigation can guarantee the safe clinical use of medicines. In this study, a combined full scan-parent ions list-dynamic exclusion acquisition-diagnostic product ions analysis strategy based on UHPLC-LTQ-Orbitrap MS was proposed for the analysis of steroidal saponins and their transformed components in sulfur-fumigated Ophiopogonis Radix (SF-OR). Based on precise mass measurements, chromatographic behavior, neutral loss ions, and diagnostic product ions, 286 constituents were screened and identified from SF-OR, including 191 steroidal saponins and 95 sulfur-containing derivatives (sulfates or sulfites). The results indicated that the established strategy was a valuable and effective analytical tool for comprehensively characterizing the material basis of SF-OR, and also provided a basis for potential chemical changes in other sulfur-fumigated herbs.

Acorus calamus var. angustatus Besser (ATT) is a traditional herb with a long medicinal history. The volatile oil of ATT (VOA) does possess many pharmacological activities. It can restore the vitality of the brain, nervous system and myocardial cells. It is used to treat various central system, cardiovascular and cerebrovascular diseases. It also showed antibacterial and antioxidant activity. Many studies have explored the benefits of VOA scientifically. This paper reviews the extraction methods, chemical components, pharmacological activities and toxicology of VOA. The molecular mechanism of VOA was elucidated. This paper will serve as a comprehensive resource for further carrying the VOA on improving its medicinal value and clinical use.

Arctigenin is a phenylpropanoid dibenzylbutyro lactone lignan compound with multiple biological functions. Previous studies have shown that arctigenin have neuroprotective effects in Alzheimer’s disease (AD) models both in vivo and in vitro; however, its metabolism in vivo has not been studied. Most traditional analytical methods only partially characterize drug metabolite prototypes, so there is an urgent need for a research strategy that can fully characterize drug metabolites. In the present study, ions fishing with a serial five-membered lactone ring as a fishhook strategy based on ultrahigh-performance liquid chromatography-Q-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) was utilised to characterise the metabolism of arctigenin, and the establishment of this strategy also solved the challenge of creating a comprehensive metabolic profile of neolignan. Based on the proposed strategy, a total of 105 metabolites were detected and characterised, 76 metabolites of which were found in rats and 49 metabolites in liver microsomes. These metabolites were postulated to be produced through oxidation, reduction, hydrolysis, and complex reactions. Subsequently, network pharmacology was utilized to elucidate the mechanism of arctigenin and its main metabolites against Alzheimer’s disease, screening 381 potential targets and 20 major signaling pathways. The study on the comprehensive metabolism of arctigenin provides a holistic metabolic profile, which will help to better understand the mechanism of arctigenin in the treatment of Alzheimer’s disease (AD) and also provide a basis for the safe administration of arctigenin.

IntroductionIron deficiency anemia (IDA) is one of the most common nutritional diseases encountered all over the world. Nowadays, oral iron supplementation is still the mainstay of IDA treatment.MethodsIn this study, a new iron nutritional supplement named pig skin collagen peptides ferrous chelates (PSCP-Fe) was prepared, and its structure was characterized by the scanning electron microscopy, sykam amino acid analyzer and Fourier transform infrared spectroscopy (FTIR). The anti-IDA activity of PSCP-Fe was evaluated in low-Fe2+ diet-induced IDA in rats. 16S amplicon sequencing technology was then used to reveal the mechanism of PSCP-Fe against IDA.ResultsThe results of amino acid analysis and FTIR showed that aspartic acid (Asp), arginine (Arg), histidine (His), glutamic acid (Glu), cystine (Cys), and lysine (Lys) residued in PSCP chelated readily with Fe2+ through their functional groups. PSCP-Fe treated reversed the hematology-related indexes, such as red blood cells (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentrate (MCHC), serum ferritin (SF), serum hepcidin (HEPC) and serum transferrin receptor (TFR). And its regulatory action was better than that of FeSO4. Moreover, PSCP-Fe alleviated the hepatocyte apoptosis and necrosis, Fe2+ loss, and injury in IDA rats. In addition, PSCP-Fe could significantly retrace the disturbed profile of gut microbiota in IDA rats (p < 0.05) and significantly up-regulated the relative abundances of nine bacterial genus, including Lactobacillus, Alloprevotella, unclassified_of_Oscillospiraceae, and NK4A214_group (p < 0.05). It could also downgrade the relative abundances of Subdoligranulum and Coriobacteriaceae_UCG-002 (p < 0.05). The results of Spearman’s correlation analysis and distance-based redundancy analysis (db-RDA) revealed that Subdoligranulum and Christensenellaceae_R-7_group may be potential microbial markers for effective PSCP-Fe action in the treatment of IDA.DiscussionOverall, our results elucidate the interactions between gut bacteria and related cytokines and reveal the mechanisms underlying the anti-IDA effect of PSCP-Fe. They will thus provide a theoretical foundation for PSCP-Fe as a new iron nutritional supplement.

The active peptide (APE) of Eupolyphaga sinensis Walker, which is prepared by bioenzymatic digestion, has significant antihyperlipidemic effects in vivo, but its mechanism of action on hyperlipidemia is not clear. Recent studies on amino acid metabolism suggested a possible link between it and hyperlipidemia. In this study, we first characterized the composition of APE using various methods. Then, the therapeutic effects of APE on hyperlipidemic rats were evaluated, including lipid levels, the inflammatory response, and oxidative stress. Finally, the metabolism-regulating mechanisms of APE on hyperlipidemic rats were analyzed using untargeted and targeted metabolomic approaches. The results showed that APE significantly reduced the accumulation of fat, oxidative stress levels, and serum pro-inflammatory cytokine levels. Untargeted metabolomic analysis showed that the mechanism of the hypolipidemic effect of APE was mainly related to tryptophan metabolism, phenylalanine metabolism, arginine biosynthesis, and purine metabolism. Amino-acid-targeted metabolomic analysis showed that significant differences in the levels of eight amino acids occurred after APE treatment. Among them, the expression of tryptophan, alanine, glutamate, threonine, valine, and phenylalanine was upregulated, and that of arginine and proline was downregulated in APE-treated rats. In addition, APE significantly downregulated the mRNA expression of SREBP-1, SREBP-2, and HMGCR. Taking these points together, we hypothesize that APE ameliorates hyperlipidemia by modulating amino acid metabolism in the metabolome of the serum and feces, mediating the SREBP/HMGCR signaling pathway, and reducing oxidative stress and inflammation levels.

The characteristics of reservoir heterogeneity of the marine gravity flow tight sandstone from the Miocene Huangliu Formation under abnormally high pressure setting at LD10 area in Yinggehai Basin are studied, and the influencing factors on reservoir heterogeneity are discussed, based on modular formation dynamics test, thin sections, XRD analysis of clay minerals, scanning electron microscopy, measurement of pore throat image, porosity and permeability, and high pressure Hg injection, as well as the stimulation of burial thermal history. The aim is to elucidate characteristics of the heterogeneity and the evolution process of heterogeneity of the reservoir, and predict the favorable reservoirs distribution. (1) The heterogeneity of the reservoir is mainly controlled by the cement heterogeneity, pore throat heterogeneity, quality of the reservoir heterogeneity, and the diagenesis under an abnormally high pressure setting. (2) The differences in pore-throat structure caused by diagenetic evolution affected the intergranular material heterogeneity and the pore throat heterogeneity, and finally controlled the heterogeneity of reservoir quality. (3) Compared with the reservoir under normal pressure, abnormally high pressure restrains strength of the compaction and cementation and enhances the dissolution of the reservoir to some extent, and abnormally high pressure thus weakening the heterogeneity of the reservoir to a certain degree. The favorable reservoirs are mainly distributed in the gravity flow sand body under the strong overpressure zone in the middle and lower part of Huangliu Formation.

Isoniazid (INH) and rifampicin (RFP) are the first-line medications for tuberculosis treatment, and liver injury is the major adverse effect. Natural medicinal ingredients provide distinct benefits in alleviating patients’ symptoms, lowering the liver injury risk, delaying disease progression, and strengthening the body’s ability to heal. This paper summarises the recent research on the mechanisms of INH and RFP-induced liver injury and the effects of natural medicinal ingredients. It is believed that INH-induced liver injury may be attributed to oxidative stress, mitochondrial dysfunction, drug metabolic enzymes, protoporphyrin IX accumulation, endoplasmic reticulum stress, bile transport imbalance, and immune response. RFP-induced liver injury is mainly related to cholestasis, endoplasmic reticulum stress, and liver lipid accumulation. However, the combined effect of INH and RFP on liver injury risk is still uncertain. RFP can increase INH-induced hepatotoxicity by regulating the expression of drug-metabolizing enzymes and transporters. In contrast, INH can antagonize RFP-induced liver injury by reducing the total bilirubin level in the blood. Sagittaria sagittifolia polysaccharide, quercetin, gallic acid, and other natural medicinal ingredients play protective roles on INH and RFP-induced liver injury by enhancing the body’s antioxidant capacity, regulating metabolism, inhibiting cell apoptosis, and reducing the inflammatory response. There are still many gaps in the literature on INH and RFP-induced liver injury mechanisms and the effects of natural medicinal ingredients. Thus, further research should be carried out from the perspectives of liver injury phenotype, injury markers, in vitro and in vivo liver injury model construction, and liver-gut axis. This paper comprehensively reviewed the literature on mechanisms involved in INH and RFP-induced liver injury and the status of developing new drugs against INH and RFP-induced liver injury. In addition, this review also highlighted the uses and advantages of natural medicinal ingredients in treating drug-induced liver injury.

The dysbiosis of gut flora and its metabolites plays important roles in the progression of hyperlipidemia (HL), and some bioactive peptides are available for HL treatment. In this study, we aimed to isolate an active peptide (AR-9) from active peptides of E. sinensis (APE) and determine whether AR-9 could improve many symptoms of a HL rat induced by a high-fat diet (HFD) by modulating gut flora and its metabolites. Above all, AR-9 was derived from APE using ion-exchange chromatography, and its structure was deconstructed by Fourier transform infrared spectrometer (FT-IR), circular dichroism (CD) spectroscopy, and UHPLC-Q-Exactive-Orbitrap MS. Then, an HFD-induced HL model in SD rats was established and used to clarify the regulatory effects of AR-9 (dose of 3 mg/kg) on HL. Normal diet–fed rats were taken as the control. The plasma samples and liver were harvested for biochemical and histopathological examinations. 16S rRNA gene sequencing and untargeted metabolomics were sequenced to assess changes in gut flora and its metabolites from rat fecal samples. Finally, Spearman’s correlation analysis was used to assess the relationship between lipid-related factors, gut flora, and its metabolites so as to evaluate the mechanism of AR-9 against HL. The results of the separation experiments showed that the amino acid sequence of AR-9 was AVFPSIVGR, which was a fragment of the actin protein from Blattaria insects. Moreover, HFD rats developed exaltation of index factors, liver lipid accumulation, and simple fibrosis for 8 weeks, and the profiles of gut flora and its metabolites were significantly altered. After treatment, AR-9 decreased the levels of lipid factors in plasma and the extent of liver damage. 16S rRNA gene sequencing results indicated that AR-9 significantly increased the relative abundance of beneficial bacteria Bacteroidetes and reduced the relative abundance of the obesity-associated bacteria Firmicutes. Furthermore, AR-9 changed gut microbiota composition and increased the relative abundance of beneficial bacteria: Lactobacillus, Clostridium, Dehalobacterium, and Candidatus arthromitus. Fecal metabolomics showed that the pathway regulated by AR-9 was “arginine biosynthesis”, in which the contents were citrulline and ornithine. Spearman’s correlation analysis revealed that two metabolites (ornithine and citrulline) showed significantly negative correlations with obesity-related parameters and positive correlations with the gut genera (Clostridium) enriched by AR-9. Overall, our results suggested interactions between gut microbial shifts and fecal amino acid/lipid metabolism and revealed the mechanisms underlying the anti-HL effect of AR-9. The abovementioned results not only reveal the initial anti-HL mechanism of AR-9 but also provide a theoretical basis for the continued development of AR-9.

Reservoir analysis data such as core, thin-section, physical property and scanning electron microscope (SEM) were applied in this paper to study the reservoir characteristics and main constrains of the first member of Eocene Liushagang Formation in the Weixinan Sag, Beibuwan Basin. Reservoir features, physical properties, sedimentation, diagenesis, and the coupling of tectonics as well as hydrocarbon generation and accumulation were analyzed. Results showed that the reservoirs of the first member of Eocene Liushagang Formation in the area of this study were mainly feldspathic debris quartz sandstones and lithic quartz sandstones with low compositional and structural maturities. The reservoir space was mainly consisted of primary intergranular residual pores and secondary dissolved pores. In the northwestern and western source areas, the reservoirs mainly had moderate porosity and medium-high permeability, while those in the eastern source area had relative low porosity and low permeability. Sedimentation caused variations in grain size, sorting and argillaceous complexes. Diagenesis such as compaction, carbonate cementation and organic acid dissolution were the main controls for the physical properties of low-permeability reservoirs. The coupling of tectonics and hydrocarbon generation and accumulation controlled early hydrocarbon charging, while abnormal high pressure protected primary pores, which, combined with fractures derived from faults, improved the physical properties of low-permeability reservoirs. In the northwestern and western source areas, the shallow-buried reservoirs in the first member of Liushagang Formation had relatively strong hydrodynamic force, coarser grain size and better sorting, and showed better properties in the area with less mud. In the eastern source area close to the No. 2 fault around the main hydrocarbon-generating depression, there exist early hydrocarbon filling, strong dissolution of organic acids and partial high-pressure protection. Secondary pores and high-pressure pores were developed at 2 500-3 500 m deep, and favorable deep-burial reservoirs were formed.

Objective To study the expression of apurinic aprimidinic endonuclease 1 (APE1) and the relationship between the expression of APE1 and the sensitivity of platinum chemotherapy for NSCLC. Methods From January 2018 to June 2019, 136 NSCLC patients with stage Ⅲ B or Ⅳ plus non driving gene mutation were selected to extract and identify the plasma exosome APE1. Western blot and ELISA were used to detect the expression of APE1 in exosomes. Immunohistochemistry was used to detect the expression of APE1 in tissues. According to the response evaluation criteria in solid tumors, the patients were divided into two groups: the effective group and the ineffective group. The relationship between APE1 expression and drug sensitivity was examined. Results APE1 was mainly located within exosomes in peripheral blood. The level of APE1 in the exosomes of NSCLC patients was significantly higher than that of normal controls (P＜ 0.001). Compared with NSCLC patients with low tissue APE1 expression, patients with high tissue APE1 expression showed a significantly higher plasma APE1 level (P＜ 0.01). The APE1 level of exosomes in the chemotherapy ineffective group was significantly higher than that in the chemotherapy effective group (P＜ 0.001). Conclusions Exosomal APE1 can be used as a sensitive indicator to evaluate the response of patients to chemotherapy with platinum.

Cardamonin is a chalcone that presents at high content in the seeds of Alpinia katsumadai Hayata. In recent decades, researchers have found that it is not only an edible spice, but also a remarkable herb with a wide range of pharmacological properties. However, its specific metabolic routes in vivo remain unclear while these metabolites may accumulate to exert pharmacological effects. Our study aimed to clarify the metabolic pathways of cardamonin after oral administration to rats. Here, an advanced UHPLC-Q-Exactive Orbitrap MS analytical technique was applied for efficient detection of metabolites in vivo, which especially showed benefits in obtainment of the fragment ions with relatively lower contents. We also established a novel strategy to identify metabolites based on typical fragmentation routes. The results indicated that a total of 40 metabolites could be categorized into 3 types with consideration of the particular structures and characteristic fragment ions. Then, diagnostic product ions (DPIs) of each type were summarized for further screening and identification of metabolites derived from cardamonin. Finally, methylation, demethylation, hydrogenation, hydroxylation, dehydroxylation, glucuronidation and sulfation were confirmed to be the major metabolic pathways in vivo. Our observation extended the metabolic mechanism of cardamonin and could be of great benefits to interpreting the action mechanism of cardamonin in vivo.

Abstract Background The effect and safety of preoperative biliary drainage (PBD) in patients with perihilar cholangiocarcinoma are still controversial; the aim of our study is to evaluate all aspects of PBD. Methods All included studies featured PBD versus non-PBD (NPBD) groups were from 1996 to 2019 and were extracted from Cochrane Library, Embase, PubMed, and Science Citation Index Expanded. Results Sixteen studies met the inclusion criteria and were included in this analysis. PBD may lead to a significantly higher incidence of overall morbidities (OR 0.67, 95% CI 0.53, 0.85; P = 0.0009) and intraoperative transfusions (OR 0.72, 95% CI 0.55, 0.94; P = 0.02); moreover, bile leakage (OR 0.58, 95% CI 0.24, 1.41; P = 0.04), infection (OR 0.31, 95% CI 0.20, 0.47; P < 0.00001), and cholangitis (OR 0.18, 95% CI 0.007, 0.48; P = 0.0007) are also related to PBD. However, NPBD was associated with more frequent hepatic insufficiency (OR 3.09, 95% CI 1.15, 8.31; P = 0.03). In the subgroup meta-analysis, the differences in the outcomes of bile leakage and overall morbidity lost significance between the PBD and NPBD groups when the mean total serum bilirubin (TSB) concentration was above 15 mg/dl. Conclusion Meta-analysis demonstrated that compared to NPBD, PBD is associated with a greater risk of several kinds of infection and morbidities, but its ability to reduce postoperative hepatic insufficiency cannot be ignored. In patients with a high TSB concentration, PBD tends to be a better choice. However, these results need to be confirmed in a future prospective randomized trial with large samples to clarify the effects and find a specific TSB concentration for PBD.

Kartagener’s syndrome is a subgroup of primary ciliary dyskinesia (PCD), a genetically heterogeneous condition characterised by sinusitis, bronchiectasis, and situs in versus. Genetic testing has importance for their diagnosis. Here, we report a chinese patient with Kartagener’s syndrome. Transthoracic echocardiography showed severely elevated right ventricular systolic pressure. Right heart catheterisation demonstrated a pre-capillary pulmonary hypertension. Whole-exome sequencing indicated that she had a novel homozygous nonsense mutation, c.2845C > T, p.Gln949*, in exon 18 of CCDC40 and a heterozygotic mutation, c.73G > A, p.Ala25Thr, in exon 1 of DNAH11. She was diagnosed as Kartagener’s syndrome with pulmonary hypertension. Her symptoms improved significantly by treatment of antibiotics, expectorant drugs, bronchodilators, and oxygen therapy treatment. Our findings extend the mutation spectrum of CCDC40 gene related Kartagener’s syndrome, which is very important for gene diagnosis of the disease.

Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

Genistin, an isoflavone, has been reported to have multiple activities. However, its improvement of hyperlipidemia is still unclear, and the same is true with regard to its mechanism. In this study, a high-fat diet (HFD) was used to induce a hyperlipidemic rat model. The metabolites of genistin in normal and hyperlipidemic rats were first identified to cause metabolic differences with Ultra-High-Performance Liquid Chromatography Quadrupole Exactive Orbitrap Mass Spectrometry (UHPLC-Q-Exactive Orbitrap MS). The relevant factors were determined via ELISA, and the pathological changes of liver tissue were examined via H&E staining and Oil red O staining, which evaluated the functions of genistin. The related mechanism was elucidated through metabolomics and Spearman correlation analysis. The results showed that 13 metabolites of genistin were identified in plasma from normal and hyperlipidemic rats. Of those metabolites, seven were found in normal rat, and three existed in two models, with those metabolites being involved in the reactions of decarbonylation, arabinosylation, hydroxylation, and methylation. Three metabolites, including the product of dehydroxymethylation, decarbonylation, and carbonyl hydrogenation, were identified in hyperlipidemic rats for the first time. Accordingly, the pharmacodynamic results first revealed that genistin could significantly reduce the level of lipid factors (p < 0.05), inhibited lipid accumulation in the liver, and reversed the liver function abnormalities caused by lipid peroxidation. For metabolomics results, HFD could significantly alter the levels of 15 endogenous metabolites, and genistin could reverse them. Creatine might be a beneficial biomarker for the activity of genistin against hyperlipidemia, as revealed via multivariate correlation analysis. These results, which have not been reported in the previous literature, may provide the foundation for genistin as a new lipid-lowering agent.

Herb–drug interactions are vital in effectively managing type-2-diabetes complications. Puerarin is a natural isoflavonoid in the Pueraria genus, and its pharmacological activities, including antidiabetic activity, are well established. The similar modes of action of puerarin and metformin in diabetic models suggest their positive pharmacodynamic interactions. This study investigated this in streptozotocin/nicotinamide-induced type-2 diabetic rats. Puerarin at doses of 80 mg/kg, 120 mg/kg and 160 mg/kg improved the activity of metformin in reversing hyperglycaemia, dysregulated lipid profiles, dysfunction of the liver, kidney, and pancreas, and inflammation. The treatment with either puerarin (high dose, 160 mg/kg intraperitoneally) or metformin (100 mg/kg intraperitoneally) did not bring the dysregulated biomarkers to normal levels in 4 weeks. By contrast, the combination of puerarin (160 mg/kg) and metformin (100 mg/kg) did. This study is the first to report scientific evidence for the positive pharmacodynamic interactions between puerarin and metformin.

Naringenin (5,7,4′-trihydroxyflavanone), belonging to the flavanone subclass, is associated with beneficial effects such as anti-oxidation, anticancer, anti-inflammatory, and anti-diabetic effects. Drug metabolism plays an essential role in drug discovery and clinical safety. However, due to the interference of numerous endogenous substances in metabolic samples, the identification and efficient characterization of drug metabolites are difficult. Here, ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry was used to obtain mass spectral information of plasma (processed by three methods), urine, feces, liver tissue, and liver microsome samples. Moreover, a novel analytical strategy named “ion induction and deduction” was proposed to systematically screen and identify naringenin metabolites in vivo and in vitro. The analysis strategy was accomplished by the establishment of multiple “net-hubs” and the induction and deduction of fragmentation behavior. Finally, 78 naringenin metabolites were detected and identified from samples of rat plasma, urine, feces, liver tissue, and liver microsomes, of which 67 were detected in vivo and 13 were detected in vitro. Naringenin primarily underwent glucuronidation, sulfation, oxidation, methylation, ring fission, and conversion into phenolic acid and their composite reactions. The current study provides significant help in extracting target information from complex samples and sets the foundation for other pharmacology and toxicology research.

Studies on herbal medicines and fermentation products have become increasingly essential with the development of modern industry and technology. In order to verify that fermentation can bring about changes, Paecilomyces cicadae [Paecilomyces cicadae (Miquel.) Samson] was used to ferment Astragali radix [Astragalus membranaceus (Fisch.) Bge. var. mongho-licus (Bge.) Hsiao]. After solid fermentation for Astragali radix produced by Paecilomyces cicadae (SF-AP) was established, an efficient strategy based on ultra-high performance liquid chromatography-linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was developed to screen and identify the chemical transformations in SF-AP and Astragali radix according to the acquired diagnostic product ions (DPIs). As a result, 114 compounds including 45 saponins and 69 flavonoids were finally identified and validated. Moreover, two kinds of antioxidative tests corresponding to the scavenging of DPPH· and ABTS·+ were applied to evaluate the antioxidative activity of Astragali radix before and after fermentation. The results demonstrated that some significant chemical transformations such as relative content fluctuations and structural isomerism owing to the occurrence of hydrolysis and conversion reactions and the antioxidative activity of SF-AP was much higher than that of the Astragali radix. This study could provide a new method for the utilization of Astragali radix and constructive guidance for the further research of fermented herbal medicines.

Release of individuals is an effective conservation approach to protect endangered species. To save this small isolated giant panda population in Liziping Nature Reserve, a few giant pandas have been released to this population. Here we assess genetic diversity and future changes in the population using noninvasive genetic sampling after releasing giant pandas. In this study, a total of 28 giant pandas (including 4 released individuals) were identified in the Liziping, China. Compared with other giant panda populations, this population has medium-level genetic diversity; however, a Bayesian-coalescent method clearly detected, quantified, and dated a recent decrease in population size. The predictions for genetic diversity and survival of the population in the next 100 years indicate that this population has a high risk of extinction. We show that released giant pandas can preserve genetic diversity and improve the probability of survival in this small isolated giant panda population. To promote the recovery of this population, we suggest that panda release should be continued and this population will need to release 10 males and 20 females in the future.