Multi-Delay Identification of Rare Earth Extraction Process Based on Improved Time-Correlation Analysis.

The rare earth extraction process has significant time delay characteristics, making it challenging to identify the time delay and establish an accurate mathematical model. This paper proposes a multi-delay identification method based on improved time-correlation analysis. Firstly, the data are preprocessed by grey relational analysis, and the time delay sequence and time-correlation data matrix are constructed. The time-correlation analysis matrix is defined, and the H∞ norm quantifies the correlation degree of the data sequence. Thus the multi-delay identification problem is transformed into an integer optimization problem. Secondly, an improved discrete state transition algorithm is used for optimization to obtain multi-delay. Finally, based on an Neodymium (Nd) component content model constructed by a wavelet neural network, the performance of the proposed method is compared with the unimproved time delay identification method and the model without an identification method. The results show that the proposed algorithm improves optimization accuracy, convergence speed, and stability. The performance of the component content model after time delay identification is significantly improved using the proposed method, which verifies its effectiveness in the time delay identification of the rare earth extraction process.

Mivebresib synergized with PZ703b, a novel Bcl-xl PROTAC degrader, induces apoptosis in bladder cancer cells via the mitochondrial pathway.

Bladder cancer is a common urinary cancer that still lacks effective treatments. In the present study, we evaluated the effect of BET inhibitor, mivebresib, in combination with PZ703b, a Bcl-xl PROTAC, on apoptosis in bladder cancer cells. The results revealed that mivebresib and PZ703b synergistically decreased the viabilities of bladder cancer cells. Co-treatment of mivebresib and PZ703b induced apoptosis in bladder cancer cells via the mitochondrial pathway in a caspase-dependent manner. Mechanistically, mivebresib and PZ703b treatment inhibited the expression of Mcl-1 and Bcl-xl, accompanied by upregulation of Bim. Hence, co-treatment of mivebresib and PZ703b rebalanced the level of pro- and anti-apoptotic Bcl-2 proteins in cells. Further investigations showed that forced expression of Mcl-1 or Bcl-xl markedly protected bladder cancer cells from apoptosis induced by combination treatment of mivebresib and PZ703b. In addition, knockdown of Bim also inhibited the cell death induced by mivebresib/PZ703b in bladder cancer cells. In summary, our findings reveal that the combination treatment of mivebresib and PZ703b represents a novel promising strategy to treat bladder cancer.

Limonoids from Swietenia macrophylla and their antitumor activities in A375 human malignant melanoma cells.

Swietelinins A - C (1-3) and swieteliacates F - R (4-16), sixteen new limonoids and 18 known limonoids (17-34) were isolated from Swietenia macrophylla. The absolute configurations of these compounds were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. Swieteliacate J (10) is the first limonoid possessing an unusual 8ß, 9ß-epoxy ring system. All of the compounds were tested for cytotoxicity against four human tumor cell lines (SMMC-7721, SW620, A549, and A375). Compounds 10, 11, and 19 exhibited selectively moderate cytotoxicity against four tumor cell lines, especially 19 exhibited significant cytotoxic effects against A375 with IC50 an value of 9.8 µM and was more active than the positive control, dacarbazine with an IC50 value of 22.4 µM. Compound 19 effectively induced apoptosis of A375, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 19 significantly induced A375 cell apoptosis in a dose-dependent manner.

Development and validation of a nomogram model for predicting the risk of gallstone recurrence after gallbladder-preserving surgery.

BACKGROUND: The high incidence of gallstone recurrence was a major concern for laparoscopic gallbladder-preserving surgery. This study aimed to investigate the risk factors for gallstone recurrence after gallbladder-preserving surgery and to establish an individualized nomogram model to predict the risk of gallstone recurrence. METHODS: The clinicopathological and follow-up data of 183 patients who were initially diagnosed with gallstones and treated with gallbladder-preserving surgery at our hospital from January 2012 to January 2019 were retrospectively collected. The independent predictive factors for gallstone recurrence following gallbladder-preserving surgery were identified by multivariate logistic regression analysis. A nomogram model for the prediction of gallstone recurrence was constructed based on the selected variables. The C-index, receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the predictive power of the nomogram model for gallstone recurrence. RESULTS: During the follow-up period, a total of 65 patients experienced gallstone recurrence, and the recurrence rate was 35.5%. Multivariate logistic regression analysis revealed that the course of gallstones > 2 years [odds ratio (OR) = 2.567, 95% confidence interval (CI): 1.270-5.187, P = 0.009], symptomatic gallstones (OR = 2.589, 95% CI: 1.059-6.329, P = 0.037), multiple gallstones (OR = 2.436, 95% CI: 1.133-5.237, P = 0.023), history of acute cholecystitis (OR = 2.778, 95% CI: 1.178-6.549, P = 0.020) and a greasy diet (OR = 2.319, 95% CI: 1.186-4.535, P = 0.014) were independent risk factors for gallstone recurrence after gallbladder-preserving surgery. A nomogram model for predicting the recurrence of gallstones was established based on the above five variables. The results showed that the C-index of the nomogram model was 0.692, suggesting it was valuable to predict gallstone recurrence. Moreover, the calibration curve showed good consistency between the predicted probability and actual probability. CONCLUSIONS: The nomogram model for the prediction of gallstone recurrence might help clinicians develop a proper treatment strategy for patients with gallstones. Gallbladder-preserving surgery should be cautiously considered for patients with high recurrence risks.

Phytochemistry and Pharmacological Activities of the Diterpenoids from the Genus Daphne.

There are abundant natural diterpenoids in the plants of the genus Daphne from the Thymelaeaceae family, featuring a 5/7/6-tricyclic ring system and usually with an orthoester group. So far, a total of 135 diterpenoids has been isolated from the species of the genus Daphne, which could be further classified into three main types according to the substitution pattern of ring A and oxygen-containing functions at ring B. A variety of studies have demonstrated that these compounds exert a wide range of bioactivities both in vitro and in vivo including anticancer, anti-inflammatory, anti-HIV, antifertility, neurotrophic, and cholesterol-lowering effects, which is reviewed herein. Meanwhile, the fascinating structure-activity relationship is also concluded in this review in the hope of providing an easy access to available information for the synthesis and optimization of efficient drugs.

Comparative transcriptome analysis and identification of candidate adaptive evolution genes of Miscanthus lutarioriparius and Miscanthus sacchariflorus.

Miscanthus species are perennial C4 grasses that are considered promising energy crops because of their high biomass yields, excellent adaptability and low management costs. Miscanthus lutarioriparius and Miscanthus sacchariflorus are closely related subspecies that are distributed in different habitats. However, there are only a few reports on the mechanisms by which Miscanthus adapts to different environments. Here, comparative transcriptomic and morphological analyses were used to study the evolutionary adaptation of M. lutarioriparius and M. sacchariflorus to different habitats. In total, among 7586 identified orthologs, 2060 orthologs involved in phenylpropanoid biosynthesis and plant hormones were differentially expressed between the two species. Through an analysis of the Ka/Ks ratios of the orthologs, we estimated that the divergence time between the two species was approximately 4.37 Mya. In addition, 37 candidate positively selected orthologs (PSGs) that played important roles in the adaptation of these species to different habitats were identified. Then, the expression levels of 20 PSGs in response to flooding and drought stress were analyzed, and the analysis revealed significant changes in their expression levels. These results facilitate our understanding of the evolutionary adaptation to habitats and the speciation of M. lutarioriparius and M. sacchariflorus. We hypothesise that lignin synthesis genes are the main cause of the morphological differences between the two species. In summary, the plant nonspecific phospholipase C gene family and the receptor-like protein kinase gene family played important roles in the evolution of these two species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01030-1.

GP73 facilitates hepatitis B virus replication by repressing the NF-κB signaling pathway.

Hepatitis B virus (HBV) chronically infects approximately 350 million people worldwide, and 600 000 deaths are caused by HBV-related hepatic failure. Golgi protein 73 (GP73) is a serum biomarker for liver diseases, including chronic hepatitis B. Here, we determine the effect of HBV infection on GP73 production and characterized the role of GP73 in HBV replication. Initially, we show that GP73 is highly produced in the sera of HBV-positive patients with chronic liver diseases and in HBV-stimulated leukocytes. In addition, HBV stimulation promotes GP73 production in peripheral blood mononuclear cells isolated from healthy donors and in macrophages derived from human acute monocytic leukemia cells (THP-1). Notably, the hepatitis B surface antigen (HBsAg), but not HBV replication, is required for the activation of GP73 expression. Moreover, in HepG2 cells and Huh7 cells, GP73 facilitates HBV replication and represses nuclear factor kappa B p50 expression, which in turn represses HBV replication and GP73 expression. Finally, we demonstrate that GP73 facilitates HBV replication by repressing the innate immune response and the nuclear factor kappa B signaling pathway. Taken together, we revealed a distinct positive feedback mechanism between HBV replication and GP73 production and suggest that GP73 acts as a potential antiviral target for HBV infection.

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2.

From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) crossed the species barriers to infect humans, causing thousands of infections and hundreds of deaths, respectively. Currently, a novel coronavirus (SARS-CoV-2), which has become the cause of the outbreak of Coronavirus Disease 2019 (COVID-19), was discovered. Until 18 February 2020, there were 72 533 confirmed COVID-19 cases (including 10 644 severe cases) and 1872 deaths in China. SARS-CoV-2 is spreading among the public and causing substantial burden due to its human-to-human transmission. However, the intermediate host of SARS-CoV-2 is still unclear. Finding the possible intermediate host of SARS-CoV-2 is imperative to prevent further spread of the epidemic. In this study, we used systematic comparison and analysis to predict the interaction between the receptor-binding domain (RBD) of coronavirus spike protein and the host receptor, angiotensin-converting enzyme 2 (ACE2). The interaction between the key amino acids of S protein RBD and ACE2 indicated that, other than pangolins and snakes, as previously suggested, turtles (Chrysemys picta bellii, Chelonia mydas, and Pelodiscus sinensis) may act as the potential intermediate hosts transmitting SARS-CoV-2 to humans.

Daphnane Diterpenoids from Daphne genkwa Inhibit PI3K/Akt/mTOR Signaling and Induce Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells.

Seven new daphnane-type diterpenoids, daphgenkins A-G (1-7), and 15 known analogues (8-22) were isolated from the flower buds of Daphne genkwa. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids (1-22) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds 1, 12, and 13 exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC50 values in the range of 3.0-9.7 µM. The most active new compound, 1, with an IC50 value of 3.0 µM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound 1 induced G0/G1 cell cycle arrest, leading to the induction of apoptosis in SW620 cells. Also, it induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound 1 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound 1 may be a suitable lead compound for further biological evaluation.

Antitumor Activity of Diterpenoids from Jatropha gossypiifolia: Cell Cycle Arrest and Apoptosis-Inducing Activity in RKO Colon Cancer Cells.

Nine new minor diterpenoids, jatrogossones A-I (1-9), and six known analogues (10-15) were separated from an extract of the branches and leaves of Jatropha gosspiifolia. Compounds 4-6 and 10, possessing a 5/11 fused-ring skeleton, and 8, 9, and 13, with a 5/9/5 fused-ring skeleton, represent rare diterpenoid skeletons that have been found only in compounds isolated from plants of the Jatropha genus. The absolute configurations of 1-10 were defined by using a combination of electronic circular dichroism data analysis and single-crystal X-ray diffraction data. The cytotoxicity of the diterpenoids was evaluated using RKO and LOVO colon cancer cells in which regenerating islet-derived protein 3-alpha (Reg3A) is highly expressed. Compound 12 exhibited cytotoxicity against RKO colon cancer cells with an IC50 value of 2.6 µM. Morphological features of apoptosis and antimigration activities were evaluated in 12-treated RKO cells. Compound 12 effectively induced apoptosis of RKO, which was associated with G2/M-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 12 significantly induced RKO cell apoptosis in a dose-dependent manner.

Saikosaponins: a review of pharmacological effects.

Over the past decades, a number of phytochemicals have been reported to possess potent pharmacological effects. Saikosaponins represent a group of oleanane derivatives, usually as glucosides, which are commonly found in medicinal plants Bupleurum spp., which have been used as traditional Chinese medicine for more than 1,000 years in China. Emerging evidence suggests that saikosaponins have many pharmacological effects, including sedation, anticonvulsant, antipyretic, antiviral, immunity, anti-inflammation, antitumor properties, protecting liver and kidney and so on. The present review provides a comprehensive summary and analysis of the pharmacological properties of saikosaponins, supporting the potential uses of saikosaponins as a medicinal agent.

Curcusone C induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2.

Telomeric repeat factor 2 (known as TRF2 or TERF2) is a key component of telomere protection protein complex named as Shelterin. TRF2 helps the folding of telomere to form T-loop structure and the suppression of ATM-dependent DNA damage response activation. TRF2 has been recognized as a potentially new therapeutic target for cancer treatment. In our routine screening of small molecule libraries, we found that Curcusone C had significant effect in disrupting the binding between TRF2 and telomeric DNA, with potent antitumor activity against cancer cells. Our result showed that Curcusone C could bind with TRF2 without binding interaction with TRF1 (telomeric repeat factor 1) although these two proteins share high sequence homology, indicating that their binding conformations and biological functions in telomere could be different. Our mechanistic studies showed that Curcusone C bound with TRF2 possibly through its DNA binding site causing blockage of its interaction with telomeric DNA. Further in cellular studies indicated that the interaction of TRF2 with Curcusone C could activate DNA-damage response, inhibit tumor cell proliferation, and cause cell cycle arrest, resulting in tumor cell apoptosis. Our studies showed that Curcusone C could become a promising lead compound for further development for cancer treatment. Here, TRF2 was firstly identified as a target of Curcusone C. It is likely that the anti-cancer activity of some other terpenes and terpenoids are related with their possible effect for telomere protection proteins.

An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma.

BACKGROUND: Nearly 30% of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis, and the prognosis for these patients is poor. Therefore, novel potential prognostic biomarkers and therapeutic targets for ccRCC could be helpful. Emerging evidence indicates that lncRNAs play important roles in cancer tumorigenesis and could be used as potential biomarkers or therapeutic targets. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) is a relatively novel lncRNA that plays an important role in the development of multiple cancers. However, the clinical significance and molecular mechanism of PANDAR in ccRCC are still elusive. In the present study, we attempted to elucidate the role of PANDAR in ccRCC. METHODS: The relative expression level of lncRNA PANDAR was quantified by real-time qPCR in 62 paired ccRCC tissues and in renal cancer cell lines, and its association with overall survival was assessed by statistical analysis. The biological functions of lncRNA PANDAR on ccRCC cells were determined both in vitro and in vivo. RESULTS: PANDAR expression was significantly upregulated in tumor tissues and cell lines compared with normal counterparts. Moreover, PANDAR served as an independent predictor of overall survival, and increased PANDAR expression was positively correlated with an advanced TNM stage. Further experiments demonstrated that PANDAR silencing can significantly inhibit cell proliferation and invasion, induce cell cycle arrest in the G1 phase and significantly promote apoptosis in 7860 and Caki-1 cell lines. In addition, in vivo experiments confirmed that downregulation of PANDAR inhibited the tumorigenic ability of 7860 cells in nude mice. Silencing of PANDAR also inhibited the expression of Bcl-2 and Mcl-1 and upregulated the expression of Bax in vivo. CONCLUSIONS: Our results suggest that PANDAR is involved in ccRCC progression and may serve as a potential prognostic biomarker and therapeutic target.

Autophagy regulated by lncRNA HOTAIR contributes to the cisplatin-induced resistance in endometrial cancer cells.

OBJECTIVES: To identify whether lncRNAs (long non-coding RNA) participate in the regulation of cisplatin-resistant induced autophagy in endometrial cancer cells. RESULTS: Autophagy activity was significantly boosted in cisplatin-resistant Ishikawa cells, a human endometrial cancer cell line, compared with that in parental Ishikawa cells. After analyzing the overall long noncoding RNA (lncRNA) profiling, a meaningful lncRNA, HOTAIR, was identified. It was down-regulated simultaneously in cisplatin-resistant Ishikawa cells and parental Ishikawa cells treated with cisplatin. RNA interference of HOTAIR reduced the proliferation of cisplatin-resistant Ishikawa cells and enhanced the autophagy activity of cisplatin-resistant Ishikawa cells with or without cisplatin treatment, in addition, beclin-1, multidrug resistance (MDR), and P-glycoprotein (P-gp) were mediated by lncRNA HOTAIR. CONCLUSIONS: It is clear that lncRNAs, specifically HOTAIR, can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by influencing Beclin-1, MDR, and P-gp expression.

Quality-Related Monitoring and Grading of Granulated Products by Weibull-Distribution Modeling of Visual Images with Semi-Supervised Learning.

The topic of online product quality inspection (OPQI) with smart visual sensors is attracting increasing interest in both the academic and industrial communities on account of the natural connection between the visual appearance of products with their underlying qualities. Visual images captured from granulated products (GPs), e.g., cereal products, fabric textiles, are comprised of a large number of independent particles or stochastically stacking locally homogeneous fragments, whose analysis and understanding remains challenging. A method of image statistical modeling-based OPQI for GP quality grading and monitoring by a Weibull distribution(WD) model with a semi-supervised learning classifier is presented. WD-model parameters (WD-MPs) of GP images' spatial structures, obtained with omnidirectional Gaussian derivative filtering (OGDF), which were demonstrated theoretically to obey a specific WD model of integral form, were extracted as the visual features. Then, a co-training-style semi-supervised classifier algorithm, named COSC-Boosting, was exploited for semi-supervised GP quality grading, by integrating two independent classifiers with complementary nature in the face of scarce labeled samples. Effectiveness of the proposed OPQI method was verified and compared in the field of automated rice quality grading with commonly-used methods and showed superior performance, which lays a foundation for the quality control of GP on assembly lines.

Determination of the absolute configuration of two pairs of C-8 - C-9' linked neolignan enantiomers.

Two pairs of new neolignan enantiomers, (±)-torreyayunan A (1a/1b) and (±)-torreyayunan B (2a/2b), featuring a rare C-8 - C-9' linked skeleton, were isolated from leaves and twigs of Torreya yunnanensis. Their absolute configuration involving two chiral centers was determined by combined spectral and Density Functional Theory (DFT) calculation. This is the first report of the absolute configuration of this group of neolignans.

Antiinflammatory effects and chemical constituents of Veronicastrum axillare.

Our study aims to ascertain the antiinflammatory activity of Veronicastrum axillare and characterize the bioactive constituents. Antiinflammatory activity of the total extract and different fractions from V. axillare was investigated by employing the xylene-induced mouse ear edema model. As a result, the ethyl acetate (EtOAc) fraction showed the highest antiinflammatory activity in vivo. From the EtOAc fraction and the inactive dichloromethane fraction, a total of five new compounds, axillasides A-C and axillactones A and B, together with four known compounds, procumboside A, buergeriside C1 , indole-3-carboxylic acid and apigenin, were isolated and identified. Their structures were elucidated on the basis of spectroscopic analysis and by comparison of their nuclear magnetic resonance data with those reported in the literature. Procumboside A, a major constituent in EtOAc fraction, showed significant antiinflammatory activity in vivo. Further studies revealed that procumboside A was a potent COX-2 inhibitor, significantly reducing the COX-2 protein level in lipopolysaccharide-stimulated RAW 264.7 macrophages.

Machine learning models for early prediction of potassium lowering effectiveness and adverse events in patients with hyperkalemia.

The aim of this study was to develop a model for early prediction of adverse events and treatment effectiveness in patients with hyperkalemia. We collected clinical data from patients with hyperkalemia in the First Hospital of Zhejiang University School of Medicine between 2015 and 2021. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to analyze the predictors on the full dataset. We randomly divided the data into a training group and a validation group, and used LASSO to filter variables in the training set. Six machine learning methods were used to develop the models. The best model was selected based on the area under the curve (AUC). Shapley additive exPlanations (SHAP) values were used to explain the best model. A total of 1074 patients with hyperkalemia were finally enrolled. Diastolic blood pressure (DBP), breathing, oxygen saturation (SPO2), Glasgow coma score (GCS), liver disease, oliguria, blood sodium, international standardized ratio (ISR), and initial blood potassium were the predictors of the occurrence of adverse events; peripheral edema, estimated glomerular filtration rate (eGFR), blood sodium, actual base residual, and initial blood potassium were the predictors of therapeutic effect. Extreme gradient boosting (XGBoost) model achieved the best performance (adverse events: AUC = 0.87; therapeutic effect: AUC = 0.75). A model based on clinical characteristics was developed and validated with good performance.

Rapid analysis of Radix Astragali using a portable Raman spectrometer with 1064-nm laser excitation and data fusion with PLS-DA.

Radix Astragali is a medicinal herb with various physiological activities. There were high similarities among Radix Astragali samples from different regions owing to similarities in their major chemical compositions. Raman spectroscopy is a non-invasive and non-des- tructive technique that can be used in in-situ analysis of herbal samples. Dispersive Raman scattering, excited at 1064 nm, produced minimal fluorescence background and facilitated easy detection of the weak Raman signal. By moving the portable Raman probe point-by- point from the centre of the Radix Astragali sample to the margin, the spectral fingerprints, composed of dozens of Raman spectra representing the entire Radix Astragali samples, were obtained. Principal component analysis and partial least squares discriminant analysis (PLS-DA) were applied to the Radix Astragali spectral data to compare classification results, leading to efficient discrimination between genuine and counterfeit products. Furthermore, based on the PLS-DA model using data fusion combined with different pre- processing methods, the samples from Shanxi Province were separated from those belonging to other habitats. The as-proposed combination method can effectively improve the recognition rate and accuracy of identification of herbal samples, which can be a valuable tool for the identification of genuine medicinal herbs with uneven qualities and various origins.