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Background Torsade de pointes is a form of polymorphic ventricular tachycardia associated with heart rate-corrected QT (QTc ) interval prolongation. With approximately 24-61% of critically ill patients experiencing QTc interval prolongation, a predictive tool to identify high-risk patients could assist in the monitoring and management in the intensive care unit (ICU). The Tisdale et al. Risk Score (TRS) is a predictive tool that was developed and validated in a cardiac critical care unit. Objectives The objective of this study was to evaluate the predictive validity (sensitivity and specificity) and likelihood ratios of the TRS in a medical ICU. Methods This was a longitudinal, retrospective, cohort study of consecutive patients who met the inclusion criteria from October 2017 to June 2018 with a sample size of 264 patients. The sample size was derived based on the number of TRS covariates and an exploratory variable. Baseline characteristics and risk factors were documented from electronic health records. The first occurrence of QTc interval prolongation, defined as a QTc interval > 500 ms or an increase ≥ 60 ms above baseline, was the primary endpoint. Main results The sensitivity and specificity of the TRS for low-risk patients against the moderate-risk and high-risk patients were 97% (95% CI 91-99%) and 16% (95% CI 11-23%), respectively. These results corresponded to a positive likelihood ratio of 1.15 (95% CI 1.07-1.24) and a negative likelihood ratio of 0.20 (95% CI 0.06-0.65). Conclusions In conclusion, the TRS showed a high sensitivity, making it useful in identifying patients at risk of developing QTc interval prolongation. Furthermore, patients categorized as low risk by the tool can be considered as having minimal risk of developing QTc interval prolongation. Given the tool's low specificity, it does not reliably identify all patients at low risk of QTc interval prolongation.

Neural tube defects (NTDs) are severe congenital malformations caused by failed neural tube closure. Recently, autophagy is revealed to play a vital role in neuroepithelium development and neurulation. Autophagy and beclin 1 regulator 1 (Ambra1) is a crucial regulator of autophagy initiation, and its deficiency in mice leads to exencephaly and/or spina bifida. However, the genetic contribution of AMBRA1 to the etiology of human NTDs remains unknown. In this study, we identified five rare missense mutations of AMBRA1 in 352 NTDs cases, which were absent in 224 matched controls. Western blotting and fluorescence puncta counting for MAP1LC3A/LC3 in HEK293T cells suggested that four of the mutations (AMBRA1 p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) affected autophagy initiation to various extents. Furthermore, these four mutations also displayed loss-of-function effects compared with wild-type AMBRA1 when we injected messenger RNA (mRNA) to overexpress or rescue ambra1a-morpholino oligos (MO) knockdown in zebrafish. It is intriguing that trehalose, a natural disaccharide, could rescue ambra1a-MO knockdown in a dose-dependent manner independently or together with AMBRA1 mRNA. Taken together, our findings suggest that rare mutations of the autophagy regulator gene AMBRA1 may contribute to the etiology of human neural tube defects, and trehalose is a promising treatment for a subset of NTDs caused by autophagy impairment.

A halide perovskite based photocatalyst has been demonstrated for the first time to simultaneously achieve efficient photocatalytic CO2 reduction and methanol oxidation, exhibiting an exciting yield of 1835 μmol g-1 for photocatalytic CO2-to-CO conversion. Moreover, almost stoichiometric value-added formic acid can be produced from methanol oxidation.

Three-dimensional (3D) bioprinting technology is an effective method for exploring the biological functions of hepatocytes by building biomimetic 3D microenvironments. Various hepatic tissue models have been developed for disease modeling, drug screening, and tissue regeneration using 3D bioprinting technology. Human-induced pluripotent stem cells (hiPSCs) are a promising cell source for the generation of functional hepatocytes for bioprinting. In this study, we introduced hiPSC-derived hepatocytes (hiPSC-Heps) as mature hepatocytes for the bioprinting of a 3D hepatic tissue model. The 3D-printed (3DP) model facilitated the formation of hiPSC-Hep spheroids with higher viability and proliferation than the commonly used non-printed sandwich-cultured model. hiPSC-Heps in the 3DP model exhibited higher mRNA expression of liver-specific functions than those in the two-dimensional-cultured model. Moreover, enhanced secretion of liver function-related proteins, including α-1-antitrypsin, albumin, and blood urea nitrogen, was observed in the 3DP model. For the evaluation of acetaminophen-induced hepatotoxicity, the 3DP model exhibited a favorable drug response with upregulation of the drug metabolism-related gene cytochrome P450-1A2 (CYP1A2). Overall, the bioprinted hepatic tissue model showed great biofunctional and drug-responsive performance, which could be potentially applied in in vitro toxicological studies.

Yinhua Luo,1,* Shengyu Cui,2,* Changjiang Zhang,2 Rui Huang,2 Jinbo Zhao,3 Ke Su,3 Dan Luo,3 Yuanhong Li3 1Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi Prefecture, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanhong Li, Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi Prefecture, People’s Republic of China, Email lyh0101@vip.163.comObjective: In-stent restenosis (ISR) is regarded as a critical limiting factor in stenting for coronary heart disease (CHD). Recent research has shown that fasting residual cholesterol (RC) has been shown to have a substantial impact on coronary heart disease. Unfortunately, there have not been much data to bear out the relationship between RC and ISR. Then, the predictive value of RC for in-stent restenosis in patients with coronary heart disease was analyzed.Patients and Methods: Aiming to explore the relationship between RC and ISR, we designed a retrospective study of patients with CHD after drug-eluting stent (DES) implantation, combining the data from a public database and selecting the best-fitting model by comparing the optical subset with least absolute shrinkage and selection operator (LASSO) regression.Results: Analysis of the abovementioned two models showed that the optical subset optimal subset model, which was based on RC, creatine, history of diabetes, smoking, multi-vessel lesions (2 vessels or more lesions), peripheral vascular lesions (PAD), and blood uric acid, had a better fit (AUC = 0.68), and that RC was an independent risk factor for ISR in the abovementioned two models. Notwithstanding its limitation, this study does suggest that RC has good predictive value for ISR.Conclusion: Remnant cholesterol is an independent risk factor for in-stent restenosis after percutaneous coronary intervention (PCI) and is a reliable predictor of ISR.Keywords: in-stent restenosis, ISR, percutaneous coronary intervention, PCI, remnant cholesterol, RC, drug-eluting stents, DES, least absolute shrinkage and selection operator, LASSO

To investigate the morphological, histological and ultrastructural changes of acute closed rupture of Achilles tendon, in order to clarify the pathological basis of the injury and to explore the significance.From January 2015 to January 2019, 35 patients with acute Achilles tendon rupture who underwent the minimally invasive Achilles tendon suture technique were retrospectively analyzed. Among these patients, 12 cases in acute open Achilles tendon rupture group included 10 males and 2 females, with an average age of (35.1±9.7) years old ranging from 19 to 50, and the time from injury to operation was 2 to 8 hours with an average of(5.6±1.8);23 cases in acute closed Achilles tendon rupture group included 21 males and 2 females, with an average age of (35.5±6.6) years old ranging from 18 to 50, and the time from injury to operation was 3 to 15 hours with an average of (7.5±3.1). The gross appearance and imaging findings of the broken end of Achilles tendon tissue in the two groups were compared by naked eye observation and foot and ankle MRI at 4 to 6 hours before operation. HE staining, scanning and fluoroscopic electron microscopy, immunohistochemistry(Sirius red staining) were performed on the intraoperative Achilles tendon tissue specimens at 1 to 2 days after operation, the collagen fiber degeneration and local fat infiltration, collagen fiber shape, cell morphology and function, and the distribution of typeⅠand type Ⅲ collagen fibers in Achilles tendon were compared between the two groups.Compared with the acute open Achilles tendon rupture group, the acute closed Achilles tendon rupture group had poor elasticity, hard texture, moderate edema, irregular shape of Achilles tendon broken end, horsetail shape, and more calcification around the broken end. HE staining results:the collagen fibers in the Achilles tendon of the acute open Achilles tendon rupture group were arranged irregularly, with hyaline degeneration and fat infiltration;The results of electron microscopy showed that collagen arranged disorderly and fibroblasts atrophied in the acute closed Achilles tendon rupture group. Immunohistochemical(Sirius staining) results:the proportion of collagenⅠin the acute open Achilles tendon rupture group and the acute closed Achilles tendon rupture group was(91.12±4.34)% and(54.71±17.78)% respectively, and the proportion of collagen Ⅲ was (8.88±4.34)% and (45.29±17.78)% respectively. The content of collagenⅠin the acute closed Achilles tendon rupture group was lower than that in the acute open Achilles tendon rupture group, and the content of collagen Ⅲ in the acute closed Achilles tendon rupture group was higher than that in the acute open Achilles tendon rupture group(The morphology, histology and ultrastructure of the acute closed ruptured Achilles tendon are significantly altered compared with the normal Achilles tendon. The original fine and orderly spatial structure cannot be maintained, part of collagen Ⅰ is replaced by collagen Ⅲ, and the toughness and strength of the tendon tissue decreased, which may be the feature of degeneration of the Achilles tendon and an important pathological basis for closed Achilles tendon rupture.

Background The optimal locoregional treatment for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is unclear. This study aimed to investigate the efficacy of Gamma knife radiosurgery (GKR) versus transcatheter arterial chemoembolization (TACE) in HCC patients with PVTT. Methods This retrospective study included 544 HCC patients with PVTT (GKR, 202; TACE, 342). Propensity score matching (PSM) analysis identified 171 matched pairs of patients. The primary endpoint was overall survival (OS). Results Before PSM, the GKR group exhibited longer median OS (mOS) than the TACE group (17.2 vs. 8.0 months, p p p = 0.001; 14.5 vs. 6.5 months, p = 0.001, respectively) and comparable OS for patients with PVTT I. After PSM, the GKR group had also a longer mOS than the TACE group (15.8 vs. 10.4 months, p p Conclusions GKR was associated better OS than TACE in HCC patients with PVTT, especially for patients with PVTT II-IV. Clinical Trials Registration The study was registered in the Chinese Clinical Trials Registry under the registration number ChiCTR2100051057.

MicroRNA-365 (miR-365) has been reported to be a tumor suppressor miRNA. However, the role of miR-365 in progression of endometrial cancer (EC) has not been explored, in this study, we have found that re-expression of miRNA-365 inhibits cell proliferation, causes apoptosis and senescence.Overexpression of miR-365 attenuated cell migration and invasion, inhibited sphere-forming capacity, and enhanced the chemosensitivity to paclitaxel. In silico prediction tools identified the potential targets of miR-365.We identifiedThe study concludes that miR-365 acts as an important tumor suppressor and contributes by suppressing cell invasiveness, proliferation, and self-renewal in cancer cell lines by regulating multiple oncogenes. We establish that miR-365-EZH2/FOS pathway is an important target for treating EC.

Effective credit risk prediction can help the financial industry avoid risks. DenseNet-BC based on Focal Loss and static restart SGD is proposed to improve credit risk prediction accuracy. It utilizes powerful feature reuse of dense convolution network to realize multi-calibration of an end-to-end feature, and the Focal Loss function is introduced into the classification layer by weight adjusting data imbalance between sample data and simple sample difficult sample quantity unbalance which enhances the accuracy of prediction accuracy in unbalanced data concentration. Meanwhile, optimizing adaptive variation learning rate parameters by static restart SGD avoids falling into local optimum during model training or missing optimal solution because the learning rate is too large. The Lending Club dataset’s experimental results show that the model has a significant improvement in the accuracy of credit risk prediction.

BackgroundNeutrophils-linked premetastatic niche plays a key role in tumor metastasis, but not much is known about the heterogeneity and diverse role of neutrophils in niche formation. Our study focuses on the existence and biological function of a rarely delved subset of neutrophils, named as tumor-associated aged neutrophils (Naged, CXCR4+CD62Llow), involved in premetastatic niche formation during breast cancer metastasis.MethodsWe explored the distributions of Naged in 206 patients and mice models (4T1 and MMTV-PyMT) by flow cytometry. The ability of Naged to form neutrophil extracellular traps (NETs) and promote tumor metastasis in patients and mice was determined by polychromatic immunohistochemistry, scanning electron microscopy and real-time video detection. Furthermore, the differences among tumor-associated Naged, Non-Naged and inflammation-associated aged neutrophils were compared by transcriptome, the biological characteristics of Naged were comprehensively analyzed from the perspectives of morphology, the metabolic capacity and mitochondrial function were investigated by Seahorse, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and transmission electron microscopy (TEM). Finally, 120 patients’ sample were applied to confirm the acceleration of Naged formation through secreted NAMPT, and the importance of blocking this pathway in mice was evaluated.ResultsWe find that Naged accumulate in the lung premetastatic niche at early stage of breast tumorigenesis in multiple mice models and also exist in peripheral blood and metastatic lung of patients with breast cancer. Naged exhibit distinct cell marker and morphological feature of oversegmented nuclei. Further transcriptome reveals that Naged are completely different from those of Non-Aged or inflammation-associated aged neutrophils and illustrates that the key transcription factor SIRT1 in Naged is the core to maintain their lifespan via mitophagy for their function. The responsible mechanism is that SIRT1 can induce the opening of mitochondrial permeability transition pore channels to release mitochondrial DNA and lead to the mitochondria-dependent vital NETs formation, rather than traditional Cit-Histone H3 dependent fatal-NETs. Further mechanically investigation found tumor derived NAMPT could induce Naged formation. Additionally, therapeutic interventions of Naged and its formation-linked pathways could effectively decrease breast cancer lung metastasis.ConclusionsNaged exerts a vital role in breast cancer lung metastasis, and strategies targeting SIRT1-Naged-NETs axis show promise for translational application.

Chang Yan,1 De-Song Shen,1 Xiao-Bo Chen,2 Dan-Ke SU,3 Zhong-Guo Liang,1 Kai-Hua Chen,1 Ling Li,1 Xia Liang,1 Hai Liao,3 Xiao-Dong Zhu1,4 1Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 2School of First Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 3Department of Radiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of China; 4Affiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, 530100, People’s Republic of ChinaCorrespondence: Xiao-Dong ZhuDepartment of Radiation Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning City, Guangxi, 530021, People’s Republic of ChinaTel +86 771 533 1466Email zhuxdonggxmu@126.comHai LiaoDepartment of Radiology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +86 771 533 4950Email 42442427@qq.comPurpose: We aimed to construct of a nomogram to predict progression-free survival (PFS) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) with risk stratification using computed tomography (CT) radiomics features and clinical factors.Patients and Methods: A total of 311 patients diagnosed with LA-NPC (stage III–IVa) at our hospital between 2010 and 2014 were included. The region of interest (ROI) of the primary nasopharyngeal mass was manually outlined. Independent sample t-test and LASSO-logistic regression were used for selecting the most predictive radiomics features of PFS, and to generate a radiomics signature. A nomogram was built with clinical factors and radiomics features, and the risk stratification model was tested accordingly.Results: In total, 20 radiomics features most associated with prognosis were selected. The radiomics nomogram, which integrated the radiomics signature and significant clinical factors, showed excellent performance in predicting PFS, with C-index of 0.873 (95% CI: 0.803∼ 0.943), which was better than that of the clinical nomogram (C-index, 0.729, 95% CI: 0.620∼ 0.838) as well as of the TNM staging system (C-index, 0.689, 95% CI: 0.592– 0.787) in validation cohort. The calibration curves and the decision curve analysis (DCA) plot obtained suggested satisfying accuracy and clinical utility of the model. The risk stratification tool was able to predict differences in prognosis of patients in different risk categories (p< 0.001).Conclusion: CT-based radiomics features, an in particular, radiomics nomograms, have the potential to become an accurate and reliable tool for assisting with prognosis prediction of LA-NPC.Keywords: computed tomography, locoregionally advanced nasopharyngeal carcinoma, radiomics, nomogram

This paper proves that the development of the digital economy has become a new vector to promote the upgrading of China’s industrial structure. In addition, heterogeneous technological innovation plays an intermediary role in the promotion of the industrial structure by the digital economy. This study aims to solve the following: whether the development level of the digital economy is positively promoting the upgrading of the industrial structure, whether technological innovation can promote the upgrading of the industrial structure, the path of the digital economy through which to promote the upgrading of the industrial structure and the heterogeneity of this path. The purpose of this study was to verify the digital economy and scientific and technological innovation to promote the upgrading of the industrial structure and the reality of the realization path, and to solve the problem of insufficient power for upgrading China’s regional industrial structure against the background of the impact of the new generation of information technology. This study mainly adopted comprehensive evaluation and multivariate statistical analysis methods. The statistical basis for the study was data from 30 Chinese provinces from 2013 to 2018. The results confirm the hypothesis that the development of the digital economy and scientific and technological innovation have a positive role in promoting the upgrading of the industrial structure, and also prove that the intermediary role of heterogeneous technological innovation is crucial in the process of the digital economy promoting industrial upgrading. This conclusion can further give play to the role of the digital economy in promoting industrial structure upgrading, build a clean and intelligent industrial chain, solve the root cause of the lack of new drivers for China’s industrial upgrading, and help to form a new development pattern of domestic and international double circulation, so as to achieve the high-quality and sustainable development of China’s economy.

The recycling and reutilization of biomass wastes are significant for environmental protection and sustainable development. Recently, there have many studies on utilizing biomass wastes to produce carbon dots. Whereas, the spectrum shift effect that occurs in the quantitative application of carbon dots as fluorescent probes limits the accuracy of the quantitative analysis. In this work, waste tobacco leaves were used as the carbon source for synthesizing a novel carbon dots (CDs(WTL)) through a facile hydrothermal method. The CDs(WTL) possess a series of excellent properties, including good water solubility, well stability, and high fluorescence quantum yield. The fluorescent intensity of the CDs(WTL) can be quenched by tetracycline (TC) obviously, but there is a spectrum shift. In order to use the CDs(WTL) as fluorescent probes to quantify TC with higher accuracy, a quantification fluorescence model (QFM) was introduced to overcome this spectrum shift effect that often occurs. The coefficient of determination (R2) of traditional quantification model (TQ), partial least squares (PLS), and QFM are 0.9672, 0.9834, and 0.9991, respectively; the average relative predictive error (ARPE) of TQ, PLS, and QFM are 8.8%, 4.5%, and 3.9% for the spiked water samples, and 21.9%, 22.0%, and 2.9% for spiked tablet samples, respectively. The obtained results suggest that QFM is more accurate than PLS and TQ for the TC detection. By utilizing QFM, the spike recoveries (mean ± standard deviation) in three kinds of real tablet samples produced by different manufacturers are 98.9 ± 3.6%, 102.5 ± 6.2%, and 98.5 ± 2.7%, respectively; the spike recovery in river water samples is 99.4 ± 5.0%. In addition, high performance liquid chromatography (HPLC) was used as a reference method, the F and t tests suggest that there are no significant differences on the precision and accuracy between QFM and HPLC methods.

To assess survival between subgroups (T1N1, T2N0, and T2N1) of patients with stage II nasopharyngeal carcinoma (NPC). This retrospective cohort study evaluated pathologically confirmed stage II NPC patients from The Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016. The included patients were divided into three subgroups: T1N1, T2N0, and T2N1. Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method among the three subgroups. This study investigated 836 patients: 383 (45.8%) patients were in the T1N1 subgroup, 175 (20.9%) patients were in the T2N0 subgroup, and 278 (33.3%) patients were in the T2N1 subgroup. The 5-year OS (75.7%, 68.6%, and 75.7%) and CSS (85.3%, 83.4%, and 84.5%) were similar among the T1N1, T2N0, and T2N1 subgroups. Univariate and multivariate regression analyses revealed that the subgroup (T1N1, T2N0, and T2N1) of stage II NPC was not an independent prognostic factor for OS or CSS. Survival was comparable among subgroups (T1N1, T2N0, and T2N1) of stage II NPC patients. However, patients with T1N1, T2N0, and T2N1 stage disease who receive different treatments might have different prognoses.

A ready-to-use hetero-tricyclic compound, 5,5'-(furan-2,5-diyl) bis (1,3,4- oxadiazol-2-amine) (5), was synthesized with a good yield; it has an suitable fluorescence characteristic and research founded that it can respond to trace Pd

Background This study aims to carry out the vitrification freezing of a large ovarian tissue in the human body, and evaluate its feasibility. Results A total of 18 ovarian tissues in the human body were selected, and each tissue was cut into three large ovarian cortex slices. These tissues were randomly divided into three groups: vitrification freezing group (group A), programmed freezing group (group B), and fresh control group (group C). Then, the morphological analysis and apoptosis detection of each ovarian tissue was carried out, followed by the recycling of ovarian tissues at three weeks after the heterotransplantation of nude mice, in order to detect the follicle preservation conditions. The immunohistochemistory method was applied to detect the follicle activity. In comparing the proportion of primordial follicle with normal morphology after unfreezing between group A and group B, the difference was not statistically significant (P > 0.05). Furthermore, the incidence of follicle apoptosis in group A and group B was higher than that in the group C (P 0.05). The interstitial cell apoptosis rate in group A was lower than that of the group B, showing that the difference was statistically significant (P

A novel tricyclic heterocyclic compound, 5,5’-(furan-2,5-diyl)bis (1,3,4- thiadiazol-2-amine) (3), was easily synthesized, which has an excellent fluorescence performance and could be a chemical sensor of Pd2+ at a very broad pH range. Fluorescence titration shows that the detection limit of Pd2+ is up to 1.07 × 10−9 M with a good accuracy. Density function theory (Guassian 09) indicates that the coordination of Pd2+ decreases the coplanarity and conjugation of compound 3, resulting in a fluorescence quenching. Generally, compound 3 could be practically applied in the convenient detection of Pd2+ with high sensitivity, excellent selectivity, good accuracy, and short response time. Compound 3 was characterized by NMR, MS, FT-IR, UV–Vis, 1H NMR, 13C NMR, and HRMS.

For earthquake and tsunami early warning and emergency response, the parameters of earthquakes should be determined rapidly and correctly. The precise displacement time series can be obtained from high-rate GPS precise point positioning (PPP) during the earthquake, but require long convergence time. In this paper, the PPP velocity estimation (PPPVE) approach is applied to estimate the velocity waveforms and integrate to displacement waveforms in real-time scenarios. A case study of the 2018 Alaska earthquake is conducted from 1 Hz GPS data. The accuracy of velocity and displacement waveforms for 1 Hz GPS data is analyzed by comparing PPPVE-derived displacements with kinematic PPP solution. The results indicate that PPP and PPPVE are both capable of detecting seismic displacement waveforms with amplitude of 1 cm horizontally, while PPPVE can detect the displacement waveforms with much faster convergence speed. The mean convergence time of PPPVE for north, east and up components are 19, 22 and 31 s, respectively. The derived ground motion parameters estimate a magnitude of Mw = 7.97 ± 0.18, showing a great consistency and agreement with the seismometer magnitude. The preliminary relationship between the seismic intensity and ground motion parameters is established and evaluated for an auxiliary reference. Furthermore, the permanent displacement induced by the earthquake is obtained from real-time PPPVE approach. The benefits of PPPVE approach for GNSS seismology are demonstrated.

BACKGROUND: Enzyme promiscuity has attracted significant attention from chemists and biochemists in recent years. However, long reaction time and use of toxic organic solvents limit its applications for industrial processes. 1,4‐Dihydropyridine (1,4‐DHP) calcium antagonists are recommended for the first line treatment of hypertension. Although some chemical protocols for the preparation of 1,4‐DHP calcium antagonists have been developed, enzymatic synthesis of these compounds still remains uncovered. RESULTS: Solvent‐free quick synthesis of 1,4‐DHP calcium antagonists felodipine, nitrendipine, nifedipine and nemadipine B and their derivatives was achieved by Lipozyme® RM IM (triacylglycerol acylhydrolase, EC3.1.1.3)‐catalyzed multicomponent reactions of aromatic aldehyde, alkyl acetoacetate and alkyl 3‐aminocrotonate under ball‐milling conditions. The products were obtained in moderate yields (up to 86.8%) and the influence of reaction conditions including catalyst loading, grinding auxiliary and grinding frequency was investigated. CONCLUSION: The protocol successfully overcame some longstanding problems in the field of enzymatic promiscuity research, such as long reaction time and use of harmful organic solvents, and demonstrated the potential application value of promiscuous enzyme‐catalyzed reactions under ball‐milling conditions for pharmaceutical synthesis. © 2019 Society of Chemical Industry

Transcription factor AP-2 alpha (TFAP2A) is an important transcriptional factor involved in various aspects of embryo development including neural tube closure. Tfap2a deficiency led to the failure of cranial neural-tube closure in mice and other model organisms. However, it remains largely unknown about the relationship between TFAP2A variants and human cranial neural tube defects (NTDs). The aim of this study was to find the association between TFAP2A intronic SNP rs3439413 and NTDs and to explore its function. We found an indel polymorphism rs3439413 in TFAP2A intron-5 from our previous target sequencing project. In this study, we validate its association with human NTDs in Shanxi group containing 266 NTD cases and 295 matched controls. Then, we investigated its function on transcriptional activity by dual-luciferase assays and EMSA. The minor allele of rs34396413 significantly increased the risk of NTD in a Han Chinese population of Shanxi Province (P = 0.0082, OR = 1.45, 95%CI = 1.10–1.90), especially the risk of encephalocele for female (P = 0.0064, OR = 2.46, 95%CI = 1.22–4.94). Functional analysis revealed the minor allele of rs34396413 decreases transcriptional activity and attenuates transcription factor binding affinity. We have demonstrated that the minor allele of rs34396413 was a risk factor of NTD in the Shanxi group, providing new insight into the study of NTD etiology.

To solve the optimization problems in port planning and operation management, particle swarm optimization, Cat mapping, and cloud model were combined. A Chaos Cloud Particle Swarm Optimization (CCPSO) algorithm was proposed. It was used in port planning management. Its application in port throughput forecasting and berthing and pontoon bridge allocation was explored and studied. By analyzing the mixed properties of Cat maps, the chaotic characteristics of the map were good. Thus, it was introduced into the hybrid optimization algorithm for chaotic perturbation of poor individuals in a particle swarm. The selection of the parameter combination of the Gauss-SVAR model was troublesome. The parameter combination of Guass-vSVR model was optimized by CCPSO algorithm, and the Guass-vSVR-CCPSO model was obtained. Using CCPSO algorithm, a discrete berth bridge allocation model was established. The results showed that the particle feasible integer processing module was developed. Therefore, a new method for multi-objective discrete berth shore-bridge allocation based on CCPSO algorithm is feasible.

Cadmium exposure is closely associated with a variety of diseases including cancers and the accumulation of cadmium has been long recognized as a public health problem. It is therefore of high importance to find methods to reduce cadmium accumulation in the human body. Herein, we report that administration of betulinic acid (BA) protects mice from cadmium chloride (CdCl2)-induced toxicity by inhibiting cadmium-induced apoptosis in both kidney and liver. Mice were given oral doses of 3 mg/kg, 10 mg/kg and 30 mg/kg of BA daily for ten consecutive days, and were injected with one dose of 1 mg/kg CdCl2 after one hour of BA administration every day. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood urea nitrogen (BUN) were assessed by ELISA. Residual cadmium was determined by atomic absorption analysis. Protein expression was evaluated by western blotting. Pretreatment with BA significantly reduced residual cadmium levels in the liver, kidney and testis, increased the cadmium output in urine, and reduced tissue damage induced by CdCl2. Moreover, BA prevented body weight loss by CdCl2 in a dose dependent manner. Furthermore, BA treatment increased the expression levels of B-cell lymphoma 2 (Bcl-2), decreased Bcl-2-associated X (Bax), and inhibited the levels of active caspase-3. Importantly, BA within a dose of 30 mg/kg did not induce any signs of toxicity, and protected mice from the toxicity induced by CdCl2 in a dose-dependent manner. Our findings suggest that BA inhibits CdCl2 induced apoptosis in the kidney and liver, and BA may be an effective agent for the prevention and treatment of cadmium-induced diseases in humans.

Herein, we report a metal-free intramolecular carbofluorination protocol for the synthesis of tetrasubstituted monofluoroalkenes from internal

Oxymatrine (OMT), a quinolizidine alkaloid extracted from traditional Chinese herb Sophora flavescens Ait, has drawn attention because of its beneficial bioactivities against hypoxic–ischemic brain damage (HIBD). However, the underlying molecular mechanism remains unclear. In this study, we determined the in vivo and in vitro effects of OMT on seven-day old Sprague–Dawley rats with HIBD and in a rat model of primary hippocampal neuron oxygen glucose deprivation reoxygenation (OGD/R). This study was aimed to evaluate whether OMT exerted neuroprotective effects mediated by the (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) PI3K/Akt/mTOR pathway after HIBD. Experimental results showed that the alkaloid significantly improved the early neurofunctional development, brain water content, abnormal pathological changes, and necrosis of neurons after HIBD. Moreover, OMT enhanced the cell viability and stabilized the mitochondrial permeability transition pore in the primary hippocampal neurons after OGD/R. OMT significantly decreased the autophagosome generation, elevated the expression of PI3K, Akt, and mTOR, and simultaneously reversed the mRNA expression of microtubule-associated protein 1-light chain 3 (LC3), Beclin-1, and sequestosomel (P62) induced by hypoxia and ischemia. However, these protective effects against HIBD could be suppressed when rapamycin, a specific inhibitor of mTOR, was included. Hence, the OMT exerted neuroprotective effects against HIBD by attenuating excessive autophagy by mediating the PI3K/Akt/mTOR pathway.

The ionospheric delays and satellite differential code biases (DCBs) act as the significant error sources in the global navigation satellite system (GNSS) positioning, navigation and timing (PNT) services, and are still challenging to estimate correctly. In this study, the ionospheric vertical total electron content (VTEC) and satellite DCBs are estimated by a refining single-frequency precise point positioning (SFPPP) method based on the multi-layer ionosphere mapping function (MF), as well as the dual-frequency methods, including the carrier-to-code leveling (CCL) and dual-frequency PPP (DFPPP). The solutions isolate the ionospheric VTEC values from the slant ionospheric delay with the generalized trigonometric series function (GTSF) and precisely estimate the satellite DCB with a zero-mean condition. The SFPPP-derived VTEC estimates are validated and evaluated by comparing with the International GNSS Service (IGS) products and using ionosphere-corrected (IC) SFPPP in both static and kinematic scenarios. Using the 74 experimental stations collected from the multi-GNSS experiment (MGEX) network from January to March 2020, the results show that the VTEC estimation precision by applying the multi-layer MF is improved for the SFPPP approach. The positioning performances of the static and kinematic BDS IC SFPPP with the ionospheric correction derived from the multi-layer MF SFPPP are better when compared to the single-layer MF. The estimated BDS DCB with the SFPPP is stable and of high accuracy. The SFPPP approach with multi-layer MF is demonstrated as a promising and reliable method to retrieve the VTEC and satellite DCB with the low-cost property for the GNSS users.

This paper illustrates several intelligent algorithms to build a short-term wind power forecasting model using data of a particular Wind Farm in Inner Mongolia. Advantages and backwards of the four different neural network models have been carefully discussed. Calculation methods and formulas are provided to prove the result. A combination prediction method is proposed in order to make a more accurate distribution power prediction by optimizing the information of multiple single models. Therefore, after analyzing the actual wind power data, the most accurate forecasting model is selected to provide an effective reference for power dispatching, operation and equipment maintenance. In order to integrate theory with practice, a wind farm in Inner Mongolia is chosen to make the short-term power prediction using the different intelligent method discussed in this paper. The most accurate prediction algorithm has been proved by real-time data.