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Abstract Background Tyrosine phosphorylation of intracellular proteins is a post‐translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross‐talk between signaling pathways. In the context of cancer, PTP‐mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth‐stimulatory signaling pathways or modulation of the immune‐suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. Areas covered This review aimed to elaborate recent insights that supported the involvement of PTP‐mediated pathways in the development of resistance to targeted therapy and immune‐checkpoint therapy. Expert opinion This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long‐term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced‐stage tumors.

Objective This study aims to explore a streamlined risk-adjusted cesarean section rate (RCSR) model and to compare its practical application effects with the traditional RCSR models. Methods Utilizing obstetric electronic health record (EHR) data from provincial multicenter hospitals, this study establishes a streamlined RCSR model alongside the traditional RCSR model and evaluates the efficacy of both models. Subsequently, the RCSRs of 56 hospitals within the province are calculated and ranked using both models. The consistency of these rankings is then quantified using Kendall's tau coefficient of concordance. Result Comparison of model effectiveness evaluation of the traditional RCSR model versus the streamlined RCSR model is as follows: AUC (0.840 vs 0.839), accuracy (0.875 vs 0.872), sensitivity (0.690 vs 0.685), specificity (0.898 vs 0.892), positive predictive value (0.908 vs 0.903), negative predictive value (0.664 vs 0.660), and Brier score (0.069 vs 0.067). In the test of the consistency of hospital rankings based on two models, Kendall's tau coefficients were observed to be 0.979 (year 2017), 0.978 (year 2018), and 0.978 (year 2019) over a span of 3 years, with an aggregate coefficient of 0.974. Conclusion In the realm of model performance evaluation as well as the pragmatic application within hospital settings, the streamlined model exhibits a substantial congruence with the traditional model. Therefore, the streamlined model can effectively serve as a viable surrogate for the traditional model, potentially establishing itself as a refined paradigm for the appraisal of quality in obstetric healthcare services.

Abstract Objective To investigate the correlation between anthropometric indexes [cardiometabolic index (CMI), lipid accumulation products (LAP), waist triglyceride index (WTI), and body mass index (BMI)] and acute pancreatitis (AP) in a Chinese adult population. Methodology The present investigation consisted of a prospective group including 117,326 subjects who were enrolled in the Kailuan investigation. The individuals were categorized into quartiles based on their baseline levels of CMI, LAP, and WIT. BMI was categorized into three distinctive groups: normal weight group (BMI

Protein–protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Objectives: The correlation between exercise type and intensity and coronary artery inflammation in patients with stable coronary artery disease (CAD) is unknown. Therefore, this study assessed the relationship between coronary inflammation quantified by coronary computed tomography angiography (CCTA) and exercise intensity and pattern in patients with CAD. Materials and methods: Patients who underwent CCTA between 2019 and 2023 in the second hospital of Lanzhou University were retrospectively examined. We calculated the pericoronary fat attenuation index (FAI) on the right coronary artery (RCA) as a marker of coronary inflammation. We compared basic information, exercise status, and RCA-FAI values between the two groups, and described the relationship between different exercise durations and RCA-FAI using analysis of variance and restricted cubic splines. Results: In total, 1222 patients were included: 774 had no CAD and 448 patients had CAD. Sex (P = 0.016; odds ratio [OR]: 0.673), high-density lipoprotein (P = 0.006; OR: 0.601), low-density lipoprotein (P = 0.001; OR. 0.762), hypertension (P = 0.000; OR: 0.762), smoking (P = 0.005; OR: 0.670), and postprandial glucose (P = 0.030; OR: 0.812), household income (P = 0.038; OR:1.117), and body mass index (P = 0.000; OR:1.084) were the risk factors for elevated RCA-FAI values in the patients with coronary artery disease group. And when the exercise modality was running and aerobics, the correlation between RCA-FAI values and exercise time showed a “U''-shaped relationship. Follow-up revealed that short periods of high-intensity exercise resulted in lower RCA-FAI values. Conclusion: RCA-FAI was significantly associated with coronary artery inflammation. Although appropriate physical activity reduced the risk of pericoronary inflammation and coronary atherosclerosis, overly prolonged exercise could exacerbate the coronary inflammatory response and increase the likelihood of CAD.

Autoimmune hepatitis (AIH) is a progressive liver disease mediated by the immune system that involves an imbalance in pro-inflammatory and regulatory mechanisms including regulatory T cells (Tregs), T helper 17 (Th17) cells, Th1, macrophages, and many other immune cells. Current steroid therapy for AIH has significant systemic side effects and is poorly tolerated by some individuals. Therefore, there is an urgent need for alternative treatments. Maintaining homeostasis in macrophage differentiation and activation is crucial for regulating immune responses in hepatitis. In this study, we loaded small interfering RNA (siRNA) targeting receptor-interacting protein kinase 3 (RIPK3) into M2-type macrophage-derived exosomes (M2 Exos) to create functionalized exosomes called M2 Exos/siRIPK3. These exosomes demonstrated a natural ability to target the liver in mice, as they were efficiently taken up by hepatic macrophages and showed significant and stable accumulation. M2 Exos/siRIPK3 effectively mitigated immune-mediated hepatitis by suppressing the expression of RIPK3, resulting in a reduced release of pro-inflammatory cytokines and chemokines in both liver tissues and serum. Additionally, M2 Exos/siRIPK3 exhibited immunomodulatory effects, as its administration resulted in a decreased proportion of hepatic and splenic Th17 cells, along with an increased ratio of Tregs. Overall, this study suggests that loading small molecule drugs onto M2 Exos could be a promising approach for developing immunomodulators that specifically target liver macrophages to treat AIH. This strategy has the potential to provide a safer and more effective alternative to current therapy for AIH patients.

Abstract Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages in cancer therapy. As opposed to noncovalent inhibitory drugs, covalent inhibitors reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming to selectively recognize and bind to protein targets and addressing some of the challenges faced by noncovalent drugs. Most successful targeted covalent inhibitors depend primarily on binding‐site cysteine residues, but this has limitations for certain protein targets that lack targetable cysteine residues. Recently, the rational design of covalent inhibitors or covalent probes targeting other nucleophilic residues, such as lysine, tyrosine, serine, has turned out to be another promising strategy for cancer therapy. Thus, the development of novel strategies to extend the scope of covalent binding and improve the binding properties is required. This review gives a summary of the development of covalent inhibitors targeting noncysteine from different aspects, including target identification, structure–activity relationships, drug discovery strategies, and binding properties, in the hope of providing a scientific reference for future covalent drug discovery as a means of expanding research in cancer therapy.

Abstract Purpose Early evaluation of the efficacy of first-line chemotherapy combined with bevacizumab in patients with colorectal cancer liver metastasis (CRLM) remains challenging. This study used 2-month post-chemotherapy spectral computed tomography (CT) to predict the overall survival (OS) and response of CRLM patients with bevacizumab-containing therapy. Method This retrospective analysis was performed in 104 patients with pathologically confirmed CRLM between April 2017 and October 2021. Patients were treated with 5-fluorouracil, leucovorin, oxaliplatin or irinotecan with bevacizumab. Portal venous phase spectral CT was performed on the target liver lesion within 2 months of commencing chemotherapy to demonstrate the iodine concentration (IoD) of the target liver lesion. The patients were classified as responders (R +) or non-responders (R −) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at 6 months. Multivariate analysis was performed to determine the relationships of the spectral CT parameters, tumor markers, morphology of target lesions with OS and response. The differences in portal venous phase spectral CT parameters between the R + and R − groups were analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive power of spectral CT parameters. Results Of the 104 patients (mean age ± standard deviation: 57.73 years ± 12.56; 60 men) evaluated, 28 (26.9%) were classified as R + . Cox multivariate analysis identified the iodine concentration (hazard ratio [HR]: 1.238; 95% confidence interval [95% CI]: 1.089–1.408; P

In this work, a flexible electrochemical sensor was developed for the detection of organophosphorus pesticides (OPs). To fabricate the sensor, graphene was generated in situ by laser-induced graphene (LIG) technology on a flexible substrate of polyimide (PI) film to form a three-electrode array, and pralidoxime (PAM) chloride was used as the probe molecule. CeO2 was used to modify the working electrode to improve the sensitivity of the sensor because of its electrocatalytic effect on the oxidation of PAM, and the Ag/AgCl reference electrode was prepared by the drop coating method. The effects of the laser power, laser scanning speed, and CeO2 modification on the electrochemical properties of the sensor were studied in detail. The results prove that the sensor has good repeatability, stability, and anti-interference ability, and it shows an excellent linear response in the chlorpyrifos concentration range from 1.4 × 10−8 M to 1.12 × 10−7 M with the detection limit of 7.01 × 10−10 M.

Recent studies have characterized the genomic structures of many eukaryotic cells, often focusing on their relation to gene expression. However, these studies have largely investigated cells grown in 2D cultures, although the transcriptomes of 3D-cultured cells are generally closer to their in vivo phenotypes. To examine the effects of spatial constraints on chromosome conformation, we investigated the genomic architecture of mouse hepatocytes grown in 2D and 3D cultures using in situ Hi-C. Our results reveal significant differences in higher-order genomic interactions, notably in compartment identity and strength as well as in topologically associating domain (TAD)–TAD interactions, but only minor differences are found at the TAD level. Our RNA-seq analysis reveals an up-regulated expression of genes involved in physiological hepatocyte functions in the 3D-cultured cells. These genes are associated with a subset of structural changes, suggesting that differences in genomic structure are critically important for transcriptional regulation. However, there are also many structural differences that are not directly associated with changes in gene expression, whose cause remains to be determined. Overall, our results indicate that growth in 3D significantly alters higher-order genomic interactions, which may be consequential for a subset of genes that are important for the physiological functioning of the cell.

Power load prediction plays an important role in the safety and stability of national power system. However, due to the nonlinear and multi-frequency characteristics of the power system itself, power load prediction is difficult. To address this problem, we propose a short-term power load prediction model based on variational mode decomposition (VMD). First, original data are decomposed into intrinsic mode function (IMF) of different frequencies using the VMD algorithm, and the decomposed sub-functions are reconstructed. After smoothing the reconstructed data by Savitzky-Golay (S-G) filtering algorithm, the change trend of raw data (CTRD) is obtained. Then, IMF, CTRD and raw data are used as inputs to predict short-term power load by long short-term memory network (LSTM). Finally, the proposed prediction model is compared with the other two groups of prediction models. The results show that the proposed VMD-SG-LSTM prediction model has high fitting ability and high prediction accuracy, and is an effective method for short-term power load prediction.

Abstract Cancer is a complex disease associated with a combination of abnormal physiological process and exhibiting dysfunctions in multiple systems. To provide effective treatment and diagnosis for cancer, current treatment strategies simultaneously focus on various tumor targets. Based on the rapid development of nanotechnology, nanocarriers have been shown to exhibit excellent potential for cancer therapy. Compared with nanoparticles with single functions, multifunctional nanoparticles are believed to be more aggressive and potent in the context of tumor targeting. However, the development of multifunctional nanoparticles is not simply an upgraded version of the original function, but involves a sophisticated system with a proper backbone, optimized modification sites, simple preparation method, and efficient function integration. Despite this, many well‐designed multifunctional nanoparticles with promising therapeutic potential have emerged recently. Here, to give a detailed understanding and analyzation of the currently developed multifunctional nanoparticles, their platform structures with organic or inorganic backbones were systemically generalized. We emphasized on the functionalization and modification strategies, which provide additional functions to the nanoparticle. We also discussed the application combination strategies that were involved in the development of nanoformulations with functional crosstalk. This review thus provides an overview of the construction strategies and application advances of multifunctional nanoparticles.

Objective: To investigate the utility of preoperative magnetic resonance imaging histogram analysis for evaluating tumor-infiltrating CD8+ T cells in patients with glioblastoma (GBM). Methods: We retrospectively analyzed the pathological and imaging data of 61 patients with GBM confirmed by surgery and pathology. Moreover, the levels of tumor-infiltrating CD8+ T cells in tumor tissue samples obtained from the patients were quantified through immunohistochemical staining and evaluated with respect to overall survival. The patients were divided into the high and low CD8 expression groups. Preoperative T1-weighted contrast-enhanced (T1C) histogram parameters of patients with GBM were extracted using Firevoxel software. We investigated the correlation between the histogram feature parameters and CD8+ T cells. We performed statistical analyses of the T1C histogram parameters in both groups and identified characteristic parameters with significant between-group differences. Additionally, we performed a receiver operating characteristic curve (ROC) analysis to determine the predictive utility of these parameters. Results: The levels of tumor-infiltrating CD8+ T cells were positively associated with overall survival in patients with GBM (P = 0.0156). Among the T1C histogram features, the mean, 5th, 10th, 25th, and 50th percentiles were negatively correlated with the levels of CD8+ T cells. Moreover, the coefficient of variation (CV) was positively correlated with the levels of CD8+ T cells (all P

S-adenosylmethionine (SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases (MTases), a major group of SAM-dependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAM-dependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second, we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzyme-mediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.

Balancing high resolution and broad genome coverage in single-cell Hi-C approaches remains challenging. Here, the authors describe a computational method for the reconstruction of a large 3D-ensemble of single-cell chromatin conformations from population Hi-C measurements and apply this model to study embryogenesis in D r o s o p h i l a.

Abstract Chromatin interactions are important for gene regulation and cellular specialization. Emerging evidence suggests many-body spatial interactions play important roles in condensing super-enhancer regions into a cohesive transcriptional apparatus. Chromosome conformation studies using Hi-C are limited to pairwise, population-averaged interactions; therefore unsuitable for direct assessment of many-body interactions. We describe a computational model, CHROMATIX, which reconstructs ensembles of single-cell chromatin structures by deconvolving Hi-C data and identifies significant many-body interactions. For a diverse set of highly active transcriptional loci with at least 2 super-enhancers, we detail the many-body functional landscape and show DNase accessibility, POLR2A binding, and decreased H3K27me3 are predictive of interaction-enriched regions.

A carbon nanowire-modified surface with interdigitated electrode (IDE) sensing system was introduced to identify abdominal aortic aneurysm biomarker “papain,” also known as cysteine protease, used as the capture probe to identify Cystatin C. Papain was immobilized through the covalent integration of amine group on papain and the carboxyl group with carbon nanowire. This papain-modified electrode surface was utilized to detect the different concentrations of Cystatin C (100 pg/mL to 3.2 ng/mL). The interaction between papain and Cystatin C was monitored using a picoammeter, and the response curves were compared. With increasing Cystatin C concentrations, the total current levels were gradually increased with a linear range from 200 pg/mL to 3.2 ng/mL, and the current differences were plotted and the detection limit of Cystatin C was calculated as 200 pg/mL. The averaging of three independent experiments (n = 3) was made with 3δ estimation, and the determination coefficient was y = 1.8477 × 0.7303 and R2 = 0.9878. Furthermore, control experiments with creatinine and gliadin failed to bind the immobilized papain, indicating the specific detection of Cystatin C.

Purpose. To investigate the expression of LPCAT1 in liver hepatocellular carcinoma (LIHC) and its relationship with prognosis and immune infiltration and predict its upstream nonencoding RNAs (ncRNAs). Method. In this study, expression analysis and survival analysis for LPCAT1 in pan cancers were first performed by using The Cancer Genome Atlas (TCGA) data, which suggested that LPCAT1 might be a potential LIHC oncogene. Then, ncRNAs contributing to the overexpression of LPCAT1 were explored in starBase by a combination of expression analysis, correlation analysis, and survival analysis. Immune cell infiltration of LPCAT1 in LIHC was finally investigated via Tumor Immune Estimation Resource (TIMER). Result. SNHG3 was observed to be the most promising upstream lncRNA for the hsa-miR-139-5p/LPCAT1 axis in LIHC. In addition, the LPCAT1 level was significantly positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression in LIHC. Conclusion. To summarize, the upregulation of LPCAT1 mediated by ncRNAs is associated with poor prognosis, immune infiltration, and immune checkpoint expression in LIHC.

The lymphatic system plays an indispensable role in humoral balance, lipid metabolism, and immune regulation. The lymph nodes (LNs) are known as the primary sites of tumor metastasis and the metastatic LNs largely affected the prognosis of the patiens. A well-designed lymphatic-targeted system favors disease treatment as well as vaccination efficacy. In recent years, development of nanotechnologies and emerging biomaterials have gained increasing attention in developing lymph-node-targeted drug-delivery systems. By mimicking the endogenous macromolecules or lipid conjugates, lymph-node-targeted nanocarries hold potential for disease diagnosis and tumor therapy. This review gives an introduction to the physiological functions of LNs and the roles of LNs in diseases, followed by a review of typical lymph-node-targeted nanomaterial-based drug-delivery systems (e.g., liposomes, micelles, inorganic nanomaterials, hydrogel, and nanocapsules). Future perspectives and conclusions concerned with lymph-node-targeted drug-delivery systems are also provided.

Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.

The novel human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which gives rise to the coronavirus disease 2019 (COVID-19), has caused a serious threat to global public health. On March 11, 2020, the WHO had officially announced COVID-19 as a pandemic. Therefore, it is vital to find effective and safe neutralizing antibodies and vaccines for COVID-19. The critical neutralizing domain (CND) that is contained in the receptor-binding domain (RBD) of the spike protein (S protein) could lead to a highly potent neutralizing antibody response as well as the cross-protection of other strains of SARS. By using RBD as an antigen, many neutralizing antibodies are isolated that are essential to the therapeutics of COVID-19. Furthermore, a subunit vaccine, which is based on the RBD, is expected to be safer than others, thus the RBD in the S protein is a more important target for vaccine development. In this review, we focus on neutralizing antibodies that are targeting RBD as well as the vaccine based on RBD under current development.

Summary: The UbiA superfamily of intramembrane prenyltransferases catalyzes an isoprenyl transfer reaction in the biosynthesis of lipophilic compounds involved in cellular physiological processes. Digeranylgeranylglyceryl phosphate (DGGGP) synthase (DGGGPase) generates unique membrane core lipids for the formation of the ether bond between the glycerol moiety and the alkyl chains in archaea and has been confirmed to be a member of the UbiA superfamily. Here, the crystal structure is reported to exhibit nine transmembrane helices along with a large lateral opening covered by a cytosolic cap domain and a unique substrate-binding central cavity. Notably, the lipid-bound states of this enzyme demonstrate that the putative substrate-binding pocket is occupied by the lipidic molecules used for crystallization, indicating the binding mode of hydrophobic substrates. Collectively, these structural and functional studies provide not only an understanding of lipid biosynthesis by substrate-specific lipid-modifying enzymes but also insights into the mechanisms of lipid membrane remodeling and adaptation.

Topologically associating domain (TAD) boundaries in flies seem to be different from those in mammals. Here, the authors use Hi-C with sub-kb resolution to identify about 4000 TADs in flies, most demarcated by the insulator complexes BEAF-32/CP190 or BEAF-32/Chromator like CTCF/cohesin in mammals.

The low dielectric constant of the nonpolar polymer poly(1-butene) (PB-1) limits its application as a diaphragm element in energy storage capacitors. In this work, Ba(Zr0.2Ti0.8)O3-coated multiwalled carbon nanotubes (BZT@MWCNTs) were first prepared by using the sol–gel hydrothermal method and then modified with polydopamine (PDA) via noncovalent polymerization. Finally, PB-1 matrix composite films filled with PDA-modified BZT@MWCNTs nanoparticles were fabricated through a solution-casting method. Results indicated that the PDA-modified BZT@MWCNTs had good dispersion and binding force in the PB-1 matrix. These characteristics improved the dielectric and energy storage performances of the films. Specifically, the PDA-modified 10 vol% BZT@ 0.5 vol% MWCNTs/PB-1 composite film exhibited the best dielectric performance. At 1 kHz, the dielectric constant of this film was 25.43, which was 12.7 times that of pure PB-1 films. Moreover, its dielectric loss was 0.0077. Furthermore, under the weak electric field of 210 MV·m−1, the highest energy density of the PDA-modified 10 vol% BZT@ 0.5 vol% MWCNTs/PB-1 composite film was 4.57 J·cm−3, which was over 3.5 times that of PB-1 film (≈1.3 J·cm−3 at 388 MV·m−1).

In this work, poly(1-butene) (PB-1) composite films with multi-walled carbon nanotubes (MWCNT) were prepared by a solution casting method. The relationship between the dielectric properties and the crystal transformation process of the films was investigated. It was indicated that there were two crystal forms of I and II of PB-1 during the solution crystallization process. With the prolongation of the phase transition time, form II was converted into form I. The addition of the conductive filler (MWCNT) accelerated the rate of phase transformation and changed the nucleation mode of PB-1. The presence of crystal form I in the system increased the breakdown strength and the dielectric constant of the films and reduced the dielectric loss, with better stability. In addition, the dielectric constant and the dielectric loss of the MWCNT/PB-1 composite films increased with the addition of MWCNT, due to the interfacial polarization between MWCNT and PB-1 matrix. When the mass fraction of the MWCNT was 1.0%, the composite film had a dielectric constant of 43.9 at 25 °C and 103 Hz, which was 20 times that of the original film.

Considering the many secondary natural metabolites available from plants, phenolic compounds play a particularly important role in human health as they occur in significant amounts in many fruits, vegetables and medicinal plants. In this review natural phenolic compounds of plant origin with significant anti-angiogenic properties are discussed. Thirteen representatives from eight different natural or natural-like phenolic subclasses are presented with an emphasis on their synthesis and methods to modify the parent compounds. When available, the consequence of structural variation on the pharmacological activity of the molecules is described.

We reported a sandwich structured Pb(Zr0.4Ti0.6)O3/BaZr0.2Ti0.8O3/Pb(Zr0.4Ti0.6)O3 (PZT/BZT/PZT) film fabricated by using the sol−gel method, which was dense and uniform with a unique perovskite structure. The PZT/BZT/PZT films displayed high dielectric constants up to 1722.45 at the frequency of 10 kHz. Additionally, the enhanced energy storage density of 39.27 J·cm−3 was achieved at room temperature and 2.00 MV/cm, which was higher than that of the individual BaZr0.2Ti0.8O3 film (21.28 J·cm−3). Furthermore, the energy storage density and efficiency of PZT/BZT/PZT film increased slightly with the increasing temperature from −140 °C to 200 °C. This work proves the feasibility and effectiveness of a sandwich structure in improving dielectric, leakage, and energy storage performances, providing a new paradigm for high-energy−density dielectrics applications.

Background: Ondansetron has been reported to attenuate the incidence of spinal anaesthesia-induced hypotension (SAIH) and norepinephrine requirement during caesarean section. However, no quantitative study has evaluated the extent of this effect. This study aimed to determine the dose-response of prophylactic infusion of norepinephrine to prevent SAIH in parturients who received intravenous ondansetron or placebo before spinal anaesthesia for caesarean section. The median effective dose (ED50) and 90% effective dose (ED90) were compared to evaluate the effect of ondansetron versus placebo on the norepinephrine requirement. Materials and methods: One hundred fifty parturients undergoing caesarean section were randomized to receive either 0.1 mg/kg ondansetron (group O) or saline control (group C) 10 min before spinal anaesthesia. The parturients were randomly assigned to one of five different norepinephrine infusion groups: 0.02, 0.04, 0.06, 0.08 or 0.10 μg/kg/min. An effective infusion dose of norepinephrine was defined as non-occurrence of hypotension during the study period. The values for ED50 and ED90 of norepinephrine infusion were determined using probit regression. Differences between the two groups were evaluated by comparing the relative median potency with 95% CIs. Results: The ED50 values were 0.033 (95% CIs, 0.024-0.043) μg/kg/min in group C and 0.021 (95%CIs, 0.013-0.029) μg/kg/min in group O. The ED90 values were 0.091 (95% CIs 0.068-0.147) μg/kg/min in group C and 0.059 (95% CIs 0.044-0.089) μg/kg/min in group O, respectively. The estimate of the relative median potency for norepinephrine in group C versus group O was 0.643 (95% CIs, 0.363-0.956). The incidence of side effects was comparable between groups. No significant difference in neonatal outcomes. Conclusion: Intravenous ondansetron 0.1 mg/kg before spinal anaesthesia significantly reduced the dose requirement of prophylactic norepinephrine infusion in parturients undergoing elective caesarean section. This finding is potentially useful for clinical practice and further research. [ABSTRACT FROM AUTHOR]