Luteolin enhances drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in paclitaxel­resistant esophageal squamous cell carcinoma.

Drug resistance is a key factor underlying the failure of tumor chemotherapy. It enhances the stem­like cell properties of cancer cells, tumor metastasis and relapse. Luteolin is a natural flavonoid with strong anti­tumor effects. However, the mechanism(s) by which luteolin protects against paclitaxel (PTX)­resistant cancer cell remains to be elucidated. The inhibitory effect of luteolin on the proliferation of EC1/PTX and EC1 cells was detected by cell counting kit­8 assay. Colony formation and flow cytometry assays were used to assess clonogenic capacity, cell cycle and apoptosis. Wound healing and Transwell invasion tests were used to investigate the effects of luteolin on the migration and invasion of EC1/PTX cells. Western blotting was used to detect the protein levels of EMT­related proteins and stem cell markers after sphere formation. Parental cells and drug­resistant cells were screened by high­throughput sequencing to detect the differential expression of RNA and differential genes. ELISA and western blotting were used to verify the screened PI3K/Akt signaling pathway, key proteins of which were explored by molecular docking. Hematoxylin and eosin staining and TUNEL staining were used to observe tumor xenografts on morphology and apoptosis in nude mice. The present study found that luteolin inhibited tumor resistance (inhibited proliferation, induced cell cycle arrest and apoptosis and hindered migration invasion, EMT and stem cell spherification) in vitro in PTX­resistant esophageal squamous cell carcinoma (ESCC) cells. In addition, luteolin enhanced drug sensitivity and promoted the apoptosis of drug­resistant ESCC cells in combination with PTX. Mechanistically, luteolin may inhibit the PI3K/AKT signaling pathway by binding to the active sites of focal adhesion kinase (FAK), Src and AKT. Notably, luteolin lowered the tumorigenic potential of PTX­resistant ESCC cells but did not show significant toxicity in vivo. Luteolin enhanced drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in PTX­resistant ESCC and could be a promising agent for the treatment of PTX­resistant ESCC cancers.

Modification of Microstructure and Mechanical Properties of Extruded AZ91-0.4Ce Magnesium Alloy through Addition of Ca.

The effect of the addition of alkali earth element Ca on the microstructure and mechanical properties of extruded AZ91-0.4Ce-xCa (x = 0, 0.4, 0.8, 1.2 wt.%) alloys was studied by using scanning electron microscopy, transmission electron microscopy, and tensile tests. The results showed that the addition of Ca could significantly refine the second phase and grain size of the extruded AZ91-0.4Ce alloy. The refinement effect was most obvious when 0.8 wt.% of Ca was added, and the recrystallized grain size was 4.75 µm after extrusion. The addition of Ca resulted in the formation of a spherical Al2Ca phase, which effectively suppressed the precipitation of the ß-Mg17Al12 phase, promoted dynamic recrystallization and grain refinement, impeded dislocation motion, and exerted a positive influence on the mechanical properties of the alloy. The yield strength (YS), ultimate tensile strength (UTS), and elongation (EL) of the AZ91-0.4Ce-0.8Ca alloy were 238.7 MPa, 338.3 MPa, and 10.8%, respectively.

YOLO SSPD: a small target cotton boll detection model during the boll-spitting period based on space-to-depth convolution.

Introduction: Cotton yield estimation is crucial in the agricultural process, where the accuracy of boll detection during the flocculation period significantly influences yield estimations in cotton fields. Unmanned Aerial Vehicles (UAVs) are frequently employed for plant detection and counting due to their cost-effectiveness and adaptability. Methods: Addressing the challenges of small target cotton bolls and low resolution of UAVs, this paper introduces a method based on the YOLO v8 framework for transfer learning, named YOLO small-scale pyramid depth-aware detection (SSPD). The method combines space-to-depth and non-strided convolution (SPD-Conv) and a small target detector head, and also integrates a simple, parameter-free attentional mechanism (SimAM) that significantly improves target boll detection accuracy. Results: The YOLO SSPD achieved a boll detection accuracy of 0.874 on UAV-scale imagery. It also recorded a coefficient of determination (R2) of 0.86, with a root mean square error (RMSE) of 12.38 and a relative root mean square error (RRMSE) of 11.19% for boll counts. Discussion: The findings indicate that YOLO SSPD can significantly improve the accuracy of cotton boll detection on UAV imagery, thereby supporting the cotton production process. This method offers a robust solution for high-precision cotton monitoring, enhancing the reliability of cotton yield estimates.

The association between shift work, shift work sleep disorders and premature ejaculation in male workers.

OBJECTIVE: Shift work and Shift Work Sleep Disorder (SWSD) are known to affect the secretion of several neurotransmitters and hormones associated with premature ejaculation (PE). However, their specific influence on the regulation of male ejaculation remains unclear. This study explores the relationship between shift work, SWSD, and PE. METHODS: From April to October 2023, a cross-sectional survey was conducted across five regions of China to explore the work schedules, sleep quality, and sexual function of male workers. Participants' sleep quality was evaluated using a validated SWSD questionnaire, and their erectile function and ejaculatory control were assessed with the International Inventory of Erectile Function (IIEF-5) scores and Premature Ejaculation Diagnostic Tool (PEDT) scores, respectively. Univariate and multivariate linear regression analyses were employed to identify risk factors associated with PE. Confounders were controlled using multiple regression models, and clinical prediction models were developed to predict PE onset and assess the contribution of risk factors. RESULTS: The study included 1239 eligible participants, comprising 840 non-shift workers and 399 shift workers (148 with SWSD and 251 without SWSD). Compared to non-shift working males, those involved in shift work (ß 1.58, 95% CI 0.75 - 2.42, p < 0.001) and those suffering from SWSD (ß 2.86, 95% CI 1.86 - 3.85, p < 0.001) they had significantly higher PEDT scores. Additionally, we identified daily sleep of less than six hours, depression, anxiety, diabetes, hyperlipidemia, frequent alcohol consumption (more than twice a week), and erectile dysfunction as risk factors for PE. The predictive model for PE demonstrated commendable efficacy. CONCLUSION: Both shift work and SWSD significantly increase the risk of premature ejaculation, with the risk magnifying in tandem with the duration of shift work. This study reveals the potential impact of shift work and SWSD on PE and provides new theoretical foundations for the risk assessment and prevention of this condition.

Artificial intelligence automated surgical phases recognition in intraoperative videos of laparoscopic pancreatoduodenectomy.

BACKGROUND: Laparoscopic pancreatoduodenectomy (LPD) is one of the most challenging operations and has a long learning curve. Artificial intelligence (AI) automated surgical phase recognition in intraoperative videos has many potential applications in surgical education, helping shorten the learning curve, but no study has made this breakthrough in LPD. Herein, we aimed to build AI models to recognize the surgical phase in LPD and explore the performance characteristics of AI models. METHODS: Among 69 LPD videos from a single surgical team, we used 42 in the building group to establish the models and used the remaining 27 videos in the analysis group to assess the models' performance characteristics. We annotated 13 surgical phases of LPD, including 4 key phases and 9 necessary phases. Two minimal invasive pancreatic surgeons annotated all the videos. We built two AI models for the key phase and necessary phase recognition, based on convolutional neural networks. The overall performance of the AI models was determined mainly by mean average precision (mAP). RESULTS: Overall mAPs of the AI models in the test set of the building group were 89.7% and 84.7% for key phases and necessary phases, respectively. In the 27-video analysis group, overall mAPs were 86.8% and 71.2%, with maximum mAPs of 98.1% and 93.9%. We found commonalities between the error of model recognition and the differences of surgeon annotation, and the AI model exhibited bad performance in cases with anatomic variation or lesion involvement with adjacent organs. CONCLUSIONS: AI automated surgical phase recognition can be achieved in LPD, with outstanding performance in selective cases. This breakthrough may be the first step toward AI- and video-based surgical education in more complex surgeries.

Synbiotics containing sea buckthorn polysaccharides ameliorate DSS-induced colitis in mice via regulating Th17/Treg homeostasis through intestinal microbiota and their production of BA metabolites and SCFAs.

Inflammatory Bowel Disease (IBD) is a chronic condition whose incidence has been rising globally. Synbiotic (SYN) is an effective means of preventing IBD. This study investigated the preventive effects and potential biological mechanisms of SYN (Bifidobacterium longum, Lactobacillus acidophilus, and sea buckthorn polysaccharides) on DSS-induced colitis in mice. The results indicated that dietary supplementation with SYN has a significant improvement effect on DSS mice. SYN ameliorated disease activity index (DAI), colon length, and intestinal barrier permeability in mice. In addition, RT-qPCR results indicated that after SYN intervention, the expression levels of pro-inflammatory factors (IL-6, IL-1ß, TNF-α, and IL-17F) and transcription factor RORγt secreted by Th17 cells were significantly reduced, and the expression levels of anti-inflammatory factors (IL-10 and TGF-ß) and transcription factor Foxp3 secreted by Treg cells were robustly increased. 16S rDNA sequencing analysis revealed that key intestinal microbiota related to Th17/Treg balance (Ligilactobacillus, Lactobacillus, Bacteroides, and Akkermansia) was significantly enriched. At the same time, a significant increase in microbial metabolites SCFAs and BAs was observed. We speculate that SYN may regulate the Th17/Treg balance by restructuring the structure and composition of the intestinal microbiota, thereby mitigating DSS-induced colitis.

Mechanochemical Synthesis of Silylcyclopentenes via Ball Milling.

The development of innovative methods for synthesizing silylcyclopentene compounds is particularly important for enriching and improving the synthetical toolbox of organosilicon compounds. Herein, a facile approach has been developed for the synthesis of silylcyclopentenes promoted by mechanochemically generated organolithium species as silicon nucleophiles under ball milling conditions, avoiding the requirement of large amounts of bulk solvent. This operationally simple method demonstrates good functional group compatibility, which provides a great opportunity for further exploration of the synthetic applications of silylcyclopentenes. Density functional theory calculations indicated that the transient lithiosilole intermediates undergo a stepwise nucleophilic addition process, which governs this mechanic-force-promoted [4+1] cycloaddition reaction.

Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale.

Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.

Oxidative stress and metabolic process responses of Chlorella pyrenoidosa to nanoplastic exposure: Insights from integrated analysis of transcriptomics and metabolomics.

Oxidative stress is a universal interpretation for the toxicity mechanism of nanoplastics to microalgae. However, there is a lack of deeper insight into the regulation mechanism in microalgae response to oxidative stress, thus affecting the prevention and control for nanoplastics hazard. The integrated analysis of transcriptomics and metabolomics was employed to investigate the mechanism for the oxidative stress response of Chlorella pyrenoidosa to nanoplastics and subsequently lock the according core pathways and driver genes induced. Results indicated that the linoleic acid metabolism, glycine (Gly)-serine (Ser)-threonine (Thr) metabolism, and arginine and proline metabolism pathways of C. pyrenoidosa were collectively involved in oxidative stress. The analysis of linoleic acid metabolism suggested that nanoplastics prompted algal cells to secrete more allelochemicals, thereby leading to destroy the immune system of cells. Gly-Ser-Thr metabolism and arginine and proline metabolism pathways were core pathways involved in algal regulation of cell membrane function and antioxidant system. Key genes, such as LOX2.3, SHM1, TRPA1, and proC1, are drivers of regulating the oxidative stress of algae cells. This investigation lays the foundation for future applications of gene editing technology to limit the hazards of nanoplastics on aquatic organism.

Zr-based metalloporphyrin MOF probe for electrochemical detection of parathion-methyl.

An electrochemical (EC) sensor based on metalloporphyrin metal-organic framework (MOF) for the detection of parathion-methyl (PM) has been developed. The prepared MOF-525(Fe) exhibits great signal enhancement toward the electrochemical detection of PM owing to its unique structural properties and electrochemical activities. Under optimal experimental conditions, the as-prepared MOF-525(Fe) based EC sensor exhibited excellent PM sensing performance with a wide linear detection range (0.1 µM-100 µM) and low limit of detection (LOD, 1.4 nM). Compared to its corresponding Fe metalloporphyrin (linker), MOF-525(Fe) exhibited a superior sensitivity (28.31 µA cm-2·µM-1), which is 3.7 times higher than the sensitivity of FeTCPP linker (7.56 µA cm-2·µM-1) towards PM. The improved performance is associated with the high specific surface area and the large pore channels of MOF-525(Fe) facilitating a better interaction between PM and the Fe metalloporphyrin active sites, especially in the lower concentration range. Moreover, a possible affinity of the PM molecules toward Zr6 clusters may also contribute to the selective enrichment of PM on MOF-525(Fe). This EC sensor further demonstrated high selectivity in the presence of interfering molecules. The recovery results further confirm accurate PM sensing in actual samples, which suggests promising applications for the rapid detection of environmental organophosphates by metalloporphyrin MOFs.

Synthesis and Characterization of Emulsifiers Based on the Maillard Reaction and Its Application in Stabilized DHA Algal Oil Nanoemulsions.

The aim of this study was to optimize the formation of sodium caseinate (CS) and gum arabic (GA) complexes through the Maillard reaction and to evaluate their effectiveness in improving the emulsification properties and stability of docosahexaenoic acid (DHA) nanoemulsions. First, the best target polysaccharides were selected, and the best modification conditions were determined using orthogonal experiments. Secondly, the response surface experiments were used to optimize the preparation process of the emulsion. The stability, in vitro digestion characteristics, and rheological characteristics of the emulsion prepared by means of CS-GA were compared with the emulsion prepared using a whey protein isolate (WPI). After the orthogonal test, the optimal modification conditions were determined to be a reaction time of 96 h, a CS-GA mass ratio of 1:2, a reaction temperature of 60 °C, and a degree of grafting of 44.91%. Changes in the infrared (IR), Raman, ultraviolet (UV), and endogenous fluorescence spectra also indicated that the complex structure was modified. The response surface test identified the optimal preparation process as follows: an emulsifier concentration of 5 g/L, an oil-phase concentration of 5 g/L, and a homogenization frequency of five, and the emulsion showed good stability. Therefore, the use of a nanoemulsion as a nanoscale DHA algal oil delivery system is very promising for extending the shelf life and improving the stability of food.

Neuroendocrine Carcinoma of the Bladder: A Case Report.

Primary bladder large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive neoplasm with high recurrence rates and poor prognosis. Traditional management has heavily relied on radical cystectomy, which, despite its aggressiveness, often results in unsatisfactory outcomes. Emerging evidence suggests the potential for less invasive, bladder-sparing approaches, yet detailed reports and long-term outcomes remain scarce. We report a groundbreaking case of a 59-year-old male diagnosed with primary bladder LCNEC, managed through a pioneering bladder-sparing multimodal treatment. This novel strategy included transurethral resection followed by a tailored chemoradiation protocol, resulting in exceptional disease control and preservation of bladder function over a 20-month follow-up period, without evidence of recurrence. This case underscores the viability of bladder conservation strategies as a legitimate alternative to radical cystectomy for managing LCNEC, presenting a beacon of hope for patients wishing to preserve bladder functionality. It prompts a reevaluation of traditional treatment paradigms and advocates for further research into multimodal, organ-sparing approaches for this challenging malignancy.

Impact of an AI-Based laparoscopic cholecystectomy coaching program on the surgical performance: a randomized controlled trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for treating symptomatic gallstones but carries inherent risks like bile duct injury (BDI). While critical view of safety (CVS) is advocated to mitigate BDI, its real-world adoption is limited. Additionally, significant variations in surgeon performance impede procedural standardization, highlighting the need for a feasible, innovative, and effective training approach. The aim of this study is to develop an Artificial Intelligence (AI)-assisted coaching program for LC to enhance surgical education and improve surgeon's performance. MATERIALS AND METHODS: We conducted a multi-center, randomized controlled trial from May 2022 to August 2023 to assess the impact of an AI-based coaching program, SmartCoach, on novice performing LC. Surgeons and patients meeting specific inclusion criteria were randomly assigned to either a coaching group with AI-enhanced feedback or a self-learning group. The primary outcome was assessed using the Laparoscopic Cholecystectomy Rating Form (LCRF), with secondary outcomes including surgical safety, efficiency, and adverse events. Statistical analyses were performed using SPSS, with significance set at P-value less than 0.05. RESULTS: Between May 2022 and August 2023, 22 surgeons were initially enrolled from 10 hospitals, with 18 completing the study. No demographic differences were noted between coaching and self-learning groups. In terms of surgical performance (LCRF scores), the coaching group showed significant improvement over time (31 to 40, P=0.008), outperforming the self-learning group by study end (40 vs 38, P=0.032). Significant improvements in CVS achievement were also noted in the coaching group (11% to 78%, P=0.021). Overall, the coaching program was well-received, outpacing traditional educational methods in both understanding and execution of CVS and participants in the intervention group expressed strongly satisfaction with the program. CONCLUSIONS: The AI-assisted surgical coaching program effectively improved surgical performance and safety for novice surgeons in LC procedures. The model holds significant promise for advancing surgical education.

Single-incision plus one port laparoscopic pancreaticoduodenectomy with major venous resection and reconstruction for pancreatic cancer with video recordings.

Laparoscopic pancreaticoduodenectomy (LPD) with superior mesenteric/portal vein (SMV/PV) resection and reconstruction was the most technically challenging procedure and had been rarely reported. However, single-incision plus one-port LPD (SILPD +1) with SMV/PV resection and reconstruction has never been reported. In this study, we will demonstrate the feasibility, safety, key surgical procedure, and long-term outcomes for SILPD +1 with SMV/PV resection and reconstruction using video evidence. Two cases of SILPD +1 with SMV/PV wedge resection were carried out by the authors. There was no tumor recurrence during the one-year follow-up. It is worth noting that skilled laparoscopic technicians are necessary to safely complete the procedure with good short-term and long-term outcomes.

Micro/nano-plastics and microalgae in aquatic environment: Influence factor, interaction, and molecular mechanisms.

Micro/nano-plastics, as emerging persistent pollutant, are frequently detected in aquatic environments together with other environmental pollutants. Microalgae are the major primary producers and bear an important responsibility for maintaining the balance of aquatic ecosystems. Numerous studies have been conducted on the influence of micro/nano-plastics on the growth, photosynthesis, oxidative stress, gene expression and metabolites of microalgae in laboratory studies. However, it is difficult to comprehensively evaluate the toxic effects of micro/nano-plastics on microalgae due to different experimental designs. Moreover, there is a lack of effective analysis of the aforementioned multi-omics data and reports on shared biological patterns. Therefore, the purpose of this review is to compare the acute, chronic, pulsed, and combined effect of micro/nano-plastics on microalgae and explore hidden rules in the molecular mechanisms of the interaction between them. Results showed that the effect of micro/nano-plastics on microalgae was related to exposure mode, exposure duration, exposure size, concentration, and type of micro/nano-plastics. Meanwhile, the phenomenon of poisoning and detoxification between micro/nano-plastics and microalgae was found. The inhibitory mechanism of micro/nano-plastics on algal growth was due to the micro/nano-plastics affected the photosynthesis, oxidative phosphorylation, and ribosome pathways of algal cells. This brought the disruption of the functions of chloroplasts, mitochondria, and ribosome, as well as impacted on energy metabolism and translation pathways, eventually leading to impairment of cell function. Besides, algae resisted this inhibitory effect by regulating the alanine, aspartate, and glutamate metabolism and purine metabolism pathways, thereby increasing the chlorophyll synthesis, inhibiting the increase of reactive oxygen species, delaying the process of lipid peroxidation, balancing the osmotic pressure of cell membrane.

Immunolabeling-compatible PEGASOS tissue clearing for high-resolution whole mouse brain imaging.

Novel brain clearing methods revolutionize imaging by increasing visualization throughout the brain at high resolution. However, combining the standard tool of immunostaining targets of interest with clearing methods has lagged behind. We integrate whole-mount immunostaining with PEGASOS tissue clearing, referred to as iPEGASOS (immunostaining-compatible PEGASOS), to address the challenge of signal quenching during clearing processes. iPEGASOS effectively enhances molecular-genetically targeted fluorescent signals that are otherwise compromised during conventional clearing procedures. Additionally, we demonstrate the utility of iPEGASOS for visualizing neurochemical markers or viral labels to augment visualization that transgenic mouse lines cannot provide. Our study encompasses three distinct applications, each showcasing the versatility and efficacy of this approach. We employ whole-mount immunostaining to enhance molecular signals in transgenic reporter mouse lines to visualize the whole-brain spatial distribution of specific cellular populations. We also significantly improve the visualization of neural circuit connections by enhancing signals from viral tracers injected into the brain. Last, we show immunostaining without genetic markers to selectively label beta-amyloid deposits in a mouse model of Alzheimer's disease, facilitating the comprehensive whole-brain study of pathological features.

Feasibility of rib fracture detection in low-dose computed tomography images with a large, multicenter datasets-based model.

Purpose: To evaluate the feasibility of rib fracture detection in low-dose computed tomography (CT) images with a RetinaNet-based approach and to evaluate the potential of lowdose CT for rib fracture detection compared with regular-dose CT images. Materials and methods: The RetinaNet-based deep learning model was trained using 7300 scans with 50,410 rib fractures that were used as internal training datasets from four multicenter. The external test datasets consisted of both regular-dose and low-dose chest-abdomen CT images of rib fractures; the MICCAI 2020 RibFrac Challenge Dataset was used as the public dataset. Radiologists' interpretations were used as reference standards. The performance of the model in rib fracture detection was compared with the radiologists' interpretation. Results: In total, 728 traumatic rib fractures of 100 patients [60 men (60 %); mean age, 53.45 ± 11.19 (standard deviation (SD)); range, 18-77 years] were assessed in the external datasets. In these patients, the regular-dose group had a mean CT dose index volume (CTDIvol) of 7.18 mGy (SD: 2.22) and a mean dose length product (DLP) of 305.38 mGy cm (SD: 95.31); the low-dose group had a mean CTDIvol of 2.79 mGy (SD: 1.11) and a mean DLP of 131.52 mGy cm (SD: 55.58). The sensitivity of the RetinaNet-based model and that of the radiologists was 0.859 and 0.721 in the low-dose CT images and 0.886 and 0.794 in the regular-dose CT images, respectively. Conclusions: These findings indicate that the RetinaNet-based model can detect rib fractures in low-dose CT images with a robust performance, indicating its feasibility in assisting radiologists with rib fracture diagnosis.

Spinel Nanostructures for the Hydrogenation of CO2 to Methanol and Hydrocarbon Chemicals.

Composite oxides have been widely applied in the hydrogenation of CO/CO2 to methanol or as the component of bifunctional oxide-zeolite for the synthesis of hydrocarbon chemicals. However, it is still challenging to disentangle the stepwise formation mechanism of CH3OH at working conditions and selectively convert CO2 to hydrocarbon chemicals with narrow distribution. Here, we investigate the reaction network of the hydrogenation of CO2 to methanol over a series of spinel oxides (AB2O4), among which the Zn-based nanostructures offer superior performance in methanol synthesis. Through a series of (quasi) in situ spectroscopic characterizations, we evidence that the dissociation of H2 tends to follow a heterolytic pathway and that hydrogenation ability can be regulated by the combination of Zn with Ga or Al. The coordinatively unsaturated metal sites over ZnAl2Ox and ZnGa2Ox originating from oxygen vacancies (OVs) are evidenced to be responsible for the dissociative adsorption and activation of CO2. The evolution of the reaction intermediates, including both carbonaceous and hydrogen species at high temperatures and pressures over the spinel oxides, has been experimentally elaborated at the atomic level. With the integration of a series of zeolites or zeotypes, high selectivities of hydrocarbon chemicals with narrow distributions can be directly produced from CO2 and H2, offering a promising route for CO2 utilization.

A polarization double-enhancement strategy to achieve super low energy consumption with ultra-high energy storage capacity in BCZT-based relaxor ferroelectrics.

Due to dielectric capacitors' already-obtained fast charge-discharge speed, research has been focused on improving their Wrec. Increasing the polarization and enhancing the voltage endurance are efficient ways to reach higher Wrec, however simultaneous modification still seems a paradox. For example, in the ferroelectric-to-relaxor ferroelectric (FE-to-RFE) phase transition strategy, which has been widely used in the latest decade, electric breakdown strength (Eb) and energy storage efficiency (η) always increase, while at the same time, the maximum polarization (Pmax) inevitably decreases. The solution to this problem can be obtained from another degree of freedom, like defect engineering. By incorporating Bi(Zn2/3Ta1/3)O3 (BZT) into the Ba0.15Ca0.85Zr0.1Ti0.9O3 (BCZT) lattice to form (1 - x)Ba0.15Ca0.85Zr0.1Ti0.9O3-xBi(Zn2/3Ta1/3)O3 (BCZT-xBZT) solid-solution ceramics, in this work, ultrahigh ferroelectric polarization was achieved in BCZT-0.15BZT, which is caused by the polarization double-enhancement, comprising the contribution of interfacial and dipole polarization. In addition, due to the electron compensation, a Schottky contact formed at the interface between the electrode and the ceramic, which in the meantime, enhanced its Eb. A Wrec of 8.03 J cm-3, which is the highest among the BCZT-based ceramics reported so far, with an extremely low energy consumption, was finally achieved. BCZT-0.15BZT also has relatively good polarization fatigue after long-term use, good energy storage frequency stability and thermal stability, as well as excellent discharge properties.

CDK4/6 inhibition sensitizes MEK inhibition by inhibiting cell cycle and proliferation in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to most chemotherapy drugs, leading to poor chemotherapy efficacy. Recently, Trametinib and Palbociclib have promising prospects in the treatment of pancreatic cancer. This article aims to explore the effects of Trametinib on pancreatic cancer and address the underlying mechanism of resistance as well as its reversal strategies. The GDSC (Genomics of Drug Sensitivity in Cancer) and CTD2 (Cancer Target Discovery and Development) were utilized to screen the potential drug candidate in PDAC cell lines. The dose-increase method combined with the high-dose shock method was applied to induce the Trametinib-resistant PANC-1 and MIA PaCa-2 cell lines. The CCK8 proliferation assay, colony formation assay, flow cytometry, and western blot were conducted to verify the inhibitory effect of Trametinib and Palbociclib. RNA-seq was performed in resistant PDAC cell lines to find the differential expression genes related to drug resistance and predict pathways leading to the reversal of Trametinib resistance. The GDSC and CTD2 database screening revealed that Trametinib demonstrates a significant inhibitory effect on PDAC. We found that Trametinib has a lower IC50 than Gemcitabine in PDAC cell lines. Both Trametinib and Gemcitabine can decrease the proliferation capacity of pancreatic cells, induce cell cycle arrest, and increase apoptosis. Simultaneously, the phosphorylation of the AKT and ERK pathways were inhibited by the treatment of Trametinib. In addition, the RNA-seq of Trametinib-induced resistance PDAC cell lines reveals that the cyclin-dependent kinase (CDK)-RB-E2F regulatory axis and G2/M DNA damage checkpoint might lead the drug resistance. Besides, the combination of Trametinib with Palbociclib could inhibit the proliferation and cell cycle of both resistant cells lines and also restore the sensitivity of drug-resistant cells to Trametinib. Last but not least, the interferon-α and interferon-γ expression were upregulated in resistance cell lines, which might lead to the reversal of drug resistance. The study shows Trametinib has a critical inhibitory effect on PDAC. Besides, the combination of Trametinib with Palbociclib can inhibit the proliferation of PDAC-resistant cells.