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Abstract Cancer vaccines are promising as an effective means of stimulating the immune system to clear tumors as well as to establish immune surveillance. In this paper, we discuss the main platforms and current status of cancer vaccines and propose a new cancer vaccine platform, the cytosolic vesicle vaccine. This vaccine has a unique structure that can integrate antigen and adjuvant carriers to improve the delivery efficiency and immune activation ability, which brings new ideas for cancer vaccine design. Tumor exosomes carry antigens and MHC-peptide complexes, which can provide tumor antigens to antigen-processing cells and increase the chances of recognition of tumor antigens by immune cells. DEVs play a role in amplifying the immune response by acting as carriers for the dissemination of antigenic substances in dendritic cells. OMVs, with their natural adjuvant properties, are one of the advantages for the preparation of antitumor vaccines. This paper presents the advantages of these three bacteria/extracellular vesicles as cancer vaccines and discusses the potential applications of functionally modified extracellular vesicles as cancer vaccines after cellular engineering or genetic engineering, as well as current clinical trials of extracellular vesicle vaccines. In summary, extracellular vesicle vaccines are a promising direction for cancer vaccine research.

Abstract Background The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. Methods The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. Results In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P

Abstract This work proposes two differential magnetic‐field resonant probes, consisting of a U‐shaped single‐loop resonant probe (S_probe) and a dual‐loops resonant probe (D_probe). These resonant probes are composed of a pair of LC resonant circuits, a pair of strip‐lines with two outputs, two rows of via fences, and two different sensing structures (single‐loop and dual‐loops). Among them, a pair of open stubs as capacitor and shorted stubs as inductor is used to form the LC resonant circuit, via fences are utilized to suppress unwanted electromagnetic wave modes, a U‐shaped single‐loop and a pair of differential dual‐loops is used to receive the electromagnetic signal. In order to prove the rationality of the design, simulation models of the S_probe and D_probe are optimized and manufactured based on four‐layers PCBs. In addition, a near‐field scanning system with a standard 50 Ω straight microstrip line as calibration kit is used to measure and calibrate these resonant probes. The tested results indicate that these designed magnetic‐field probes could operate at 1.575 GHz and have high detection sensitivity and electric‐field suppression.

Abstract Realizing air‐processed blue halide perovskite films with tailored emission is significant for promoting the commercialization of perovskite light‐emitting diodes (PeLEDs). However, the intrinsically inferior thermodynamic stability and laborious crystallization kinetics control under humidity interference limit the fabrication of blue perovskite emitters in ambient air. Here, air‐processed pure‐bromide quasi‐2D blue perovskite films are achieved with stabilized lattice and tunable emission by interstitial doping of trivalent metallic cations. This strategy improves the formation energy of the perovskite lattice, promotes energy transfer between different n phases, and suppresses intrinsic electron‐phonon coupling in the perovskite films. The emission‐controllable blue PeLEDs are fabricated in ambient air for the first time. The champion deep blue PeLED shows maximum external quantum efficiency (EQE) of 2.05% and luminance of 246.56 cd m−2, which are comparable to the state‐of‐the‐art of similar devices fabricated in glovebox. The work pioneers a simple method of electronic structure engineering to tune the emission of air‐processed blue perovskite, breaking the limitations of thermodynamic stability and crystallization kinetics control of perovskite in ambient air.

Soda saline-alkali significantly hinders rice growth, phosphorus utilization efficiency, and yield formation. The application of biochar can alleviate the adverse effects of saline-alkali stress on crops. However, there is limited research on the interaction between biochar and phosphorus fertilizer concerning ionic accumulation, phosphorus utilization efficiency, and rice yield in soda saline-alkali soils. A two-year field experiment was conducted to study the combined effects of biochar and phosphate fertilizer on ionic accumulation, physiological status, phosphorus utilization efficiency, and rice yield in soda saline-alkali soil. Four treatments were established for the study: NK (225 kg N, 75 kg K ha−1 year−1), NPK (225 kg N, 70 kg P, 75 kg K ha−1 year−1), NK + B [225 kg N, 75 kg K ha−1 year−1, 1.5% biochar (w/w)], and NPK + B [225 kg N, 70 kg P, 75 kg K ha−1 year−1, 1.5% biochar (w/w)]. The findings indicated that the combined application of biochar and phosphorus fertilizer (NPK + B) significantly reduced the Na+ concentration, Na+/K+ ratio, malondialdehyde (MDA), superoxide anion (O2−), and hydrogen peroxide (H2O2) levels in rice plants. Furthermore, it resulted in a significant increase in K+ concentration and elevated the levels of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), proline (Pro), soluble protein (SP), soluble sugar (SS), and acid phosphatase (ACP). The NPK + B treatment exhibited a significant difference compared to the other treatments (p < 0.05). Compared with NK, phosphorus accumulation and phosphorus utilization efficiency under NPK + B were significantly increased (p < 0.05). The average of biomass yield, grain yield, and harvest index of NPK + B, NK + B, and NPK significantly surpassed those of NK by 6.28–12.25%, 19.80–42.13%, and 11.59–24.64%, respectively. Moreover, a significant difference was observed between NPK + B and the other treatments (p < 0.05). Principal component analysis of the two-year mean data revealed a strong positive correlation of 89.5% for PC1 and a minor negative correlation of 4.4% for PC2. Our research findings demonstrate that the combination of biochar and phosphorus fertilizer effectively enhances salt and alkali tolerance in rice plants, resulting in increased yield through improved ionic balance and physiological status.

Abstract Background Pseudoenzymes, catalytically deficient variants of active enzymes, have a wide range of regulatory functions. ADP-ribosylhydrolase-like 1 (ADPRHL1), a pseudoenzyme belonging to a small group of ADP-ribosylhydrolase enzymes that lacks the amino acid residues necessary for catalytic activity, may have a significant role in heart development based on accumulating evidence. However, the specific function of ADPRHL1 in this process has not been elucidated. To investigate the role of ADPRHL1 in the heart, we generated the first in vitro human embryonic stem cell model with an ADPRHL1 knockout. Method Using the CRISPR/Cas9 system, we generated ADPRHL1 knockout in the human embryonic stem cell (hESC) H9 line. The cells were differentiated into cardiomyocytes using a chemically defined and xeno-free method. We employed confocal laser microscopy to detect calcium transients and microelectrode array (MEA) to assess the electrophysiological activity of ADPRHL1 deficiency cardiomyocytes. Additionally, we investigated the cellular mechanism of ADPRHL1 by Bulk RNA sequencing and western blot. Results The results indicate that the absence of ADPRHL1 in cardiomyocytes led to adhered abnormally, as well as perturbations in calcium transients and electrophysiological activity. We also revealed that disruption of focal adhesion formation in these cardiomyocytes was due to an excessive upregulation of the ROCK–myosin II pathway. Notably, inhibition of ROCK and myosin II effectively restores focal adhesions in ADPRHL1-deficient cardiomyocytes and improved electrical conduction and calcium activity. Conclusions Our findings demonstrate that ADPRHL1 plays a critical role in maintaining the proper function of cardiomyocytes by regulating the ROCK–myosin II pathway, suggesting that it may serve as a potential drug target for the treatment of ADPRHL1-related diseases.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus’ regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice.

Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation.Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel.Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine.Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

BackgroundMaternal stress is pervasive in the neonatal intensive care unit (NICU). Maternal stress is associated with changes in human milk (HM) immunomodulatory agents, which may impact neonatal health. We sought to determine the association between maternal stress, HM immunoglobulin A (IgA) and cortisol, and to assess how these milk components correlate with infant immune and neurodevelopmental outcomes. We then compared how these associations persist over time.MethodsThe study design involved a cohort study of exclusively breastfeeding mothers and their singleton moderately preterm (28–34 weeks) infants admitted to the NICU. We collected maternal serum, maternal saliva, and first-morning whole milk samples, and administered maternal stress questionnaires at 1 and 5 weeks postpartum. We analyzed the samples for HM IgA (using a customized immunoassay in skim milk) and for HM and salivary cortisol (using a chemiluminescent immunoassay). Infant illness was assessed using the Score for Neonatal Acute Physiology II (SNAP II) and SNAP II with Perinatal Extension (SNAPPE II), and infant neurodevelopment were assessed using the Test of Infant Motor Performance. We analyzed changes in HM IgA and cortisol over time using paired t-tests. Furthermore, we performed correlation and regression analyses after adjusting for gestational age (GA), corrected GA, and infant days of life.ResultsIn our study, we enrolled 26 dyads, with a mean maternal age of 28.1 years, consisting of 69% white, 19% Black, and 8% Hispanic. Cortisol: Salivary and HM cortisol were closely associated in week 1 but not in week 5. Though mean salivary cortisol remained stable over time [2.41 ng/mL (SD 2.43) to 2.32 (SD 1.77), p = 0.17], mean HM cortisol increased [1.96 ng/mL (SD 1.93) to 5.93 ng/mL (SD 3.83), p

Soda saline–alkaline stress significantly impedes the rice grain filling process and ultimately impacts rice yield. Biochar has been shown to mitigate the negative impacts of saline–alkaline stress on plants. However, the exact mechanism by which biochar influences the rice grain-filling rate in soda saline–alkaline soil is still not fully understood. A two-year field experiment was conducted with two nitrogen fertilizer levels (0 and 225 kg ha−1) and five biochar application rates [0% (B0), 0.5% (B1), 1.5% (B2), 3.0% (B3), and 4.5% (B4) biochar, w/w]. The results demonstrated that biochar had a significant impact on reducing the Na+ concentration and Na+/K+ ratio in rice grown in soda saline–alkaline lands, while also improving its stress physiological conditions. B1, B2, B3, and B4 showed a notable increase in the average grain-filling rate by 5.76%, 6.59%, 9.80%, and 10.79%, respectively, compared to B0; the time to reach the maximum grain-filling rate and the maximum grain weight saw increases ranging from 6.02% to 12.47% and from 7.85% to 14.68%, respectively. Meanwhile, biochar, particularly when used in conjunction with nitrogen fertilizer, notably enhanced the activities of sucrose synthase (SuSase), ADPG pyrophosphorylase (AGPase), starch synthase (StSase), and starch branching enzyme (SBE) of rice grains in soda saline–alkaline lands. Furthermore, rice yield increased by 11.95–42.74% in the B1, B2, B3, and B4 treatments compared to the B0 treatment. These findings showed that biochar improves yield by regulating ionic balance, physiological indicators, starch synthesis key enzyme activities, and the grain-filling rate in soda saline–alkaline paddy fields.

In this paper, we are interested in identifying the coefficients of the interaction terms in a parabolic system, which describes two subpopulations of the same species competing for the same resources. We use optimal the control theory to study the identification problem. Taking the unknown coefficients as control functions, the identification problem is transformed into an optimal control problem. We prove the existence and local uniqueness of the optimal control, derive the first-order necessary condition, and get the formula of the optimal control.

A GTPase binding protein, Ras interacting protein 1 (RASIP1), has been reported with a tumor-promoting role in lung cancer cells, and its role in lymphoma remains unknown. The analysis of medical databank shows that RASIP1 is upregulated in diffuse large B-cell lymphoma (DLBCL) specimens. In this article, we demonstrated that RASIP1 is highly expressed in DLBCL cell lines, compared with primary B cells. The gain- and loss-of-function experiments were performed to investigate the effects of RASIP1 on DLBCL cells. CCK-8, flow cytometry, western blot, and transwell assays demonstrated that silence of RASIP1 inhibited proliferation, cell cycle transition, and invasion and induced significant apoptosis in DLBCL cells, and ectopic expression of RASIP1 played opposite roles. Xenograft results revealed that RASIP1 facilitated the growth of DLBCL cells in vivo. These findings suggest that RASIP1 may be required for malignancy of DLBCL cells. In addition, we also found that the expression of RASIP1 was negatively regulated by forkhead box O3 (FOXO3), which has been reported to suppress the proliferation of DLBCL cells. Our results indicate that FOXO3 is bound to the promoter sequence of RASIP1 and inhibits its transcription. The suppressive effects of FOXO3 on proliferation and invasion of DLBCL cells were neutralized by RASIP1. In conclusion, we demonstrate that FOXO3 negatively regulated RASIP1 facilitates growth and invasion of DLBCL cells, provides novel diagnostic markers and therapeutic targets for DLBCL in clinic.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.

Abstract Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder characterized by cardiomyocyte hypertrophy and cardiac fibrosis. Pathological cardiac remodeling in the myocardium of HCM patients may progress to heart failure. An in-depth elucidation of the lineage-specific changes in pathological cardiac remodeling of HCM is pivotal for the development of therapies to mitigate the progression. Here, we performed single-nucleus RNA-seq of the cardiac tissues from HCM patients or healthy donors and conducted spatial transcriptomic assays on tissue sections from patients. Unbiased clustering of 55,122 nuclei from HCM and healthy conditions revealed 9 cell lineages and 28 clusters. Lineage-specific changes in gene expression, subpopulation composition, and intercellular communication in HCM were discovered through comparative analyses. According to the results of pseudotime ordering, differential expression analysis, and differential regulatory network analysis, potential key genes during the transition towards a failing state of cardiomyocytes such as FGF12, IL31RA, and CREB5 were identified. Transcriptomic dynamics underlying cardiac fibroblast activation were also uncovered, and potential key genes involved in cardiac fibrosis were obtained such as AEBP1, RUNX1, MEOX1, LEF1, and NRXN3. Using the spatial transcriptomic data, spatial activity patterns of the candidate genes, pathways, and subpopulations were confirmed on patient tissue sections. Moreover, we showed experimental evidence that in vitro knockdown of AEBP1 could promote the activation of human cardiac fibroblasts, and overexpression of AEBP1 could attenuate the TGFβ-induced activation. Our study provided a comprehensive analysis of the lineage-specific regulatory changes in HCM, which laid the foundation for targeted drug development in HCM.

In a shallow aquatic environment, a mathematical model with variable cell quota is proposed to characterize asymmetric resource competition for light and nutrients among aquatic producers. We investigate the dynamics of asymmetric competition models with constant and variable cell quotas and obtain the basic ecological reproductive indexes for aquatic producer invasions. The similarities and differences between the two types of cell quotas for dynamical properties and influences on asymmetric resource competition are explored through theoretical and numerical analysis. These results contribute to further revealing the role of constant and variable cell quotas in aquatic ecosystems.

Background: To evaluate the efficacy of a simulation-based mastery curriculum to train clinicians with limited-to-no sonography experience how to use ultrasound (US) to assess neonatal endotracheal tube (ETT) positioning. Methods: In a single-centered, prospective, educational study, 29 neonatology clinicians participated in a simulation-based mastery curriculum composed of a didactic lecture, followed by a one-on-one simulation session using a newly designed, three-dimensional (3D) printed US phantom model of the neonatal trachea and aorta. After mastery training, clinicians were evaluated with a performance checklist on their skills obtaining US images and assessing ETT positioning in the US phantom model. They also completed pre- and postcurriculum knowledge assessment tests and self-assessment surveys. The data were analyzed using Wilcoxon signed rank tests and repeated measures analysis of variance. Results: The mean checklist score improved significantly during three attempts (mean difference: 2.6552; 95% confidence interval [CI]: 2.2578–3.0525; P < 0.0001). The mean time to perform US decreased significantly from the first to third attempt (mean difference: −1.8276 min; 95% CI: −3.3391 to − 0.3161; P = 0.0196). In addition, there was a significant improvement in median knowledge assessment scores (50% vs. 80%; P < 0.0001) and survey ratings on knowledge and self-efficacy (P < 0.0001). Conclusion: Clinicians with limited-to-no sonography experience demonstrated improved knowledge and skill acquisition in using US to assess ETT positioning through simulation-based mastery training. The use of 3D modeling enhances simulation experiences and optimizes the quality of training during limited opportunities to achieve procedural competency in a controlled environment before further application into the clinical setting.

Evidence suggests an association between exposure to electronic cigarette (e-cigarette) marketing and e-cigarette use (vaping) among adolescents. However, there is limited evidence on exposure to e-cigarette marketing and susceptibility to future vaping, especially among Black and Latino adolescents. This study aimed to examine associations between exposure to e-cigarette marketing and susceptibility to future vaping among Black and Latino adolescents in the United States (US). Participants (N = 362; equal representation between Black and Latino adolescents) completed a baseline assessment (available in English and Spanish) including sociodemographic characteristics (e.g., racial/ethnic group, age, gender, sexual orientation, etc.), exposure to e-cigarette marketing, and susceptibility to future vaping. Exposure to e-cigarette marketing was recoded and organized into two categories (high exposure = 2 to 3; low exposure = 0 to 1). Cochran–Mantel–Haenszel tests were used to evaluate the association between exposure to e-cigarette marketing and susceptibility to future vaping, stratified by racial/ethnic group. Multiple logistic regressions assessed the association between exposure to e-cigarette marketing and susceptibility to future vaping, controlling for gender, sexual orientation, grade, and academic performance within each racial/ethnic group. Black adolescents reported significantly higher frequencies of exposure to e-cigarette marketing (p = 0.005). A significant interaction was found between exposure to e-cigarette marketing and racial/ethnic group (X2 (1) = 6.294, p = 0.012). Among Black adolescents, high exposure to e-cigarette marketing (vs. low exposure) was associated with a higher probability of susceptibility to future vaping (OR: 2.399, 95% CI 1.147–5.021, p = 0.020). For Latino adolescents, exposure to e-cigarette marketing was not associated with susceptibility to future vaping (OR: 0.503, 95% CI 0.245–1.03, p = 0.062). Future studies should evaluate how and where adolescents are exposed to e-cigarette marketing. Prevention efforts must include the implementation of effective counter-marketing campaigns and the reduction of exposure to e-cigarette marketing among Black and Latino adolescents.

In this paper, high-temperature storage of hydrogen-treated AlGaN/GaN HEMTs is conducted for the first time to study the effect of high temperature on the electrical characteristics of the devices after hydrogen treatment, and it is found that high-temperature storage can effectively reduce the impact of hydrogen on the devices. After hydrogen treatment, the output current and the maximum transconductance of the device increase, and the threshold voltage drifts negatively. However, after high-temperature treatment at 200 °C for 24 h, the output current, threshold voltage, and the maximum transconductance of the device all approach their initial values before hydrogen treatment. By using low-frequency noise analysis technology, the trap density of the hydrogen-treated AlGaN/GaN HEMT is determined to be 8.9 × 1023 cm−3·eV−1, while it changes to 4.46 × 1022 cm−3·eV−1 after high-temperature storage. We believe that the change in the electrical characteristics of the device in hydrogen is due to the passivation of hydrogen on the inherent trap of the device, and the variation in the electrical properties of the device in the process of high-temperature storage involves the influence of two effects, namely the dehydrogenation effect and the improvement of the metal–semiconductor interface caused by high temperatures.

Abstract Introduction and objectives hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood. Methods By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan–Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method. Results HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells. Conclusions Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes.

The voltage-gated potassium channel KvLQT1 encoded by KCNQ1 plays an important role in the repolarization of myocardial action potentials. KCNQ1 mutations can cause Long QT syndrome type 1 (LQT1), which is considered to be the most common causative gene of LQT. In this study, we established a human embryonic stem cell line KCNQ1L114P/+ (WAe009-A-79) carrying a LQT1 related mutation in KCNQ1. The WAe009-A-79 line maintains the morphology, pluripotency, and normal karyotype of stem cells, and can differentiate into all three germ layers in vivo.

Abstract In this work, a novel AlGaN/GaN lateral field‐effect rectifier (L‐FER) with ultralow turn‐on voltage (VT) and low reverse leakage current (IR) is proposed and verified by technology computer aided design (TCAD) Sentaurus. Through shortly contacting the short‐channel metal–oxide–semiconductor (MOS) structure with an Ohmic‐contact structure as the anode of the proposed L‐FER, an ultralow VT can be realized. And by inserting a floating clamp (FC) electrode near the cathode‐side MOS edge, the transverse channel potential at the MOS edge could be clamped to a small value. Thus, the high IR induced by the short‐channel effect in the MOS structure could be suppressed. In contrast to the conventional short‐channel L‐FER, the proposed FC‐L‐FER exhibits about four orders of magnitude reduction in IR, without obvious degeneration in the forward current and VT. Moreover, the proposed FC‐L‐FER also delivers excellent reverse recovery characteristics.

Abstract Background and objective Bioprostheses are the most common prostheses used for valve replacement in the Western medicine. The major flaw of bioprostheses is the occurrence of structural valve deterioration (SVD). This study aimed to assess the pathological features of porcine aortic valve (PAV)-SVD based on histomorphological and immunopathological characteristics of a large cohort of patients. Methods Histopathological data of 109 cases with resected PAV were collected. The type and amount of infiltrated cells were evaluated in the different types of bioprosthetic SVD by immunohistochemical staining. Results The most common cause of SVD was calcification, leaflet tear, and dehiscence (23.9%, 19.3%, and 18.3%, respectively). Immunohistochemical staining demonstrated that macrophages were infiltrated in the calcified, lacerated and dehiscence PAV, in which both M1 and M2 macrophages were existed in the calcified PAV. Importantly, the higher content of M1 macrophages and less content of M2 macrophages were found in the lacerated and dehiscence PAV, and MMP-1 expression was mainly found in the lacerated PAV. The endothelialization rate of leaflet dehiscence was higher than that of calcified and lacerated leaflets. A large number of CD31+/CD11b+ cells was aggregated in the spongy layer in the lacerated and dehiscence PAV. Conclusion Cell regeneration and infiltration is a double edged sword for the PAV deterioration. Macrophage infiltration is involved in the different types of SVD, while only MMP-1 expression is involved in lacerated leaflets. The macrophage subtype of circulating angiogenic cells in dehiscence and tear PAV could be identified, which could reserve macrophages in the PAV-SVD.

Abstract Background The slowly activated delayed rectifier potassium current (IKs) mediated by the KCNQ1 gene is one of the main currents involved in repolarization. KCNQ1 mutation can result in long-QT syndrome type 1 (LQT1). IKs does not participate in repolarization in mice; thus, no good model is currently available for research on the mechanism of and drug screening for LQT1. In this study, we established a KCNQ1-deficient human cardiomyocyte (CM) model and performed a series of microelectrode array (MEA) detection experiments on KCNQ1-mutant CMs constructed in other studies to explore the pathogenic mechanism of KCNQ1 deletion and mutation and perform drug screening. Method KCNQ1 was knocked out in human embryonic stem cell (hESC) H9 line using the CRISPR/cas9 system. KCNQ1-deficient and KCNQ1-mutant hESCs were differentiated into CMs through a chemically defined differentiation protocol. Subsequently, high-throughput MEA analysis and drug intervention were performed to determine the electrophysiological characteristics of KCNQ1-deficient and KCNQ1-mutant CMs. Results During high-throughput MEA analysis, the electric field potential and action potential durations in KCNQ1-deficient CMs were significantly longer than those in wild-type CMs. KCNQ1-deficient CMs also showed an irregular rhythm. Furthermore, KCNQ1-deficient and KCNQ1-mutant CMs showed different responses to different drug treatments, which reflected the differences in their pathogenic mechanisms. Conclusion We established a human CM model with KCNQ1 deficiency showing a prolonged QT interval and an irregular heart rhythm. Further, we used various drugs to treat KCNQ1-deficient and KCNQ1-mutant CMs, and the three models showed different responses to these drugs. These models can be used as important tools for studying the different pathogenic mechanisms of KCNQ1 mutation and the relationship between the genotype and phenotype of KCNQ1, thereby facilitating drug development.

This work presents highly responsive gate-controlled p-GaN/AlGaN/GaN ultraviolet photodetectors (UVPDs) on Si substrates with a high-transmittance ITO gate. The two-dimensional electron gas (2DEG) in the quantum well of the polarized AlGaN/GaN heterojunction was efficiently depleted by the p-GaN gate, leading to a high photo-to-dark current ratio (PDCR) of 3.2 × 105. The quantum wells of the p-GaN/AlGaN and AlGaN/GaN heterojunctions can trap the holes and electrons excited by the UV illumination, thus efficiently triggering a photovoltaic effect and photoconductive effect, separately. Furthermore, the prepared photodetectors allow flexible adjustment of the static bias point, making it adaptable to different environments. Compared to traditional thin-film semi-transparent Ni/Au gates, indium tin oxide (ITO) exhibits higher transmittance. Under 355 nm illumination, the photodetector exhibited a super-high responsivity exceeding 3.5 × 104 A/W, and it could even exceed 106 A/W under 300 nm illumination. The well-designed UVPD combines both the advantages of the high-transmittance ITO gate and the structure of the commercialized p-GaN/AlGaN/GaN high-electron-mobility transistors (HEMTs), which opens a new possibility of fabricating large-scale, low-cost, and high-performance UVPDs in the future.

Tropospheric ozone pollution poses a major environmental challenge in China. As its primary natural source, Stratosphere-to-Troposphere Transport (STT) has been recognized as a significant contributor to tropospheric ozone in western, northeastern, and eastern China. However, the extent of STT’s influence on southeastern China has been less studied due to data limitations. Using a recently available one-year dataset of ozonesonde observations from a regional background station, we find that STT contributes significantly to tropospheric and surface ozone elevation in southeastern China. Our results show that STT plays a more substantial role in shaping tropospheric ozone during spring than previously believed, accounting for over 30% of ozone concentrations above 4 km. Without the stratospheric contribution, the spring seasonal peak almost disappears. STT can also significantly influence ozone concentrations at the surface. For example, a distinct ozone profile was observed on 4 May 2022, with a notable increase in tropospheric ozone. This tropospheric ozone increase was caused by a STT event triggered by a robust horizontal trough and subsequent southward movement of subtropical jets in the upper troposphere. According to a stratospheric tracer derived from an atmospheric chemistry model, this STT event contributed to 25%–30% of the surface ozone increase. Overall, this study highlights the important role of STT in driving tropospheric ozone variations, even in regions with comparatively lower ozone levels in southeastern China.

Kidney disease (KD) is a life-threatening disease characterized by high morbidity and mortality in clinical settings, which can be caused by many reasons, and the incidence increases with age. However, supportive therapy and kidney transplantation still have limitations in alleviating KD progression. Recently, mesenchymal stem cells (MSCs) have shown great potential in repairing injury through their multidirectional differentiation and self-renewal ability. Of note, MSCs serve as a safe and effective therapeutic strategy for treating KD in preclinical and clinical trials. Functionally, MSCs ameliorate KD progression by regulating the immune response, renal tubular cell apoptosis, tubular epithelial–mesenchymal transition, oxidative stress, angiogenesis, and so on. In addition, MSCs exhibit remarkable efficacy in both acute kidney injury (AKI) and chronic kidney disease (CKD) through paracrine mechanisms. In this review, we outline the biological characteristics of MSCs, discuss the efficacy and mechanisms of MSCs-based therapy for KD, summarize the completed and ongoing clinical trials, as well as analyze limitations and new strategies, aiming to provide new ideas and approaches for the preclinical experiments and clinical trials of MSCs transplantation for KD.

Background Sarcomere gene mutation and myocardial fibrosis are both associated with poorer clinical outcomes in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the relationship between sarcomere gene mutation and myocardial fibrosis measured by both histopathology and cardiac magnetic resonance (CMR). Methods and Results Two hundred twenty‐seven patients with HCM who underwent surgical treatment, genetic testing, and CMR were enrolled. We retrospectively analyzed basic characteristics, sarcomere gene mutation, and myocardial fibrosis measured by CMR and histopathology. In our study, the mean age was 43 years, and 152 patients (67.0%) were men. A total of 107 patients (47.1%) carried a positive sarcomere gene mutation. The myocardial fibrosis ratio was significantly higher in the late gadolinium enhancement (LGE)+ group (LGE+ 14.3±7.5% versus LGE− 9.0±4.3%; P=0.001). Patients with HCM with SARC+ showed a high probability of fibrosis both in histopathology (myocardial fibrosis ratio 15.3±8.0% versus 12.4±6.5%; P=0.003) and CMR examination (LGE+ 98.1% versus 84.2%; P

Background: The pharmacological activity of dimethyl fumarate (DMF) in treating psoriasis and multiple sclerosis (MS) is not fully understood. DMF is hydrolysed to monomethyl fumarate (MMF) in vivo, which is believed to account for the therapeutic effects of DMF. However, previous studies have provided evidence that DMF also enters the circulation. Given that DMF is short-lived in the blood, whether DMF has a therapeutic impact is still unclear.Methods: Lipopolysaccharide (LPS)-mediated RAW264.7 cell activation was used as a model of inflammation to explore the anti-inflammatory effects of short-term DMF exposure in vitro. Whole blood LPS stimulation assay was applied to compare the anti-inflammatory effects of DMF and MMF in vivo. Griess assay was performed to examined nitrite release. The expression of pro-inflammatory cytokines and transcription factors were measured by quantitative PCR (qPCR), ELISA and Western blot. Depletion of intracellular glutathione (GSH) was evaluated by Ellman’s assay. Luciferase reporter assays were performed to evaluate DMF effects on Nrf2-ARE pathway activation, promoter activity of Nfkbiz and mRNA stability of Nfkbiz. Binding of STAT3 to the IκBζ promoter were examined using Chromatin immunoprecipitation (ChIP) assay.Results: Short-term exposure to DMF significantly inhibited the inflammatory response of RAW264.7 cells and suppressed LPS-induced IκBζ expression. Importantly, oral DMF but not oral MMF administration significantly inhibited IκBζ transcription in murine peripheral blood cells. We demonstrated that the expression of IκBζ is affected by the availability of intracellular GSH and regulated by the transcription factor Nrf2 and STAT3. DMF with strong electrophilicity can rapidly deplete intracellular GSH, activate the Nrf2-ARE pathway, and inhibit the binding of STAT3 to the IκBζ promoter, thereby suppressing IκBζ expression in macrophages.Conclusion: These results demonstrate the rapid anti-inflammatory effects of DMF in macrophages, providing evidence to support the direct anti-inflammatory activity of DMF.

BackgroundFood protein–induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy characterized by delayed, repetitive vomiting. FPIES is improving in recognition; however, there remains a lag in diagnosis. This study aimed to further explore this lag, as well as referral patterns and healthcare utilization, to help determine areas for earlier recognition.MethodsA retrospective chart review of pediatric FPIES patients at two hospital systems in New York was completed. Charts were reviewed for FPIES episodes and healthcare visits prior to diagnosis, and reason/source of referral to an allergist. A cohort of patients with IgE-mediated food allergy was reviewed for comparison of demographics and the time to the diagnosis.ResultsIn total, 110 patients with FPIES were identified. The median time to diagnosis was 3 months, vs. 2 months in IgE-mediated food allergy (p

Background The dietary agent sulforaphane (SFN) has been reported to reduce diabetes-induced renal fibrosis, as well as inhibit histone deacetylase (HDAC) activity. Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. The aim of this study was to investigate the epigenetic effect of SFN on BMP-7 expression in diabetes-induced renal fibrosis. Methods Streptozotocin (STZ)-induced diabetic mice and age-matched controls were subcutaneously injected with SFN or vehicle for 4 months to measure the in vivo effects of SFN on the kidneys. The human renal proximal tubular (HK11) cell line was used to mimic diabetic conditions in vitro. HK11 cells were transfected to over-express HDAC2 and treated with high glucose/palmitate (HG/Pal) to explore the epigenetic modulation of BMP-7 in SFN-mediated protection against HG/Pal-induced renal fibrosis. Results SFN significantly attenuated diabetes-induced renal fibrosis in vivo. Among all of the HDACs we detected, HDAC2 activity was markedly elevated in the STZ-induced diabetic kidneys and HG/Pal-treated HK11 cells. SFN inhibited the diabetes-induced increase in HDAC2 activity which was associated with histone acetylation and transcriptional activation of the BMP-7 promoter. HDAC2 over-expression reduced BMP-7 expression and abolished the SFN-mediated protection against HG/Pal-induced fibrosis in vitro. Conclusion Our study demonstrates that the HDAC inhibitor SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.

A common consequence of chronic renal disease is secondary hyperparathyroidism (SHPT) and is closely related to the mortality and morbidity of uremia patients. Secondary hyperparathyroidism (SHPT) is caused by excessive PTH production and release, as well as parathyroid enlargement. At present, the mechanism of cell proliferation in secondary hyperparathyroidism (SHPT) is not completely clear. Decreased expression of the vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), and 1,25(OH)2D3 insufficiency all lead to a decrease in cell proliferation suppression, and activation of multiple pathways is also involved in cell proliferation in renal hyperparathyroidism. The interaction between the parathormone (PTH) and parathyroid hyperplasia and 1,25(OH)2D3 has received considerable attention. 1,25(OH)2D3 is commonly applied in the therapy of renal hyperparathyroidism. It regulates the production of parathormone (PTH) and parathyroid cell proliferation through transcription and post-transcription mechanisms. This article reviews the role of 1,25(OH)2D3 in parathyroid cells in secondary hyperparathyroidism and its current understanding and potential molecular mechanism.

S100 calcium binding protein beta (S100B) is an S-100 low molecular weight binding protein that regulates intracellular processes. This protein is involved in myocardial contractility and calcium handling capacity. In this study, a human embryonic stem cell (hESC) line with homozygous S100B knockout (S100B-KO) was generated using the CRISPR/Cas9 editing system. This S100B-KO hESC line maintained normal cell morphology and karyotype, expressed pluripotency markers, and could differentiate into cells of all three germ layers.

Abstract Aims This study aims to demonstrate the characteristics of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance (CMR) imaging in patients with giant cell myocarditis (GCM). Methods and results Six patients histologically diagnosed with GCM were retrospectively recruited in this study. All of them underwent CMR during hospitalization. The distribution and extent of LGE were assessed on both ventricles, and the AHA‐17 segment model was used for left ventricular (LV) analysis. Nine case reports with CMR in GCM were reviewed and summarized to investigate the features of LGE further. LGE was detected on both ventricular walls in all subjects. For a detailed analysis of LGE in the LV, the extent ranged from 21.6% to 56%. Among 70 segments (68.6%) involved by LGE, the subendocardial LGE was the most common pattern (46/102, including 24 segments located in the right‐sided septum), followed by the subepicardial pattern (23/102). The right‐sided septum, the subepicardial anterior wall, and the subendocardial right ventricular (RV) wall were observed in all subjects. To summarize the results of the present study with these case reports, the three most common patterns of LGE are the right‐sided septum (73%), the subepicardial anterior wall (60%), and the subendocardial RV wall (53%). Conclusions Extensive LGE seems to be common in GCM, affecting both LV and RV walls. Apart from subepicardial LGE, subendocardial LGE, which was used to be implicated in ischaemic disease, was frequently presented in GCM. The right‐sided subendocardial septum, the subepicardial anterior wall, and the subendocardial RV wall might be the vulnerable areas of LGE in GCM.

Abstract Primary pulmonary artery sarcoma (PAS) is an extremely rare malignant disorder that presents like pulmonary thromboembolism (PE). Primary osteogenic sarcoma in the pulmonary artery (PA) is even rarer and can produce osteoid or cartilaginous matrix. Few studies have described the radiographic characteristics of osteosarcoma of the PA. We there report a case of a 78‐year‐old male patient with osteosarcoma in the PA where the patient went through surgical treatment after careful multimodalityimaging assessment. The patient was admitted to our hospital with the nonspecific symptom of heart failure. Multimodality imaging showed the primary lesion adhering to the arterial wall but without invading into surrounding tissues. PET/CT showed signs of hypometabolic activity within the lumen of the main PA. Cardiac MRI showed preserved left ventricular systolic function. CT showed distinctive features of PA osteosarcoma (a slightly hyperdense mass with calcification in pulmonary trunk).

Suppose we have a sample of subjects in two treatment groups. To study the difference of the treatment effects, we can analyse the data using all subjects (overall analysis). We may also divide the subjects into several subgroups based on some covariates of interest (eg, gender), and study the treatment effects within each subgroup. The results of these two analyses may be different or even in opposite directions. In this paper, we give a general sufficient condition of consistency between the overall and subgroup analyses.

Abstract In this work, a novel GaN MIS‐HEMT (metal‐insulator‐semiconductor high electron mobility transistors) featuring a floating clamp (FC) electrode is proposed for suppressing the short‐channel effect. By inserting the FC electrode near to the drain‐side gate edge, the transverse potential at the gate edge can be clamped to less than 2 V, thereby the short‐channel effect can be suppressed. Compared to the conventional short‐channel GaN MIS‐HEMT, the proposed device exhibits much decreased off‐state electron density at the drain voltage of 10 V, which leads to the off‐state leakage current decreasing from 10–1 to 10–7 A/mm, without an obvious sacrifice of the on‐state current. Meanwhile, the proposed GaN MIS‐HEMT also delivers a much lower reverse gate‐to‐drain capacitor. The excellent characteristics of the proposed GaN MIS‐HEMT show that the device is promising for the future power applications.

Abstract Background Isoflurane can lead to neuron damage to the developing brain, resulting in learning and memory disability. The aim of this study was to investigate the role of miR-142-5p on isoflurane-induced neurological impairment. Methods The Morris water maze (MWM) test was performed to evaluate spatial learning and memory of rats. The expression level of miR-142-5p was measured using qRT-PCR. MTT assay was used to calculate the viability of hippocampal neuronal cells. The cell apoptosis was analyzed using Flow cytometric assay. Results Isoflurane treatment led to the increase of neurological function score and escape latency, and the reduction of time spent in the original quadrant in rats. The expression level of miR-142-5p was increased significantly in isoflurane-treated rats. MiR-142-5p downregulation protected against isoflurane-induced neurological impairment, which was reflected by the decrease of neurological function score and escape latency, and the increase of time spent in the original quadrant. In vitro, downregulation of miR-142-5p alleviated isoflurane-induced neuron cell viability inhibition, and relieved isoflurane-induced cell apoptosis. Conclusions MiR-142-5p downregulation plays a neuroprotective role in protecting against isoflurane-induced neurological impairment through regulating neuron cell viability and apoptosis. It provides a theoretical basis for the investigation of the mechanism underlying the effect on isoflurane-induced neurological impairment.

Abstract Background The aim of this study was to gain further investigation of non-small cell lung cancer (NSCLC) tumorigenesis and identify biomarkers for clinical management of patients through comprehensive bioinformatics analysis. Methods miRNA and mRNA microarray datasets were downloaded from GEO (Gene Expression Omnibus) database under the accession number GSE102286 and GSE101929, respectively. Genes and miRNAs with differential expression were identified in NSCLC samples compared with controls, respectively. The interaction between differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) was predicted, followed by functional enrichment analysis, and construction of miRNA-gene regulatory network, protein-protein interaction (PPI) network, and competing endogenous RNA (ceRNA) network. Through comprehensive bioinformatics analysis, we anticipate to find novel therapeutic targets and biomarkers for NSCLC. Results A total of 123 DEmiRs (5 up- and 118 down-regulated miRNAs) and 924 DEGs (309 up- and 615 down-regulated genes) were identified. These genes and miRNAs were significantly involved in different pathways including adherens junction, relaxin signaling pathway, and axon guidance. Furthermore, hsa-miR-9-5p, has-miR-196a-5p and hsa-miR-31-5p, as well as hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p were shown to have higher degree in the miRNA-gene regulatory network and ceRNA network, respectively. Furthermore, BIRC5 and FGF2, as well as RTKN2 and SLIT3 were hubs in the PPI network and ceRNA network, respectively. Conclusion Several pathways (adherens junction, relaxin signaling pathway, and axon guidance) miRNAs (hsa-miR-9-5p, has-miR-196a-5p, hsa-miR-31-5p, hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p) and genes (BIRC5, FGF2, RTKN2 and SLIT3) may play important roles in the pathogenesis of NSCLC.

The East China Sea (ECS) is featured by the broad continental shelf, huge terrigenous sediment input and striking river-sea interaction during the Quaternary. Despite the numerous studies, mostly on the delta, coastal and inner shelf areas, the late Quaternary stratigraphy and sedimentary environment on the mid-outer ECS shelf were poorly documented. In particular, it is still controversial in issues such as the recognition of marine transgression deposits in the interglacial period and the occurrence and ages of deposits in the glacial period. This study presents new data of high-resolution seismic reflection profiles and collective evidences from lithology, microfossil assemblages and geochronology of borehole SFK-1 on the ECS outer shelf, aiming to revisit the sedimentary stratigraphic evolution and environmental changes since the Marine Isotopic Stage 5 (MIS 5). Sixty-one ages were obtained by radiocarbon and Optical Stimulation Luminescence (OSL), providing robust constraints on the chronostratigraphy. Three marine regression/transgression cycles were identified, which primarily constrained the sedimentary environmental evolution over the past 100 kyrs. Although the strong river-sea interaction accompanied with sea level fluctuations characterized the late Quaternary depositional environment on the shelf, this study clearly identified the stratigraphic boundaries between MIS 1 and MIS 5, and confirmed the tide-influenced fluvial deposition formed during the Last Glacial Maximum on the outer shelf. We infer that tidal forcing significantly superimposed its influence on sea level change and thus formed the most striking feature on the late Quaternary stratigraphy of the open ECS shelf. With the combination of a large number of absolute depositional ages with high-resolution core records, the major findings of this study may allow better understanding of the Quaternary sedimentary evolution and river-sea interaction on open shelves dominated by siliciclastic sedimentation.

The bias temperature instability (BTI) effect of p-GaN gate high-electron-mobility transistors (HEMTs) is a serious problem for reliability. To uncover the essential cause of this effect, in this paper, we precisely monitored the shifting process of the threshold voltage (VTH) of HEMTs under BTI stress by fast sweeping characterizations. The HEMTs without time-dependent gate breakdown (TDGB) stress featured a high VTH shift of 0.62 V. In contrast, the HEMT that underwent 424 s of TDGB stress clearly saw a limited VTH shift of 0.16 V. The mechanism is that the TDGB stress can induce a Schottky barrier lowering effect on the metal/p-GaN junction, thus boosting the hole injection from the gate metal to the p-GaN layer. This hole injection eventually improves the VTH stability by replenishing the holes lost under BTI stress. It is the first time that we experimentally proved that the BTI effect of p-GaN gate HEMTs was directly dominated by the gate Schottky barrier that impeded the hole supply to the p-GaN layer.

In summertime, eastern China experiences severe ozone pollution. Stratosphere-to-troposphere transport (STT), as the primary natural source of tropospheric ozone, may have a non-negligible contribution to ground-level ozone. Rossby wave breaking (RWB) is a leading mechanism that triggers STT, which can be categorized as anticyclonic wave breakings (AWBs) and cyclonic wave breakings (CWBs). This study uses an objective method to diagnose AWBs and CWBs and to investigate their influence on the surface ozone in eastern China using ground-based ozone observations, satellite ozone data from AIRS, a stratospheric ozone tracer simulated by CAM-chem, and meteorological fields from MERRA-2. The results indicate that AWBs occur mainly and frequently over northeast China, while CWBs occur mostly over the northern Sea of Japan. STTs triggered by AWBs mainly have sinking areas over the North China Plain, increasing the ground-level ozone concentrations by 5–10 ppbv in eastern China. The downwelling zones in the CWBs extend from Mongolia to the East China Sea, potentially causing an elevation of 5–10 ppbv of ozone in both central and eastern China. This study gives an overview of the impacts of AWBs and CWBs on surface ozone in eastern China and helps to improve our understanding of summertime ozone pollution in eastern China.

The channel temperature distribution and breakdown points are difficult to monitor for the traditional p-GaN gate HEMTs under high power stress, because the metal gate blocks the light. To solve this problem, we processed p-GaN gate HEMTs with transparent indium tin oxide (ITO) as the gate terminal and successfully captured the information mentioned above, utilizing ultraviolet reflectivity thermal imaging equipment. The fabricated ITO-gated HEMTs exhibited a saturation drain current of 276 mA/mm and an on-resistance of 16.6 Ω·mm. During the test, the heat was found to concentrate in the vicinity of the gate field in the access area, under the stress of VGS = 6 V and VDS = 10/20/30 V. After 691 s high power stress, the device failed, and a hot spot appeared on the p-GaN. After failure, luminescence was observed on the sidewall of the p-GaN while positively biasing the gate, revealing the side wall is the weakest spot under high power stress. The findings of this study provide a powerful tool for reliability analysis and also point to a way for improving the reliability of the p-GaN gate HEMTs in the future.

Chiral amino alcohols are prevalent synthons in pharmaceuticals and synthetic bioactive compounds. The efficient synthesis of chiral amino alcohols using ammonia as the sole amino donor under mild conditions is highly desired and challenging in organic chemistry and biotechnology. Our previous work explored a panel of engineered amine dehydrogenases (AmDHs) derived from amino acid dehydrogenase (AADH), enabling the one-step synthesis of chiral amino alcohols via the asymmetric reductive amination of α-hydroxy ketones. Although the AmDH-directed asymmetric reduction is in a high stereoselective manner, the activity is yet fully excavated. Herein, an engineered AmDH derived from a leucine dehydrogenase from Sporosarcina psychrophila (SpAmDH) was recruited as the starting enzyme, and the combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was applied to improve the activity. After three rounds of mutagenesis in an iterative fashion, the best variant wh84 was obtained and proved to be effective in the asymmetric reductive amination of 1-hydroxy-2-butanone with 4-fold improvements in kcat/Km and total turnover number (TTN) values compared to those of the starting enzyme, while maintaining high enantioselectivity (ee >99%) and thermostability (T5015 >53°C). In preparative-scale reaction, the conversion of 100 and 200 mM 1-hydroxy-2-butanone catalyzed by wh84 was up to 91–99%. Insights into the source of an enhanced activity were gained by the computational analysis. Our work expands the catalytic repertoire and toolbox of AmDHs.

BackgroundCatheter ablation target at the site with large His activation in the left ventricle poses a high risk of atrioventricular (AV) block. We aimed to identify far-field (FF) and near-field (NF) His activation at left upper septum (LUS).MethodsThree-D mapping of the aortic root and left ventricle was performed in 12 dogs. Two sites located at either the base or apex of the triangle interposed between the hinges of the the noncornary coronary cusp (NCC) - right coronary cusp (RCC) were chosen for a single radiofrequency (RF) application. Bipolar and unipolar pacing with different outputs at both sites was attempted to discern NF and FF His activation.ResultsThe sites chosen for NF and FF ablation were located at the base and apex of the triangle, which were 8.03 ± 1.18 mm (group 1) and 3.42 ± 0.61 mm (group 2) away from the RCC-NCC junction. Lower A/V ratios were found in group 1. Pacing could not differentiate NF from FF His activation. In group 1, ablation resulted in III degree AV block in all 6 dogs, whereas neither PR prolongation nor AV block occurred in group 2. Pathologic examination of group 1 showed complete/partial necrosis of the His bundle (HB) and left bundle branch in all 6 dogs. In group 2, no necrosis of the HB was seen in the 6/6 dogs.ConclusionAnatomical localization in the triangle of RCC-NCC junction can help differentiate NF from FF His activation.

Myosin heavy chain 7 (MYH7) encodes the human heart myosin heavy chain subunit, which plays an important role in myocardial contraction. MYH7 is the main pathogenic gene that causes Hypertrophic cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM). In this experiment, a MYH7 homozygous knockout human embryonic stem cell (hESC) line, WAe009-A-69, was generated using an episomal vector-based CRISPR/Cas9 system. It can be an ideal tool to further study the function of MYH7. The cell line was confirmed with pluripotency, normal karyotype and trilineage differentiation potential.

Background: Cardiac magnetic resonance (CMR) has been shown to improve the diagnosis of myocarditis, but no systematic comparison of this technique is currently available. The purpose of this study was to compare the 2009 and 2018 Lake Louise Criteria (LLC) for the diagnosis of acute myocarditis using 3.0 T MRI with endomyocardial biopsy (EMB) as a reference and to provide the cutoff values for multiparametric CMR techniques.Methods: A total of 73 patients (32 ± 14 years, 71.2% men) with clinically suspected myocarditis undergoing EMB and CMR with 3.0 T were enrolled in the study. Patients were divided into two groups according to EMB results (EMB-positive and -negative groups). The CMR protocol consisted of cine-SSFP, T2 STIR, T2 mapping, early and late gadolinium enhancement (EGE, LGE), and pre- and post-contrast T1 mapping. Their potential diagnostic ability was assessed with receiver operating characteristic curves.Results: The myocardial T1 and T2 relaxation times were significantly higher in the EMB-positive group than in the EMB-negative group. Optimal cutoff values were 1,228 ms for T1 relaxation times and 58.5 ms for T2 relaxation times with sensitivities of 86.0 and 83.7% and specificities of 93.3 and 93.3%, respectively. The 2018 LLC had a better diagnostic performance than the 2009 LLC in terms of sensitivity, specificity, positive predictive value, and negative predictive value. T1 mapping + T2 mapping had the largest area under the curve (0.95) compared to other single or combined parameters (2018 LLC: 0.91; 2009 LLC: 0.76; T2 ratio: 0.71; EGEr: 0.67; LGE: 0.73; ). The diagnostic accuracy for the 2018 LLC was the highest (91.8%), followed by T1 mapping (89.0%) and T2 mapping (87.7%).Conclusion: Emerging technologies such as T1/ T2 mapping have significantly improved the diagnostic performance of CMR for the diagnosis of acute myocarditis. The 2018 LLC provided the overall best diagnostic performance in acute myocarditis compared to other single standard CMR parameters or combined parameters. There was no significant gain when 2018LLC is combined with the EGE sequence.

Background The interaction of long non-coding RNAs (lncRNAs)-microRNAs (miRs) exerts crucial functions in mediating inflammatory reaction. It is still unclear whether myocardial infarction associated transcript 2 (Mirt2)-miR-377 mediates the inflammatory pathogenesis in Sjögren's syndrome (SS).Methods The inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) by interferon gamma (IFN-γ). Mirt2- and/or miR-377-transfected SGECs, as well as their negative controls, were applied to investigate the biological functions in inflammation. Cell viability and apoptosis were examined using commercial kits. Western blot was applied to quantify protein level, and enzyme-linked immuno sorbent assay (ELISA) was used to value the secretion of cytokines.Results The up-regulation of Mirt2 was observed in IFN-γ-treated SGECs. Mirt2 overexpression restored the expression of miR-377 which was repressed by IFN-γ. However, miR-377 silence abolished the protective effect on cell viability, inhibitory effect on apoptosis and prohibitive role in pro-inflammatory factors. Mirt2 diminished the phosphorylated expression of crucial regulators while miR-377 silence restored the phosphorylation in IFN-γ-treated SGECs.Conclusion Mirt2 was elevated in IFN-γ-treated SGECs and then up-regulated miR-377 in response to inflammatory lesions. Mechanically, in synergy with miR-377 Mirt2 blocked IFN-γ-evoked activation of NF-κB and JAK/STAT signalling pathway.

Tropospheric ozone is an important atmospheric pollutant as well as an efficient greenhouse gas. Beijing is one of the cities with the most serious ozone pollution. However, long-term date of observed ozone in Beijing are limited. In this paper, we combine the measurements of the In-service Aircraft for a Global Observing System (IAGOS), ozonesonde observations as well as the recently available ozone monitoring network observations to produce a unique data record of surface ozone (at 14:00 Beijing time) in Beijing from 1995 to 2020. Using this merged dataset, we investigate the variability in surface ozone in Beijing on multiple timescales. The long-term change is primarily characterized by a sudden drop in 2011–2012 with an insignificant linear trend during the full period. Based on CAM-chem model simulations, meteorological factors played important roles in the 2011–2012 ozone drop. Before and after this sudden drop, ozone levels in Beijing increased significantly by 0.42 ± 0.27 ppbv year−1 before 2011 and 0.43 ± 0.41 ppbv year−1 after 2013. We also found a substantial increase in the amplitude of the ozone annual cycle in Beijing, which has not been documented in previous studies. This is consistent with ozone increases in summer and ozone decreases in winter. In addition, the results by the Ensemble Empirical Mode Decomposition (EEMD) analysis indicate significant interannual variations in ozone levels in Beijing with different time oscillation periods, which may be associated with natural variabilities and subsequent changes in meteorological conditions.

To study the working performance of 3D stacked chips, a double-layer stacked GaN MISHEMTs structure was designed to study the electro-thermal characteristics and heat transfer process of stacked chips. Firstly, the electrical characteristics of double-layer and single-layer GaN MISHEMTs are compared at room temperature. Under the same conditions, the output current of double-layer GaN MISHEMTs is twice that of single-layer GaN MISHEMTs, but its off-state current is much higher than that of a single-layer device. Meanwhile, there is no significant difference between the threshold voltages of the double-layer and single-layer GaN MISHEMTs. Then, the effect of temperature on the electrical characteristics of double-layer GaN MISHEMTs is also investigated. When the temperature increased from room temperature to 150 °C, the device’s threshold voltage gradually shifted negatively, the output current of the device decreased, and the off-state current of the device increased. Furthermore, a thermal resistance network model has been established to analyze the thermal characteristics of the stacked GaN MISHEMTs. The relative error between the results calculated according to the model and the experimental results does not exceed 4.26%, which verified the correctness and accuracy of the presented model to predict the temperature distribution of the stacked GaN MISHEMTs.

Abstract Oxygen evolution reaction (OER) occurring on photoanode is considered as the key step for photo‐electronchemical (PEC) water splitting. Among many potential photoanode materials, hematite (α‐Fe2O3) shows high promise considering its ideal band position, long‐term chemical stability, and earth abundance. Unfortunately, its sluggish oxygen evolution kinetics at photoanode/electrolyte interfaces and poor bulk charge transport limit the PEC performance. Herein, the most recent developments on interfacial engineering of hematite photoanode are summarized. We first describe the optical and electronic properties of the α‐Fe2O3 that are related to the PEC performance. Subsequently, we introduce the recent endeavors on the morphological engineering of the hematite photoanode. Then, the effective strategies of interfacial engineering are highlighted to address the limitations of α‐Fe2O3 photoanode at the surfaces and/or interfaces, as well as at the grain boundaries within the film. And the most recent progress of α‐Fe2O3 photoanode‐based tandem cells for self‐assisted overall water splitting is also discussed. Finally, an outlook is presented for future efforts on promoting the interfacial charge transport for boosted PEC performance of hematite‐based photo‐electrodes.