Search

Abstract Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness. Graphical Abstract

Abstract Hepatocellular Carcinoma (HCC) remains a leading cause of cancer deaths. Despite the rise of immunotherapies, many HCC patients don't benefit. There's a clear need for biomarkers to guide treatment decisions. This research aims to identify such biomarkers by combining radiological data and machine learning. We analyzed clinical and CT imaging data of 54 HCC patients undergoing immunotherapy. Radiologic features were examined to develop a model predicting short-term immunotherapy effects. We utilized 9 machine learning and 2 ensemble learning techniques using RapidMiner for model construction. We conducted the validation of the above feature combination using 29 HCC patients who received immunotherapy from another hospital, and tested and validated it using XGBoost combined with a genetic algorithm. In 54 HCC patients, radiomics features varied significantly between those with partial response (PR) and stable disease (SD). Key features in Gray Level Run Length Matrix (GLRLM) and in adjacent tissues' Intensity Direct, Neighborhood Gray Tone Difference Matrix (NGTDM), and Shape correlated with short-term immunotherapy efficacy. Selected feature combinations of 15, 19, and 8/15 features yielded better outcomes. Deep learning, random forest, and naive bayes outperformed other methods, with Bagging being more reliable than Adaboost. In the validation set of 29 HCC patients, the mentioned feature combination also demonstrated favorable performance. Furthermore, we achieved improved results when employing XGBoost in conjunction with a genetic algorithm for testing and validation. The machine learning model built with CT image features derived from GLCM, GLRLM, IntensityDirect, NGTDM, and Shape can accurately forecast the short-term efficacy of immunotherapy for HCC.

Abstract Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin β2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.

Abstract Pinellia ternata (Thunb.) Breit is a traditional Chinese medicine with important pharmacological effects. However, its cultivation is challenged by soil degradation following excessive use of chemical fertilizer. We conducted an experiment exploring the effects of replacing chemical fertilizers with organic fertilizers (OF) on the growth and yield of P. ternata, as well as on the soil physicochemical properties and microbial community composition using containerized plants. Six fertilization treatments were evaluated, including control (CK), chemical fertilizer (CF), different proportions of replacing chemical fertilizer with organic fertilizer (OM1−4). Containerized P. ternata plants in each OF treatment had greater growth and yield than the CK and CF treatments while maintaining alkaloid content. The OM3 treatment had the greatest yield among all treatments, with an increase of 42.35% and 44.93% compared to the CK and CF treatments, respectively. OF treatments improved soil quality and fertility by enhancing the activities of soil urease (S-UE) and sucrase (S-SC) enzymes while increasing soil organic matter and trace mineral elements. OF treatments increased bacterial abundance and changed soil community structure. In comparison to the CK microbial groups enriched in OM3 were OLB13, Vicinamibacteraceae, and Blrii41. There were also changes in the abundance of gene transcripts among treatments. The abundance of genes involved in the nitrogen cycle in the OM3 has increased, specifically promoting the transformation of N-NO3 − into N-NH4 +, a type of nitrogen more easily absorbed by P. ternata. Also, genes involved in "starch and sucrose metabolism" and "plant hormone signal transduction" pathways were positively correlated to P. ternata yield and were upregulated in the OM3 treatment. Overall, OF in P. ternata cultivation is a feasible practice in advancing sustainable agriculture and is potentially profitable in commercial production.

IntroductionObservational studies have discovered a contradictory phenomenon between Helicobacter pylori (H. pylori) infection and inflammatory bowel disease (IBD). The study aimed to confirm the causal association between H. pylori and IBD, including ulcerative colitis (UC) and Crohn's disease (CD).MethodsWe conducted a Mendelian randomization (MR) study with two sample Genome-Wide Association Studies (GWAS) to determine whether there is a causal relationship between H. pylori infection and IBD, as well as the possible pathogenic factors that may be involved. The reliability of the main MR assumptions was examined through a series of sensitivity analyses.ResultsTwo genetic variants (SNPs) previously identified were employed as instrumental variables (IVs) for H. pylori infection. GWAS data for IBD, UC, and CD were obtained from the recent DF10 release10 of the FinnGen study. Our findings indicated a significant association between H. pylori seropositivity and an increased risk of IBD and UC (IBD: OR: 1.16, 95% CI, 1.03–1.31, P < 0.05; UC: OR: 1.22, 95% CI, 1.08–1.37, P < 0.001) while no causal relationship with CD (P > 0.05). Analysis of the main virulence pathogenic factors revealed a causal relationship between cytotoxin-associated protein A (CagA) and IBD and UC (IBD: OR: 1. 06, 95% CI, 1.001–1.11, P < 0.05; UC: OR: 1.07, 95% CI, 1.004–1.14, P < 0.05), while no correlation was found for vacuolar cytotoxin A (VacA) (P > 0.05). After applying the False Discovery Rate (FDR) correction, the causal relationship between CagA and the risk of IBD or UC was no longer statistically significant.ConclusionThis study suggests a potential causal relationship between H. pylori infection and IBD, particularly UC. The effect may be more pronounced in individuals with previous H. pylori infections.

Abstract Microplastics (MPs) are contaminants ubiquitously found in the global biosphere that enter the body through inhalation or ingestion, posing significant risks to human health. Recent studies emerge that MPs are present in the bone marrow and damage the hematopoietic system. However, it remains largely elusive about the specific mechanisms by which MPs affect hematopoietic stem cells (HSCs) and their clinical relevance in HSC transplantation (HSCT). Here, we established a long-term MPs intake mouse model and found that MPs caused severe damage to the hematopoietic system. Oral gavage administration of MPs or fecal transplantation of microbiota from MPs-treated mice markedly undermined the self-renewal and reconstitution capacities of HSCs. Mechanistically, MPs did not directly kill HSCs but disrupted gut structure and permeability, which eventually ameliorated the abundance of Rikenellaceae and hypoxanthine in the intestine and inactivated the HPRT-Wnt signaling in bone marrow HSCs. Furthermore, administration of Rikenellaceae or hypoxanthine in mice as well as treatment of WNT10A in the culture system substantially rescued the MPs-induced HSC defects. Finally, we validated in a cohort of human patients receiving allogenic HSCT from healthy donors, and revealed that the survival time of patients was negatively correlated with levels of MPs, while positively with the abundance of Rikenellaceae, and hypoxanthine in the HSC donors’ feces and blood. Overall, our study unleashes the detrimental roles and mechanisms of MPs in HSCs, which provides potential strategies to prevent hematopoietic damage from MPs and serves as a fundamental critique for selecting suitable donors for HSCT in clinical practice.

Abstract Renal cancer is a highlyheterogeneous malignancy characterized by rising global incidence and mortalityrates. The complex interplay and dysregulation of multiple signaling pathways,including von Hippel–Lindau (VHL)/hypoxia‐inducible factor (HIF), phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Hippo–yes‐associated protein (YAP), Wnt/ß‐catenin, cyclic adenosine monophosphate (cAMP), and hepatocyte growth factor (HGF)/c‐Met, contribute to theinitiation and progression of renal cancer. Although surgical resection is thestandard treatment for localized renal cancer, recurrence and metastasiscontinue to pose significant challenges. Advanced renal cancer is associatedwith a poor prognosis, and current therapies, such as targeted agents andimmunotherapies, have limitations. This review presents a comprehensiveoverview of the molecular mechanisms underlying aberrant signaling pathways inrenal cancer, emphasizing their intricate crosstalk and synergisticinteractions. We discuss recent advancements in targeted therapies, includingtyrosine kinase inhibitors, and immunotherapies, such as checkpoint inhibitors.Moreover, we underscore the importance of multiomics approaches and networkanalysis in elucidating the complex regulatory networks governing renal cancerpathogenesis. By integrating cutting‐edge research and clinical insights, this review contributesto the development of innovative diagnostic and therapeutic strategies, whichhave the potential to improve risk stratification, precision medicine, andultimately, patient outcomes in renal cancer.

Renal cell carcinoma (RCC) is recognized as one of the three primary malignant tumors affecting the urinary system, posing a significant risk to human health and life. Despite advancements in understanding RCC, challenges persist in its diagnosis and treatment, particularly in early detection and diagnosis due to issues of low specificity and sensitivity. Consequently, there is an urgent need for the development of effective strategies to enhance diagnostic accuracy and treatment outcomes for RCC. In recent years, with the extensive research on materials for applications in the biomedical field, some materials have been identified as promising for clinical applications, e.g., in the diagnosis and treatment of many tumors, including RCC. Herein, we summarize the latest materials that are being studied and have been applied in the early diagnosis and treatment of RCC. While focusing on their adjuvant effects, we also discuss their technical principles and safety, thus highlighting the value and potential of their application. In addition, we also discuss the limitations of the application of these materials and possible future directions, providing new insights for improving RCC diagnosis and treatment.

Artemisia argyi Lévl. et Vant. is a traditional Chinese medicinal plant that is widely distributed across Asia, Europe, and the Americas, especially in East Asian countries such as China, Japan, South Korea, and Mongolia. The widespread application of A. argyi in medicine, foods, and folk customs gives it great economic value and strong cultural relevance in China. It has been used in treating diseases for over 2000 years, with modern pharmacological research validating diverse functions (including anti-inflammatory, anti-tumor, antioxidant, and analgesic activities) of metabolites produced by A. argyi. Surges in clinical demand have led to the formation of a domesticated A. argyi industry, which has produced a relatively mature artificial planting technology system and comprehensive quality evaluation standards in China. In recent years, the assembly and release of A. argyi chloroplast and chromosome-scale nuclear genomes have enabled identification of key genes in the biosynthetic pathways of various important active compounds. In addition, non-medicinal applications of A. argyi have received widespread attention due to the plant's promising herbicidal, antibacterial, and preservative effects, which could allow its use in place of chemical products. We here review recent progress in A. argyi research with a focus on botanical characteristics, artificial cultivation methods, quality evaluation, genomic and molecular research, pharmacological effects, and non-medicinal value development. This review lays a strong foundation for future research to develop and increase the value of A. argyi and other traditionally medicinal plants.

IntroductionChrysanthemum morifolium Ramat. is a perennial herb in the Compositae family, often employed in traditional Chinese medicine due to its medicinal value. The planting of C. morifolium faces the challenges of continuous cropping, and intercropping is able to somewhat overcome the obstacles of continuous cropping.MethodsIn our study, we designed two different C. morifolium-maize intercropping patterns, including C. morifolium-maize narrow-wide row planting (IS) and C. morifolium-maize middle row planting (IM). Compared with monoculture, the agronomic traits, yield, active ingredients, soil physicochemical properties, soil enzyme activities, and rhizosphere soil microbial communities of C. morifolium and maize were measured under the two C. morifolium-maize intercropping patterns.ResultsThe findings indicated that (1) Intercropping elevated the agronomic traits, yield, and active ingredients of C. morifolium, especially in C. morifolium-maize narrow-wide row planting pattern, which indicating that interspecific distance played an important role in intercropping system; (2) Intercropping enhanced soil physicochemical properties and enzyme activities of C. morifolium and maize; (3) Intercropping altered rhizosphere soil microbial communities of C. morifolium and maize, making microbial interrelationships more complex. (4) Intercropping could recruit a large number of beneficial microorganisms enrich in the soil, including Bacillus, Sphingomonas, Burkholderia-Caballeronia-Paraburkholderia, Chaetomium, and Ceratorhiza, which may increase the content of AN, NN, AvK, ExCa, AvCu, AvZn and other nutrients in soil and promoted the growth and quality of C. morifolium.DiscussionIn summary, intercropping with maize could promote the accumulation of beneficial microorganisms in the soil, thus improving the overall growing environment, and finally realizing the growth and improvement of C. morifolium.

Summary: Epigenetic modification shapes differentiation trajectory and regulates the exhaustion state of chimeric antigen receptor T (CAR-T) cells. Limited efficacy induced by terminal exhaustion closely ties with intrinsic transcriptional regulation. However, the comprehensive regulatory mechanisms remain largely elusive. Here, we identify class I histone deacetylase inhibitors (HDACi) as boosters of CAR-T cell function by high-throughput screening of chromatin-modifying drugs, in which M344 and chidamide enhance memory maintenance and resistance to exhaustion of CAR-T cells that induce sustained antitumor efficacy both in vitro and in vivo. Mechanistically, HDACi decrease HDAC1 expression and enhance H3K27ac activity. Multi-omics analyses from RNA-seq, ATAC-seq, and H3K27ac CUT&Tag-seq show that HDACi upregulate expression of TCF4, LEF1, and CTNNB1, which subsequently activate the canonical Wnt/β-catenin pathway. Collectively, our findings elucidate the functional roles of class I HDACi in enhancing CAR-T cell function, which provides the basis and therapeutic targets for synergic combination of CAR-T cell therapy and HDACi treatment.

The accuracy of the cutting simulation model greatly depends on the constitutive models, thermophysical models, and friction models. However, accurate modeling of physical and mechanical relationships is not enough. The physical and mechanical behavior of the machined surface from the last cut should be modelled in the FE model. In this study, the cutting simulation model of S316L stainless steel was established. The above model consists of two subsequent simulated cuts. The first simulated cut was used to obtain the machined surface with the residual stress, and the second simulated cut was subsequent with the first cut to obtain the actual simulated results. The constitutive model was obtained by the split Hopkinson pressure bar (SHPB) and high-temperature hardness experiments. The specific heat capacity and thermal conductivity models were developed by laser thermal conductivity experiments with various temperatures. The friction model between the workpiece and the tool was established by orthogonal cutting experiments. The simulated cutting forces of the first and second cut were extracted and compared with the experimental results to verify the accuracy of the simulation models. The results showed that the average error of cutting forces for the first cut is 28.33 %, but that for the second cut is 8.02 %, which verifies the accuracy of the two-subsequent cutting simulation model. Additionally, the significant differences in the simulated cutting forces between the first and second cutting depict that the residual stress cannot be ignored for the accuracy verification of cutting simulation models.

Abstract Breast cancer is the most common malignant cancer in women worldwide. Cancer metastasis is the major cause of cancer-related deaths. BCKDK is associated with various diseases, including proliferation, migration, and invasion in multiple types of human cancers. However, the relevance of BCKDK to the development and progression of breast cancers and its function is unclear. This study found that BCKDK was overexpressed in breast cancer, associated with poor prognosis, and implicated in tumor metastasis. The downregulation of BCKDK expression inhibited the migration of human breast cancer cells in vitro and diminished lung metastasis in vivo. BCKDK perturbed the cadherin-catenin complex at the adherens junctions (AJs) and assembled focal adhesions (FAs) onto the extracellular matrix, thereby promoting the directed migration of breast cancer cells. We observed that BCKDK acted as a conserved regulator of the ubiquitination of cytoskeletal protein talin1 and the activation of the FAK/MAPK pathway. Further studies revealed that BCKDK inhibited the binding of talin1 to E3 ubiquitin ligase-TRIM21, leading to the decreased ubiquitination/degradation of talin1. In conclusion, identifying BCKDK as a biomarker for breast cancer metastasis facilitated further research on diagnostic biomarkers. Elucidating the mechanism by which BCKDK exerted its biological effect could provide a new theoretical basis for developing new markers for breast cancer metastasis and contribute to developing new therapies for the clinical treatment of breast cancer patients.

Abstract Hematologic malignancies (HMs) pose a serious threat to patients’ health and life, and the five-year overall survival of HMs remains low. The lack of understanding of the pathogenesis and the complex clinical symptoms brings immense challenges to the diagnosis and treatment of HMs. Traditional therapeutic strategies for HMs include radiotherapy, chemotherapy, targeted therapy and hematopoietic stem cell transplantation. Although immunotherapy and cell therapy have made considerable progress in the last decade, nearly half of patients still relapse or suffer from drug resistance. Recently, studies have emerged that nanomaterials, nanotechnology and nanomedicine show great promise in cancer therapy by enhancing drug targeting, reducing toxicity and side effects and boosting the immune response to promote durable immunological memory. In this review, we summarized the strategies of recently developed nanomaterials, nanotechnology and nanomedicines against HMs and then proposed emerging strategies for the future designment of nanomedicines to treat HMs based on urgent clinical needs and technological progress.

Organic acids are a key active component of Pinellia ternata (Thunb.) Breit, and their concentration is closely associated with the quality of P. ternata. Developing an efficient and rapid method for detecting organic acids can offer a valuable technology for real-time assessment of P. ternata quality. In this work, a high-performance liquid chromatography coupled to triple quadrupole mass spectrometry (HPLC-QqQ-MS/MS) approach, combining the optimization of extraction conditions using response surface methodology (RSM), was developed for the simultaneous quantitative analysis of six organic acids in P. ternata. The optimal extraction conditions for organic acids in P. ternata were ultrasonic extraction with a solid–liquid ratio of 1:50, ultrasonic time of 60 min, and extraction temperature of 55 °C. Multiple-reaction monitoring (MRM) scanning was employed for quantification using HPLC-QqQ-MS/MS in negative ionization mode through a single run of 10 min, and the limit of detection (LLOD) and limit of quantification (LLOQ) for organic acids were as low as 0.138 ng/mL and 0.614 ng/mL, respectively. The relative standard deviations (RSDs) of reproducibility, precision, and stability were all lower than 5.0%, and recovery rates were 97.75–107.14%, with RSDs < 5.0%. Finally, this method was successfully applied to determine the investigated organic acids in 12 production regions of P. ternata, revealing significant differences between different production areas. This indicates that the optimized method is suitable for further accurate investigations of organic acids of P. ternata.

Abstract To adapt to the complex and changeable electromagnetic environment of radar detection, improve the jamming effect on frequency‐agile radar and low probability of intercept radar, and solve the problem of poor jamming effect caused by intra‐pulse jamming lagging behind target radar signal, a Convolutional Neural Network—Deep Neural Network jamming waveform generation method, based on prior global information of radar signal, is presented in this study. This proposed method uses two networks to generate the overall interference waveforms. One Convolutional Neural Network—Deep Neural Network derives prior global radar information from local prior radar information, which is used by the other Convolutional Neural Network—Deep Neural Network to generate interference. In the whole scheme, an algorithm to design the intra‐pulse interference waveform based on the prior global information of the radar signal is proposed. The algorithm can generate the interference waveform samples from the number and area of multiple false targets and the relative peak between multiple false targets and the real target area by the relevant parameters. Then, an evaluation system (Matched filter, Constant False Alarm Rate Detector, and Distance resolution etc.) is established to evaluate the global effect of the designed interference waveforms. Finally, the time‐domain Root Mean Squared Errors is used as the loss function to optimise the training of the network and ultimately achieve the requirement of generating intra‐pulse adaptive interference waveforms based on radar signal fragments. The principle of generating interference waveforms is based on various aspects of the evaluation of the interference effect, which enhances the time domain correlation between multiple false target areas, thereby boosting the interference effect on the radar. The experimental results show that the proposed method based on the Convolutional Neural Network—Deep Neural Network can effectively solve the problem of intra‐pulse interference lag and small effective interference area after the pulse pressure of the interference waveform matching filter. This study offers certain reference significance for the adaptive interference waveform design based on radar prior global information.

In order to improve the thermal stability of PCD during practical application, the mixed solution of sulfuric acid and hydrogen peroxide was selected to remove cobalt from PCD. The effect of decobaltization on microstructure and mechanical property of PCD as well as its mechanism were studied. According to the SEM results, several deep corrosion pits were observed on the surface of PCD after the 48 h decobaltization process under room temperature, indicating that the cobalt phase was almost removed. Besides, the depths of decobaltization on the upper and lower surfaces were 176 μm and 162 μm, respectively. Based on the EDS results, the remaining mass fraction of cobalt in the decobaltized layer was determined to be 0.93%, while that in the non-decobaltized layer was 7.64%. This suggested that 87.83% of cobalt was dissolved and removed in the mixed solution of sulfuric acid and hydrogen peroxide. The residual stress of PCD samples was also measured. The residual stress before and after decobaltization was 483.91 MPa and 330.35 MPa, respectively. The reduction of 31.73% indicated that decobaltization could effectively reduce the residual thermal stress in PCD.

Abstract A novel algorithm for multi‐subband signal fusion achieves performance superior to traditional all‐pole model, matrix pencil algorithm and deep‐neural‐network (Deep neural network (DNN)). The method uses a deep‐learning autoencoder more fully described as a multi‐subband fusion autoencoder (MSFAE). This autoencoder comprises two parts: a multi‐subband encoder and a full‐band decoder. Full‐band echo distance envelopes are used as training data for the full‐band autoencoder, to obtain the full‐band coding and the full‐band decoder. Then, the multi‐subband echo distance envelopes are used as training data, and the full‐band coding is used as labels, to train the multi‐subband encoder. Finally, the multi‐subband encoder and the full‐band decoder are combined to obtain the MSFAE. The multi‐subband distance envelopes are input to the MSFAE to obtain the full‐band distance envelopes, improving the radar distance resolution and obtaining high‐resolution range profiles. In contrast with the traditional all‐pole model and matrix pencil algorithm, the authors’ MSFAE directly processes the information in the frequency domain, avoiding the error of pole estimation in the echo domain. In contrast with DNN, the authors’ MSFAE needs only multi‐subband distance envelopes as input, avoiding noise subband redundancy. The experimental results show that the fusion accuracy of MSFAE is higher than the traditional all‐pole model, matrix pencil algorithm and DNN. The MSFAE has superior performance using the fusion method, even at low signal‐to‐noise ratio.

DNA methyltransferase 3A, a mutated gene associated with hematologic malignancies in age-related clonal haematopoiesis lacks targeted therapies. Here, the authors screen carbon nanomaterials and find graphdiyne oxide binds to mutant cells and disrupts cellular processes with a therapeutic effect in vitro and in vivo.

Summary: Although anti-PD-L1 therapy has been used in the clinical treatment of renal cell carcinoma (RCC), a proportion of patients are not sensitive to it, which may be attributed to the heterogeneity of PD-L1 expression. Here, we demonstrated that high TOPK (T-LAK cell-originated Protein Kinase) expression in RCC promoted PD-L1 expression by activating ERK2 and TGF-β/Smad pathways. TOPK was positively correlated with PD-L1 expression levels in RCC. Meanwhile, TOPK significantly inhibited the infiltration and function of CD8+ T cells and promoted the immune escape of RCC. Moreover, inhibition of TOPK significantly enhanced CD8+ T cell infiltration, promoted CD8+ T cell activation, enhanced anti-PD-L1 therapeutic efficacy, and synergistically enhanced anti-RCC immune response. In conclusion, this study proposes a new PD-L1 regulatory mechanism that is expected to improve the effectiveness of immunotherapy for RCC.

IntroductionDuck circovirus (DuCV) infection is currently recognized as an important immunosuppressive disease in commercial duck flocks in China. Specific antibodies against DuCV viral proteins are required to improve diagnostic assays and understand the pathogenesis of DuCV infection.Methods and resultsTo generate DuCV-specific monoclonal antibodies (mAbs), a recombinant DuCV capsid protein without the first 36 N-terminal amino acids was produced in Escherichia coli. Using the recombinant protein as an immunogen, a mAb was developed that reacted specifically with the DuCV capsid protein, expressed in E. coli and baculovirus systems. Using homology modeling and recombinant truncated capsid proteins, the antibody-binding epitope was mapped within the region of 144IDKDGQIV151, which is exposed to solvent in the virion capsid model structure. To assess the applicability of the mAb to probe the native virus antigen, the murine macrophage cell line RAW267.4 was tested for DuCV replicative permissiveness. Immunofluorescence and Western blot analysis revealed that the mAb recognized the virus in infected cells and the viral antigen in tissue samples collected from clinically infected ducks.DiscussionThis mAb, combined with the in vitro culturing method, would have widespread applications in diagnosing and investigating DuCV pathogenesis.

Recently, a novel poplar mosaic disease caused by bean common mosaic virus (BCMV) was investigated in Populus alba var. pyramidalis in China. Symptom characteristics, physiological performance of the host, histopathology, genome sequences and vectors, and gene regulation at the transcriptional and posttranscriptional levels were analyzed and RT−qPCR (quantitative reverse transcription PCR) validation of expression was performed in our experiments. In this work, the mechanisms by which the BCMV pathogen impacts physiological performance and the molecular mechanisms of the poplar response to viral infection were reported. The results showed that BCMV infection decreased the chlorophyll content, inhibited the net photosynthesis rate (Pn) and stomatal conductance (Gs), and significantly changed chlorophyll fluorescence parameters in diseased leaves. Transcriptome analysis revealed that the expression of the majority of DEGs (differentially expressed genes) involved in the flavonoid biosynthesis pathway was promoted, but the expression of all or almost all DEGs associated with photosynthesis-antenna proteins and the photosynthesis pathway was inhibited in poplar leaves, suggesting that BCMV infection increased the accumulation of flavonoids but decreased photosynthesis in hosts. Gene set enrichment analysis (GSEA) illustrated that viral infection promoted the expression of genes involved in the defense response or plant-pathogen interaction. MicroRNA-seq analysis illustrated that 10 miRNA families were upregulated while 6 families were downregulated in diseased poplar leaves; moreover, miR156, the largest family with the most miRNA members and target genes, was only differentially upregulated in long-period disease (LD) poplar leaves. Integrated transcriptome and miRNA-seq analyses revealed 29 and 145 candidate miRNA−target gene pairs; however, only 17 and 76 pairs, accounting for 2.2% and 3.2% of all DEGs, were authentically negatively regulated in short-period disease (SD) and LD leaves, respectively. Interestingly, 4 miR156/SPL (squamosa promoter-binding-like protein) miRNA−target gene pairs were identified in LD leaves: the miR156 molecules were upregulated, but SPL genes were downregulated. In conclusion, BCMV infection significantly changed transcriptional and posttranscriptional gene expression in poplar leaves, inhibited photosynthesis, increased the accumulation of flavonoids, induced systematic mosaic symptoms, and decreased physiological performance in diseased poplar leaves. This study elucidated the fine-tuned regulation of poplar gene expression by BCMV; moreover, the results also suggested that miR156/SPL modules played important roles in the virus response and development of viral systematic symptoms in plant virus disease.

Mulberry fruits are rich in bioactive components renowned for their antioxidant properties and potential health benefits. This study thoroughly investigated the impact of cultivation modes on the phenological stages, yield, bioactive components, and antioxidant activity of two mulberry cultivars, Yueshen Dashi (YS-DS) and Xinjiang Baisang (XJ-BS). Notably, greenhouse cultivation led to earlier phenology and shorter fruit development maturation durations compared to field cultivation. Despite a decrease in fruit production and firmness, the greenhouse-grown mulberries exhibited higher individual fruit fresh weight. The content of bioactive components, encompassing anthocyanins, polyphenols, flavonoids, and vitamin C, and of antioxidant activity (measured in the FRAP and DPPH radical scavenging assays) was found to be lower in the greenhouse-grown mulberries than in those cultivated in the field. The contents of total polyphenols and flavonoids showed robust positive correlations in the FRAP and DPPH radical scavenging assays, which suggests that the antioxidant activity of mulberry fruit might be primarily attributable to the bioactive components of total polyphenols and flavonoids. Interestingly, the sugar content and hydroxyl radical scavenging activity (HRSA) displayed an inverse relationship between the two cultivars in the greenhouse versus field conditions. The multivariate analysis highlighted distinct patterns for different cultivars under varying cultivation modes. This study underscores the potential to enhance bioactive components and antioxidant activity through effective manipulation of climate conditions, thereby unlocking the full nutritional potential of mulberry fruits on a large scale in greenhouse environments.

Abstract Background Allelopathy is expressed through the release of plant chemicals and is considered a natural alternative for sustainable weed management. Artemisia argyi (A. argyi) is widely distributed throughout Asia, and often dominates fields due to its strong allelopathy. However, the mechanism of A. argyi allelopathy is largely unknown and need to be elucidated at the physiological and molecular levels. Results In this study, we used electron microscopy, ionomics analysis, phytohormone profiling, and transcriptome analysis to investigate the physiological and molecular mechanisms of A. argyi allelopathy using the model plant rice (Oryza sativa) as receptor plants. A. argyi water extract (AAWE)-treated rice plants grow poorly and display root morphological anomalies and leaf yellowing. We found that AAWE significantly inhibits rice growth by destroying the root and leaf system in multiple ways, including the integrity of ultrastructure, reactive oxygen species (ROS) homeostasis, and the accumulation of soluble sugar and chlorophyll synthesis. Further detection of the hormone contents suggests that AAWE leads to indole-3-acetic acid (IAA) accumulation in roots. Moreover, ionomics analysis shows that AAWE inhibits the absorption and transportation of photosynthesis-essential mineral elements, especially Mg, Fe, and Mn. In addition, the results of transcriptome analysis revealed that AAWE affects a series of crucial primary metabolic processes comprising photosynthesis in rice plants. Conclusions This study indicates that A. argyi realizes its strongly allelopathy through comprehensive effects on recipient plants including large-scale IAA synthesis and accumulation, ROS explosion, damaging the membrane system and organelles, and obstructing ion absorption and transport, photosynthesis and other pivotal primary metabolic processes of plants. Therefore, AAWE could potentially be developed as an environmentally friendly botanical herbicide due to its strong allelopathic effects.

Equity in the inheritance culture of family property is an important component of humanistic health in modern living environments. The inheritance of property under Chinese traditional family culture is the material basis for the continuation of family and clan. This study demonstrates the equity component embedded in traditional family inheritance culture and further studies of the healthy human settlements environment. Based on the theory of “equal share for all sons” in ancient China and the “equity” and “justice” that are of modern significance, this paper analyzes the family division culture of individual traditional housing and the corresponding impact indices of family division equity. Taking Renhe Village, a typical local residential building of the middle and late Qing Dynasty as the research object, this study built a spatial syntax data model and 3D simulation technology for the simulation analysis of space and climate. The results show that Renhe Village meets the requirements of the equity evaluation system of housing property rights distribution in terms of the natural unit indicator (quantity, lighting, ventilation) and the overall spatial indicator (privacy, centrality, convenience). In other words, equity does not mean an absolute average share, but an equity culture formed after six evaluation indices under the subdivision of two indicators are balanced. Based on the above, an equity system model of housing property rights distribution was established, and the weight of the ancients' attention to the housing distribution standard was explored. It is further found that the ancients attached more importance to light among the natural unit indicators, and attached the most importance to centrality in the overall spatial indicators. These findings provide new ideas for understanding the equity of property inheritance under Chinese traditional family culture. They also provide quantifiable criteria for the distribution of modern rural housing and social security housing, and ultimately provide a reference for the humanistic public health of the modern living environment.

Summary: Cyclic GMP-AMP synthase (cGAS), as the major DNA sensor, initiates DNA-stimulated innate immune responses and is essential for a healthy immune system. Although some regulators of cGAS have been reported, it still remains largely unclear how cGAS is precisely and dynamically regulated and how many potential regulators govern cGAS. Here we carry out proximity labeling of cGAS with TurboID in cells and identify a number of potential cGAS-interacting or -adjacent proteins. Deubiquitinase OTUD3, one candidate identified in cytosolic cGAS-DNA complex, is further validated to not only stabilize cGAS but also enhance cGAS enzymatic activity, which eventually promotes anti-DNA virus immune response. We show that OTUD3 can directly bind DNA and is recruited to the cytosolic DNA complex, increasing its association with cGAS. Our findings reveal OTUD3 as a versatile cGAS regulator and find one more layer of regulatory mechanism in DNA-stimulated innate immune responses.

Abstract TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.

It is an economical way to use the pile-supported embankment for the construction of the embankment over soft soil. The combined use of piles and reinforcement effectively reduces the differential settlement of the embankment surface. However, the previous analysis of embankment stress and settlement did not take into account the anisotropy in the embankment filler. In this paper, the UMAT subroutine is developed by using the material subroutine interface in ABAQUS 2016 finite element software. The anisotropy of soil cohesion and friction angle has been incorporated into the Mohr–Coulomb yield criterion so that it can consider the anisotropy of soil. The accuracy of the anisotropic yield criterion in this paper is verified by an ABAQUS source program and related engineering examples. It is found that the anisotropy value of soil cohesion is inversely proportional to the stress ratio on the pile–soil interface while being directly proportional to the tensile stress applied to the geogrid. The results show that the anisotropy of the friction angle decreases with the soil arching effect but increases by 23.1% with the tensile stress on the geogrid. The position of the settlement plane remains relatively constant at 2.3 m as the friction angle anisotropy coefficient increases. These research results provide valuable theoretical guidance for on-site construction design.

The plastic region of piles under seismic loads is a crucial concern in seafloor improvement design. This paper establishes a physical model of the sand compaction pile-immersed tunnel–water pressure system. This research studies pile arrangements that minimize the sand compaction pile plastic region under seismic loads. The experiments were validated through numerical simulations. The results show that “X-shaped” and rectangular pile groups increase the Energy Residual Index (ERI) due to differences in pile spacing and the instability of the quadrilateral prism damping units formed by piles and soil. In this scenario, piles are limited to heavy and mild plastic regions, with boundary depths at L = 2.25 D and L = 2.08 D (L represents the pile length, and D is the pile diameter). Furthermore, increased water pressure amplifies the structural resonance injury, increasing ERI. In conjunction with the soil, hexagonal pile groups create triangular prism damping units that counteract seismic wavefronts. The total kinetic energy and strain energy of the piled foundation are lower than those of the “X-shaped” and rectangular pile groups. The boundaries between the heavy plastic region, the moderate plastic region, and the mild plastic region are located at depths of L = 4 D and L = 8 D, respectively. This study also reveals that a top-heavy mass distribution in the structure leads to maximum deformation in the heavy plastic region. Pile–soil damping units primarily operate within the moderate plastic region.

Psoriasis is an immune-mediated, persistent inflammatory disease with a genetic predisposition, and the involvement of multiple organs in psoriasis remains indicative of systemic disease. Atherosclerosis (AS) is a common complication of patients with severe or prolonged psoriasis. The specific pathogenesis of psoriasis is still unclear. Current studies suggest that psoriasis is a polygenic genetic disease with the interaction of multiple factors such as heredity and environment. Keratinocytes are proliferated through immune-mediated inflammatory pathway, which leads to cell activation, infiltration of dermis cells and release of inflammatory factors. Activation of inflammatory cells and pro-inflammatory factors play an important role in the progression of psoriasis and atherosclerosis. Studies have found that there is a close relationship between psoriasis and atherosclerosis, and systemic inflammation may be the common feature of psoriasis and AS. This paper attempts to explore the possibility of the relationship between psoriasis and atherosclerotic comorbidities from the aspects of potential epidemiology and immune mechanism, in order to provide some reference for the subsequent scientific research.

Abstract Background A supination-adduction (SAD) ankle fracture is a special type of ankle fracture that results in collapse of the distal tibial articular surface; as such, orthopaedic surgeons require greater awareness of this type of fracture. The severity of this injury lies between that of an ordinary ankle fracture and a pilon fracture, and the treatment of such fractures based on the ankle fracture concept leads to extremely high rates of postoperative complications and a poor prognosis. In this retrospective study, we aimed to explore the treatment of SAD fractures based on the pilon fracture concept. Methods We retrospectively analysed the clinical data of 67 patients with Lauge-Hansen supination-adduction type II (SAD-II) ankle fractures, most of whom had a 44-A AO classification. Patients underwent surgical treatment at the Second Affiliated Hospital of Anhui Medical University from January 2009 to June 2019. The patients were divided into two groups based on the surgical concept employed: 43 patients were included in the ankle fracture surgical concept group, and 24 patients were included in the medial pilon fracture surgical concept group. The therapeutic effect was evaluated based on the Burwell-Charnley radiological reduction standard, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and postoperative visual analogue scale (VAS) pain score 1 year after surgery using regression with adjustment for confounding factors. Results All 67 patients were followed up. Twenty-four patients were treated according to the medial pilon fracture concept, and forty-three patients were treated according to the ankle fracture concept. The AOFAS score 1 year after surgery in the medial pilon group (89.83 ± 2.77) was higher than that in the ankle fracture group (83.63 ± 7.97) (p

Fungal pathogens can induce canker lesions, wilting, and even dieback in many species. Trees can suffer serious physiological effects from stem cankers. In this study, we investigated the effects of Botryosphaeria dothidea (B. dothidea) on Populus bolleana (P. bolleana) leaves photosynthesis and stomatal responses, when stems were inoculated with the pathogen. To provide experimental and theoretical basis for preventing poplar canker early. One-year-old poplar stems were inoculated with B. dothidea using an epidermal scraping method. In the early stage of B. dothidea inoculation (2–14 days post inoculation, dpi), the gas exchange, stomatal dynamics, hormone content, photosynthetic pigments content, chlorophyll fluorescence parameters, and non-structural carbohydrate (NSC) were evaluated to elucidate the pathophysiological mechanism of B. dothidea inhibiting photosynthesis. Compared with the control groups, B. dothidea noteworthily inhibited the net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci), transpiration rate (Tr), and other photosynthetic parameters of poplar leaves, but stomatal limit value (Ls) increased. Consistent with the above results, B. dothidea also reduced stomatal aperture and stomatal opening rate. In addition, B. dothidea not only remarkably reduced the content of photosynthetic pigments, but also decreased the maximum photochemical efficiency (Fv/Fm), actual photochemical efficiency (ΦPSII), electron transfer efficiency (ETR), and photochemical quenching coefficient (qP). Furthermore, both chlorophyll and ΦPSII were positively correlated with Pn. In summary, the main reason for the abated Pn under stem canker pathogen was that B. dothidea not merely inhibited the stomatal opening, but hindered the conversion of light energy, electron transfer and light energy utilization of poplar leaves. In general, the lessened CO2 and Pn would reduce the synthesis of photosynthetic products. Whereas, sucrose and starch accumulated in poplar leaves, which may be due to the local damage caused by B. dothidea inoculation in phloem, hindering downward transport of these products.

China faces challenges of food security and sustainable agricultural production. However, current studies rarely address the spatial distribution patterns of water consumption and carbon emissions. We studied the irrigation water use efficiency and carbon emission differences of crops in arid areas and their spatial distribution using wheat and maize, two major food crops in the middle reaches of the Heihe River, as examples. Furthermore, we have optimized low-carbon cropping of crops under the multiple objectives of water conservation and economic development. The results show that: (1) The carbon emissions per unit of water consumption for maize are 0.03 × 10−6 t mm−1 and 0.49 × 10−6 t mm−1 for wheat. Irrigation water consumption per unit yield is 515.6 mm t−1 for maize and 426.7 mm t−1 for wheat. (2) The spatial distribution patterns of irrigation water consumption were opposites for maize and wheat. The former has lower irrigation water consumption in the planting area upstream of the Heihe River and higher in the lower reaches. In contrast, the pattern of wheat irrigation is the opposite. (3) After optimizing the cropping mix for both crops, the area planted with wheat should be reduced to 59% of the current size, while maize should be expanded to 104%. The results of the research hold immense importance in guiding the future grain crop planting patterns for water-saving agriculture and low-carbon agriculture development in arid zones worldwide, aligning with the United Nations’ Sustainable Development Goals.

We herein report on the synthesis of a pentacyclic triterpene functionalized through derivation of betulinic acid with hydroxybenzotriazole. The compound was fully characterized by proton (1H-NMR), carbon-13 (13C-NMR), heteronuclear single quantum coherence (HSQC) and distortionless enhancement by polarization transfer (DEPT-135 and DEPT-90) nuclear magnetic resonance. Ultraviolet (UV), and Fourier-transform infrared (FTIR) spectroscopies as well as and high-resolution mass spectrometry (HRMS) were also adopted. Computational studies were conducted to foresee the interactions between compound 3 and phosphodiesterase 9, a relevant target in the field of neurodegenerative diseases. Additionally, preliminary calculation of physico-chemical descriptors was performed to evaluate the drug-likeness of compound 3.

Artemisia argyi Levl. et Van is an important Asteraceae species with a high medicinal value. There are abundant A. argyi germplasm resources in Asia, especially in China, but the evolutionary relationships of these varieties and the systematic localization of A. argyi in the family Asteraceae are still unclear. In this study, the chloroplast (cp) genomes of 72 A. argyi varieties were systematically analyzed. The 72 varieties originated from 47 regions in China at different longitudes, latitudes and altitudes, and included both wild and cultivated varieties. The A. argyi cp genome was found to be ∼151 kb in size and to contain 114 genes, including 82 protein-coding, 28 tRNA, and 4 rRNA genes. The number of short sequence repeats (SSRs) in A. argyi cp genomes ranged from 35 to 42, and most of them were mononucleotide A/T repeats. A total of 196 polymorphic sites were detected in the cp genomes of the 72 varieties. Phylogenetic analysis demonstrated that the genetic relationship between A. argyi varieties had a weak relationship with their geographical distribution. Furthermore, inverted repeat (IR) boundaries of 10 Artemisia species were found to be significantly different. A sequence divergence analysis of Asteraceae cp genomes showed that the variable regions were mostly located in single-copy (SC) regions and that the coding regions were more conserved than the non-coding regions. A phylogenetic tree was constructed using 43 protein-coding genes common to 67 Asteraceae species. The resulting tree was consistent with the traditional classification system; Artemisia species were clustered into one group, and A. argyi was shown to be closely related to Artemisia lactiflora and Artemisia montana. In summary, this study systematically analyzed the cp genome characteristics of A. argyi and compared cp genomes of Asteraceae species. The results provide valuable information for the definitive identification of A. argyi varieties and for the understanding of the evolutionary relationships between Asteraceae species.

During recent years, microrobots have drawn extensive attention owing to their good controllability and great potential in biomedicine. Powered by external physical fields or chemical reactions, these untethered microdevices are promising candidates for in vivo complex tasks, such as targeted delivery, imaging and sensing, tissue engineering, hyperthermia, and assisted fertilization, among others. However, in clinical use, the biodegradability of microrobots is significant for avoiding toxic residue in the human body. The selection of biodegradable materials and the corresponding in vivo environment needed for degradation are increasingly receiving attention in this regard. This review aims at analyzing different types of biodegradable microrobots by critically discussing their advantages and limitations. The chemical degradation mechanisms behind biodegradable microrobots and their typical applications are also thoroughly investigated. Furthermore, we examine their feasibility and deal with the in vivo suitability of different biodegradable microrobots in terms of their degradation mechanisms; pathological environments; and corresponding biomedical applications, especially targeted delivery. Ultimately, we highlight the prevailing obstacles and perspective solutions, ranging from their manufacturing methods, control of movement, and degradation rate to insufficient and limited in vivo tests, that could be of benefit to forthcoming clinical applications.

Abstract Allelopathy means that one plant produces chemical substances to affect the growth and development of other plants. Usually, allelochemicals can stimulate or inhibit the germination and growth of plants, which have been considered as potential strategy for drug development of environmentally friendly biological herbicides. Obviously, the discovery of plant materials with extensive sources, low cost and markedly allelopathic effect will have far-reaching ecological impacts as the biological herbicide. At present, a large number of researches have already reported that certain plant-derived allelochemicals can inhibit weed growth. In this study, the allelopathic effect of Artemisia argyi was investigated via a series of laboratory experiments and field trial. Firstly, water-soluble extracts exhibited the strongest allelopathic inhibitory effects on various plants under incubator conditions, after the different extracts authenticated by UPLC-Q-TOF-MS. Then, the allelopathic effect of the A. argyi was systematacially evaluated on the seed germination and growth of Brassica pekinensis, Lactuca sativa, Oryza sativa, Portulaca oleracea, Oxalis corniculata and Setaria viridis in pot experiments, it suggested that the A. argyi could inhibit both dicotyledons and monocotyledons not only by seed germination but also by seedling growth. Furthermore, field trial showed that the A. argyi significantly inhibited the growth of weeds in Chrysanthemum morifolium field with no adverse effect on the growth of C. morifolium. At last, RNA-Seq analysis and key gene detection analysis indicated that A.argyi inhibited the germination and growth of weed via multi-targets and multi-paths while the inhibiting of chlorophyll synthesis of target plants was one of the key mechanisms. In summary, the A. argyi was confirmed as a potential raw material for the development of preventive herbicides against various weeds in this research. Importantly, this discovery maybe provide scientific evidence for the research and development of environmentally friendly herbicides in the future.

Background and objectives: Since December 2019, the rapid epidemic spread of COVID-19 in China has aroused the attention of the government and the public. The purpose of this study is to investigate the attitude and knowledge among medical students and non-medical students toward SARS-CoV-2 infection. Methods: A web-based survey was disseminated to the students from medical colleges and comprehensive universities via the survey website (www.wjx.cn) and via WeChat. Participation in the study was voluntary with the instruction to click on the website or scan the QR code to complete the anonymous electronic questionnaire from February 5 to 7, 2020. Results: The questionnaire was completed by 588 students from 20 colleges and universities in China. Of the respondents, 66.0% were medical students and 34.0% were non-medical students. 99.6 % of the students held an optimistic attitude toward the COVID-19 epidemic situation. The majority of participants had a good level of knowledge of common symptoms, transmission, and prevention of the disease. In a comparison between non-medical students with medical students, the medical students had a deeper understanding of COVID-19. In this study, we also found that female students had a better understanding of transmission and prevention than male students did. Conclusions: The majority of students who participated in the questionnaire had a positive attitude and a good perception about COVID-19.

Artemisia argyi is widely distributed in Asia, and it often becomes the dominant population in the field because of its strong ecological niche competitiveness. Allelochemicals secreted by plants are generally considered an important reason for their dominance in ecological competition. In this study, the allelochemicals in A. argyi were screened by a series of experiments and their mechanisms were explored via transcriptomics. First, the inhibitory effects of A. argyi on Echinochloa crusgalli, Setaria viridis, Portulaca oleracea and Amaranthus retroflexus were evaluated. Then, we carried out a qualitative and quantitative analysis of the chemical composition of the aqueous extract of A. argyi to screen for potential allelochemicals that can inhibit weed growth. Four potential allelochemicals were quantified: neochlorogenic acid (5-CQA), chlorogenic acid (3-CQA), cryptochlorogenic acid (4-CQA), and caffeic acid (CA). Coincidentally, their allelopathic effects on weeds seemed to be identical to their content, in the order CA>4−CQA>5−CQA>3-CQA. These findings suggested that CA might be the main allelopathic compound in the aqueous extract of A. argyi. Subsequently, the allelopathic effect and molecular mechanism of CA on S. viridis leaves were investigated. The physiological results showed that CA significantly induced reactive oxygen species (ROS) production, led to malondialdehyde (MDA) accumulation, and disrupted enzyme activities (POD, SOD, CAT) in S. viridis leaves. Moreover, transcriptome results revealed that CA inhibited S. viridis growth by downregulating multiple genes involved in gibberellin (GA) and phytoalexin biosynthesis and Mitogen-activated protein kinase (MAPK) signaling pathways. In addition, differentially expressed genes (DEGs) related to the biosynthesis and signaling pathways of phytohormones were verified by Quantitative Real-Time PCR (RT-qPCR). Taken together, this study may be the first to identify allelochemicals and explore their molecular mechanism about A. argyi. Importantly, the ecological advantages of A. argyi could be applied to ecological regulation and the development of botanical herbicides.

Artemisia argyi Levl. et Van (A. argyi) is a traditional medicinal plant, which is widely used in health, food and medicine. Thujone is an important cyclic monoterpene derivative in the volatile oil of A. argyi leaves with multiple efficacy. Although the thujone synthetic pathway has been preliminarily analyzed in very few species, genes related to the thujone content in A. argyi leaves remain largely unknown. In this study, we identify candidate genes involved in the synthesis and regulation of thujone content in A. argyi leaves by the comparative transcriptome analysis of two group materials with high and low thujone content. A total of 89 candidate genes related to thujone content are identified including one gene involved in the mevalonate pathway, three genes involved in the methylerythritol phosphate pathway, 19 genes involved in the metabolic process from geranyl pyrophosphate to thujone (four b-terpene synthase, five cytochrome P450, five dehydrogenase, and five reductase-encoding genes) and 66 transcription factor-encoding genes. Taken together, our results provide valuable gene resources for further analyzing the synthetic and regulatory pathway of thujone in A. argyi.

Mulberry (Morus L.; Moraceae; Rosales) is an economically important tree with a long history in China and valued for its rich nutrient, flavor content, medicinal value and useful ecological functions. Morus species are widely distributed in Asia, Europe, North and South America and Africa and exhibit obvious differences in morphological characteristics and phenological stages due to being distributed in diverse climate zones. The morphological description of the phenological stages of black mulberry (Morus nigra L.) has been established in Mediterranean climates and this study extended the BBCH scale for application in different Morus species, especially for mulberry trees grown in subtropical monsoon climates. In this study, we used the BBCH (Biologische Bundesanstalt, Bundessortenamt and CHemische Industrie) scale to describe in detail the phenological growth stages for Morus species in Wuhan, China (a subtropical monsoon climate). Based on this general scale, eight principal stages, i.e., bud, leaf and shoot development stage, inflorescence emergence stage, flowering stage, fruit development stage, fruit maturation stage, senescence and beginning of dormancy stage, were described. We provide photographic images of some primary and secondary developmental stages to better define and standardize morphological characteristics and phenological descriptions of these mulberries (Morus spp.). In addition, because the color of mulberry fruit varies from white, purple, black, or pink to red at maturity, with mostly monosexual flowers, we have also presented detailed descriptions of morphological traits of flower sexuality and fruit color among these four species. In addition, two late phenological germplasms (late bud sprouting associated with late blooming and late fruit ripening) were screened out according to the BBCH scale. Overall, this study will contribute to advance the field of mulberry breeding and implementation of agronomic practices and facilitate convenient communication between mulberry cultivators and researchers in different areas.

Mulberry fruits are rich in anthocyanins, which are important secondary metabolites that give mulberries their bright color, favorable taste and high nutritional quality, making them a popular fruit. However, few studies have focused on the molecular mechanism underlying anthocyanin accumulation in mulberries and the gene regulatory networks of anthocyanin biosynthetic pathways remain largely unknown. In this study, we performed RNA sequencing to identify differentially expressed genes (DEGs) associated with anthocyanin accumulation between two mulberry genotypes (‘Zi Jing’, ZJ and ‘Zhen Zhu Bai’, ZZB, with purple and white fruit flesh, respectively) at 5, 18, 27 and 31 days after flower. Using transcriptome analysis, we explored several key DEGs involved in the anthocyanin biosynthetic pathway, including the structural genes: CHS, CHI, F3H, DFR1, DFR2 and ANS, known as MBW complex genes: MYB (M.alba_G0017209), MYB (M.alba_G0017689), bHLH (M.alba_G0012659), bHLH (M.alba_G0009347) and bHLH3 (M.alba_G0016257) and the ethylene response factor: ERF (M.alba_G0016603). Of these, changing trends related to expression pattern and anthocyanin content showed their most positive correlation at the post-flowering stage in both genotypes. Our results indicated that ethylene enhances anthocyanin accumulation in mulberry fruits. Furthermore, qRT-PCR was performed to confirm the above-mentioned genes’ expression (except for MYB (M.alba_G0017689) and bHLH (M.alba_G0009347) was significantly up-regulated under ethylene treatment at 300 mg/L. These findings help uncover the gene regulatory networks of the anthocyanin biosynthetic pathway and will contribute to engineering purposes in future mulberry breeding programs.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease synthesized primarily by the liver. It mainly promotes the degradation of low-density lipoprotein receptor (LDL-R) by binding LDL-R, reducing low-density lipoprotein cholesterol (LDL-C) clearance. In addition to regulating LDL-R, PCSK9 inhibitors can also bind Toll-like receptors (TLRs), scavenger receptor B (SR-B/CD36), low-density lipoprotein receptor-related protein 1 (LRP1), apolipoprotein E receptor-2 (ApoER2) and very-low-density lipoprotein receptor (VLDL-R) reducing the lipoprotein concentration and slowing thrombosis. In addition to cardiovascular diseases, PCSK9 is also used in pancreatic cancer, sepsis, and Parkinson’s disease. Currently marketed PCSK9 inhibitors include alirocumab, evolocumab, and inclisiran, as well as small molecules, nucleic acid drugs, and vaccines under development. This review systematically summarized the application, preclinical studies, safety, mechanism of action, and latest research progress of PCSK9 inhibitors, aiming to provide ideas for the drug research and development and the clinical application of PCSK9 in cardiovascular diseases and expand its application in other diseases.

Abstract Carbon starvation is the current leading hypothesis of plant mortality mechanisms under drought stress; recently, it is also used to explain tree die-off in plant diseases. However, the molecular biology of the carbon starvation pathway is unclear. Here, using a punch inoculation system, we conducted transcriptome and physiological assays to investigate pathogen response in poplar stems at the early stages of Botryosphaeria and Valsa canker diseases. Transcriptome assays showed that the majority of differentially expressed genes (DEGs) in stem phloem and xylem, such as genes involved in carbon metabolism and transportation, aquaporin genes (in xylem) and genes related to the biosynthesis of secondary metabolites and the phenylpropanoid pathway (related to lignin synthesis), were downregulated at 7 days after inoculation (DAI). Results also showed that the expression of the majority of disease-resistance genes upregulated in poplar stems, which may be connected with the downregulation expression of the majority of WRKY family genes. Physiological assays showed that transpiration rate decreased but WUE (water use efficiency) increased the 3 and 7 DAI, while the net photosynthetic rate decreased at 11 DAI in Botryosphaeria infected poplars (ANOVA, P

A 55-65-GHz CMOS high power amplifier (PA) is designed with the help of a spirally folded 1:2 balun. By this size-folded balun, balance-unbalanced conversion and high-power combination are accomplished concurrently. Within the internal of PA, differential signal pairs benefit simplification of inter-stage matching topologies. The designed three-stage PA offers above 16.3-dB gain from 55.1 to 65.0 GHz. It is able to deliver 17.8-dBm output referred 1-dB compression point (P1 dB) and 22.2-dBm saturated output power (Psat) with a peak power-added efficiency of 10.9%.

Hypsizygus marmoreus is a representative edible mushroom with low-temperature fruiting after a long postripening (LFLP). Clarifying the mechanism of LFLP and applying a rigorous low-temperature-limited process will optimize the mushroom cultivation process. This study performed an integrative multi-omics analysis of the molecular mechanism of LFLP in combination with genetic, physiological, and cultivation confirmation. The results showed that the amino acid content was increased during LFLP, mainly arginine. pH analysis showed acidification in the postripening stage and alkalization in the substrates of the reproductive growth stage. An enzyme activity test confirmed the increased enzyme activity of arginase and citrate synthase in the postripening stage. Weighted gene coexpression network analysis of the transcriptome and metabolomics indicated that pH variation is correlated mainly with changes in citrate and arginine. Multi-omics reveals a straightforward way of providing enriched materials for amino acid biosynthesis, namely, synergistically elevating citric acid and arginine through enhanced activity of the arginine synthesis branch pathway in the citrate cycle. Our study confirmed that GCN2 mediated metabolic adaptation by enhancing protein translation, highlighting its regulatory role during LFLP. Exogenously added citric acid and arginine shortened the postripening period by 10 days and increased the fruiting body yield by 10.2~15.5%. This research sheds light on the molecular mechanism of LFLP in H. marmoreus and highlights the promising application of nutrient accumulation in high-efficiency cultivation.

In this study, an easily prepared bio-based abrasive grinding wheel based on tannin–glyoxal–urea (TGU)thermosetting matrix is presented.The synthesised resin was prepared via co-polycondensation reaction of glyoxal and ureawith condensed tannin, which is a forest-derived product. Fourier transform infrared spectroscopy and electrospray ionisation mass spectrometry results confirmed that urea and glyoxal react well under acidic conditions and that –(OH)CH–NH–group is primarily involved in TGU cross-linking. Differential scanning calorimetry, thermomechanical analysis and thermogravimetric analysis investigations showed that the preparation of TGU resin is easier compared to commercial phenol–formaldehyde (PF) resin; moreover, TGU resin has a more robust chemical network structure, which contributes efficiently to heat resistance and improved mechanical properties. This observation is supported by Brinell hardness, compression resistance and grinding testing; these showed that the new grinding wheel acquired higher hardness, superior resistance against compression and stronger abrasion resistance compared with a PF-based grinding wheel prepared in the laboratory. Moreover, few holes and no cracks were found in the new grinding wheel.

Hybrid perovskites have been investigated for various potential applications because of their tunable optical properties. In this paper, we report the synthesis of quantum dots (QDs) of two-dimensional (2D) Ruddlesden–Popper (RP) hybrid perovskite using a top-down approach. The QDs of the developed 2D RP perovskite exhibit high and sharp photoluminescence in the ultraviolet region. The sharp peak in the absorption spectrum and the intense photoluminescence in the ultraviolet region indicate strong quantum confinement in these particles, which is further confirmed by x-ray photoelectron spectroscopy. These QDs show superior nonlinear optical scattering and absorption properties with the optical z-scan technique and strong nonlinear absorption property with the photoacoustic z-scan technique. Evaluating the nonlinear optical properties using two complementary techniques provides a deeper understanding of the nonlinear mechanism involved in the optical limiting process. The two-photon absorption coefficient obtained by optical z-scan is 7.2 × 102 cm/GW, which is larger than that of most perovskite nanocrystals and nanosheets. Our studies, therefore, reveal a new class of material, 2D RP perovskite QDs, which show important nonlinear properties that are important for optical limiting applications.