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Abstract Abscisic acid (ABA) is a key plant hormone that regulates plant growth and response to stress . Pyrabactin resistance 1-like (PYR/PYL) proteins are ABA receptors involved in the initial steps of ABA signaling. Triticum monococcum L. subsp. aegilopoides is an important germplasm resource for wheat. In this study, we identified 15 PYL genes from T. monococcum L. subsp. aegilopoides and found that they were distributed across five chromosomes. Based on phylogenetic analysis, we classified these genes into three subfamilies. Members of each subfamily have similar gene structures and contain a common motif. Further analysis revealed that the promoters have multiple hormone-related elements. We found 7, 33, and 49 collinear gene pairs in three different ploidy wheat species (T. urartu, T. turgidum and T. aestivum), indicating that PYL genes are relatively conserved during the process of wheat polyploidization. Additionally, interaction networks and miRNA targets were predicted, revealing interactions between PYL proteins and key components of the abscisic acid signaling network. miR9666b-3p may serve as a central factor in PYL involvement in the abscisic acid network. Through RNA-seq analysis and qPCR validation, three genes (TbPYL2, TbPYL5, and TbPYL12) were found to potentially play a role in cold stress. These findings lay the groundwork for further research on PYL genes in T. monococcum L. subsp. aegilopoides.

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that leads to multiple organ dysfunction. The advent of disease-modifying treatments makes the early diagnosis of SMA critical. Health information literacy is vital for obtaining, understanding, screening, and using health information. Considering the importance of early diagnosis and the challenges in obtaining accurate information on patients with SMA, this cross-sectional study assessed health information literacy among children with SMA and their caregivers in China. Methods Interviews with the caregivers of 10 patients with SMA were conducted by neurologists specializing in SMA. A questionnaire for evaluating the level of health information literacy was further developed among 145 children with SMA aged 10.0–120.0 months, with the average age of 81.9 months, and their caregivers. Parameters, such as the age at the onset of the first symptom and time from recognition of the first symptom to diagnosis, were examined. Health information literacy was measured using four dimensions: cognition, search, evaluation, and application. Results The average time from the first symptom to first medical consultation was 4.8 months, and that from the first symptom to diagnosis was 10.8 months. There is a significant delay from the onset of the initial symptoms to a definitive diagnosis. Thirty-five (24%) patients had poor while 26 (18%) had high health information literacy. The overall score for health information literacy was 69; the scores for health information cognition and application were 90 and 84, respectively. The scores for evaluation (61) and search (57) were low. Medical personnel were considered the most professional and credible sources of information. Additionally, search engines and patient organizations were the other two most important sources of health literacy. Conclusion Patients with SMA and their caregivers had low levels of health information literacy. SMA information visibility and standardization need to be improved. Medical personnel with experience in the diagnosis and treatment of SMA and media should aim to share knowledge and increase the quality of life of those with SMA.

Abstract Tripartite motif-containing 24 (TRIM24), also known as transcriptional intermediary factor 1α (TIF1α), is the founding member of TIF1 family. Recent evidence indicates that aberrant expression of TRIM24, functions as an oncogene, is associated with poor prognosis across various cancer types. TRIM24 exhibits a multifaceted structure comprising an N-terminal TRIM region with a RING domain, B-box type 1 and type 2 domains, and a coiled-coil region, as well as a C-terminal plant-homeodomain (PHD)-bromodomain. The bromodomain serves as a ‘reader’ of epigenetic histone marks, regulating chromatin structure and gene expression by linking associated proteins to acetylated nucleosomal targets, thereby controlling transcription of genes. Notably, bromodomains have emerged as compelling targets for cancer therapeutic development. In addition, TRIM24 plays specialized roles as a signal transduction molecule, orchestrating various cellular signaling cascades in cancer cells. Herein, we review the recent advancements in understanding the functions of TRIM24, and demonstrate the research progress in utilizing TRIM24 as a target for cancer therapy.

ABSTRACT: A deep understanding of the dynamics and mechanisms of male reproductive tract development is necessary for adoption of either genetic techniques or environmental management practices for improving fertility and hatchability in poultry. However, compared with other poultry such as chickens and ducks, less is known about the age- and breed-related changes in the reproductive tract development of domestic goose ganders exhibiting relatively poor reproductive performance as well as the regulatory mechanisms. In the present study, by taking 2 Chinese domestic goose breeds (Sichuan White goose, SW and Gang goose, GE; Anser cygnoides) and one European goose breed (Landes goose, LD; Anser anser) as the experimental objects, we comprehensive analyzed the morphological, histological, and genome-wide transcriptomic variations in their testicular and external genital development during the period from hatching to sexual maturity. Results from histomorphological analysis demonstrated that the reproductive tract of all goose breeds developed in both age- and breed-dependent manners, and the left and right testis developed asymmetrically throughout posthatch development. The tenth week posthatch was a critical developmental stage for all goose ganders, because both the testicular and external genital histomorphological parameters significantly changed before and after this period. During the first 10 wk posthatch, the weight, organ index, or size of male reproductive organs developed more rapidly in SW than in LD, and so were the testicular parenchymal-to-interstitial ratio and the external genital lymphatic lumen diameter. However, the testicular seminiferous epithelium thickness, seminiferous tubule diameter, and Leydig cell number, as well as the external genital keratinized epithelium thickness were significantly higher in LD than in SW at 10 wk of age. Through comparative transcriptomics analysis and RT-qPCR validation, several pathways related to germ and somatic cell function, organ remodeling, and energy metabolism were thought to be responsible for the developmental variations in the early testicular development between Chinese and European domestic ganders, where 10 hub genes involved in the cell cycle, RNA polymerase II-dependent transcription, and mitotic cell division pathways might play essential roles. These data shed new light on the interbreed differences in the male goose reproductive tract development and the molecular mechanisms regulating male goose testicular functions and fertility.

Physician trust is necessary for improving physician–patient relationships and maintaining an effective health-care system. Most studies on the theory of segmentation assimilation have mainly focused on comparing immigrants in different countries and few studies have applied segmented assimilation to clarify physician–patient relationships, especially physician trust among internal migrants in the context of Chinese megacities. A random sample of 1200 internal migrants was collected through an online questionnaire conducted in Shanghai from August to December 2021. An exploratory K-means cluster analysis and multivariate logistic regression models were employed to identify patterns of segmented assimilation and examine their relationships with physician trust, as well as the factors influencing physician trust among internal migrants in Shanghai. Results show four main patterns were revealed, namely first-generation classic assimilation, first-generation integrative assimilation, first-generation segmentation, and second-generation underclass assimilation, supporting the theory of segmented assimilation. Association between assimilation pattern and physician trust was observed. A relationship was found between assimilation patterns and trust in physicians. Migrants belonging to the first-generation classic and integrative assimilation groups exhibited a higher level of trust in doctors compared to those in the segmented assimilation groups. Additionally, undergraduate and postgraduate education attainment, an annual income of

Abstract La-related proteins (LARPs) regulate gene expression by binding to RNAs and exhibit critical effects on disease progression, including tumors. However, the role of LARP4B and its underlying mechanisms in the progression of hepatocellular carcinoma (HCC) remain largely unclear. In this study, we found that LARP4B expression is upregulated and correlates with poor prognosis in patients with HCC. Gain- and loss-of-function assays showed that LARP4B promotes stemness, proliferation, metastasis, and angiogenesis in vitro and in vivo. Furthermore, LARP4B inhibition enhances the antitumor effects of sorafenib and blocks the metastasis-enhancing effects of low sorafenib concentrations in HCC. Mechanistically, LARP4B expression is upregulated by METTL3-mediated N6-methyladenosine (m6A)-IGF2BP3-dependent modification in HCC. RNA- and RNA immunoprecipitation (RIP)- sequencing uncovered that LARP4B upregulates SPINK1 by binding to SPINK1 mRNA via the La motif and maintaining mRNA stability. LARP4B activates the SPINK1-mediated EGFR signaling pathway, which supports stemness, progression and sorafenib resistance in HCC. Additionally, a positive feedback loop with the LARP4B/SPINK1/p-AKT/C/EBP-β axis is responsible for the sorafenib-therapeutic benefit of LARP4B depletion. Overall, this study demonstrated that LARP4B facilitates HCC progression, and LARP4B inhibition provides benefits to sorafenib treatment in HCC, suggesting that LARP4B might be a potential therapeutic target for HCC.

Abstract Physical factors in the cellular microenvironment have critical effects on stem cell differentiation. The utilization of physical factors to promote the osteogenic differentiation of stem cells has been established as a new strategy for developing bone tissue engineering scaffolds. In this context, scaffolds with multiscale anisotropy are considered to possess biomimetic properties, which are advantageous for their biological performance. In the present study, a novel magnetic anisotropic hydrogel (MAH) with magnetic and topographic anisotropy was designed by combining static magnetic field-induced magnetic nanomaterials and a hydrogel. In in vitro studies, the MAH exhibited excellent biocompatibility and osteogenic bioactivity. The alkaline phosphatase activity and the expression of osteogenic-related genes and proteins induced by the MAH were greater than those induced by the pure PEGDA–GelMA hydrogel (PGH) and the magnetic isotropic hydrogel (MIH). In addition, the present study revealed that the dual anisotropic properties of the MAH activated the NOTCH1/2 pathway by upregulating SNHG5 and downstream SIRT6, which modulates the level of NOTCH1/2 by antagonizing DNMT1 protein stability, ultimately inducing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Furthermore, the MAH, MIH, and PGH were tested for in vivo bone regeneration in rabbits with femur defects, and the results demonstrated that the MAH effectively stimulated bone regeneration. Taken together, these findings suggest that this magnetically and topographically anisotropic biomimetic hydrogel might be a promising candidate for application in the field of bone tissue regeneration.

ABSTRACTTo summarize the distribution of types of human papillomavirus (HPV) associated with HPV-related diseases and investigate the potential causes of high prevalence of HPV 52 and 58 by summarizing the prevalence of lineages, sub-lineages, and mutations among Chinese women. We searched PubMed, EMBASE, CNKI, and WanFang from January, 2012 to June, 2023 to identify all the eligible studies. We excluded patients who had received HPV vaccinations. Data were summarized in tables and cloud/rain maps. A total of 102 studies reporting HPV distribution and 15 studies reporting HPV52/HPV58 variants were extracted. Among Chinese women, the top five prevalent HPV types associated with cervical cancer (CC) were HPV16, 18, 58, 52, and 33. In patients with vaginal cancers and precancerous lesions, the most common HPV types were 16 and 52 followed by 58. For women with condyloma acuminatum (CA), the most common HPV types were 11 and 6. In Chinese women with HPV infection, lineage B was the most prominently identified for HPV52, and lineage A was the most common for HPV58. In addition to HPV types 16, which is prevalent worldwide, our findings revealed the unique high prevalence of HPV 52/58 among Chinese women with HPV-related diseases. HPV 52 variants were predominantly biased toward lineage B and sub-lineage B2, and HPV 58 variants were strongly biased toward lineage A and sub-lineage A1. Further investigations on the association between the high prevalent lineage and sub-lineage in HPV 52/58 and the risk of cancer risk are needed. Our findings underscore the importance of vaccination with the nine-valent HPV vaccine in China.

Abstract The bridge bottom crack detection provides important state information for bridge disease control and safety assessment. This paper proposes a detection method based on deep learning Faster R‐CNN and BIM (Building Information Modeling). The UAV (Unmanned Aerial Vehicle) was used for close aerial photography to obtain high‐resolution crack images of the concrete surface at the bottom of a bridge. Through deep learning algorithms, a Faster R‐CNN model is trained and established for crack identifications. The crack identification accuracy rate and recall rate reach 92.03% and 96.54%, respectively. Crack images are mapped to a BIM model developed for the chosen bridge, and the box girder family with cracks and the three crack families of transverse cracks, longitudinal cracks and turtle cracks are established. The cracks are located and the visualization of the beam bridge with cracks was completed. In order to better assess the health condition of the bridge. The results show that the combination of UAV bridge crack detection and modelling solves the remote, visual and automated detection of cracks on the surface of bridge structures, which are difficult to reach manually, and has important scientific research and engineering application value.

BackgroundPrior research has indicated a link between psoriasis and the susceptibility to breast cancer (BC); however, a definitive causal relationship remains elusive. This study sought to elucidate the causal connection and shared underlying mechanisms between psoriasis and BC through bidirectional Mendelian randomization (MR) and bioinformatic approaches.MethodsWe employed a bidirectional MR approach to examine the potential causal connection between psoriasis and BC. Genetic data pertaining to psoriasis and BC were sourced from extensive published genome-wide association studies. The inverse -variance weighted or wald ratio served as the primary method for estimating causal effects. Sensitivity analysis of the MR results was applied with multiple methods. Leveraged datasets from the Gene Expression Omnibus and the Cancer Genome Atlas repositories to identify common differentially expressed genes, shedding light on the shared mechanisms underlying these two conditions.ResultsThe MR analysis revealed that when considering psoriasis as an exposure factor, the incidences of BC (OR=1.027) and estrogen receptor negative (ER-) BC (OR=1.054) were higher than in the general population. When using Her2+ BC as an exposure factor, the risk of psoriasis was 0.822 times higher (OR=0.822) than in the general population. Sensitivity analysis indicated that the results were robust. Transcriptome analysis showed that CXCL13 and CCL20 were activated in both BC and psoriasis. Both diseases were also linked to neutrophil chemotaxis, the IL-17 pathway, and the chemokine pathway.ConclusionThe results suggest that psoriasis may increase the risk of BC, especially ER- BC, while reverse MR suggests a decreased risk of psoriasis in Her2+ BC. Transcriptome analysis revealed a shared mechanism between psoriasis and BC.

Abstract Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.

Knowledge graph completion (KGC) utilizes known knowledge graph triples to infer and predict missing knowledge, making it one of the research hotspots in the field of knowledge graphs. There are still limitations in generating high-quality entity embeddings and fully understanding the contextual information of entities and relationships. To overcome these challenges, this paper introduces a novel pre-trained language model-based method for knowledge graph completion that significantly enhances the quality of entity embeddings by integrating entity categorical information with textual descriptions. Additionally, this method employs an innovative multi-layer residual attention network in combination with PLMs, deepening the understanding of the joint contextual information of entities and relationships. Experimental results on the FB15k-237 and WN18RR datasets demonstrate that our proposed model significantly outperforms existing baseline models in link prediction tasks.

Cancer presents a formidable threat to human health, with the majority of cases currently lacking a complete cure. Frequently, chemotherapy drugs are required to impede its progression. However, these drugs frequently suffer from drawbacks such as poor selectivity, limited water solubility, low bioavailability, and a propensity for causing organ toxicity. Consequently, a concerted effort has been made to seek improved drug delivery systems. Nano-drug delivery systems based on biodegradable polyesters have emerged as a subject of widespread interest in this pursuit. Extensive research has demonstrated their potential for offering high bioavailability, effective encapsulation, controlled release, and minimal toxicity. Notably, poly (ε-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), and polylactic acid (PLA) have gained prominence as the most widely utilized options as carriers of the nano drug delivery system. This paper comprehensively reviews recent research on these materials as nano-carriers for delivering chemotherapeutic drugs, summarizing their latest advancements, acknowledging their limitations, and forecasting future research directions.

We observe the strong photorefractive (PR)-like effect in silica micro-fibers, which is different from the previously reported nonlinear behaviors in optical fiber devices. The micro-fiber is fabricated by tapering a standard silica single-mode fiber using the hydrogen flame. Two fiber Bragg gratings are fused at each end of the micro-fiber to form a Fabry–Pérot cavity, enabling us to observe the nonlinear dynamics. By situating the silica micro-fiber in a gas medium (i.e., N2, Ar, He, and air), we observe the remarkable PR-like effect, especially under the low-pressure condition below 80 Torr. In fact, the nonlinear effect increases with the reduced pressure as a power function. Such a nonlinear effect is also affected by the laser wavelength detuning rate, input laser power, and micro-fiber diameter. Finally, a nonlinear cavity dynamics model is adopted to well describe the observed nonlinear effect.

Abstract Over 40 years ago, primary health care (PHC) was defined in the Alma‐Ata Declaration as a critical component of the health care system to address the basic health demand of the people. In China, the Government attaches great importance to health care at the primary level. After the launch of the historical Reform of the Medical and Health Care System in 2009, the PHC system in China has witnessed major progress and breakthroughs, especially in its steadily increased capacity, continuously improved accessibility, and betterment in equality. In this review, we summarized published literatures and official policies, synthesized data from the electronic registration information system of the National Health Commission, national statistical reports, and yearbooks in health care. The review is intended to describe the systematic development of PHC in China in the last decade. The main results include: the solid national policy foundation, increasing number of PHC institutions and workforce, better training of PHC professionals, major achievements in primary health indicators, government financial support to PHC institutions, improved PHC budgeting and insurance coverage, and the advancement of supporting technologies. Challenges and prospects are also discussed.

Background : The year 2022 marks the 30th anniversary of heart transplant service in Hong Kong (HK). In this study, we describe prevailing trends and outcomes of advanced heart failure (AHF), including heart transplantations (HTx), in HK over the past 30 years. Methods : Trends in heart failure prevalence in HK from 1993 to 2021 were analyzed based on data from the Hospital Authority Clinical Data and Reporting System. All AHF patients referred for HTx consideration between 1992 and 2021 were reviewed. The bridge-to-transplant (BTT) utilization of short-term mechanical circulatory support (ST-MCS) devices, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and durable left ventricular assist devices (LVADs), from 2010 to 2021 was reviewed. Results : Overall, 237 heart transplants were performed in HK, with 10-year posttransplant and median survival of 68.1% and 18.7 years, respectively. An increase in AHF clinic referrals was correlated with increasing heart failure prevalence (R2=0.635, P

ABSTRACT: Rhododendron fortune belongs to a scented Rhododendron species native to China, which produces fragrant flowers of great ornamental and environmental values for landscaping or indoor beautification. However, the scents in Rhododendron fortuneihave not yet been investigated, let alone the mechanism of the formation of these fragrance in the flowers. In this study, we measured the scents in terms of its volatile components and contents (VOC) in Rhododendron fortuneiat four different flowering stages and in different tissues of the plant by headspace solid-phase micro-extraction combined (HS-SPME) with gas chromatography-mass spectrometry (GC-MS). Then the characteristic aromatic values, which reflects the degree of scent perception by human, of each VOC in the plant was calculated according to its respective aromatic thresholds. Results showed that three main VOCs measured from highest to lowest are methyl benzoates, terpenes and fatty acid derivatives. Their content increased after the flower bud opening and reached the highest at half to full blossom. In a flower most VOC contents were measured in petals and only trace amount in other tissues such as stamen, pistil. A small amount of VOCs was determined in leaves as well.All aromatic values were almost corresponded to the contents of three main VOCs, indicating that the flower fragrance arises truly from these VOC components. S-adenosyl-L-methionine: benzoic acid carboxyl methyl transferase (BAMT) catalyzes the final step to form methyl benzoates. To understand the mechanism of the formation of this main type fragrance and its regulation, we firstly isolate a gene of RfBAMT from petal of Rhododendron fortuneiby using homologous cloning and RACE technology. The full length of its cDNA was 1383 bp，with an open reading frame of 1104 bp, encoding a total of 368 amino acids. The phylogenetic tree analysis showed that RfBAMT was the closest to the BSMT of Camellia japonica, belonging to methyltransferases family. Then we measured the expression level of RfBAMT again at four flower developmental stages and in different flower tissues and leaves. The results showed that the expression level of this gene was highly positively correlated with the emitted content of methyl benzoates in the flowering, implying that RfBAMT plays a pivotal role in the formation and regulation of methyl benzoates in Rhododendron fortune.Thisresearchshowed that the RfBAMT was cloned and identified in our study and its expression level was highly positively correlated with the emitted content of methyl benzoates in the flowers and leaves, which indicated this gene may play an important role on regulation of methyl benzoate synthesis in Rhododendron fortunei.

The purpose of this work is to investigate the varied effects of China’s free trade zone (FTZ) strategy on agricultural trade and its underlying mechanisms. This work utilizes the propensity score matching–staggered difference-in-differences (PSM–Staggered DID) approach and synthetic control method (SCM) as its analysis methods. This study analyzes trade volume data between China and various countries alongside diverse economic indicators spanning from 1995 to 2020. The data sources include CEPII_BACI, the China Free Trade Zone Services website, the Penn World Tables, and the CEPII database. The novelty of this work lies in exploring the multidimensional heterogeneity of agricultural product trade effects in FTZs and their underlying mechanisms and extending the application of causal inference methods to the assessment of FTZs’ trade effects. Empirical analysis indicates that the establishment of FTZs with partner countries has contributed to the growth of China’s agricultural trade. The effects of agricultural trade resulting from China’s FTZ strategy exhibit multidimensional heterogeneity in the aspects of agreement terms, years, product categories, and network positions. Specifically, when it comes to the agreement terms, FTZs negotiated by China with broader scope, deeper terms, and stronger constraints have a more significant impact on agricultural trade due to the establishment of FTZs; in terms of years, the agricultural trade effects have gradually expanded over time; in terms of product categories, China has expanded its imports of primary agricultural products and semiprocessed agricultural products from partner countries, thus augmenting its exports of horticultural agricultural products and processed agricultural products. In terms of network positions, China, as a hub country, has greater agricultural trade effects than partner countries after the establishment of the FTZs. Finally, the paper proposes policy recommendations for optimizing the implementation strategy of FTZs.

Abstract Background Surgical tourism is an emerging economic sector, with the most growth potential demonstrated in China's health industry before the COVID-19 pandemic. Surgical tourism accounts for a large part of medical tourism services in China, with high requirements in terms of quality and safety. By contrast, China suffers from insufficient measurement tools and theoretical research. The aim of this study was to develop a set of reliable and feasible indicators by augmenting the Donabedian model to evaluate the quality of surgical tourism services. Methods A literature review and focus group interview were used to generate indicators for the quality of surgical tourism services. The basic framework of the evaluation system was based on the structure–process–outcome Donabedian model. The screening and weight setting were conducted through an analytical hierarchy process (AHP) and a two-round Delphi consultation with 13 panelists. The validity and reliability of experts were tested by the experts' positive coefficient, authority coefficient, and coordination coefficient. The reliability of the questionnaire was assessed by a pre-test distributed within an International Medical Department of a public hospital in China. Results Based on the Donabedian quality theory, a novel evaluation system of surgical tourism service institutions was constructed with three dimensions, nine first-level items and 39 second-level items. The three dimensions consisted of the structure (0.315), process (0.287), and outcome (0.398), with several indicators for each dimension and each indicator was given a weight. Of the two rounds of Delphi consultation, the response rates were 86.67% and 100%. The coordination coefficient of expert opinions in the two rounds of consultation were 0.49 and 0.65 (p

Abstract Background Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF. Methods A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration. Results There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844–1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth. Conclusions These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients. Trial registration The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.

Abstract Background Cinnamomum longepaniculatum (Gamble) N. Chao ex H. W. Li, whose leaves produce essential oils, is a traditional Chinese medicine and economically important tree species. In our study, two C. longepaniculatum varieties that have significantly different essential oil contents and leaf phenotypes were selected as the materials to investigate secondary metabolism. Result The essential oil content and leaf phenotypes were different between the two varieties. When the results of both transcriptome and metabolomic analyses were combined, it was found that the differences were related to phenylalanine metabolic pathways, particularly the metabolism of flavonoids and terpenoids. The transcriptome results based on KEGG pathway enrichment analysis showed that pathways involving phenylpropanoids, tryptophan biosynthesis and terpenoids significantly differed between the two varieties; 11 DEGs (2 upregulated and 9 downregulated) were associated with the biosynthesis of other secondary metabolites, and 12 DEGs (2 upregulated and 10 downregulated) were related to the metabolism of terpenoids and polyketides. Through further analysis of the leaves, we detected 196 metabolites in C. longepaniculatum. The abundance of 49 (26 downregulated and 23 upregulated) metabolites differed between the two varieties, which is likely related to the differences in the accumulation of these metabolites. We identified 12 flavonoids, 8 terpenoids and 8 alkaloids and identified 4 kinds of PMFs from the leaves of C. longepaniculatum. Conclusions The combined results of transcriptome and metabolomic analyses revealed a strong correlation between metabolite contents and gene expression. We speculate that light leads to differences in the secondary metabolism and phenotypes of leaves of different varieties of C. longepaniculatum. This research provides data for secondary metabolite studies and lays a solid foundation for breeding ideal C. longepaniculatum plants.

Detailed quantification of nanoparticle distribution in tumor tissues can provide the prediction of drug delivery efficacy and therapeutic outcome. Here the authors develop a pH/light dual responsive monochromatic ratiometric-imaging nanoparticle which can quantify extracellular and intracellular nanoparticle distribution in several tumor models.

Endometriosis (EM) is a prevalent estrogen-dependent disorder that adversely affects the life quality of many reproductive-age women. Previous evidence has suggested the significant role of miR-429 in EM; however, its molecular mechanisms underlying EM pathogenesis are unclarified. Human endometrial stromal cells (HESCs) were identified using immunofluorescence staining and flow cytometry. A mouse EM model was established by endometrial auto-transplantation. RNA and protein expression of molecules was examined using real-time quantitative polymerase chain reaction and western blotting, respectively. In vitro functional experiments showed that inhibiting miR-429 restrained HESC proliferation, migration, and invasiveness. Luciferase reporter assay confirmed that miR-429 targeted hypoxia-inducible factor 1 subunit alpha inhibitor (HIF1AN) in HESCs. HIF1AN silencing offset the negative regulation of miR-429 inhibition on the HIF1A/vascular endothelial growth factor (VEGF) signaling pathway. In vivo experiments showed that depletion of miR-429 attenuated ectopic lesion development in the mouse EM model. Collectively, suppressing miR-429 hinders the invasive behaviors of HESCs and EM progression in mice by targeting HIF1AN and regulating the HIF1A/VEGF signaling pathway.

The tower crane is a typical soaring and complex frame structure, and buckling is an important factor affecting its safety and carrying capacity. Considering the special characteristics of the boundary conditions for the boom structure, a numerical analysis method based on movable boundaries is proposed in this paper. In order to demonstrate the accuracy of the method, numerical analysis and stress tests are carried out on the tower crane. The results show that the numerical results are basically consistent with the experimental results. A geometric buckling analysis for extremely severe conditions is carried out in order to understand the buckling behaviors. The failure modes and complete load-response curves obtained for the tower crane are comprehensively analyzed. A dual (geometric and material) nonlinear buckling analysis of the tower crane is then investigated. Finally, the influences of the deflection load parameters on the buckling response of the tower crane are explored. It is demonstrated that bifurcation point buckling and limiting point buckling are excited by different deflection load parameters, respectively. The proposed method can accurately predict the buckling of the tower cranes, given the coupling of structure and mechanism, to ensure the safety of giant cranes in actual engineering use.

In October 2015, the 12th Conference of the Parties (COP12) of the United Nations Convention to Combat Desertification (UNCCD) proposed a definition for land degradation neutrality (LDN). In the same year, the United Nations made LDN one of the targets of Sustainable Development Goal 15 (Life on Land, 15.3 By 2030, combat desertification, restore degraded land and soil, including land affected by desertification, drought and floods, and strive to achieve a land degradation-neutral world). LDN has critical to global environmental change and sustainable development research. The available LDN reviews mainly focus on the concept of LDN and do not sufficiently elaborate on the progress of LDN research. The objectives of our work aim (1) to summarise the overview of articles on LDN (number of articles, countries of publication, and research hotspots); (2) to outline LDN assessment indicators; (3) to clarify the analysis methods of LDN driver factors; (4) to understand the research progress of predicting LDN; and (5) to assess the relation between LDN and land degradation, land restoration, and SDGs. To achieve our objectives, we searched articles focused on “land degradation neutrality” between 2013 and 2021 on the Web of Science. In total, we found 183 articles. By reviewing these papers, We found that (1) the number of articles on “land degradation neutrality” increased from 2013 to 2021; the articles on LDN mainly originate from Australia, Germany, the UK, Russia, Switzerland, and the USA; the research hotspots are focused on land degradation, desertification, sustainable land management, conservation, climate change, and land cover; (2) most of the research methods adopt the three indicators stipulated by the UNCCD (productivity, land cover, and soil organic carbon), and sole studies have improved the indicators; (3) there are few studies on the drivers and future projections of LDN, which have broad research prospects; and (4) LDN is a dynamic balance between land degradation and restoration, and there are trade-offs and synergies between LDN and other SDGs. The review revealed the need to (1) identify the LDN indicators in different regions and develop a method to qualitatively and quantitatively monitor LDN changes; (2) quantify LDN drivers and clarify the factors that affect LDN; and (3) clarify future LDN trends and promote SDG 15.3 implementation.

The ignition reliability of the combustion chamber is crucial for the overall performance of an engine. As the aero-engine combustion chambers continue to advance, the scope of the ignition problem has also expanded. This study employs large eddy simulation to investigate the flow characteristics and ignition process of a double-swirl combustor. The non-reacting flow field and ignition propagation process are acquired using particle image velocimetry (PIV) and high-speed cameras. Experimental findings are employed to validate the numerical simulations. The results demonstrate a close relationship between the ignition process of the double-swirl combustor and the flow field within the combustor. Following the spark discharge, a core is generated at the edge of the recirculation zone. Over time, the spark gradually propagates towards the center of the combustor along the direction of swirl due to the flow. Once the flame reaches the head, the fuel and gas mixture ignited by the core within the recirculation zone stabilizes within the boundary layer of the primary and pilot stages. The flame continues to propagate throughout the combustor until complete ignition is achieved. Additionally, the swirl intensity of the pilot mode is identified as a key factor influencing the ignition propagation process of the double-swirl combustor.

Abstract Male genitalia present an extraordinary pattern of rapid divergence in animals with internal fertilization, which is usually attributed to sexual selection. However, the effect of ecological factors on genitalia divergence could also be important, especially so in animals with nonretractable genitalia because of their stronger interaction with the surrounding environment in comparison with animals with retractable genitalia. Here, we examine the potential of a pervasive ecological factor (predation) to influence the length and allometry of the male genitalia in guppies. We sampled guppies from pairs of low‐predation (LP) and high‐predation (HP) populations in seven rivers in Trinidad, and measured their body and gonopodium length. A key finding was that HP adult males do not have consistently longer gonopodia than do LP adult males, as had been described in previous work. However, we did find such divergence for juvenile males: HP juveniles have longer gonopodia than do LP juveniles. We therefore suggest that an evolutionary trend toward the development of longer gonopodia in HP males (as seen in the juveniles) is erased after maturity owing to the higher mortality of mature males with longer gonopodia. Beyond these generalities, gonopodium length and gonopodium allometry were remarkably variable among populations even within a predation regime, thus indicating strong context dependence to their development/evolution. Our findings highlight the complex dynamics of genitalia evolution in Trinidadian guppies.

Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism‐based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull‐down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem‐like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human‐derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co‐control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC.

Quantification of intratumoral nanoparticles internalisation in vivo is crucial but challenging. Here, the authors develop a binary ratiometric nanoreporter that can quantify internalisation and predict nanotherapeutic responses based on intracellular nanoparticle exposure.

The high-temperature solid-phase approach was used to synthesize Eu3+-doped SrMo0.5W0.5O4 phosphors, whose morphological structure and luminescence properties were then characterized by XRD, SEM, FT-IR, excitation spectra, emission spectra, and fluorescence decay curves. The results reveal that the best phosphor synthesis temperature was 900 °C and that the doping of Eu3+ and charge compensators (K+, Li+, Na+, NH4+) had no effect on the crystal phase change. SrMo0.5W0.5O4:Eu3+ has major excitation peaks at 273 nm, 397 nm, and 464 nm, and a main emission peak at 615 nm, making it a potential red fluorescent material to be used as a down converter in UV LEDs (273 nm and 397 nm) and blue light LEDs (464 nm) to achieve Red emission. The emission spectra of Sr1−yMo0.5W0.5O4:yEu3+(y = 0.005, 0.01, 0.02, 0.05, 0.07) excited at 273 were depicted, with the Eu3+ concentration increasing the luminescence intensity first increases and then decreases, the emission peak intensity of SrMo0.5W0.5O4:Eu3+ achieves its maximum when the doping concentration of Eu3+ is 1%, and the critical transfer distance is calculated as 25.57 Å. When various charge compensators such as K+, Li+, Na+, and NH4+ are added to SrMo0.5W0.5O4:Eu3+, the NH4+ shows the best effect with the optimal doping concentration of 3wt%. The SrMo0.5W0.5O4:Eu3+,NH4+ color coordinate is (0.656,0.343), which is close to that of the ideal red light (0.670,0.333).

The enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) is an intermediate enzyme in triglyceride synthesis. The aim was to study the regulatory mechanism of AGPAT2 on Nile tilapia, Oreochromis niloticus. In this study, antisense RNA technology was used to knock-down AGPAT2 in Nile tilapia. Compared with the control groups (transfected with ultrapure water or the blank expression vector), the AGPAT2 knock-down group showed a significantly higher weight gain rate, special growth rate, visceral somatic index, and hepatopancreas somatic index; and significantly increased the total cholesterol, triglycerides, glucose, low-density lipoprotein cholesterol, and insulin levels in serum. In addition, the contents of total cholesterol and triglycerides and the abundance of superoxide dismutase, catalase, and glutathione peroxidase in the liver significantly increased, while the malondialdehyde content significantly decreased. The liver cells became severely vacuolated and accumulated lipids in the AGPAT2 knock-down group. Comparative transcriptome analyses (AGPAT2 knock-down vs. control group) revealed 1789 differentially expressed genes (DEGs), including 472 upregulated genes and 1313 downregulated genes in the AGPAT2 knock-down group. Functional analysis showed that the main pathway of differentially expressed genes enrichment was lipid metabolism and oxidative stress, such as steroid biosynthesis, unsaturated fatty acid biosynthesis, the PPAR signaling pathway, and the P53 pathway. We used qRT-PCR to verify the mRNA expression changes of 13 downstream differential genes in related signaling pathways. These findings demonstrate that knock-down of AGPAT2 in tilapia leads to abnormal lipid metabolism and oxidative stress.

Abstract Objective PCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring. Methods After the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice. Results The serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p

Abstract Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.

Abstract Objectives We aimed to reconstitute T2 and T3 stage classification in nasopharyngeal carcinoma (NPC) cases and verify its utility in clinical settings. Materials and Methods We enrolled 792 NPC patients. Cox proportional hazards model was used to compare the effect sizes (hazard ratio [HR]) of the cranial structure invasion on survival and select the structures for up‐staging or downstaging T2 and T3 NPC. The samples were reclassified and the survival curves for T2 and T3 stages were analyzed. The proposed new staging system was validated on an external sample (n = 433). Results Thirteen cranial structures were examined. American Joint Committee on Cancer (AJCC) T3 stage patients with the invasion of the base of the sphenoid (HR = 2.58, 95% CI = 1.16‐5.77) or base of the pterygoid (HR = 2.00, 95% CI = 0.84‐4.77) had significantly lower hazard ratios than T2 stage patients with the invasion of soft tissues in the bilateral parapharyngeal space (HR = 5.26, 95% CI = 2.02‐13.68) and single/bilateral carotid sheath (HR = 7.78, 95% CI = 3.06‐19.76). T3 stage with the invasion of the above‐mentioned bones was reclassified as T2, and T2 stage with the invasion of the above‐mentioned soft‐tissue structures was reclassified as T3. Survival analysis showed a significant difference between the reclassified T2 and T3 stages (P

Abstract Background Periodontal diseases are regarded as the most common diseases of mankind. The prevalence rate of periodontal disease assumes a clear growth tendency, increasing by 57.3% from 1990 to 2010. Thereby, effective periodontal therapy is still a long-term task and a difficult problem. The goals of periodontal therapy are to eliminate the infectious and inflammatory processes of periodontal diseases. Root planing, in order to eliminate the “infected cementum,” has been an important step in the treatment of periodontitis since the 1970s. However, along with the understanding of the effects of endotoxin on the root surface, the necessity of manual root planing has been gradually queried. Ultrasonic instruments, which are more recent innovations, would not remove the cementum excessively, and are also more time-saving and labor-saving compared to using hand instruments. Hence, an increasing number of dentists prefer to do scaling with ultrasonic instruments only. However, the necessity of root planing remains emphasized in the international mainstream views of periodontal mechanical treatment. Therefore, this study is devoted to compare the clinical effect of ultrasonic subgingival debridement and ultrasonic subgingival scaling combined with manual root planing, which takes the implementation of root planing as the only variable and is more in line with the current clinical situation, thus hoping to provide some valuable reference to dentists. Methods/design Forty adult patients who fit the inclusion criteria are being recruited from the Peking University Hospital of Stomatology (Beijing, China). By means of randomization tables, one quadrant of the upper and lower teeth is the test group and the other is the control group. Test group: ultrasonic subgingival scaling combined with manual root planing. Control group: ultrasonic subgingival debridement. In a 24-week follow-up period, plaque index, probing depth, clinical attachment loss, bleeding index, furcation involvement, mobility, and patient-reported outcome (Visual Analog Scale for pain and sensitivity) will be observed and documented. Discussion This study evaluates the effectiveness of ultrasonic subgingival scaling combined with manual root planing and ultrasonic subgingival debridement alone in the nonsurgical treatment of periodontitis with a split-mouth design after 1, 3 and 6 months. The result of the trial should potentially contribute to an advanced treatment strategy for periodontitis with an ideal clinical outcome. Trial registration International Clinical Trials Registry Platform (ICTRP), ID: ChiCTR1800017122. Registered on 12 July 2018.

An electromagnetic flowmeter (EMF) can be used to measure the speed of slurry fluid. In this paper, according to Maxwell's equations and the dB/dt vortex electric field, a step excitation scheme is proposed. The original excitation process of the primary excitation current rise time is divided into a two-step excitation process. Without increasing the excitation current rise time, the equivalent excitation frequency is increased by increasing the primary dB/dt. This method can enhance the EMF's ability to overcome slurry noise. The paper analyzes the design parameters of the step excitation scheme and designs the software and hardware. After that, the paper compares the step excitation scheme with the three-value rectangular wave excitation scheme based on wavelet transform signal processing. Experiments show that the step excitation EMF has a lower steady-state fluctuation rate when measuring mortar and has a stronger ability to overcome slurry noise. Additionally, the step excitation EMF and Yokogawa AXF 040G EMF are compared experimentally. Through flow calibration, clean water measurement, mortar measurement and dynamic response experiment, it is verified that the step excitation EMF has the ability to enhance the resistance to slurry noise at the same excitation frequency.

The electric multiple units (EMUs) have become a very convenient and powerful means of transportation in our daily life. Safe and punctual trajectory tracking control is the key to improve the performance of the EMUs system, but it is difficult to realize due to the influence of environmental uncertainty, coupling and nonlinearity. In this paper, a model-free adaptive sliding mode control (MFASMC) method is proposed for the EMUs. This method can solve the dependence of the model-based control method on the train model and eliminate the influence of external disturbances on the robust performance of the system. In this method, the running process of the EMUs is equivalent to a full format dynamic linearization (FFDL) data model, and a model-free adaptive controller (MFAC) is designed based on the data model. Then, to reduce the influence of measurement disturbance and improve the robustness of the system, a discrete sliding mode control (SMC) algorithm is introduced. Furthermore, to prevent the control input from being too large, the parameter estimation error is introduced as an additional correction term of the algorithm. In the end, the simulation experiment is carried out with CRH380A EMUs as the object. Compared with the traditional MFAC and the traditional SMC, the speed tracking effect of each power unit of the MFASMC algorithm is more effective, the change of control force is stable, the acceleration meets the requirements of driving, and has a strong inhibitory effect on external disturbances.

Anti-Müllerian hormone (amh), an important regulator of gonad development in male teleosts, regulates the development and differentiation of germ cells. We performed transcriptional knock-down of amh in Nile tilapia (Oreochromis niloticus) using antisense RNA technology, resulting in down-regulation in the expression of amh transcription and Amh protein in males. Compared with the control groups, the fish in treatment groups with down-regulated amh had increased weight and an extremely significant decrease in the gonadosomatic index. Hematoxylin–eosin staining revealed impaired testis development and significant reductions in numbers of sperm. Serum estradiol levels were significantly increased, and the levels of testosterone, luteinizing hormone, and follicle-stimulating hormone were significantly decreased. RNA-sequencing analysis of the fish in the down-regulated amh and control groups identified 12,048 differentially expressed genes, of which 1281 were up-regulated and 10,767 were down-regulated. Kyoto Encyclopedia of Genes and Genomes analysis revealed that differentially expressed genes related to growth and development were mainly enriched in the Cell cycle, Endocytosis, TGF-beta signaling pathway, Wnt signaling pathway, FoxO signaling pathway, Insulin signaling pathway, and MAPK signaling pathway. The RNA-sequencing data accuracy was verified by qRT-PCR analysis of the expression levels of selected differentially expressed genes. The abnormal TGF-beta signaling pathway may cause fish weight gain, testis dysplasia, and abnormal spermatogenesis: smad5, smad3a, tgfb2, tgfbr1b, gsdf, and amh were significantly down-regulated. These findings indicated that antisense RNA technology has strong application prospects and can specifically knock down amh in Nile tilapia, resulting in an abnormal TGF-beta signaling pathway, inhibiting testis development and inducing weight gain.

Summary: Catalytic transfer hydrogenation (CTH) of biomass-derived furfural (FAL) to furfuryl alcohol is recognized as one of the most versatile techniques for biomass valorization. However, the irreversible sintering of metal sites under the high-temperature reaction or during the coke removal regeneration process poses a serious concern. Herein, we present a silicalite-1-confined ultrasmall CuO structure (CuO@silicalite-1) and then compared its catalytic efficiency against conventional surface-supported CuO structure (CuO/silicalite-1) toward CTF of FAL with alcohols. Characterization results revealed that CuO nanoparticles encapsulated within the silicalite-1 matrix are ∼1.3 nm in size in CuO@silicalite-1, exhibiting better dispersion as compared to that in the CuO/silicalite-1. The CuO@silicalite-1, as a result, exhibited nearly 100-fold higher Cu-mass-based activity than the CuO/silicalite-1 counterpart. More importantly, the activity of the CuO@silicalite-1 catalyst can be regenerated via facile calcination to remove the surface-bound carbon deposits, unlike the CuO/silicalite-1 that suffered severe deactivation after use and cannot be effectively regenerated.

Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer–CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment.

Abstract Active‐targeted nanoparticles are attractive carriers due to their potentials to facilitate specific delivery of drugs into tumor cells while sparing normal cells. However, the therapeutic outcomes of active‐targeted nanomedicines are hampered by the multiple physiological barriers in the tumor microenvironment (TME). Herein, an epidermal growth factor receptor‐targeted ultra‐pH‐sensitive nanophotosensitizer is fabricated, and the regulation of the TME to augment the active targeting ability and therapeutic efficacy is pinpointed. The results reveal that tumor vasculature normalization with thalidomide indiscriminately enhance the tumor accumulation of passive and active targeted nanoparticles, both of which are sequestered in the stromal bed of tumor mass. Whereas, photoablation of stromal cells located in perivascular regions significantly improves the accessibility of antibody‐modified nanophotosensitizer to receptor‐overexpressed cancer cells. After sequential regulation of TME, the antitumor efficacy of antibody‐modified nanophotosensitizer is drastically enhanced through synergistic enhancements of tumor accumulation and cancer cell accessibility of active‐targeted nanoparticles. The study offers deep insights about the intratumoral barriers that hinder the active‐targeted nanoparticles delivery, and provides a basis for developing more effective strategies to accelerate the clinical translation of active‐targeted nanomedicines.

Background: Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR. Methods: The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay. Results: Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. Conclusions: Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.

With the update and iteration of Internet technology, the socialized Q&A (question-and-answer) platform realizes the cross-border dissemination of knowledge with the main purpose of disseminating and sharing knowledge. Zhihu, as a knowledge-sharing platform that relies on the user-generated content model to maintain operation and the strong willingness of users to share knowledge, plays a key role in the development of the community. Currently, social Q&A platforms are facing problems such as low user participation rate and gradual decrease in the number of active users. It is very important and urgent to explore the factors that affect users’ willingness to share knowledge. In response to this problem, this paper builds a theoretical model of the factors that are affecting users’ willingness to share knowledge and uses questionnaire research methods to conduct research design and collect sample data and uses methods such as correlation analysis and structural equation modeling to verify the model and hypothesis. The research results show that the theoretical model of planned behavior has strong explanatory power and self-efficacy and material rewards have a positive effect on knowledge-sharing attitudes. Finally, according to some research results, this paper shows that, with the change of time, young people have different needs for knowledge sharing than before, while realizing self-worth through sharing experience, and we also hope to protect own interests and hope that there are more factors to encourage more users to share their knowledge and experience. Therefore, we propose that the platform can use incentive mechanisms to promote knowledge sharing while helping sharers realize their self-worth, improve the existing functions of the platform, or carry out activities to encourage users to participate, so as to achieve the purpose of knowledge sharing and maintain the operation of the Zhihu platform.

In this paper, we develop the Fudan-CCDC model by adding a source term to describe the imported infectors. The model is applied to analyze the situation of COVID-19 in East Asia, and then in Singapore. By data fitting, our model reveals that Singapore has a much higher isolation rate and earlier quarantine measures compared to other countries. We conclude that Singapore has been doing extraordinarily well on epidemic prevention and control. Finally we discuss the specific measures in Singapore’s success, and suggest other countries to learn from the Singapore’s style, so as to be well prepared in the future.

Distant metastasis is among the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. To identify patients with a high risk of distant metastasis is important to guide posttreatment surveillance, appropriate time treatments, and prolonging their long-term survival. In this study, we systematically examined the associations between a series of nodal-related characteristics and distant metastasis-free survival (DMFS) by detailed MRI reading and established a nomogram for DMFS in NPC patients. T-stage, age group, Epstein–Barr virus (EBV) level, central nodal necrosis, and nodal number were identified as independent risk factors for distant metastasis and were included into the final nomogram. The calibration plot showed a high agreement between the prediction by the nomogram and actual observations. Our established nomogram achieved a high C-index in predicting distant metastasis in both of the training cohort (0.737) and the validation cohort (0.718). This nomogram incorporated several readily available nodal features from the MR images, and it might be useful for guiding clinical decision and NPC patients' posttreatment surveillance. It also provides cues for how to redefine N-stage. Additional research is needed to confirm our conclusions.