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Abstract Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221.

Background:. As a systemic disease, pancreatic cancer (PC) can be treated systemically to raise the R0 resection rate and enhance patient prognosis. The best ways to assess the treatment response to systemic treatment of patients with PC are still lacking. Methods:. A total of 122 PC patients were enrolled; 25 of these patients were used as an independent testing set. According to the pathologic response, PC patients were classified into the responder and nonresponder groups. The whole tumor, core, edge, and peritumoral were segmented from the enhanced computed tomography (CT) images. Machine-learning models were created by extracting the variations in radionics features before and after therapy (delta radiomics features). Finally, we compared the performance of models based on radiomics features, changes in tumor markers, and radiologic evaluation. Results:. The model based on the core (area under curve [AUC] = 0.864) and edge features (AUC = 0.853) showed better performance than that based on the whole tumor (AUC = 0.847) or peritumoral area (AUC = 0.846). Moreover, the tumor core_edge combination model (AUC = 0.899) could better increase confidence in treatment response than using either of them alone. The accuracies of models based on changes in tumor markers and radiologic evaluation were relatively poorer than of the radiomics model. Moreover, Patients predicted to respond to therapy using the radiomics model showed a relatively longer overall survival (43 vs 27 months), although there were no significant differences (P = .063). Conclusions:. The tumor core_edge combination delta radiomics model is an effective approach to evaluate pathologic response in PC patients with systemic treatment.

Abstract Background Certain infectious diseases are caused by specific bacterial pathogens, including syphilis, gonorrhea, typhoid and paratyphoid fever, diphtheria, pertussis, tetanus, leprosy, and tuberculosis. These diseases significantly impact global health, contributing heavily to the disease burden. The study aims to thoroughly evaluate the global burden of syphilis, gonorrhea, typhoid and paratyphoid fever, diphtheria, pertussis, tetanus, and leprosy. Methods Leveraging the Global Burden of Disease (GBD) study 2021, age-specific and Socio-demographic Index (SDI)-specific incidence, disability-adjusted life-years (DALYs), and death for eight specific bacterial infections across 204 countries and territories from 1990 to 2021 were analyzed. Percentage changes in age-standardized incidence rate (ASIR), DALY rate, and mortality rate (ASMR) were also examined, with a focus on disease distribution across different regions, age groups, genders, and SDI. Results By 2021, among the eight diseases, gonococcal infection had the highest global ASIR [1096.58 per 100,000 population, 95% uncertainty interval (UI): 838.70, 1385.47 per 100,000 population], and syphilis had the highest global age-standardized DALY rate (107.13 per 100,000 population, 95% UI: 41.77, 212.12 per 100,000 population). Except for syphilis and gonococcal infection, the age-standardized DALY rate of the remaining diseases decreased by at least 55% compared to 1990, with tetanus showing the largest decrease by at least 90%. Globally, significant declines in the ASIR, age-standardized DALY rate, and ASMR for these eight bacterial infections have been observed in association with increases in the SDI. Regions with lower SDI, such as sub-Saharan Africa, experienced a relatively higher burden of these eight bacterial infections. Conclusions Although there has been an overall decline in these eight diseases, they continue to pose significant public health challenges, particularly in low SDI regions. To further reduce this burden in these areas, targeted intervention strategies are essential, including multi-sectoral collaboration, policy support, improved WASH management, and enhanced research efforts. Graphical Abstract

Objective: To determine the main components of Astragalus membranaceus (Fisch.) Bge (A. membranaceus, Huang Qi), Astragaloside IV (AIV) and Astragalus polysaccharides (AP), to characterize their properties, evaluate their in vivo efficacy, and to analyze drug diffusion using dissolving microneedle (DMN) technology in vivo. Methods: Respectively, AIV- and AP-loaded DMNs comprising chitosan (CTS) and polyvinyl alcohol (PVA) were prepared via dual-mold forming. Their morphology, mechanical properties, in vivo solubility, and skin irritation characteristics were tested. In vivo efficacy was assessed in cyclophosphamide-induced immunosuppressed mice, in vivo diffusion of AIV and AP by DMNs and conventional methods was compared, and the rheological properties of AIV-CTS-PVA and AP-CTS-PVA mixtures were measured. Results: Subcutaneous dissolution and absorption of AIV-CTS-PVA and AP-CTS-PVA microneedles (MNs) at low doses (50%–17% of intraperitoneal AIV injection and 12%–4% of intravenous AP injection) reduced the spleen index and acid phosphatase activity in immunosuppressed mouse models, increased the thymus index, and achieved equivalent or better systemic therapeutic effects. Compared with injections, AIV and AP achieved controllable solid-liquid conversion through delivery with CTS-PVA MNs, resulting in highly localized aggregation within 48 h, reducing the initial explosive effect of the drug, and achieving stable and slow drug release. Conclusion: The present study enhances our understanding of the efficacy and remote effects of drug-loaded DMNs from a traditional Chinese medicine (TCM) perspective, thereby promoting the development of precise and efficient delivery of TCM and further expanding the drug-loading range and application scenarios for DMNs.

Abstract The microscopic mechanism for the disappearance of superconductivity in overdoped cuprates is still under heated debate. Here we use scanning tunneling spectroscopy to investigate the evolution of quasiparticle interference phenomenon in Bi2Sr2CuO6+δ over a wide range of hole densities. We find that when the system enters the overdoped regime, a peculiar quasiparticle interference wavevector with arc-like pattern starts to emerge even at zero bias, and its intensity grows with increasing doping level. Its energy dispersion is incompatible with the octet model for d-wave superconductivity, but is highly consistent with the scattering interference of gapless normal carriers. The gapless quasiparticles are mainly located near the antinodes and are independent of temperature, consistent with the disorder scattering mechanism. We propose that a branch of normal fluid emerges from the pair-breaking scattering between flat antinodal bands in the quantum ground state, which is the primary cause for the reduction of superfluid density and suppression of superconductivity in overdoped cuprates.

Abstract Background YouTube, a widely recognized global video platform, is inaccessible in China, whereas Bilibili and TikTok are popular platforms for long and short videos, respectively. There are many videos related to laryngeal carcinoma on these platforms. This study aims to identify upload sources, contents, and feature information of these videos on YouTube, Bilibili, and TikTok, and further evaluate the video quality. Methods On January 1, 2024, we searched the top 100 videos by default sort order (300 videos in total) with the terms “laryngeal carcinoma” and “throat cancer” on YouTube, “喉癌” on Bilibili and TikTok. Videos were screened for relevance and similarity. Video characteristics were documented, and quality was assessed by using the Patient Education Materials Assessment Tool (PEMAT), Video Information and Quality Index (VIQI), Global Quality Score (GQS), and modified DISCERN (mDISCERN). Results The analysis included 99 YouTube videos, 76 from Bilibili, and 73 from TikTok. Median video lengths were 193 s (YouTube), 136 s (Bilibili), and 42 s (TikTok). TikTok videos demonstrated higher audience interaction. Bilibili had the lowest ratio of original contents (69.7%). Treatment was the most popular topic on YouTube and Bilibili, while that was the prognosis on TikTok. Solo narration was the most common video style across all platforms. Video uploaders were predominantly non-profit organizations (YouTube), self-media (Bilibili), and doctors (TikTok), with TikTok authors having the highest certification rate (83.3%). Video quality, assessed using PEMAT, VIQI, GQS, and mDISCERN, varied across platforms, with YouTube generally showing the highest scores. Videos from professional authors performed better than videos from non-professionals based on the GQS and mDISCERN scores. Spearman correlation analysis showed no strong relationships between the video quality and the audience interaction. Conclusions Videos on social media platforms can help the public learn about the knowledge of laryngeal cancer to some extent. TikTok achieves the best flow, but videos on YouTube are of the best quality. However, the video quality across all platforms still needs enhancement. We need more professional uploaders to ameliorate the video quality related to laryngeal carcinoma. Content creators also should be aware of the certification, the originality, and the style of video shooting. As for the platforms, refining the algorithm will allow users to receive more high-quality videos.

The process of viruses entering host cells is complex, involving multiple aspects of the molecular organization of the cell membrane, viral proteins, the interaction of receptor molecules, and cellular signaling. Most viruses depend on endocytosis for uptake, when viruses reach the appropriate location, they are released from the vesicles, undergo uncoating, and release their genomes. Heat shock cognate protein 70(HSC70): also known as HSPA8, a protein involved in mediating clathrin-mediated endocytosis (CME), is involved in various viral entry processes. In this mini-review, our goal is to provide a summary of the function of HSC70 in viral entry. Understanding the interaction networks of HSC70 with viral proteins helps to provide new directions for targeted therapeutic strategies against viral infections.

Bone morphogenetic proteins (BMPs) play an important biological role in pearl biomineralization in pearl mussels. In this study, based on the genome data of the triangular sail mussel (Hyriopsis cumingii), the genome-wide identification and bioinformatic analysis of BMP gene family were performed, and the expression pattern of the BMP genes was investigated by the insertion experiments. The results showed that a total of 12 BMP gene family members (BMP2a/2b, BMP3, BMP5a/5b, BMP7a/7b/7c, BMP9, BMP10a/10b, and BMP11) were identified, which were unevenly distributed on chromosome 3/14/18, encoding 169–583 amino acids, with molecular weights ranging from 19.32 to 65.99 kDa. BMP2a, BMP7b, and BMP10a were distributed, respectively, in the cytoplasm, endoplasmic reticulum and mitochondria, others were distributed in the nucleus. qRT-PCR results showed the significant tissue specificity in BMPs gene expression. The HcBMPs were differentially expressed in the mantle and visceral mass, and the expression level was higher in the visceral mass. The expressing trends of HcBMPs were not consistent between the mantle and visceral mass insertion, suggesting that HcBMPs may perform different functions. We also found that insertion surgery in the mantle and visceral mass significantly alters the expression profiling of the BMP gene family. Insertion of the mantle induced the biomineralization function of BMP2a, BMP7a, and BMP7b, while BMP3 and BMP10b played opposite roles in visceral mass insertion. Visceral mass insertion could suppress BMP9 expression at 5 d and BMP5b expression at 90 d after insertion This work lays the foundation and data support for the preliminary elucidation of regulatory role and mechanism of HcBMPs in the pearl-cultivating process of mantle and visceral mass.

Valencene, a sesquiterpene with the odor of sweet and fresh citrus, is widely used in the food, beverage, flavor and fragrance industry. Valencene is traditionally obtained from citrus fruits, which possess low concentrations of this compound. In the past decades, the great market demand for valencene has attracted considerable attention from researchers to develop novel microbial cell factories for more efficient and sustainable production modes. This review initially discusses the biosynthesis of valencene in plants, and summarizes the current knowledge of the key enzyme valencene synthase in detail. In particular, we highlight the heterologous production of valencene in different hosts including bacteria, fungi, microalgae and plants, and focus on describing the engineering strategies used to improve valencene production. Finally, we propose potential engineering directions aiming to further increase the production of valencene in microorganisms.

Sensorineural hearing loss (SNHL) is a prevalent condition in otolaryngology. A key obstacle is finding effective strategies for regenerating damaged cochlear hair cells in adult animals. A practical and reliable approach has been developed to create a superior cell source for stem cell transplantation in the inner ear to treat SNHL. Atoh1 is involved in the differentiation of neurons, intestinal secretory cells, and mechanoreceptors including auditory hair cells, and thus plays an important role in neurogenesis. Lentivirus-mediated transfection of bone marrow mesenchymal stem cells (BMSCs) was utilized to achieve stable expression of the essential transcription factor Atoh1, which is crucial for developing auditory hair cells without compromising cell survival. By manipulating the induction conditions through altering the cell growth environment using anti-adherent culture, the synergistic impact of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) was effectively applied to significantly improve the differentiation efficiency of bone marrow-derived mesenchymal stem cells (BMSC) into neural stem cells (NSCs) following Atoh1 transfection, thereby reducing the induction time. The study indicated that the newly proposed transdifferentiation method effectively transformed BMSCs into NSCs in a controlled environment, presenting a potential approach for stem cell transplantation to promote hair cell regeneration.

To determine the effect of cofermentation of Saccharomyces cerevisiae and different LABs on prune wine quality, this study compared phenolic compounds, organic acids, soluble sugars, biogenic amines and volatile flavor compounds among different treatments. The results showed that inoculation of LAB increased DPPH and total flavonoid content. Malic acid content was reduced in HS, HB and HF. Histamine content in S, F and B was lower than the limits in French and Australian wines. 15 phenolic compounds were identified. Yangmeilin and chlorogenic acid were detected only in HS, HF and HB. 51 volatile flavor compounds were identified, esters being the most diverse and abundant. 14 volatile flavor compounds with OAV > 1 contributed highly to the aroma of prune wine. 9 chemical markers including resveratrol, rutin, and catechin were screened to explain intergroup differences by OPLS-DA. This study provides new insights into the processing and quality analysis of prunes.

Abstract This study presents a novel method for optimizing parameters in urban flood models, aiming to address the tedious and complex issues associated with parameter optimization. First, a coupled one-dimensional pipe network runoff model and a two-dimensional surface runoff model were integrated to construct an interpretable urban flood model. Next, a principle for dividing urban hydrological response units was introduced, incorporating surface attribute features. The K-means algorithm was used to explore the clustering patterns of the uncertain parameters in the model, and an artificial neural network (ANN) was employed to identify the sensitive parameters. Finally, a genetic algorithm (GA) was used to calibrate the parameter thresholds of the sub-catchment units in different urban land-use zones within the flood model. The results demonstrate that the parameter optimization method based on K-means-ANN-GA achieved an average Nash-Sutcliffe efficiency coefficient (NSE) of 0.81. Compared to the ANN-GA and K-means-deep neural networks (DNN) methods, the proposed method better characterizes the runoff generation and flow processes. This study demonstrates the significant potential of combining machine learning techniques with physical knowledge in parameter optimization research for flood models.

Abstract Coronary chronic total occlusion (CTO) often occurs in patients with obstructive coronary artery disease, which remains one of the greatest challenges for interventional cardiologists. Coronary computed tomography angiography (CCTA) with its emerging post-processing techniques can provide a detailed assessment of CTO lesions before percutaneous coronary intervention (PCI), playing an important role in the clinical management of CTO PCI, from early diagnosis, pre-procedural outcome prediction, the crossing algorithm planning, intraprocedural guidance, and finally post-procedural assessment and follow-up. In addition, the feasibility of CT perfusion (CTP) in patients with CTO has been validated. Combined CCTA and CTP have the great potential to be the one-stop-shop imaging modality for assessing both anatomy and function of CTO lesions. This review aims to make radiologists understand the role of CCTA in the diagnosis and assessment of CTO lesions, thus assisting interventionalists in optimizing CTO PCI crossing strategies with the expertise of radiologists. Critical relevance statement The anatomical features of CTO on CCTA can reveal the complexity of CTO lesions and are associated with CTO PCI outcome, thus helping interventionalists optimize CTO PCI crossing strategies. Key points • CTO is the common lesion in invasive coronary angiography, and CTO PCI is technically difficult and its success rate is relatively low. • Length, collaterals, and attenuation-related signs can help distinguish CTO from subtotal occlusion. • The anatomical features of CTO lesions can help grade the difficulty of CTO PCI and predict procedural outcomes and long-term outcomes of CTO PCI. • The real-time fusion of CCTA with fluoroscopic angiography can be applied in highly complicated CTO lesions. • After CTO PCI, CCTA can help guide a second CTO PCI re-entry or follow up stent patency. Graphical Abstract

Abstract Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.

Abstract To serve in a more aggressive chlorine (Cl−) ions-containing environment, a chlorine ions insensitivity Mg-Nd-Zr alloys is fabricated, exhibiting a stable corrosion resistance in either 3.5wt.% or 10 wt.% NaCl solution. Unlike pure Mg who exhibit a negligible protection of the matrix, a distinct “hindering effect” of Cl− diffusion caused by doping elements within the corrosion film was observed. Its underlying mechanism is demonstrated by X-ray photoelectron spectroscopy (XPS) and Density functional theory (DFT) analysis. The introducing with Nd and Zr elements can effectively passivate vacancies and alter diffusion energy of chlorine ions.

This paper studies households’ expenditure on the education of children in China’s cities to assess how internal migrant families’ investment in the human capital of their offspring differs from that of local urban families. The private education-related expenditure reflects both households’ willingness to invest in human capital and institutional constraints, as China’s household registration (hukou) system prevents children without a local city hukou from enrolling in urban public schools. In-school fees (consisting of statutory tuition and institutional tuition fees) are commonly topped-up with substantial private tutoring expenditure. We apply multiple regression to the 2008 “Rural–Urban Migration Survey in China” data to analyze the average expenditure differences between temporary migrants, permanent migrants and locals. The findings are, after controlling for social and economic characteristics, that: (1) the overall spending on education of migrant households overwhelmingly exceeds that of locals, which is expected since migrants must finance privately all education-related expenses their children incur; (2) migrant households spend more on institutional tuition fees compared to households with a local city hukou, reflecting the varying severity of administrative hurdles faced by families; and (3) temporary migrants spend more on institutional tuition fees than permanent migrant households, but less in private tutoring.

The performance of the anode varies from the impurity ions in the copper electrowinning process. This work focused on the variation of the electrochemical behavior of the Pb-0.06%Ca-1.2%Sn anode as the Fe ions (Fe3+ and/or Fe2+) existed in the electrolyte by electrochemical characterization. Copper electrodeposition experiments were conducted under a current density of 300 A/m2, with the Fe ion concentration in the electrolyte controlled within the range of 0 to 20 g/L and the Cu ion concentration maintained at 45 g/L at a temperature of 45 °C. The variation in the corrosion resistance, catalytic activity, and structural composition of the anode film layer was analyzed in-depth according to the presence of Fe ions. The results show that the structure of PbO2 on the surface of the film was changed as Fe ions doped into the anode film, and the oxygen evolution activity of the anode was also improved. However, the corrosion resistance decreased with increasing Fe3+ concentration. Furthermore, the addition of 2 g/L Fe2+ in the electrolyte containing 2 g/L Fe3+ led to an elevation in the corrosion resistance of the anode to some extent and further increased the oxygen evolution activity.

Methicillin-resistant Staphylococcus aureus (MRSA) has been recognized in hospitals, community and livestock animals and the epidemiology of MRSA is undergoing a major evolution among humans and animals in the last decade. This study investigated the prevalence of MRSA isolates from ground pork, retail whole chicken, and patient samples in Hanzhong, China. The further characterization was performed by antimicrobial susceptibility testing and in-depth genome-based analysis to identify the resistant determinants and their phylogenetic relationship. A total of 93 MRSA isolates were recovered from patients (n = 67) and retail livestock products (n = 26) in Hanzhong, China. 83.9% (78/93) MRSA isolates showed multiple drug resistant phenotype. Three dominant livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) sequence types were identified: ST59-t437 (n = 47), ST9-t899 (n = 10) and ST398 (n = 7). There was a wide variation among sequence types in the distribution of tetracycline-resistance, scn-negative livestock markers and virulence genes. A previous major human MRSA ST59 became the predominant interspecies MRSA sequence type among humans and retail livestock products. A few LA-MRSA isolates from patients and livestock products showed close genetic similarity. The spreading of MRSA ST59 among livestock products deserving special attention and active surveillance should be enacted for the further epidemic spread of MRSA ST59 in China. Data generated from this study will contribute to formulation of new strategies for combating spread of MRSA.

IntroductionIn response to the increasing demand for long-term care services for older people, the Chinese government has launched a pilot program for long-term care insurance (LTCI) since 2016. The objective of this study is to evaluate the performance and effectiveness of this program in China and provide recommendations for the future development and expansion of the LTCI system.MethodsWe developed a comprehensive evaluation framework to assess these LTCI policies implemented in all 49 pilot cities in China.ResultsBased on our evaluation, the average assessment score for the LTCI program across all pilot cities was 71.8 points, with scores ranging from 57.5 to 92.5 points in these cities. Furthermore, most of the pilot cities achieved higher scores in the fact-based assessment compared to the value-based assessment.DiscussionThe results suggested that the overall pilot effect regarding LTCI was favorable, but there were significant regional disparities. Moreover, in most of pilot cities, current LTCI policies were designed to alleviate both the financial burden and the burden of caring for people with disabilities that families faced. However, some challenges still remained, such as the lack of community and home-based care services, the need to expand the coverage of insurance, and the importance of diversifying funding sources.

During field surveys and culture procedures, large growth disparities in Anguilla japonica have been observed. However, the potential causes are unknown. This study explored differences in digestive ability, metabolic levels, and transcriptomic profiles of appetite-related genes between growth-retarded eel (GRE) and normal-growing eel (NGE) under the same rearing conditions. The results showed that growth hormone (gh) mRNA expression in GREs was considerably lower than NGEs. The levels of total protein (TP), total cholesterol (T-CHO), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), blood ammonia (BA), blood urea nitrogen (BUN), and alkaline phosphatase (ALP) in GREs were significantly lower than in NGEs. Conversely, levels of glucose (GLU), alanine aminotransferase (ALT), and aspartate transaminase (AST) were higher in GREs. The activities of SOD, CAT, and T-AOC levels were also significantly lower in GREs, as were the activities of glucose-related enzymes including hexokinase (HK), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PASE). Additionally, orexigenic genes (npy and ghrelin) were dramatically downregulated, whereas anorexigenic genes (crh and pyy) were significantly upregulated in GREs. These findings suggested that variances in growth hormone, metabolic activities, and appetite level could be associated with the different growth rates of A. japonica. The present research not only revealed the characteristics of the growth, metabolism, and appetite of GREs but also offered new perspectives into the substantial growth discrepancies in A. japonica, providing novel ideas for enhancing fish growth.

The co-application of N and Fe can improve wine grape composition and promote the formation of flavor compounds. To understand the effects of foliar co-application of N and Fe on wine grape quality and flavonoid content, urea and EDTA-FE were sprayed at three different developmental stages. Urea and EDTA-Fe were sprayed during the early stage of the expansion period, at the end of the early stage of the expansion period to the late stage of the veraison period, and during the late stage of the veraison period. The results demonstrated that the co-application of urea and EDTA-Fe, particularly N application during the late stage of the veraison period and Fe application during the early stage of the berry expansion period (N3Fe1), significantly improved grape quality. Specifically, the soluble solid content of berries increased by 2.78–19.13%, titratable acidity decreased by 6.67–18.84%, the sugar-acid ratio became more balanced, and yield increased by 13.08–40.71%. Further, there was a significant increase in the relative content of amino acids and flavonoids. In conclusion, the application of Fe and N fertilizers at the pre-expansion and late veraison stages of grapes can significantly improve the quality and yield of berries; ultimately, this establishes a foundation for future improvement in the nutritional value of grapes and wine.

The acquisition of vegetation coverage information is crucial for crop field management, and utilizing visible light spectrum vegetation indices to extract vegetation coverage information is a commonly used method. However, most visible light spectrum vegetation indices do not fully consider the relationships between the red, green, and blue bands during their construction, making it difficult to ensure the accurate extraction of coverage information throughout the crop’s entire growth cycle. To rapidly and accurately obtain potato vegetation coverage information, drones were used in this study to obtain high-resolution digital orthoimages of potato growth stages. Based on the differences in the grayscale values of potato plants, soil, shadows, and drip irrigation belts, this study presents a combination index of blue and green bands (BGCI) and a combination index of red and green bands (RGCI). The vegetation index intersection method was used with 10 vegetation information indices to extract vegetation coverage, and the differences in extraction accuracy were compared with those of the maximum entropy method and bimodal histogram method. Based on the high-precision fraction vegetation coverage (FVC) extraction results, the Pearson correlation coefficient method and random forest feature selection were used to screen 10 vegetation and 24 texture features, and the top six vegetation indices most strongly correlated with the FVC were selected for potato growth stage FVC estimation and accuracy verification. A high-precision potato vegetation coverage estimation model was successfully established. This study revealed that during the potato tuber formation and expansion stages, the BGCI combined with the vegetation index intersection method achieved the highest vegetation coverage extraction accuracy, with overall accuracies of 99.61% and 98.84%, respectively. The RGCI combined with the vegetation index intersection method achieved the highest accuracy, 98.63%, during the maturation stage. For the potato vegetation coverage estimation models, the model based on the BGCI achieved the highest estimation accuracy (R2 = 0.9116, RMSE = 5.7903), and the RGCI also achieved good accuracy in terms of vegetation coverage estimation (R2 = 0.8987, RMSE = 5.8633). In the generality verification of the models, the R2 values of the FVC estimation models based on the BGCI and RGCI were both greater than 0.94. A potato vegetation coverage estimation model was constructed based on two new vegetation information indices, demonstrating good accuracy and universality.

To fully realize the potential application of spalled thermal barrier coating systems (TBCs) in gas turbine blades, it is essential to evaluate the service behavior of TBCs and the critical spallation size for safety servicing. For this purpose, the evaluation of the localized spallation of TBCs under high-temperature gas was investigated experimentally and numerically. Thermal insulation experiments and a conjugate heat transfer numerical algorithm were used to clarify the over-temperature phenomenon, temperature distributions, the relevant flow characteristics of the high-temperature gas in the localized spallation region of TBCs, and the influencing mechanisms that consider the spallation width were identified. The results suggested that when the spallation width was less than 10 μm, the temperature in the TBCs did not change due to the weak impression of gas. When the spallation width exceeded the security coefficient of about 3 mm, the TBCs were difficult to service safely due to the impact of high-temperature gas. Furthermore, the concept of an over-temperature coefficient was proposed to describe the over-temperature damage and a nonlinear fitting equation was obtained to reveal and predict the evolution of the over-temperature coefficient. The over-temperature coefficient may serve as a valuable metric in determining the performance degradation of TBCs.

Abstract Background Local tumor microenvironment (TME) plays a crucial role in immunotherapy for breast cancer (BC). Whereas, the molecular mechanism responsible for the crosstalk between BC cells and surrounding immune cells remains unclear. The present study aimed to determine the interplay between GPR81-mediated glucometabolic reprogramming of BC and the immune landscape in TME. Materials and Methods Immunohistochemistry (IHC) assay was first performed to evaluate the association between GPR81 and the immune landscape. Then, several stable BC cell lines with down-regulated GPR81 expression were established to directly identify the role of GPR81 in glucometabolic reprogramming, and western blotting assay was used to detect the underlying molecular mechanism. Finally, a transwell co-culture system confirmed the crosstalk between glucometabolic regulation mediated by GPR81 in BC and induced immune attenuation. Results IHC analysis demonstrated that the representation of infiltrating CD8+ T cells and FOXP3+ T cells were dramatically higher in BC with a triple negative (TN) subtype in comparison with that with a non-TN subtype (P

The low frequency ripple of the input side current of the single-phase inverter will reduce the efficiency of the power generation system and affect the overall performance of the system. Aiming at this problem, this paper proposes a two-modal modulation method and its MPC multi-loop composite control strategy on the circuit topology of a single-stage boost inverter with a buffer unit. The control strategy achieves the balance of active power on both sides of AC and DC by controlling the stable average value of the buffer capacitor voltage, and provides a current reference for inductance current of the DC input side. At the same time, the MPC controller uses the minimum inductor current error as the cost function to control inductor current to track its reference to achieve low frequency ripple suppression of the input current. In principle, it is expounded that the inverter using the proposed control strategy has better low frequency ripple suppression effect than the multi-loop PI control strategy, and the conclusion is proved by the simulation data. Finally, an experimental device of a single-stage boost inverter using MPC multi-loop composite control strategy is designed and fabricated, and the experimental results show that the proposed research scheme has good low frequency ripple suppression effect and strong adaptability to different types of loads.

Food security is a crucial issue that has caused extensive concern, and the use of food flavors has become prevalent over time. we used the molecular biological techniques, preservative susceptibility testing, viable but non-culturable (VBNC) state induction testing, and a transcriptome analysis to examine the bacterial contamination of favored syrup and identify the causes and develop effective control measures. The results showed that Asaia lannensis WLS1-1 is a microorganism that can spoil food and is a member of the acetic acid bacteria families. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests showed that WLS1-1 was susceptible to potassium sorbate (PS), sodium benzoate (SB), and sodium sulffte (SS) at pH 4.0. It revealed a progressive increase in resistance to these preservatives at increasing pH values. WLS1-1 was resistant to PS, SB and SS with an MIC of 4.0, 2.0 and 0.5 g/L at pH 5.0, respectively. The MIC values exceed the maximum permissible concentrations that can be added. The induction test of the VBNC state demonstrated that WLS1-1 lost its ability to grow after 321 days of PS induction, 229 days of SB induction and 52 days of SS induction combined with low temperature at 4°C. Additionally, laser confocal microscopy and a propidium monoazide-quantitative polymerase chain reaction (PMA-qPCR) assay showed that WLS1-1 was still alive after VBNC formation. There were 7.192 ± 0.081 (PS), 5.416 ± 0.149 (SB) and 2.837 ± 0.134 (SS) log10(CFU/mL) of viable bacteria. An analysis of the transcriptome data suggests that Asaia lannensis can enter the VBNC state by regulating oxidative stress and decreasing protein synthesis and metabolic activity in response to low temperature and preservatives. The relative resistance of Asaia lannensis to preservatives and the induction of the VBNC state by preservatives are the primary factors that contribute to the contamination of favored syrup by this bacterium. To our knowledge, this study represents the first evidence of the ability of Asaia lannensis to enter the VBNC state and provides a theoretical foundation for the control of organisms with similar types of activity.

Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the second leading cause of death from a single infectious disease globally and poses a significant economic and clinical burden in the world in 2022. Of particular concern is the emergence of drug-resistant TB, accounting for 15%–20% of TB deaths. It is imperative to delve into the global trends of incidence and death rate for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), drawing upon the comprehensive Global Burden of Disease (GBD) 2021 drug-resistant tuberculosis dataset. Methods: From the GBD 2021, data on incidence, prevalence, disability-adjusted life years (DALYs), and death of MDR-TB and XDR-TB from 1990 to 2021 were collected. We calculated the estimated annual percentage changes in age standardized incidence rate (ASIR) and age-standardized death rate (ASDR), segmented by age, sex, and Socio-demographic Index (SDI). The impacts of various risk factors on MDR-TB and XDR-TB were also analyzed. Results: In 2021, there were an estimated 443,680 (95% uncertainty interval [UI]: 259,196–766,545) incident cases of MDR-TB, and an estimated 106,818 (95% UI: 41,612–211,854) death cases of MDR-TB, while there were an estimated 24,036 (95% UI: 17,144–34,587) incident cases of XDR-TB and 7,946 (95% UI: 3,326–14,859) death cases of XDR-TB. The incidence and death cases of MDR-TB were lowest in high SDI regions, whereas the incidence rates of XDR-TB in high-middle SDI regions were higher than those in middle SDI and high SDI regions. Conclusion: This study reported the disease burden of drug-resistant TB from 1990 to 2021. Until 2021, drug-resistant TB is still a serious problem in low SDI countries, especially for high-risk age populations with high-risk factors. Controlling drug-resistant TB requires effective control strategies and healthcare systems.

Background Human demand for meat and dairy products will increase as a result of economic development and population growth, and the farming of ruminants, such as cattle and sheep, will also increase. Methane (CH4) emission from the enteric fermentation of ruminant livestock is a major source of greenhouse gas emissions and a significant contributor to global warming. Meanwhile, growth performance is often limited and animals are more vulnerable to diseases in high-density, intensive farming, greatly reducing livestock productivity, so developing ways to reduce CH4 emissions and improve ruminant productivity has become a research hotspot. Studies have reported that fenugreek (Trigonella foenum-graecum L.) as feed additives have the potential to reduce ruminant methane and improve the productivity. However, systematic reviews of such studies are lacking. Methodology In this review, databases of Google Scholar, Web of Science, PubMed, Scopus and Science Direct were used for the literature search. The initial keywords search was fenugreek or Trigonella foenum-graecum L. For more focused search, we added terms such as methane, rumen fermentation, growth, milk production and antioxidants. All were done for ruminants. The literature that conforms to the theme of this article is selected, summarized, and finally completed this article. Results By regulating the rumen microbiome (suppressing protozoans, methanogenic bacteria, and fungi), fenugreek can lower CH4 emissions according to many in vitro anaerobic fermentation experiments. Fenugreek secondary metabolites (saponins and tannins) are responsible for this impact, but it is still unclear exactly how they work. Therefore, more long-term in vivo experiments are needed to verify its efficacy. Fenugreek is also rich in alkaloids, amino acids, flavonoids, saponins and phenolic acids. These compounds have been shown to have beneficial effects on ruminant growth, lactation, and total antioxidant capacity. Therefore, fenugreek has a great opportunity to develop into a new green feed additive. Conclusions This review provides a summary of the effect of fenugreek and its bioactive compounds on rumen fermentation, CH4 emissions and production performance by ruminants. In addition, based on the available data, the possible biochemical pathway of fenugreek to reduce CH4 emissions in ruminants was described. Overall, the livestock feed industry has the opportunity to develop natural, environmentally-friendly feed additives based on fenugreek.

Abstract Competitive fitness assays are widely used in evolutionary biology and typically rely on a reference strain to compare different focal genotypes. This approach implicitly relies on the absence of interaction between the competing genotypes. In other words, the performance of the reference strain must not depend on the competitor. This report scrutinized this assumption by competing diverged Drosophila simulans populations against a common reference strain. We detected strong evidence for interaction between the competing genotypes: (1) Frequency‐dependent selection was common with opposite effects in genetically diverged populations. (2) Temporal heterogeneity of fitness estimates, which can be partially attributed to a competitor‐specific delay in the eclosion of the reference strain. We propose that this inconsistent behavior of the reference strain can be considered a specific case of a genotype × environment interaction. Focal populations could modify the environment of the reference strain, either indirectly by altering the microbiome composition and food availability or directly by genotype‐specific cannibalism. Our results provide new insights into the interaction of diverged genotypes and have important implications for the interpretation of competitive fitness assays.

BackgroundNurses at the frontline faced high risks of the COVID-19 infection, undertook heavy workloads of patient care, and experienced tremendous stress that often led to compassion fatigue.AimThis study was to explore the role of positive psychosocial resources (i.e., perceived social support and emotional regulation efficacy) in the relationship between role stress and compassion fatigue.MethodsA cross-sectional design was conducted in Hubei Province, China between May and September 2021. The Role Stress Questionnaire, the Perceived Social Support Scale, the Emotional Regulation Efficacy Scale, and the Professional Quality of Life Scale were used to measure key variables of interest. Nurse socio-demographic data were also collected. Structural equation modeling was used to explore the relationships, including potential mediating effect, among role stress, perceived social support, emotional regulation efficacy, and compassion fatigue.ResultsA total of 542 nurses participated in this investigation, and 500 were eventually enrolled in the analysis. The incidence of compassion fatigue among nurses was 94.2%, including 65.8% of nurses reporting at least moderate compassion fatigue. Univariate analysis showed that educational level, marital status, hospital rank, sleep time were the factors affecting compassion fatigue of the nurses. The structural equation modeling revealed that: Role stress had a direct positive effect on compassion fatigue; Perceived social support and emotional regulation efficacy partially mediated the link between role stress and compassion fatigue respectively; And there was a chain mediating role of perceived social support and emotional regulation efficacy between role stress and compassion fatigue.ConclusionThe incidence of compassion fatigue was high during the COVID-19 pandemic among bedside nurses in China. Improving social support and enhancing the efficacy of emotion regulation may help alleviate compassion fatigue directly and/or via buffering the impact of role stress.

An adequate thermodynamic model is required for describing the long-period stacking ordered (LPSO) phase because previously developed models cannot account for the accurate atomic occupancy of the LPSO structure. In this study, atomic structures of the equilibrated 18R and 10H phases in Mg–Y–Al alloys were systematically investigated via atomic-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF-TEM) and first-principles calculations. Three structures (α-type, β-type, and γ-type) with different numbers of Mg layers (one, two, and three, respectively) sandwiched between L12 structures were present in the 18R phase. Meanwhile, δ-type (without Mg layers), ε-type (with one Mg layer), and ζ-type (with two Mg layers) structures were detected in the 10H phase. The presence of the interstitial atoms in the L12 structure was confirmed by TEM and theoretical calculations. Based on the obtained results, a new thermodynamic model for the LPSO phase was constructed and successfully applied to establish the thermodynamic description of the Mg–Y–Al system. The CALPHAD-type calculation data obtained using the proposed thermodynamic description were in good agreement with the experimental results. The findings of this study can help elucidate the formation mechanism of LPSO phases and guide Mg–Y–Al alloy design.

Soil salinization is a severe problem in arid and semi-arid regions that substantially reduces local agricultural productivity and poses long-term risks to sustainable food production. Traditional soil conditioners and drip irrigation alone fall short in mitigating soil salinity, necessitating the development of more effective soil amendments with higher water retention capacity. This study conducted maize field trials from 2021 to 2022 on loamy alluvial soil in Ningxia, northwest China, aiming to evaluate the impact of three treatments: CK (flood irrigation with irrigation quota of 900 mm), D (drip irrigation with irrigation quota of 450 mm), and DC (drip irrigation with irrigation quota of 450 mm and 300 kg ha-1 carboxymethyl cellulose potassium (CMC-K) application). We investigated water-salt transport, soil fertility, and maize growth. The results revealed that a high frequency of drip irrigation significantly reduced surface soil salinity, thereby generating a desalination layer centered on the drip emitters. During the mature stage of maize growth in the second year of the experiment, the D and DC significantly increased soil moisture content by 11.61–20.43% in the 0–40 cm soil depth and reduced soil salinity by 17.50–23.10% compared with CK, yielding an average desalination rate of 23.42%. Compared to D, DC significantly increased soil organic carbon (6.70−44.62%), mineralized nitrogen (11.86−27.42%), effective phosphorus (6.52−65.13%), and soluble potassium (8.64−36.42%), mitigated surface evaporation, curbed groundwater loss, minimized transpiration of maize, and improved water use efficiency of maize cultivation, resulting in a marked 21.29% increase in grain yield. In summary, CMC-K was found to have a pronounced influence on water retention, salinity reduction, and crop productivity, and can be considered a promising novel soil amendment.

Abstract Background With the advent of intensive combination regimens, an increasing number of patients with unresectable pancreatic cancer (UPC) have regained the opportunity for surgery. We investigated the clinical benefits and prognostic factors of conversion surgery (CS) in UPC patients. Methods We retrospectively enrolled patients with UPC who had received CS following first-line systemic treatment in our center between 2014 to 2022. Treatment response, safety of the surgical procedure and clinicopathological data were collected. We analyzed the prognostic factors for postoperative survival among UPC patients who had CS. Results Sixty-seven patients with UPC were enrolled (53 with locally advanced pancreatic cancer (LAPC) and 14 with metastatic pancreatic cancer (MPC)). The duration of preoperative systemic treatment was 4.17 months for LAPC patients and 6.52 months for MPC patients. All patients experienced a partial response (PR) or had stable disease (SD) preoperatively according to imaging. Tumor resection was unsuccessful in four patients and, finally, R0 resection was obtained in 81% of cases. Downstaging was determined pathologically in 87% of cases; four patients achieved a complete pathological response. Median postoperative-progression-free survival (PO-PFS) was 9.77 months and postoperative overall survival (PO-OS) was 31.2 months. Multivariate logistic regression analyses revealed that the resection margin and postoperative changes in levels of tumor markers were significant prognostic factors for PO-PFS. No factors were associated significantly with PO-OS according to multivariate analyses. Conclusions CS is a promising strategy for improving the prognosis of UPC patients. The resection margin and postoperative change in levels of tumor markers are the most important prognostic factors for prolonged PFS. Multidisciplinary treatment in high-volume centers is strongly recommended. Prospective studies must be undertaken to resolve the various problems regarding optimal regimens, the duration of treatment, and detailed criteria for CS.

ABSTRACTAirway epithelial cells function as both a physical barrier against harmful substances and pathogenic microorganisms and as an important participant in the innate immune system. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in modulating inflammatory responses during respiratory infections. However, the signalling cascade that induces MMP-9 secretion from epithelial cells infected with Mycoplasma pneumoniae remains poorly understood. In this study, we investigated the mechanism of MMP-9 secretion in airway epithelial cells infected with M. pneumoniae. Our data clearly showed that M. pneumoniae induced the secretion of MMP-9 from bronchial epithelial cells and upregulated its enzymatic activity in a time- and dose-dependent manner. Using specific inhibitors and chromatin co-precipitation experiments, we confirmed that the expression of MMP-9 is reliant on the activation of the Toll-like receptor 2 (TLR2) and TLR6-dependent mitogen-activated protein kinase/nuclear factor- κB/activator protein-1 (MAPK/NF-κB/AP-1) pathways. Additionally, epigenetic modifications such as histone acetylation and the nuclear transcription factor Sp1 also regulate MMP-9 expression. M. pneumoniae infection also decreased the expression of the tumour suppressor reversion-inducing cysteine-rich protein with Kazal motifs (RECK) by inducing Sp1 phosphorylation. Overexpression of RECK significantly impaired the M. pneumoniae-triggered increase in MMP-9 enzymatic activity, although the level of MMP-9 protein remained constant. The study demonstrated that M. pneumoniae-triggered MMP-9 expression is modulated by TLR2 and 6, the MAPK/NF-κB/AP-1 signalling cascade, and histone acetylation, and M. pneumoniae downregulated the expression of RECK, thereby increasing MMP-9 activity to modulate the inflammatory response, which could play a role in airway remodelling.

Secondary soil salinization in arid and semi-arid regions is a serious problem that severely hampers local agricultural productivity and poses a threat to the long-term sustainability of food production. the utilization of organic soil amendments presents a promising approach to mitigate yield losses and promote sustainable agricultural production in saline-alkali soil. In this study, we established four distinct treatments, chemical fertilizer (CK), humic acid with chemical fertilizer (HA), carboxymethyl cellulose with chemical fertilizer (CMC), and amino acid with chemical fertilizer (AA), to elucidate their respective impacts on the reclamation of saline soil and the growth of maize. The findings of our study reveal notable variations in desalination rates within the 0-40 cm soil layer due to the application of distinct soil amendments, ranging from 11.66% to 37.17%. Moreover, application of amendments significantly increased the percentage of soil macro-aggregates as compared to the CK treatment. Furthermore, HA and AA treatments significantly augmented soil nutrient content (HA: 48.07%; AA: 39.50%), net photosynthetic rate (HA: 12.68%; AA: 13.94%), intercellular CO2 concentration (HA: 57.20%; AA: 35.93%) and maize yield (HA:18.32%; AA:16.81%). Correlation analysis and structural equation modeling unveiled diverse mechanisms of yield enhancement for HA, CMC, and AA treatments. HA enhanced yield by increasing organic matter and promoting soil aggregate formation, CMC improved soil water content and facilitated salt leaching due to its excellent water-holding properties, while AA increased yield by elevating soil organic matter and effective nitrogen content. Among the array of soil amendment materials scrutinized, HA treatment emerged as the most promising agent for enhancing soil conditions and is thus recommended as the preferred choice for treating local saline soils.

Biomineralization is a widespread phenomenon in marine mollusks and is responsible for the production of shells and pearls. However, the regulatory mechanisms governing the adaptive immune responses in the mollusk mantle and visceral mass during mineralization remain unclear. In this work, we examined the mantle and visceral mass immune responses of Hyriopsis cumingii during pearl culture using high-throughput sequencing techniques. A mantle transcriptome database was established using transcriptome sequencing technology and reference to the major databases. Digital gene expression profiling was used to identify the differentially expressed genes of mantle and visceral mass at different insertion periods. Moreover, quantitative real-time PCR was used to verify the expression of five immune-related genes. Transcriptome sequencing results showed 257,457 unigenes were identified. Digital gene expression profiles showed 1389, 3572, 1888, and 2613 differentially expressed genes (DEGs) in the mantle and visceral mass at 5, 20, 50, and 90 d after insertion, respectively, with the highest number at 20 d and the lowest at 5 d after insertion (q < 0.05). A cluster analysis of the DEGs showed similar clustering and expression features in the mantle to the control group, and at 5, 50 and 90 d, after mantle insertion. The DEGs in the visceral mass showed similar clustering and expression features to the control group and at 5, 20 and 50 d after insertion. We also screened 22 immune-related DEGs in the mantle and visceral mass during the same pearl culture period, including serine/threonine-protein kinase NLK, C-type lectin, and galectin. The greatest number of DEGs was found 90 d after insertion. Compared with the mantle, more immune-related DEGs were down-regulated than up-regulated in the visceral mass during pearl culture, indicating that the immune regulatory mechanisms in the visceral mass and the mantle differ during pearl culture, and that the visceral mass is liable to higher infection and mortality rates. Quantitative real-time PCR results showed that the expression of five immune-related genes was consistent with DGE results. Our findings will further knowledge of the immune systems that are present in the mantle and visceral mass during pearl culture.

BackgroundPreeclampsia (PE) is the primary cause of perinatal maternal-fetal mortality and morbidity. The exact molecular mechanisms of PE pathogenesis are largely unknown. This study aims to identify the hub genes in PE and explore their potential molecular regulatory network.MethodsWe downloaded the GSE148241, GSE190971, GSE74341, and GSE114691 datasets for the placenta and performed a differential expression analysis to identify hub genes. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), Gene Set Enrichment Analysis (GSEA), and Protein–Protein Interaction (PPI) Analysis to determine functional roles and regulatory networks of differentially expressed genes (DEGs). We then verified the DEGs at transcriptional and translational levels by analyzing the GSE44711 and GSE177049 datasets and our clinical samples, respectively.ResultsWe identified 60 DEGs in the discovery phase, consisting of 7 downregulated genes and 53 upregulated genes. We then identified seven hub genes using Cytoscape software. In the verification phase, 4 and 3 of the seven genes exhibited the same variation patterns at the transcriptional level in the GSE44711 and GSE177049 datasets, respectively. Validation of our clinical samples showed that CADM3 has the best discriminative performance for predicting PEConclusionThese findings may enhance the understanding of PE and provide new insight into identifying potential therapeutic targets for PE.

Abstract Microneedles, especially hollow microneedles (HMNs), play an important role in drug delivery, but most of the current HMNs are manufactured based on silicon microfabrication (lithography, etching, etc.), which are slightly conservative due to the lack of low‐cost, batch‐scale and customized preparation approach, especially for the HMNs with flexible substrate. For the first time, we propose the use of a high‐precision 3D printed master mold followed by a dual‐molding process for the preparation of HMNs with different shapes, heights, and inner and outer diameters to satisfy different drug delivery needs. The 3D printed master mold and negative mold can be reused, thereby significantly reducing the cost. HMNs are based on biocompatible materials, such as heat‐curing polymers or light‐curing resins. The thickness and rigidity/flexibility characteristics of the substrate can be customized for different applications. The drug delivery efficiency of the fabricated HMNs was verified by the in situ treatment of psoriasis on the backs of mice, which required only a 0.1‐fold oral dose to achieve similar efficacy, and the associated side effects and drug toxicity were reduced. Thus, this dual‐molding process can reinvigorate HMNs development.

In order to investigate the influence of various factors on working performance, mechanical properties and durability of sustainable Reactive Powder Concrete (RPC), and make it convenient for choose more cost-effective RPC incorporating industrial byproducts. The effective parameters (water-binder ratio, contents of water reducer, replacement ratios of fly ash (FA), silica fume (SF) and slag powder (SL)) of RPCs were examined by the tests of paste fluidity, compressive and flexural strength as well as water absorption. Besides, the effect of the active mineral admixtures on pore size distribution and surface morphology of RPCs was studied by Mercury Injection Porosimeter (MIP) and Scanning electron microscope (SEM). Results indicate that an obvious reduction in the workability of RPC, enhancement of strength, and reduction in water absorption can be achieved by substituting part of the cement with silica fume. Fly ash and slag powder can be used to substitute some cement in producing RPC, and the workability is improved, meanwhile the effect of fly ash is higher than that of slag powder. However, excessive replacement of cement with slag powder or fly ash leads to a reduction of the strength in the early stage and a greater absorption of water. Increment of curing age is associated with an enhancement of strength and a decrease in water absorption. The porosity is reduced by 5.2 % when cement is partially replaced with silica fume, and the microstructure is dominated by harmless pores. When replacement of silica fume is kept at 25 %, using slag powder or fly ash substitute part of cement also reduces the number of less harmful pores. It is beneficial to add slag powder to increase the number of gel pores, whereas fly ash reduces the number of gel pores. RPC can achieve a high strength, low water absorption, and improved economy and environmental protection when silica fume replaces up to 25 % cement, slag powder or fly ash replaces up to 30 % cement. This investigation is expected to provide a practical method in the mix design and engineering application of economical and sustainable RPC.

Our previous study showed that COPPER-CONTAINING AMINE OXIDASE (CuAO) and AMINOALDEHYDE DEHYDROGENASE (AMADH) could regulate the accumulation of γ-aminobutyric acid (GABA) in tea through the polyamine degradation pathway. However, their biological function in drought tolerance has not been determined. In this study, Camellia sinensis (Cs) CsCuAO1 associated with CsAMADH1 conferred drought tolerance, which modulated GABA levels in tea plants. The results showed that exogenous GABA spraying effectively alleviated the drought-induced physical damage. Arabidopsis lines overexpressing CsCuAO1 and CsAMADH1 exhibited enhanced resistance to drought, which promoted the synthesis of GABA and putrescine by stimulating reactive oxygen species’ scavenging capacity and stomatal movement. However, the suppression of CsCuAO1 or CsAMADH1 in tea plants resulted in increased sensitivity to drought treatment. Moreover, co-overexpressing plants increased GABA accumulation both in an Agrobacterium-mediated Nicotiana benthamiana transient assay and transgenic Arabidopsis plants. In addition, a GABA transporter gene, CsGAT1, was identified, whose expression was strongly correlated with GABA accumulation levels in different tissues under drought stress. Taken together, CsCuAO1 and CsAMADH1 were involved in the response to drought stress through a dynamic GABA-putrescine balance. Our data will contribute to the characterization of GABA’s biological functions in response to environmental stresses in plants.

Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.

Background The risks of diabetic retinopathy and carotid atherosclerosis (CAS) may be increased in diabetics with poor glycemic control, and CAS is a risk factor for both coronary heart disease and stroke. Understanding the relationship between diabetic retinopathy and CAS may offer insights into the development of new clinical decision-making strategies for improving diabetic complications. Objective To assess the correlation between CAS and proliferative diabetic retinopathy (PDR) in patients with type 2 diabetes mellitus (T2DM) with a long duration of diabetes and poor glycemic control. Methods A retrospective, case-control design was adopted. One hundred and fifty-eight T2DM patients〔glycosylated hemoglobin (HbA1c) ≥7.5%, glomerular filtration rate (eGFR) ≥60 ml·min-1· (1.73 m2) -1, and diabetes duration≥10 years; 53 with PDR, and other 105 without; 48 with normal carotid arteries and other 110 with CAS〕 were consecutively recruited from Department of Endocrinology, Beijing Tongren Hospital, CMU, from October 2014 to November 2015. Clinical characteristics and laboratory indices were recorded. Results Compared with patients without diabetic retinopathy, those with PDR had higher systolic blood pressure, 24-hour urinary microalbumin excretion rate, and resting heart rate, as well as lower eGFR (P

The spatiotemporal dynamics of the microglial inflammatory response to single vessel occlusion and recanalization are analysed, revealing four different response phases.

Emerging evidence suggests that cryptic translation within long noncoding RNAs (lncRNAs) may produce novel proteins with important developmental/physiological functions. However, the role of this cryptic translation in complex diseases (e.g., cancer) remains elusive. Here, we applied an integrative strategy combining ribosome profiling and CRISPR/Cas9 screening with large-scale analysis of molecular/clinical data for breast cancer (BC) and identified estrogen receptor α–positive (ER+) BC dependency on the cryptic ORFs encoded by lncRNA genes that were upregulated in luminal tumors. We confirmed the in vivo tumor-promoting function of an unannotated protein, GATA3-interacting cryptic protein (GT3-INCP) encoded by LINC00992, the expression of which was associated with poor prognosis in luminal tumors. GTE-INCP was upregulated by estrogen/ER and regulated estrogen-dependent cell growth. Mechanistically, GT3-INCP interacted with GATA3, a master transcription factor key to mammary gland development/BC cell proliferation, and coregulated a gene expression program that involved many BC susceptibility/risk genes and impacted estrogen response/cell proliferation. GT3-INCP/GATA3 bound to common cis regulatory elements and upregulated the expression of the tumor-promoting and estrogen-regulated BC susceptibility/risk genes MYB and PDZK1. Our study indicates that cryptic lncRNA-encoded proteins can be an important integrated component of the master transcriptional regulatory network driving aberrant transcription in cancer, and suggests that the “hidden” lncRNA-encoded proteome might be a new space for therapeutic target discovery.

Background and aims:. Many patients with HCC of Barcelona Clinic Liver Cancer (BCLC) stage A exceeding the Milan criteria, or of BCLC stage B, can undergo resection after successful preoperative therapy, but an optimal approach has not been identified. We investigated preoperative drug-eluting bead transarterial chemoembolization (DEB-TACE) plus sintilimab, in this setting. Approach and Results:. In this prospective, phase II study (NCT04174781), adults with HCC of BCLC stage A exceeding the Milan criteria, or BCLC stage B, and ineligible for surgical resection, received sintilimab 200 mg and DEB-TACE. The primary endpoint was progression-free survival by modified RECIST. Secondary endpoints included objective response rate, pathologic response rate, and safety. At the data cutoff (July 2022), among 60 patients, the objective response rate was 62% (37/60) and 51 patients had undergone surgery. After a median follow-up of 26.0 months (range, 3.4–31.8), the median progression-free survival was 30.5 months (95% CI: 16.1–not reached). Among patients undergoing surgery, median progression-free survival was not reached and the 12-month progression-free survival rate was 76% (95% CI: 67–91). A pathologic complete response was achieved in 14% (7/51) of these patients. All patients experienced at least one adverse event, but these were generally manageable. Exploratory analyses showed an association between cytokeratin, V-domain Ig-containing Suppressor of T-cell Activation, CD68, CD169, and cluster 13 fibroblasts and recurrence after surgery. Conclusions. Sintilimab plus DEB-TACE before surgery showed good efficacy and safety in patients with HCC of BCLC stage A exceeding the Milan criteria or BCLC stage B.

A novel magnetically-coupled energy storage inductor boost inverter circuit for renewable energy and the dual-mode control strategy with instantaneous value feedback of output voltage are proposed. In-depth research and analysis on the circuit, control strategy, voltage transmission characteristics, etc., providing the parameter design method of magnetically-coupled energy storage inductors and output filter. The circuit topology is cascaded by the input source ��in, the input filter ��in, a single-phase inverter bridge with a magnetically-coupled energy storage inductor, and a CL filter; The control strategy serves the output voltage as a reference to achieve the switch of step-down and step-up modes smoothly. The simulation results of a 1000 VA 100–200 VDC, 220 V 50 Hz AC inverter show that the proposed inverter can realize single-stage boost power conversion, which can adapt to resistive, capacitive and inductive loads, has high power density and low output waveform distortion. It has good application prospects in small and medium-capacity single-phase inverter occasions with low input voltage.

Abstract Psoriasis is a chronic inflammatory cutaneous disease; it has been discovered that stimulation of the nervous system increases susceptibility to psoriasis. Although the cholinergic anti-inflammatory pathway, which is mediated by the alpha-7 nicotinic acetylcholine receptor (α7nAChR), is critical for controlling multiple types of inflammation, its expression pattern and pathogenesis function in psoriatic lesioned skin tissue are unknown. We hereby analyzed the expression of α7nAchR in human and mouse psoriatic skin tissue. In vivo, PNU-282987 or Methyllycaconitine, a specific agonist or antagonist of α7nAchR, were administered to imiquimod (IMQ)-induced psoriatic mouse models. The macroscopic appearance and histopathological features of the psoriatic mice skin were evaluated. In addition, cell proliferation and differentiation markers were investigated. The level of pro-inflammatory cytokines released from the lesioned skin, as well as the activation of the relevant signaling pathways, were measured. Our findings indicated that psoriatic lesional skin expressed an increased level of α7nAChR, with its tissue distribution being primarily in skin keratinocytes and macrophages. In an IMQ-induced murine psoriasis model, α7nAChR agonist PNU-282987 treatment alleviated psoriasis-like inflammation by down-regulating the expression of multiple types of pro-inflammatory mediators and normalized keratinocyte proliferation and differentiation, whereas α7nAChR antagonist treatment exacerbated its effect. Mechanically, we observed that activation of the α7nAChR inhibited the activation of the STAT3 and NF-κB signaling pathways in in vitro cultured HaCaT cells induced by Th17-related cytokine IL-6/IL-22 or Th1-related cytokine TNF-α. Taken together, these findings demonstrate that attenuation of psoriatic inflammation via the cholinergic anti-inflammatory pathway is dependent on α7nAChR activation.

Abstract Background Ovarian cancer (OC) is one of the serious threats to the health of women worldwide, and accurate biomarkers are urgently demanded for early diagnosis of OC. We have previously confirmed that miR-205 promotes the invasion and metastasis of OC cells by inhibiting the expression of the tumor suppressor gene TCF21. In this study, we used liquid biopsy technology to detect the expression levels of the four genes, miR-205, CA125, HE4 and TCF21, in the exosomes of plasma of OC patients. Combined with analysis of clinicopathological parameters of OC patients, we aimed to provide efficient and non-invasive laboratory biomarkers for early diagnosis of OC. Methods 36 OC patients who were diagnosed in local hospitals from September 2020 to July 2021 were selected as OC group, 31 cases of surgically diagnosed with ovarian benign lesions were selected as benign group, and 32 healthy people who underwent physical examination during the same period were selected as a control group. We employed transmission electron microscope (TEM), Western blotting (WB), and nanoparticle tracking analysis (NTA) to identify biomarkers in the exosomes extracted from plasma of the three groups. The RNA levels of miR-205, CA125, HE4 and TCF21 genes in plasma exosomes were detected by real-time quantitative PCR (qRT-PCR) method. We used clinical pathological parameters and the Receiver Operating Characteristic (ROC) curves to evaluate the diagnostic efficacy for the genes detected in plasma exosomes. Results We found that the expression level of miR-205 in plasma exosomes of the OC group was significantly higher than that of the benign and control groups (P

The sequence determinants governing CRISPR/Cas9 specificity are not fully understood. Here, the authors devise a high-throughput dual-target synthetic system to explore the sequence features associated with CRISPR/Cas9 off-target effect, reveal a set of sequence-dependent rules, and develop an off-target prediction model and a strategy for Cas9-based allele-specific editing.