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Abstract There is a growing interest in the health impacts of PM2.5 originating from landscape fires. We conducted a time-series study to investigate the association between daily exposure to landscape fire PM2.5 and hospital admissions for cardiovascular events in 184 major Chinese cities. We developed a machine learning model combining outputs from chemical transport models, meteorological information and observed air pollution data to determine daily concentrations of landscape fire PM2.5. Furthermore, we fitted quasi-Poisson regression to evaluate the link between landscape fire PM2.5 concentrations and cardiovascular hospitalizations in each city, and conducted random-effects meta-analysis to pool the city-specific estimates. Here we show that, on a national scale, a rise of 1-μg/m3 in landscape fire PM2.5 concentrations is positively related to a same-day 0.16% (95% confidence interval: 0.01%–0.32%) increase in hospital admissions for cardiovascular disease, 0.28% (0.12%–0.44%) for ischemic heart disease, and 0.25% (0.02%–0.47%) for ischemic stroke. The associations remain significant even after adjusting for other sources of PM2.5. Our findings indicate that transient elevation in landscape fire PM2.5 levels may increase risk of cardiovascular diseases.

Abstract Background The integration of high-risk human papilloma virus (HPV) DNA into the human genome has been implicated in cervical carcinogenesis and head and neck squamous cell cancer. However, its role in lung squamous cell carcinoma is not well understood. In addition, tuberculosis (TB) and lung cancer(LC) share similar clinical symptoms and imaging features, increasing the risk of misdiagnosis. Case Presentation The patient presented with a 16-month history of hemoptysis, chest pain, and occasional fatigue, without fever, chills, or history of mechanical damage or autoimmune diseases. Examination revealed normal vital signs and laboratory parameters, except for a positive interferon-gamma release assay indicating tuberculosis infection. Bronchoscopic examinations identified congestion and edema of the tracheal wall, along with a tiny lesion in the right wall of the trachea. She had been misdiagnosed with tuberculosis. However, the diagnosis of squamous cell carcinoma was eventually confirmed by endoscopic biopsy. The patient’s macrogenomic second-generation sequencing (mNGS) of the bronchoscopic biopsy specimen was positive for HPV-16.The patient’s sex partner tested positive for HPV-16 in penile scrapings, indicating HPV transmission through oral sex. Conclusions This case highlights the potential for HPV infection acquired through oral sex to lead to lung squamous cell carcinoma. It emphasizes the importance of considering HPV-associated malignancies in patients with respiratory symptoms who engage in oral sexual behaviors.

Abstract Background This study was to analyze the roles of red blood cell distribution width (RDW), anion gap (AG) levels and their combined effects on the risk of acute kidney injury (AKI) following cardiac surgery. Methods This cohort study extracted the data of 1951 participants aged ≥ 18 years with the assessment of AKI after cardiac surgery during ICU stay from MIMIC-IV database between 2008 and 2019. Receiver operator characteristic (ROC) curve was used to determine the optimal cut-off value AG and RDW. The associations between AG, RDW, and the combined effects of AG and effects were evaluated via univariable and multivariable Logistic models. Odds ratio (OR) with 95% confidence interval (CI) were imputed. Results Among all the participants, 831 participants had AKI, and 1120 did not have AKI. ROC curves revealed that the optimum cut of points of AG and RDW were 12.75 mmol/L, and 13.65%, respectively. Increased risk of AKI was found in patients after cardiac surgery with AG > 12.75 mmol/L (OR = 1.44, 95%CI 1.15–1.80) or RDW > 13.65% group (OR = 1.23, 95%CI 1.01–1.50). In comparison to subjects with AG ≤ 12.75 mmol/L and RDW ≤ 13.65%, AG > 12.75 mmol/L and RDW ≤ 13.65% (OR = 1.42, 95%CI 1.07–1.89), and AG > 12.75 mmol/L and RDW > 13.65% (OR = 1.75, 95%CI 1.24–2.47) were associated with increased odds of AKI in patients after cardiac surgery. Conclusions AG and RDW had combined effects on risk of AKI in patients after cardiac surgery, which might offer an insight for the management of patients after cardiac surgery.

Abstract Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2 fl/fl ;Prx1 Cre ) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2 fl/fl ;Prx1 Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.

Abstract Background Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects. Methods In the present study, human umbilical cord-derived MSC spheroids (hUC-MSCsp) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSCsp on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSCsp was traced with RNA scope technology. Results We found that hUC-MSCsp significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSCsp also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-β1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSCsp were also tracked, and we found that hUC-MSCsp distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSCsp were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver. Conclusions This study reveals the distributions of transplanted hUC-MSCsp after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSCsp.

Abstract Background Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. Methods The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. Results Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. Conclusions Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy.

Abstract The clustering algorithm is an effective method for developing energy efficiency routing protocol for wireless sensor networks (WSNs). In clustered WSNs, cluster heads must handle high traffic, thus consuming more energy. Therefore, forming balanced clusters and selecting optimal cluster heads are significant challenges. The paper proposes a sector clustering algorithm based on K-means called KMSC. KMSC improves efficiency and balances the cluster size by employing symmetric dividing sectors in conjunction with K-means. For the selection of cluster heads (CHs), KMSC uses the residual energy and distance to calculate the weight of the node, then selects the node with the highest weight as CH. A hybrid single-hop and multi-hop communication is utilized to reduce long-distance transmissions. Furthermore, the impact of the number of sectors, the threshold for clustering, and the network size on the performance of KMSC has been explored. The simulation results show that KMSC outperforms EECPK-means, K-means, TSC, LSC, and SEECP in terms of FND, HND, and LND.

In this work, the influence of Mn and Ca doping on the microstructure and mechanical properties of Mg–3Zn, Mg–3Zn-0.5Mn, and Mg–3Zn-0.5Mn-1.2Ca alloys is systematically investigated. The addition of Mn elements is shown to exert no obvious effect on the microstructure of as-cast, as-homogenized, and extruded Mg–3Zn alloys. In contrast, the introduction of Ca into the extruded Mg–3Zn-0.5Mn alloy promotes the formation of nano-sized compounds and enhances grain refinement compared to the other two alloys. The extruded Mg–3Zn-0.5Mn alloy exhibits the higher yield strength (YS, 155 MPa) and ultimate tensile strength (UTS, 183 MPa) but the lower elongation (13%) than the extruded Mg–3Zn alloy (YS of 130 MPa, UTS of 175 MPa, and elongation of 25%). The improved strength of the extruded Mg–3Zn-0.5Mn alloy is mainly attributed to the refined grains, while both the lack of twinning deformation and strong texture result in ductility loss. The most optimal combination of strength and ductility is achieved in an extruded Mg–3Zn-0.5Mn-1.2Ca alloy (YS of 180 MPa, UTS of 250 MPa, and elongation of 26%). This suggests that fine grains and high volume fraction of nano-sized MgZn2 compounds contribute mainly to the strength of Mg–3Zn-0.5Mn-1.2Ca alloy. Although the grain refinement also facilitates the suppression of twinning in the extruded Mg–3Zn-0.5Mn-1.2Ca alloy, the weak texture and fine homogeneous grains are conducive to the high ductility.

The prevalence of collaborative learning in online virtual environments is on the rise. It is vital to investigate the effect of emotional interaction on the learning engagement of students. The university students who participated in 16 h of online collaborative learning responded to an anonymous survey. The instruments included Collaborative Learning Emotional Interaction Scale, Loneliness Scale, Positive and Negative Rumination Scale, and Learning Engagement Scale. The mediating and moderating roles of variables were tested. Both positive and negative emotional interactions in online collaborative learning positively predicted learning engagement. Positive emotional interaction can inversely predict loneliness, while negative emotional interaction has a positive effect on loneliness. Loneliness inversely predicts learning engagement. In the low level of positive rumination, loneliness has a significant inhibitory effect on learning engagement, and the effect is much greater than that in the high level of positive rumination. In online collaborative learning, loneliness mediates the effect of learners' emotional interaction on learning engagement. The level of positive rumination moderated the connection between loneliness and learning engagement, the second part of the mediation model. We can begin by increasing learners' positive rumination and reducing the detrimental impact of negative emotional interaction and isolation on learning engagement in online collaborative learning.

Guvermectin, a purine nucleoside natural product produced by the genus Streptomyces, has recently been registered as a new biopesticide to boost rice yield. Despite its economic and agricultural significance, the regulatory mechanisms of guvermectin biosynthesis remain essentially unknown, hindering industrial production and widespread agricultural application. Here, we examined the roles of two LacI family regulators, gvmR and gvmR2, located within and adjacent to the guvermectin biosynthesis cluster, respectively, in guvermectin production in Streptomyces caniferus NEAU6. GvmR activated the expression of the guvermectin cluster by binding to the promoters of gvmR, gvmA, and O1, while GvmR2 repressed the guvermectin cluster via competitive binding to promoters containing GvmR-binding sites, specifically, a 14-bp palindromic sequences: 5′-RTCATWCGYATGAY-3′ (R = G/A, W = A/T, Y = T/C). Moreover, GvmR indirectly activates the expression of gvmR2 while GvmR2 feedback inhibits gvmR transcription, suggesting a functional interaction between the two regulators for coordinating guvermectin production. Overexpression of gvmR via the T7 RNA polymerase-T7 promoter system in the gvmR2 mutant significantly elevated guvermectin production by 125 % (from 631 mg L−1 to 1422 mg L−1), compared to the parental strain NEAU6. This suggested that combinatorial manipulation of gvmR and gvmR2 is useful for improving guvermectin production. These findings enrich our knowledge of the regulatory network for guvermectin biosynthesis, and offer key targets and effective strategies for high-titer guvermectin production.

Southern China encountered two rounds of rainfall/snowfall and freezing weather accompanied by intensive lightning flashes from January 31 to February 5 and February 18-25,2024 (hereinafter referred to as "0131" and "0218" events,respectively). In this paper,three-dimensional lightning location data,CLDAS-V2.0 precipitation product,and infrared cloud image data of Himawari-9 satellite are used to analyze and compare the temporal and spatial distribution of cloud-to-ground (CG) flashes,the number of return strokes and the cumulative probability distribution of lightning current during these two events. The relationship between CG flashes with precipitation and satellite blackbody brightness temperature (TBB) is also investigated. The results are as follows. (1) More than 130,000 CG lightning flashes were detected in the two events,with positive and negative CG lightning strokes being more than 20,000 and 110,000,respectively. The CG flashes of the two events showed a nocturnal pattern,with the peak of the positive CG distribution lagging behind the total CG flashes and negative CG flashes by about 1-2 h. The probability of large current events generated by positive CG flashes was greater than that of negative CG flashes. (2) In the "0131" event,the large value of CG flash density appeared in the southern part of Guizhou and the junction of Guizhou,Chongqing,and Hubei provinces; In the "0218" event,the large value of CG density occurred in the eastern part of Hubei,the northern part of Jiangxi,Anhui,Jiangsu and most of Zhejiang. (3) The spatial and temporal distribution of precipitation and CG flashes during the "0131" event was inconsistent. The peak precipitation was concentrated in the daytime,with the precipitation mainly appearing in southeastern Hunan,Jiangxi,Anhui,and southern Jiangsu,and most of Zhejiang and Fujian. During the "0218" event,the spatial and temporal distribution of precipitation and CG flashes were consistent,with the peak of CG flashes being 2 h later than the peak of precipitation. (4) In both events,the distribution of CG flashes well indicated the convection regions. The CG flashes were mainly distributed in the southern tail of the convective cloud cluster,where the TBB gradient was large. Convective merging may lead to a jump in the frequency of CG flashes at the merging area. Almost no CG flashes were detected in the core of the cold clouds,where convection developed most vigorously. The CG flash density in both events increased first and then decreased with the increase of TBB.

Phosphorylation, the most extensive and pleiotropic form of protein posttranslation modification, is central to cellular signal transduction. Throughout the extensive co-evolution of plant hosts and viruses, modifications to phosphorylation have served multiple purposes. Such modifications highlight the evolutionary trajectories of viruses and their hosts, with pivotal roles in regulation and refinement of host-virus interactions. In plant hosts, protein phosphorylation orchestrates immune responses, enhancing the activities of defense-related proteins such as kinases and transcription factors, thereby strengthening pathogen resistance in plants. Moreover, phosphorylation influences the interactions between host and viral proteins, altering viral spread and replication within host plants. In the context of plant viruses, protein phosphorylation controls key aspects of the infection cycle, including viral protein functionality and the interplay between viruses and host plant cells, leading to effects on viral accumulation and dissemination within plant tissues. Explorations of the nuances of protein phosphorylation in plant hosts and their interactions with viruses are particularly important. This review provides a systematic summary of the biological roles of the proteins of plant viruses carrying diverse genomes in regulating infection and host responses through changes in the phosphorylation status. [Figure: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) is a severe disease with substantial economic consequences for the swine industry. The DEAD-box helicase 3 (DDX3X) is an RNA helicase that plays a crucial role in regulating RNA metabolism, immunological response, and even RNA virus infection. However, it is unclear whether it contributes to PRRSV infection. Recent studies have found that the expression of DDX3X considerably increases in Marc-145 cells when infected with live PRRSV strains Ch-1R and SD16; however, it was observed that inactivated viruses did not lead to any changes. By using the RK-33 inhibitor or DDX3X-specific siRNAs to reduce DDX3X expression, there was a significant decrease in the production of PRRSV progenies. In contrast, the overexpression of DDX3X in host cells substantially increased the proliferation of PRRSV. A combination of transcriptomics and metabolomics investigations revealed that in PRRSV-infected cells, DDX3X gene silencing severely affected biological processes such as ferroptosis, the FoxO signalling pathway, and glutathione metabolism. The subsequent transmission electron microscopy (TEM) imaging displayed the typical ferroptosis features in PRRSV-infected cells, such as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and cytoplasmic membrane rupture. Conversely, the mitochondrial morphology was unchanged in DDX3X-inhibited cells. Furthermore, silencing of the DDX3X gene changed the expression of ferroptosis-related genes and inhibited the virus proliferation, while the drug-induced ferroptosis inversely promoted PRRSV replication. In summary, these results present an updated perspective of how PRRSV infection uses DDX3X for self-replication, potentially leading to ferroptosis via various mechanisms that promote PRRSV replication.

Abstract Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin’s lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to “Watson–Crick” base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL. Graphical abstract

To examine how different harvesting periods affect the storage quality of 'Satsuma' plum fruits, this study analyzed 13 quality and physiological metrics post-harvest and utilized principal component analysis (PCA) and mathematical models to assess (0±0.5)℃ low temperature storage quality across three different harvesting periods (100 d after flowering, 103 d after flowering, 106 d after flowering). The results showed that harvesting at 103 days after full bloom led to the best preservation effect. Additionally, the hardness and total acidity of plum fruit decreased by 37.37% and 27.06% respectively until the end of the storage period, which was the slowest. Furthermore, changes in relative conductivity, anthocyanins, total soluble solids, malondialdehyde, total phenols, and flavonoids were relatively smooth. The activity of polyphenol oxidase was low, while peroxidase, superoxide dismutase, and catalase activities were high, specifically catalase activities. After conducting PCA analysis, it was determined that PC1, PC2, and PC3 accurately capture 87.472% of the relevant information. These results suggested that varying harvesting periods would have significant impacts on all indicators. The mathematical model analysis revealed that the plum fruits harvested at 100, 103, and 106 days after bloom, and stored for 56 days, had comprehensive scores of 1.06, 0.99, and 2.69, respectively. Lower comprehensive scores indicated better quality, so the order of preservation effect was as follows: 103 days after bloom>100 days after bloom>106 days after bloom. The study provides a theoretical framework for evaluating postharvest preservation and quality of plum fruits, along with technical parameters to enable timely harvesting.

Abstract MuB is a non-specific DNA-binding protein and AAA+ ATPase that significantly influences the DNA transposition process of bacteriophage Mu, especially in target DNA selection for transposition. While studies have established the ATP-dependent formation of MuB filament as pivotal to this process, the high-resolution structure of a full-length MuB protomer and the underlying molecular mechanisms governing its oligomerization remain elusive. Here, we use cryo-EM to obtain a 3.4-Å resolution structure of the ATP(+)-DNA(+)-MuB helical filament, which encapsulates the DNA substrate within its axial channel. The structure categorizes MuB within the initiator clade of the AAA+ protein family and precisely locates the ATP and DNA binding sites. Further investigation into the oligomeric states of MuB show the existence of various forms of the filament. These findings lead to a mechanistic model where MuB forms opposite helical filaments along the DNA, exposing potential target sites on the bare DNA and then recruiting MuA, which stimulates MuB’s ATPase activity and disrupts the previously formed helical structure. When this happens, MuB generates larger ring structures and dissociates from the DNA.

Abstract Background Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

A method is proposed here for the automatic generation of piano fingerings based on a temporal difference reinforcement learning model. For the special scene generated by piano fingering, this method adopts the temporal difference reinforcement learning algorithm of Q-learning as the learning model, which is concise and clear, with high learning speed. A set of applicable music and visual mapping rules are proposed, and based on the analysis of existing music visualization cases, a music visualization design strategy suitable for piano learning is proposed. Then, an application is designed to assist users in piano learning. The visualization design, intelligent sparring, and evaluation visualization design, enable piano learners to understand the characteristics and emotional expression of music in multiple dimensions during the learning process, and can also intuitively understand their performance. In addition, you can also use the sparring mode to interact with the community to improve your performance and aesthetic level further. On the problems existing in online piano sparring learning at this stage and how to make it play an active role in the overall development of people, some suggestions and thinking are put forward, and it is believed that better sparring requires the joint efforts of society, platforms, teachers, and parents. From the current point of view, integrating online and offline should be the most suitable way for students to learn piano. Still, in the future, with the continuous development of network technology and the continuous progress of human thinking and ability, this model will be further improved.

ABSTRACT: Hematological parameters refer to the assessment of changes in the number and distribution of blood cells, including leukocytes (LES), erythrocytes (ERS), and platelets (PLS), which are essential for the early diagnosis of hematological system disorders and other systemic diseases in livestock. In this context, the primary objectives of this study were to investigate the genomic background of 19 hematological parameters in Holstein cattle, focusing on LES, ERS, and PLS blood components. Genetic and phenotypic (co)variances of hematological parameters were calculated based on the average information restricted maximum likelihood method and 1,610 genotyped individuals and 5,499 hematological parameter records from 4,543 cows. Furthermore, we assessed the genetic relationship between these hematological parameters and other economically important traits in dairy cattle breeding programs. We also carried out genome-wide association studies and candidate gene analyses. Blood samples from 21 primiparous cows were used to identify candidate genes further through RNA sequencing (RNA-seq) analyses. Hematological parameters generally exhibited low-to-moderate heritabilities ranging from 0.01 to 0.29, with genetic correlations between them ranging from −0.88 ± 0.09 (between mononuclear cell ratio and lymphocyte cell ratio) to 0.99 ± 0.01 (between white blood cell count and granulocyte cell count). Furthermore, low-to-moderate approximate genetic correlations between hematological parameters with one longevity, 4 fertility, and 5 health traits were observed. One hundred ninety-nine significant SNP located primarily on the Bos taurus autosomes (BTA) BTA4, BTA6, and BTA8 were associated with 16 hematological parameters. Based on the RNA-seq analyses, 6,687 genes were significantly downregulated and 4,119 genes were upregulated when comparing 2 groups of cows with high and low phenotypic values. By integrating genome-wide association studies (GWAS), RNA-seq, and previously published results, the main candidate genes associated with hematological parameters in Holstein cattle were ACRBP, ADAMTS3, CANT1, CCM2L, CNN3, CPLANE1, GPAT3, GRIP2, PLAGL2, RTL6, SOX4, WDFY3, and ZNF614. Hematological parameters are heritable and moderately to highly genetically correlated among themselves. The large number of candidate genes identified based on GWAS and RNA-seq indicate the polygenic nature and complex genetic determinism of hematological parameters in Holstein cattle.

Abstract: Objective: This paper explores the relationship between alcohol consumption and psychological health outcome in an economically underdeveloped area of China. Methods: We conducted convenience sampling and recruited 439 participants at alcohol-related risk as identified by Alcohol Use Disorder Identification Test. Well-being and mental health were the primary outcomes. We employed multiple regression analysis to determine the correlation between alcohol consumption and health outcome. Results: Participants with higher scores for alcohol dependence were more likely to obtain higher scores for stress (0.11 [95% CI: 0.03, 0.19]), anxiety (0.15 [95% CI: 0.07, 0.23]) and depression (0.11 [95% CI: 0.03, 0.19]). Similarly, increasing scores for harmful alcohol use items were associated with higher scores for anxiety (0.08 [95% CI: 0.01,0.16]) and stress (0.08 [95% CI: 0.01,0.15]) and lower scores for positiveness (0.07 [95% CI: –0.14, –0.01]). Participants with stable incomes and the ethnic minority reported more favorable psychological outcomes or fewer negative emotions. Conversely, individuals who drank passively were more prone to experiencing lower positive and higher negative psychological effects. Conclusions: Higher scores on measures of alcohol dependence and harmful alcohol use indicate elevated psychological risks. Socioeconomic status, ethnicity, and drinking motivations modified the associations.

This study examined the potential correlation between the immoderate intake of sugar-sweetened beverages (SSBs) and the subsequent rate of diabetes remission (DR). 206 individuals who met the eligibility criteria between January 2019 and June 2022 were recruited. Inquiries were conducted to gather information on the participants’ beverage consumption before the onset. Subsequently, the participants were separated into the diabetes remission group (DR group) and nondiabetes remission group (NDR group) depending on whether they met the diagnostic criteria for diabetes remission. Baseline clinical elements within the two groups were juxtaposed, and factors influencing diabetes remission were identified through logistic regression analyses. The cutoff values of each critical factor were determined based on the receiver operating characteristic curve. One hundred and nine patients reported a history of SSB consumption, while the remaining 58 reported no such history. After 1 year, 40 patients achieved remission from diabetes. Compared with the NDR group, a higher SSBs ratio, body mass index (BMI), and blood creatinine (BCr) was observed in the DR group after adjusting for confounders, SSBs (odds ratio [OR] = 3.503; 95% confidence interval [CI] = 1.334–9.202; p = 0.011) and BCr (OR = 1.038; 95% CI = 1.003–1.079; p = 0.042) emerged as independent predictors of DR. The composite index of SSBs and BCr efficaciously predicted DR (area under the ROC curve [AUC] = 0.810, p < 0.001). SSBs and BCr were independent risk factors for DR. The amalgamation of these markers could more accurately predict DR.

Abstract Background A long-term follow-up of close contacts to monitor their infection status is essential to formulate a promising screening strategy. The study aimed to assess the dynamics of tuberculosis (TB) infection using Interferon-γ release assay (IGRA) and determine risk factors associated with TB infection. Methods Definite TB patients were interviewed and their household contacts were screened for TB infection by IGRA during 12-month longitudinal investigation. Results We included in our analyses 184 household contacts of 92 index TB patients. 87 individuals (47.3%) in contact group progressed to TB infection, of whom 86 developed into IGRA positive within 24 weeks. Close contacts with a higher age and comorbidities are easier to exhibit TB infection. Analysis showed that risk factors for becoming IGRA-positive individuals included residence, older age, comorbidities, BCG scar and high bacterial load. Contacts with BCG scar had a lower IGRA-positive rate. Conclusion IGRA conversion generally occurs within 24 weeks after exposure. The TB transmission happens since subclinical TB stage and the presence of BCG scar is an independent protective factor reducing risk of TB infection among close contacts. Repeated IGRA tests are sensible to conducted among close contacts at 24 weeks after exposure to identify the IGRA-positive individuals.

Abstract Background Osteoporosis and atherosclerosis frequently afflict older adults, and recent insights suggest a deeper connection between these conditions that surpasses mere aging effects. The ratio of non-high-density to high-density lipoprotein cholesterol (NHHR) has emerged as a novel lipid marker for evaluating the risk of cardiovascular diseases. Nonetheless, investigations into the correlation of the NHHR with the risk of developing osteoporosis remain unexplored. Methods We collected NHHR and bone mineral density (BMD) data from 11,024 National Health and Nutrition Examination Survey (NHANES) participants between 2011 and 2018. Multivariate linear regression was employed to examine the correlation between BMD and NHHR. Smooth curves were employed to deal with the nonlinearity. To further account for the nonlinear link, we used a two-part linear regression model. The threshold effects were estimated using two components of a linear regression model. Subgroup and sensitivity analyses were carried out to ascertain the stability of the findings. Results We discovered a negative relationship between the NHHR and lumbar spine BMD in all three models. An L-shaped curvilinear association existed between the NHHR and lumbar spine BMD, with a key inflection point of 6.91. The fully adjusted model showed that the BMD of the lumbar spine fell by 0.03 g/cm2 in those who were in the fourth quartile as opposed to the lowest quartile. The sensitivity analysis using unweighted logistic analysis verified the stability of the results. In addition, BMD in the nondiabetic group was more significantly affected by the negative effect of the NHHR in the subgroup analysis. Conclusions According to this research, there appears to be a negative correlation between BMD and NHHR in US Adults. To clarify the precise physiological mechanisms by which the NHHR contributes to the onset of osteoporosis, more research is necessary.

The kidney plays a crucial role in maintaining the body’s microenvironment homeostasis. However, current treatment options and therapeutic agents for chronic kidney disease (CKD) are limited. Fortunately, the advent of kidney organoids has introduced a novel in vitro model for studying kidney diseases and drug screening. Despite significant efforts has been leveraged to mimic the spatial-temporal dynamics of fetal renal development in various types of kidney organoids, there is still a discrepancy in cell types and maturity compared to native kidney tissue. The extracellular matrix (ECM) plays a crucial role in regulating cellular signaling, which ultimately affects cell fate decision. As a result, ECM can refine the microenvironment of organoids, promoting their efficient differentiation and maturation. This review examines the existing techniques for culturing kidney organoids, evaluates the strengths and weaknesses of various types of kidney organoids, and assesses the advancements and limitations associated with the utilization of the ECM in kidney organoid culture. Additionally, it presents a discussion on constructing specific physiological and pathological microenvironments using decellularized extracellular matrix during certain developmental stages or disease occurrences, aiding the development of kidney organoids and disease models.

Background: Non-optimum temperatures are associated with a considerable mortality burden. However, there is a lack of evaluation of labour productivity losses related to premature deaths due to non-optimum temperatures. This study aimed to quantify the labour productivity burden associated with premature deaths related to non-optimum temperatures and explore the potential socio-economic vulnerabilities. Methods: Daily all-cause mortality data were collected from 1,066 locations in 7 countries (Australia, Brazil, Canada, Chile, New Zealand, South Korea, and Thailand). Productivity-Adjusted Life-Year (PALY) loss due to each premature death was calculated to measure the labour productivity loss, by multiplying the years of working life lost by the proportion of the equivalent full-time (EFT) workers. A two-stage times series design and the generalized linear regression model with a quasi-Poisson family were applied to assess the association between non-optimum temperatures and the PALY loss due to premature deaths. Results: We observed a U-shaped relationship between temperature and PALY lost due to premature mortality. We estimated that 2.51% (95% eCI: 2.05%, 2.92%) of PALY losses could be attributed to non-optimal temperatures, with cold-related deaths contributing 1.26% (95% eCI: 0.94%, 1.54%) and heat-related deaths contributing 1.25% (95% eCI: 0.96%, 1.51%). Cold temperature contributed to the most PALYs lost in those aged 45–54 and 55–64, while heat-related losses predominated among the 15–44 age group. We also observed that the fractions of PALY lost attributed to extreme heat were positively associated with the relative deprivation index, while negatively associated with GDP per capita. Conclusion: This multi-country study highlights that non-optimum temperatures led to a considerable labour productivity loss and socioeconomically disadvantaged communities experience greater losses.

Pseudomonas plecoglossicida is a causative agent of visceral granulomas in large yellow croaker (Larimichthys crocea). Quorum sensing (QS) is widely involved in imparting virulence to pathogenic bacteria; however, it has not been studied in P. plecoglossicida. In this study, we annotated a LuxR family transcriptional regulator in P. plecoglossicida NB2011 and designated as PplR. We aligned the protein sequence by BlastP and Clustal X2, monitored the N-acyl-homoserine lactone (AHL) signal production through cross-feeding bioassay and HC-MS/MS; investigated exogenous AHL signal binding by recombinant expression and thin layer chromatography; constructed a deletion mutant of the target gene by method of double homologous recombination; sequenced the transcript RNA and analyzed the data; additionally, characterized phenotypes of wild type and mutant strain. The LuxR homolog PplR was found to share high similarity with PpoR—the LuxR solo of Pseudomonas putida—without a cognate LuxI. The wild-type strain did not produce any AHL signals and the recombinant LuxR protein was found to bind C6-L-homoserine lactone (C6-HSL), C8-HSL, 3-oxo-C10-HSL, and 3-oxo-C12-HSL. RNA-seq analysis indicated 84 differentially expressed genes—5 upregulated and 79 downregulated—mainly enriched in gene ontology terms, such as flagella-dependent motility, integral component of membrane, DNA binding and transcription, and metal ion binding, suggesting that PplR is a master transcription regulator. The mutant strain showed attenuated biofilm-forming ability and stress resistance, and the data support a role for PplR in the regulation of these traits in P. plecoglossicida NB2011 independent of the presence of AHL signals. This is the first study to provide QS-related information on P. plecoglossicida.

Abstract Surface chirality plays an important role in determining the biological effect, but the molecular nature beyond stereoselectivity is still unknown. Herein, through surface‐enhanced infrared absorption spectroscopy, electrochemistry, and theoretical simulations, we found diasteromeric monolayers induced by assembled density on chiral gold nanofilm and identified the positive contribution of water dipole potential at chiral interface and their different interfacial interactions, which result in a difference both in the positive dipoles of interfacial water compensating the negative surface potential of the SAM and in the hindrance effect of interface dehydration, thereby regulating the interaction between amyloid‐β peptide (Aβ) and N‐isobutyryl‐cysteine (NIBC). Water on L‐NIBC interface which shows stronger positive dipole potential weakens the negative surface potential, but its local weak binding to the isopropyl group facilitates hydrophobic interaction between Aβ42 and L‐NIBC and resulted fiber aggregate. Conversely, electrostatic interaction between Aβ42 and D‐NIBC induces spherical oligomer. These findings provide new insight into molecular nature of chirality‐regulated biological effect.

A crucial strategic choice for China’s sustainable growth in the new era is the carbon peak & carbon neutral (30–60) aim, which has set new and higher requirements for the green and sustainable development of cities in the new era, and the carbon peak & carbon neutral level is gradually becoming one of the important indicators of the green and sustainable development of cities. Based on disentangling the connotation of urban green development under the vision of carbon neutrality, this study constructed a framework system for assessing urban green development in the new era, measured and portrayed the spatial and temporal variation characteristics of green development efficiency (C-GDE) under the carbon neutrality constraint in 284 prefecture-level and above cities in China using the SBM-Undesirable model, and further explored the effect of multi-subject factors on urban C-GDE using the panel Tobit model. The main findings are as follows. (1) The average allocation level of C-GDE in Chinese cities has remained at a low level from 2009 to 2019, with an overall “V”-shaped trend of “down → up”, increasing from 0.4031 to 0.5206, an overall increase of 29.15 %. (2) The overall C-GDE of Chinese cities showed the decreasing characteristics of “western cities > eastern cities > central cities”, “super cities > small cities > medium cities > large cities > mega cities > mega cities”, “non class cluster cities > class II cities > class III cities > class I cities”, and “agriculture-led cities > industry-led cities > balanced development cities > business and tourism service cities”. (3) The spatio-temporal pattern of urban C-GDE was influenced by multiple factors such as individual-level factors, enterprise-level factors, government-level factors, and other basic-level characteristic factors. Each factor, through its own evolution or coupling with other factors, continuously shaped the internal development of the urban system and promotes the greening process and urban C-GDE. Finally, targeted recommendations were made based on the findings of the study.

Wildfires have devastating effects on society and public health. However, little evidence from population-based cohort has been performed to analyze the relationship of wildfire-related PM2.5, an important component of wildfire smoke, with cancer-specific mortality. We aimed to explore this relationship and identify vulnerable populations in UK with lower levels of wildfire-related PM2.5 exposure. The study consisted of 492394 participants (age: 38–73 years) recruited by UK Biobank during 2004–2010. The cumulative wildfire-related PM2.5 within 10 kilometers of residence over three years was used as exposure, which was assessed by chemical transport and machine learning models. A time-varying Cox regression was utilized to explore the relationship of exposure with diverse cancer-specific mortality outcomes. Subgroup analyses of a range of potential modifiers were performed. Each 10 μg/m3 increment of 3-year cumulative exposure was related to a 0.4 % greater risk of total cancer (95 %CI: 1.001–1.007), a 1.1 % greater risk of lung cancer (95 %CI: 1.004–1.018), and a 2.7 % greater risk of lip, oral cavity and pharynx (LOP) cancer (95 %CI: 1.005–1.049). Higher vulnerability in the wildfire-related PM2.5-lung cancer relationship was found among participants being retired than those with other employment status. Even lower levels of exposure to PM2.5 from wildfires were related to elevated mortality risks for cancer from total, lung, LOP, highlighting the importance of wildfire prevention and control. Further investigations are warranted to enrich and extend existing knowledge in this field.

Prior research has explored the relationship between occupational exposure to nickel and lung function. Nonetheless, there is limited research examining the correlation between blood nickel levels and lung function among young adults in the general population. The metabolomic changes associated with nickel exposure have not been well elucidated. On August 23, 2019, we enrolled 257 undergraduate participants from the Chinese Undergraduates Cohort to undergo measurements of blood nickel levels and lung function. The follow-up study was conducted in May 2021. A linear mixed-effects model was employed to assess the relationship between blood nickel levels and lung function. We also conducted stratified analyses by home address. In addition, in order to explore the biological mechanism of lung function damage caused by nickel exposure, we performed metabolomic analyses of baseline serum samples (N = 251). Both analysis of variance and mixed linear effect models were utilized to assess the impact of blood nickel exposure on metabolism. Our findings from cross-sectional and cohort analyses revealed a significant association between blood nickel levels and decreased forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) among young adults in the general population. Furthermore, we found stronger associations in urban areas. In metabolomics analysis, a total of nine metabolites were significantly changed under blood nickel exposure. The changed metabolites were mainly enriched in six pathways including carbohydrate, amino acid, and cofactor vitamin metabolism. These metabolic pathways involve inflammation and oxidative stress, indicating that high concentrations of nickel exposure can cause inflammation and oxidative stress by disrupting the above metabolism of the body.

Background: Cardiovascular disease originates in early life. We aimed to investigate the association between breastfeeding in infancy and cardiovascular disease in adult life. Methods: We followed 364,240 participants from UK Biobank aged 40–73 years from 2006 – 2010 to 2021. Information on breastfeeding in infancy was self-reported by questionnaire. Cox proportional hazard regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between breastfeeding and cardiovascular disease in middle-aged and older adulthood. The multivariable Cox models were used by adjusting for the age (used as the time scale), sex, ethnicity, assessment centre, birth weight, multiple birth status, maternal smoking during pregnancy, Townsend deprivation index, smoking status, alcohol drinker status, physical activity, and menopausal status for women. Binary and multinomial multivariable logistic regression models were used to explore the associations of breastfeeding in infancy with cardiovascular disease risk factors including obesity, body composition, metabolic and inflammatory disorders. Results: During a median of 12.6 years of follow-up, we documented 29,796 new cases of cardiovascular disease, including 24,797 coronary heart disease and 6229 stroke. The multivariable adjusted HRs for breastfed versus non-breastfed were 0.94 (95% CI: 0.91, 0.96) for cardiovascular disease, 0.94 (95% CI: 0.91, 0.96) for coronary heart disease, and 0.95 (95% CI: 0.89, 1.01) for stroke. Furthermore, the strength of observed association between breastfeeding and cardiovascular disease seems to decrease with age (P for interaction

Red blood cells (RBCs) naturally trap some bacterial pathogens in the circulation and kill them by oxidative stress. Following neutralization, the bacteria are presented to antigen-presenting cells in the spleen by the RBCs. This ability of RBCs has been harnessed to develop a system where they play a crucial role in enhancing the immune response, offering a novel approach to enhance the body’s immunity. In this work, a conjugate, G-OVA, was formed by connecting β-glucan and OVA through a disulfide bond. Poly (lactic-co-glycolic acid) (PLGA) was then employed to encapsulate G-OVA, yielding G-OVA-PLGA. Finally, the nanoparticles were adsorbed onto RBCs to develop G-OVA-PLGA@RBC. The results demonstrated that the delivery of nanoparticles by RBCs enhanced the antibody response to antigens both in vitro and in vivo. The objective of this study was to investigate the increased immune activity of G-OVA-PLGA nanoparticles facilitated by RBCs transportation and to elucidate some of its underlying mechanisms. These findings are anticipated to contribute valuable insights for the development of efficient and safe immune enhancers.

Objective: Recent studies reveal that necroptosis is pivotal in tumorigenesis, cancer metastasis, cancer immunity, and cancer subtypes. Apoptosis or necroptosis of hepatocytes in the liver microenvironment can determine the subtype of liver cancer. However, necroptosis-related genomes have rarely been analyzed in hepatocellular carcinoma (HCC). Therefore, this study aims to construct an HCC risk scoring model based on necroptosis-related genes and to validate its predictive performance in overall survival prediction and immunotherapy efficacy evaluation in HCC, as well as to analyze drug treatment responses. Methods: This study analyzed clinical information and RNA-seq expression data of liver cancer patients from TCGA public data, identified necroptosis-related genes, and conducted GO and KEGG enrichment analyses. Using Cox regression analysis and LASSO analysis to identify independent prognostic factors, a predictive model was established and validated in clinical subgroups, and correlation analysis with immune cells and ssGSEA differential analysis were conducted. Finally, potential drugs for HCC were screened to explore the drug sensitivity of different subtypes. Results: We identified 19 differentially expressed necroptosis-related genes and constructed a predictive model with 3 independent prognostic factors through stepwise Cox regression. Validation results from clinical subgroups showed that the constructed model performed well in risk prediction, and ssGSEA differential analysis results were significant. We analyzed 55 immunotherapy drugs, and clustered them by distinct IC50 values to guide drug selection for HCC patients. Notable, Bleomycin, Obatoclax. Mesylate, PF.562271, PF.02341066, QS11, X17. AAG, and Bl. D1870 exhibited significantly different sensitivities in different subtypes, providing references for clinical practice in HCC patients.

It is crucial to explore the earth-abundant, high-efficient and stable electrocatalysts suitable for accelerating water splitting kinetics of oxygen evolution reaction (OER) in alkaline electrolytes. Herein, FexCo1-xS2 (x = 0, 0.25, 0.5, 0.75 and 1) nanoparticles were fabricated via hydrothermal method and sulfidizing. Remarkably, the FeS2 delivers the most outstanding OER activity among prepared catalysts, with the overpotential of 240 mV for 10 mA/cm2, ultra-low Tafel slope of 45 mV/decades and high stability for 16 h. XRD, SEM, HRTEM, Raman and XPS characteristics before and OER process, TOF and electrochemical results indicate that surface reconstruction, strong combination of Fe-S and uniform dispersion of particles endow FeS2 with excellent catalytic property. The strong combination of Fe-S bond and uniform dispersion of FeS2 facilitates electron transfer. And the reconstructed crystalline-amorphous Fe2O3/FeOOH with rough surface may have a low energy barrier for the elementary reaction of O*→OOH*, which is responsible for boosting the generation of O2. In the practical two-electrode overall water splitting system in 1 M KOH, the FeS2/NF//Pt/C/NF system only needs an ultra-low cell voltage of 1.46 and 1.642 V to generate the current densities of 10 and 50 mA/cm2, respectively.

Abstract Fatty acid metabolism has been identified as an emerging hallmark of cancer, which was closely associated with cancer prognosis. Whether fatty acid metabolism-related genes (FMGs) signature play a more crucial role in biological behavior of esophageal squamous cell carcinoma (ESCC) prognosis remains unknown. Thus, we aimed to identify a reliable FMGs signature for assisting treatment decisions and prognosis evaluation of ESCC. In the present study, we conducted consensus clustering analysis on 259 publicly available ESCC samples. The clinical information was downloaded from The Cancer Genome Atlas (TCGA, 80 ESCC samples) and Gene Expression Omnibus (GEO) database (GSE53625, 179 ESCC samples). A consensus clustering arithmetic was used to determine the FMGs molecular subtypes, and survival outcomes and immune features were evaluated among the different subtypes. Kaplan–Meier analysis and the receiver operating characteristic (ROC) was applied to evaluate the reliability of the risk model in training cohort, validation cohort and all cohorts. A nomogram to predict patients’ 1-year, 3-year and 5-year survival rate was also studied. Finally, CCK-8 assay, wound healing assay, and transwell assay were implemented to evaluate the inherent mechanisms of FMGs for tumorigenesis in ESCC. Two subtypes were identified by consensus clustering, of which cluster 2 is preferentially associated with poor prognosis, lower immune cell infiltration. A fatty acid (FA) metabolism-related risk model containing eight genes (FZD10, TACSTD2, MUC4, PDLIM1, PRSS12, BAALC, DNAJA2 and ALOX12B) was established. High-risk group patients displayed worse survival, higher stromal, immune and ESTIMATE scores than in the low-risk group. Moreover, a nomogram revealed good predictive ability of clinical outcomes in ESCC patients. The results of qRT-PCR analysis revealed that the MUC4 and BAALC had high expression level, and FZD10, PDLIM1, TACSTD2, ALOX12B had low expression level in ESCC cells. In vitro, silencing MUC4 remarkably inhibited ESCC cell proliferation, invasion and migration. Our study fills the gap of FMGs signature in predicting the prognosis of ESCC patients. These findings revealed that cluster subtypes and risk model of FMGs had effects on survival prediction, and were expected to be the potential promising targets for ESCC.

Abstract Aims Additional evidence has indicated a correlation between N6-methyladenosine (m6A) RNA methylation and cardiovascular disease. Nevertheless, the alterations in RNA methylation modification and the expression of numerous genes remains unclear. This study aimed to identify the role of m6A in ST-segment elevation myocardial infarction (STEMI). Methods Two microarray datasets (GSE123342 and GSE59867) were downloaded from the GEO database. After merging the data and batch normalization, differentially expressed regulators were identified using the limma package. Subtyping consistency analysis was performed to group samples. The random forest algorithm and support vector machine were used to identify diagnostic biomarkers. Immune infiltration and inflammation levels among the subtypes were assessed using a single-sample gene set enrichment analysis. Results A total of 15 key differential m6A regulators (RBM15B, ELAVL1, ALKBH5, METTL16, ZC3H13, RBM15, YTHDC1, YTHDC2, YTHDF3, HNRNPC, FMR1, LRPPRC, HNRNPA2B1, RBMX, FTO) were identified using the random forest classifier and were found to be highly correlated by PPI analysis. Two distinct RNA modification patterns (cluster A and B) were validated based on the expression levels of the 15 key m6A regulators. GO and KEGG annotations showed that immunity and inflammation pathways were enriched. Immune infiltration analysis revealed that cluster 2 had higher immune activation than cluster 1. Further analysis showed that cluster 2 had a higher inflammation level, with IL-4 and IL-33 showing differential expression (p

Abstract Narrative medicine has become a meaningful solution to promote medical students’ professional and personal growth. However, there is a lack of study on how students benefit from the narrative medicine approach when developing identities. This study aimed to establish and implement an integrated English reading and writing curriculum based on collaborative reflection and discussion using the narrative medicine approach, exploring how students presented and constructed physician identities by performing speech acts. First-year undergraduate students majoring in clinical medicine were recruited. Collaborative reflection and discussion were conducted in the integrated course involving 14 pieces of medical-related narrative works, along with essential elements that guided the students to engage in classroom activities. In the following analysis, the qualitative analysis software NVivo was used to identify the main speech acts and their frequency to analyze students’ perception and recognition of different physician identities. Our analysis presented 33 major speech acts and revealed their frequency and characteristics, which we summarize in five interrelated physician identities. The fine-grained analysis showed how these identities were influenced by the narrative medicine approach, which provides enlightenment for supporting students to develop their professional identities. Another unique contribution of this study was to present the teaching basis and essential elements in an integrated humanistic curriculum. The results helped clarify the relationship between speech acts and physician identity and suggested that collaborative reflection and discussion using the narrative medicine approach improved the humanistic component that was in short supply in medical education through its interdisciplinary advantages, thus promoting professional identity development that can lead to higher-quality medical and emotional care.

Abstract The Hendra and Nipah viruses (HNVs) are highly pathogenic pathogens without approved interventions for human use. In addition, the interaction pattern between the attachment (G) and fusion (F) glycoproteins required for virus entry remains unclear. Here, we isolate a panel of Macaca-derived G-specific antibodies that cross-neutralize HNVs via multiple mechanisms. The most potent antibody, 1E5, confers adequate protection against the Nipah virus challenge in female hamsters. Crystallography demonstrates that 1E5 has a highly similar binding pattern to the receptor. In cryo-electron microscopy studies, the tendency of 1E5 to bind to the upper or lower heads results in two distinct quaternary structures of G. Furthermore, we identify the extended outer loop β1S2-β1S3 of G and two pockets on the apical region of fusion (F) glycoprotein as the essential sites for G-F interactions. This work highlights promising drug candidates against HNVs and contributes deeper insights into the viruses.

Abstract Background Hypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment. Methods Pol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood–brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated. Results This hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients. Conclusion Our study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury. Graphical Abstract

Abstract Background Floods are the most frequent weather-related disaster, causing significant health impacts worldwide. Limited studies have examined the long-term consequences of flooding exposure. Methods Flood data were retrieved from the Dartmouth Flood Observatory and linked with health data from 499,487 UK Biobank participants. To calculate the annual cumulative flooding exposure, we multiplied the duration and severity of each flood event and then summed these values for each year. We conducted a nested case-control analysis to evaluate the long-term effect of flooding exposure on all-cause and cause-specific mortality. Each case was matched with eight controls. Flooding exposure was modelled using a distributed lag non-linear model to capture its nonlinear and lagged effects. Results The risk of all-cause mortality increased by 6.7% (odds ratio (OR): 1.067, 95% confidence interval (CI): 1.063–1.071) for every unit increase in flood index after confounders had been controlled for. The mortality risk from neurological and mental diseases was negligible in the current year, but strongest in the lag years 3 and 4. By contrast, the risk of mortality from suicide was the strongest in the current year (OR: 1.018, 95% CI: 1.008–1.028), and attenuated to lag year 5. Participants with higher levels of education and household income had a higher estimated risk of death from most causes whereas the risk of suicide-related mortality was higher among participants who were obese, had lower household income, engaged in less physical activity, were non-moderate alcohol consumers, and those living in more deprived areas. Conclusions Long-term exposure to floods is associated with an increased risk of mortality. The health consequences of flooding exposure would vary across different periods after the event, with different profiles of vulnerable populations identified for different causes of death. These findings contribute to a better understanding of the long-term impacts of flooding exposure.

Abstract Honey authentication and traceability are crucial not only for economic purposes but also for ensuring safety. However, the widespread adoption of cutting-edge technologies in practical applications has been hampered by complex, time-consuming sample pre-treatment processes, the need for skilled personnel, and substantial associated expenses. This study aimed to develop a simple and cost-effective molecular technique to verify the entomological source of honey. By utilizing newly designed primers, we successfully amplified the mitochondrial 16S ribosomal RNA gene of honey bees from honey, confirming the high quality of the extracted DNA. Employing RFLP analysis with AseI endonuclease, species-specific restriction patterns were generated for honey derived from six closely related honey bees of the Apis genus. Remarkably, this method was proven equally effective in identifying heat-treated and aged honey by presenting the same RFLP profiles as raw honey. As far as we know, this is the initial research of the simultaneous differentiation of honey from closely related honey bee species using the restriction endonuclease AseI and mitochondrial 16S rRNA gene fragments. As a result, it holds tremendous potential as a standardized guideline for regulatory agencies to ascertain the insect origins of honey and achieve comprehensive traceability.

In order to make the active ingredients and flavor substances of fruit juice after sterilization treatment closer to the original freshly squeezed fruit juice, the compound juice was prepared with kiwifruit, pineapple and mango as raw materials in this paper. The effects of ultra-high pressure and heat treatment (85 ℃, 5 min) on the quality and shelf life of freshly squeezed compound juice were compared. The results showed that, as the volume ratio of the mixed juice was Vpineapple pulp:Vkiwi pulp:Vmango pulp=4:2:4, the pH, b* value and soluble solid content of the juice treated at 450 MPa, 25 ℃ and 15 min of ultra-high pressure had no significant difference (P>0.05) with the traditional heat treatment, but the loss of vitamin C content and polyphenol content decreased by 12.1% and 17.5%, respectively. By analyzing the main volatile components of the compound juice, it was found that the loss of flavor substances such as enes, esters, alcohols, ketones, and aldehydes in the UHP treatment juice was significantly less than that in the heat treatment juice (P

Background Gallbladder cancer is featured by difficult early detection, poor treatment effectiveness and high mortality. An in-depth epidemiology research of gallbladder cancer can provide valuable data for the formulation of prevention and treatment strategies for gallbladder cancer. Objective To analyze the trend of disease burden of gallbladder cancer in China from 1990 to 2019, and to estimate its onset age, period, cohort effects and future trends. Methods Data of disease burden of gallbladder cancer, including the incidence, prevalence, mortality, disability adjusted life year (DALYs) rate and corresponding standardized rates in China from 1990 to 2019 were extracted from the 2019 Global Burden of Disease Research (GBD 2019) database from March to June 2023. The annual percentage change (APC) and average annual percentage change (AAPC) were calculated using Joinpoint to analyze the trend of disease burden of gallbladder cancer in China from 1990 to 2019. A Bayesian age-period-cohort analysis (BAPC) model was created to predict the incidence of gallbladder cancer in China from 2020 to 2030. Results From 1990 to 2019, the standardized incidence rate of gallbladder cancer in China significantly rose from 1.58/100 000 in 1990 to 2.01/100 000 in 2019, with the AAPC of 0.82% (95%CI=0.65%-1.00%, P

Abstract The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2FEM1B. Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2FEM1B-mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.