Search

Massive open online courses (MOOCs) have become one of the most popular ways of learning in recent years due to their flexibility and convenience. However, high dropout rate has become a prominent problem that hinders the further development of MOOCs. Therefore, the prediction of student dropouts is the key to further enhance the MOOCs platform. The traditional dropout prediction models based on machine learning are difficult to guarantee the prediction effect due to the shortcomings such as insufficient mining of feature information and not considering the influence of time series. To address this problem, in this paper, we propose the learning behavior feature fused deep learning network model (LBDL) for MOOC dropout prediction. The core of the model lies in modeling different types of information separately and incorporating them into an overall framework. In the data processing stage, the LBDL model divides the data features into video learning behavior features containing time series information and general information features. For video learning behavior features, the model uses Bi-LSTM and attention mechanisms to mine time series information, and for general information features, it uses embedding layer and fully connected layer for processing. A hidden vector containing both types of feature information can be obtained by two different modeling approaches. Then the original feature information is combined to train the gradient boosting framework LightGBM. Experiments on the MOOCCube video dataset show that the AUC and F1-Score of our model can reach 82.39% and 74.89%, respectively, which are higher than other baseline models. It indicates that the proposed LBDL model has better performance in the dropout rate prediction problem.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a group of chronic interstitial pulmonary diseases characterized by myofibroblast proliferation and extracellular matrix (ECM) deposition. However, current treatments are not satisfactory. Therefore, more effective therapies need to be explored. Cepharanthine (CEP) is a naturally occurring alkaloid that has recently been reported to have multiple pharmacological effects, particularly in chronic inflammation. Methods For in vivo experiments, first, a pulmonary fibrosis murine model was generated via tracheal injection of bleomycin (BLM). Second, the clinical manifestations and histopathological changes of the mice were used to verify that treatment with CEP might significantly reduce BLM-induced fibrosis. Furthermore, flow cytometric analysis was used to analyze the changes in the number of M2 macrophages in the lung tissues before and after treatment with CEP to explore the relationship between macrophage M2 polarization and pulmonary fibrosis. In vitro, we constructed two co-culture systems (THP-1 and MRC5 cells, RAW264.7 and NIH 3T3 cells), and measured the expression of fibrosis-related proteins to explore whether CEP could reduce pulmonary fibrosis by regulating macrophage M2 polarization and fibroblast activation. Results The results showed that the intranasal treatment of CEP significantly attenuated the symptoms of pulmonary fibrosis induced by BLM in a murine model. Our findings also indicated that CEP treatment markedly reduced the expression of fibrosis markers, including TGF-β1, collagen I, fibronectin and α-SMA, in the mouse lung. Furthermore, in vitro studies demonstrated that CEP attenuated pulmonary fibrosis by inhibiting fibroblast activation through modulating macrophage M2 polarization and reducing TGF-β1 expression. Conclusions This study demonstrated the potential and efficacy of CEP in the treatment of pulmonary fibrosis. In particular, this study revealed a novel mechanism of CEP in inhibiting fibroblast activation by regulating macrophage M2 polarization and reducing the expression of fibrosis-associated factors. Our findings open a new direction for future research into the treatment of pulmonary fibrosis.

Abstract Copper (Cu)-based catalysts show promise for electrocatalytic CO2 reduction (CO2RR) to multi-carbon alcohols, but thermodynamic constraints lead to competitive hydrocarbon (e.g., ethylene) production. Achieving selective ethanol production with high Faradaic efficiency (FE) and current density is still challenging. Here we show a multivalent Cu-based catalyst, Cu-2,3,7,8-tetraaminophenazine-1,4,6,9-tetraone (Cu-TAPT) with Cu2+ and Cu+ atomic ratio of about 1:2 for CO2RR. Cu-TAPT exhibits an ethanol FE of 54.3 ± 3% at an industrial-scale current density of 429 mA cm−2, with the ethanol-to-ethylene ratio reaching 3.14:1. Experimental and theoretical calculations collectively unveil that the catalyst is stable during CO2RR, resulting from suitable coordination of the Cu2+ and Cu+ with the functional groups in TAPT. Additionally, mechanism studies show that the increased ethanol selectivity originates from synergy of multivalent Cu sites, which can promote asymmetric C–C coupling and adjust the adsorption strength of different carbonaceous intermediates, favoring hydroxy-containing C2 intermediate (*HCCHOH) formation and formation of ethanol.

The burgeoning field of photocatalytic reduction of CO2 has emerged as a remarkable promising solution to address some of the most pressing global energy and environmental issues which we face today. Researchers around the global have been striving to augment the efficiency of CO2 photocatalytic reduction, employing strategies that range from modifying the fundamental properties of photocatalysts to suppress the electron-hole recombination, optimizing reaction conditions to achieve the highest yield, and conceptualizing and constructing photoreactors to improve the adsorption process. Among these factors, the photoreactor plays a critical role in enhancing the overall photocatalytic efficiency. Understanding the various types of photoreactors and their operational dynamic can significantly influence the experimental design, thus guiding the data collecting and analysis. Compared to the solid-liquid phase, gas-solid phase photocatalytic reduction of CO2 is gaining recognition for its potential advantages, such as rapid molecular diffusion rates, adjustable CO2 concentrations, and uniform and sufficient light exposure. Nonetheless, the currently reported gas-solid phase photoreactors are still in their infancy. In this review, we dissect the underlying mechanism of photocatalytic CO2 reduction and the performance evaluation criteria of photoreactors, and review the development process of gas-solid phase photoreactors. Furthermore, we explore the evolution of gas-solid phase photoreactors, elucidating their growth trajectory and future possibilities. We present a comprehensive classification of gas-solid phase photoreactors, offering a new insight into their design and functionality, summarizing their strengths and inevitable limitations. Finally, we provide a forward-looking perspective on the future developmental prospects of carbon neutrality.

SiC-based composites are widely used as electromagnetic wave absorbers due to their excellent dielectric properties. However, the constraints associated with structural design and the intricacies of the preparation process hinder their broader application. In this study, novel mullite anti-gyroid/SiC gyroid metastructures are designed to integrate the mechanical and electromagnetic wave (EMW) absorption properties of composite materials. Mullite anti-gyroid/SiC gyroid composites are fabricated utilizing a combination of digital light processing (DLP) three-dimensional (3D) printing and precursor infiltration and pyrolysis (PIP) processes. Through the modulation of structural units, the electromagnetic parameters can be effectively regulated, thus improving the impedance matching characteristics of the composites. The structural composites show outstanding EMW absorption properties, with a minimum reflection loss of −54 dB at a thickness of 1.9 mm and an effective absorption bandwidth of 3.20 GHz at a thickness of 2.2 mm. Furthermore, the PIP process significantly enhances the mechanical properties of the composites; compared with those of the mullite/SiC ceramics, the flexural strength of the composites is improved by 3.69–5.85 times (13.28±1.15 MPa vs. (49.05±1.07)–(77.78±3.72) MPa), and the compressive strength is improved by 4.59–13.58 times (8.55±0.90 MPa vs. (39.02±1.63)–(116.13±2.58) MPa). This approach offers a novel and effective method for fabricating structural composites with an expanded range of higher electromagnetic wave absorption properties and improved mechanical properties.

Purpose: To evaluate the effect of anterior-segment structure on vault and position after implantable collamer lens (ICL) implantation using ultrasound biomicroscopy. Methods: The retrospective case-control study included insufficient vault eyes (750 µm). The preoperative biometric parameters of the anterior-segment structure and basic data between the three groups were analyzed using one-way analysis of variance. Results: There were significant differences (P < 0.05) between the three groups in maximum ciliary body thickness (CBTmax), iris-zonule distance (IZD), and trabecular-ciliary angle (TCA). The vault gradually decreased as CBTmax decreased and TCA increased. In the pairwise comparison, the CBTmax comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.024, 95% CI: −0.17–0.017 µm); the TCA comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.005, 95% CI: 1.78°–12.15°); The IZD comparison between the insufficient vault (750 µm) group was statistically significant (P = 0.037, 95% CI: 0.0027–0.1119 µm). The analysis of 284 ICL haptics locations showed that there were 16.67%, 32.69%, and 70.83% haptics located in the ciliary sulcus in three groups, respectively. Conclusion: The vault and ICL haptics position are related to anterior-segment structure. A thinner and posteriorly positioned ciliary body would increase the risk of low vault and fewer ICL haptics located in the ciliary sulcus after ICL implantation. This provides guidance for the selection of the ICL size and placement position before surgery.

Abstract This study aims to explore the efficacy of a hybrid deep learning and radiomics approach, supplemented with patient metadata, in the noninvasive dermoscopic imaging-based diagnosis of skin lesions. We analyzed dermoscopic images from the International Skin Imaging Collaboration (ISIC) dataset, spanning 2016–2020, encompassing a variety of skin lesions. Our approach integrates deep learning with a comprehensive radiomics analysis, utilizing a vast array of quantitative image features to precisely quantify skin lesion patterns. The dataset includes cases of three, four, and eight different skin lesion types. Our methodology was benchmarked against seven classification methods from the ISIC 2020 challenge and prior research using a binary decision framework. The proposed hybrid model demonstrated superior performance in distinguishing benign from malignant lesions, achieving area under the receiver operating characteristic curve (AUROC) scores of 99%, 95%, and 96%, and multiclass decoding AUROCs of 98.5%, 94.9%, and 96.4%, with sensitivities of 97.6%, 93.9%, and 96.0% and specificities of 98.4%, 96.7%, and 96.9% in the internal ISIC 2018 challenge, as well as in the external Jinan and Longhua datasets, respectively. Our findings suggest that the integration of radiomics and deep learning, utilizing dermoscopic images, effectively captures the heterogeneity and pattern expression of skin lesions.

The Pearl River Basin, China’s second-largest freshwater basin, hosts a significant diversity of species and a highly endemic freshwater mussel fauna. In this study, a new species from the Liuxi River in Guangzhou, Guangdong, China, Pletholophus guangzhouensis sp. nov., is described based on morphological diagnostic features and molecular phylogenetics. The glochidia shells of the new species are subtriangular, medium-sized, and have a styliform hook on the ventral angle of each valve. Phylogenetic analyses based on the COI and 28S rRNA gene fragments indicated that Pletholophus guangzhouensis sp. nov. is the sister to Pletholophus tenuis + Pletholophus reinianus. The pairwise uncorrected COI p-distance analysis demonstrated genetic distances ranging from 5.27% (between P. guangzhouensis sp. nov. and P. tenuis) to 11.06% (between P. guangzhouensis sp. nov. and P. honglinhensis). Our findings suggest a significant underestimation of the diversity of freshwater mussel species in Guangdong. Further field collections and systematic studies are necessary to fully explore the biodiversity of this region. Furthermore, integrative classification methods and genetic research are essential for informing the development of effective conservation strategies.

Abstract Microflow catalysis is a cutting-edge approach to advancing chemical synthesis and manufacturing, but the challenge lies in developing efficient and stable multiphase catalysts. Here we showcase incorporating amine-containing metal-organic cages into automated microfluidic reactors through covalent bonds, enabling highly continuous flow catalysis. Two Fe4L4 tetrahedral cages bearing four uncoordinated amines were designed and synthesized. Post-synthetic modifications of the amine groups with 3-isocyanatopropyltriethoxysilane, introducing silane chains immobilized on the inner walls of the microfluidic reactor. The immobilized cages prove highly efficient for the reaction of anthranilamide with aldehydes, showing superior reactivity and recyclability relative to free cages. This superiority arises from the large cavity, facilitating substrate accommodation and conversion, a high mass transfer rate and stable covalent bonds between cage and microreactor. This study exemplifies the synergy of cages with microreactor technology, highlighting the benefits of heterogenous cages and the potential for future automated synthesis processes

Abstract Resolving the detailed structures of metal organic frameworks is of great significance for understanding their structure-property relation. Real-space imaging methods could exhibit superiority in revealing not only the local structure but also the bulk symmetry of these complex porous materials, compared to reciprocal-space diffraction methods, despite the technical challenges. Here we apply a low-dose imaging technique to clearly resolve the atomic structures of building units in a metal-organic framework, MIL-125. An unexpected node structure is discovered by directly imaging the rotation of Ti-O nodes, different from the unrotated structure predicted by previous X-ray diffraction. The imaged structure and symmetry can be confirmed by the structural simulations and energy calculations. Then, the distribution of node rotation from the edge to the center of a MIL-125 particle is revealed by the image analysis of Ti-O rotation. The related defects and surface terminations in MIL-125 are also investigated in the real-space images. These results not only unraveled the node symmetry in MIL-125 with atomic resolution but also inspired further studies on discovering more unpredicted structural changes in other porous materials by real-space imaging methods.

Abstract The secondary injury is more serious after traumatic brain injury (TBI) compared with primary injury. Release of excessive reactive oxygen species (ROS) and Ca2+ influx at the damaged site trigger the secondary injury. Herein, a neutrophil-like cell membrane-functionalized nanoparticle was developed to prevent ROS-associated secondary injury. NCM@MP was composed of three parts: (1) Differentiated neutrophil-like cell membrane (NCM) was synthesized, with inflammation-responsive ability to achieve effective targeting and to increase the retention time of Mn3O4 and nimodipine (MP) in deep injury brain tissue via C-X-C chemokine receptor type 4, integrin beta 1 and macrophage antigen-1. (2) Nimodipine was used to inhibit Ca2+ influx, eliminating the ROS at source. (3) Mn3O4 further eradicated the existing ROS. In addition, NCM@MP also exhibited desirable properties for T1 enhanced imaging and low toxicity which may serve as promising multifunctional nanoplatforms for precise therapies. In our study, NCM@MP obviously alleviated oxidative stress response, reduced neuroinflammation, protected blood–brain barrier integrity, relieved brain edema, promoted the regeneration of neurons, and improved the cognition of TBI mice. This study provides a promising TBI management to relieve the secondary spread of damage. Graphical Abstract

Abstract Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Abstract Background Patient experience plays an essential role in improving clinical effectiveness and patient safety. It’s important to identify factors influencing patient experience and to improve quality of healthcare. Objective To identify factors that influence patient experience in hospital wards. Methods We conducted a systematic review including six databases; they were PubMed, CINAHL, Embase, PsycInfo, ProQuest, and Cochrane. Studies were included if they met the inclusion criteria. The JBI checklist was used to perform quality appraisal. We used 5 domains of the ecological model to organize and synthesize our findings to comprehensively understand the multi-level factors influencing the issue. Result A total of 138 studies were included, and 164 factors were identified. These factors were integrated into 6 domains. All domains but one (survey-related factors) could be mapped onto the attributes of the ecological framework: intrapersonal, interpersonal, institutional, community, and public policy level factors. All factors had mixed effect on patient experience. The intrapersonal level refers to individual characteristics of patients. The interpersonal level refers to interactions between patients and healthcare providers, such as the caring time spent by a nurse. The institutional level refers to organizational characteristics, rules and regulations for operations, such as hospital size and accreditation. The community level refers to relationships among organizations, institutions, and informational networks within defined boundaries, such as a hospital located in a larger population area. Public policy level refers to local, state, national, and global laws and policies, including health insurance policies. The sixth domain, survey-related factors, was added to the framework and included factors such as survey response rate and survey response time. Conclusion The factors influencing patient experience are comprehensive, ranging from intrapersonal to public policy. Providers should adopt a holistic and integrated perspective to assess patient experience and develop context-specific interventions to improve the quality of care. PROSPERO registration number CRD42023401066

Abstract Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Abstract Bladder cancer remains a significant health challenge due to its high recurrence and progression rates. This study aims to evaluate the role of POLR3G in the development and progression of bladder cancer and the potential of POLR3G to serve as a novel therapeutic target. We constructed a bladder cancer model in Wistar rats by administering N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which successfully induced a transition from normal mucosa to hyperplasia and ultimately to urothelial carcinoma. We observed a progressive upregulation of POLR3G expression during the bladder cancer development and progression. To investigate the functional role of POLR3G, we performed functional experiments in bladder cancer cell lines. The results demonstrated that knocking down POLR3G significantly inhibited cell proliferation, migration, and invasion. We further conducted RNA sequencing on POLR3G-knockdown bladder cancer cells, and Metascape was employed to perform the functional enrichment analysis of the differentially expressed genes (DEGs). Enrichment analysis revealed the enrichment of DEGs in the RNA polymerase and apoptotic cleavage of cellular proteins pathways, as well as their involvement in the Wnt and MAPK signaling pathways. The downregulation of Wnt pathway-related proteins such as Wnt5a/b, DVL2, LRP-6, and phosphorylated LRP-6 upon POLR3G knockdown was further confirmed by Western blotting, indicating that POLR3G might influence bladder cancer behavior through the Wnt signaling pathway. Our findings suggest that POLR3G plays a crucial role in bladder cancer progression and could serve as a potential therapeutic target. Future studies should focus on the detailed mechanisms by which POLR3G regulates these signaling pathways and its potential as a biomarker for early detection and prognosis of bladder cancer.

Abstract Background Doxorubicin (Dox) is an effective chemotherapeutic drug for various cancers, but its clinical application is limited by severe cardiotoxicity. Dox treatment can transcriptionally activate multiple cardiotoxicity-associated genes in cardiomyocytes, the mechanisms underlying this global gene activation remain poorly understood. Methods and results Herein, we integrated data from animal models, CUT&Tag and RNA-seq after Dox treatment, and discovered that the level of H3K27ac (a histone modification associated with gene activation) significantly increased in cardiomyocytes following Dox treatment. C646, an inhibitor of histone acetyltransferase, reversed Dox-induced H3K27ac accumulation in cardiomyocytes, which subsequently prevented the increase of Dox-induced DNA damage and apoptosis. Furthermore, C646 alleviated cardiac dysfunction in Dox-treated mice by restoring ejection fraction and reversing fractional shortening percentages. Additionally, Dox treatment increased H3K27ac deposition at the promoters of multiple cardiotoxic genes including Bax, Fas and Bnip3, resulting in their up-regulation. Moreover, the deposition of H3K27ac at cardiotoxicity-related genes exhibited a broad feature across the genome. Based on the deposition of H3K27ac and mRNA expression levels, several potential genes that might contribute to Dox-induced cardiotoxicity were predicted. Finally, the up-regulation of H3K27ac-regulated cardiotoxic genes upon Dox treatment is conservative across species. Conclusions Taken together, Dox-induced epigenetic modification, specifically H3K27ac, acts as a molecular switch for the activation of robust cardiotoxicity-related genes, leading to cardiomyocyte death and cardiac dysfunction. These findings provide new insights into the relationship between Dox-induced cardiotoxicity and epigenetic regulation, and identify H3K27ac as a potential target for the prevention and treatment of Dox-induced cardiotoxicity.

Abstract To analyze the mechanism of how interfering with the cytokeratin 19 (CK19) pathway via the ferroptosis pathway affects tumor biological behaviors in the process of oral squamous cell carcinoma (OSCC) development. TCGA was used to analyze the expression of CK19 in pan-cancer and head and neck squamous cell carcinoma (HNSC) and to explore the ferroptosis-related genes related to HNSC. The effect of silencing CK19 on the migration ability of HSC-4 cells was verified by wound healing and migration assay. HSC-4 cells with silencing of CK19 and tumor-bearing nude mouse model were constructed. RT-qPCR, immunofluorescence and western blot were used to analyze the expression of ferroptosis-related genes. CK19 is highly expressed in human OSCC and nude mice. The migration ability of cells in the CK19-silenced group was lower than that of the control group. In vivo and in vitro, CK19 was negatively correlated with the expression of ACSL4 and positively correlated with the expression of GPX4. Compared with the control group, GPX4 expression was down-regulated and ACSL4 expression was up-regulated in the CK19-silenced group. Silencing CK19 also increased intracellular Fe2+ content and MDA content. Silencing CK19 can affect the expression of GPX4 and ACSL4 to regulate ferroptosis and at the same time increase the content of MDA, Fe2+ and ROS levels, thereby activating the regulation of ferroptosis pathway in the development of OSCC.

Abstract Objectives This review aims to comprehensively summarize the differences in anticholinergic drug burden (ADB) scores between older hospitalized patients with and without delirium. Methods We searched PubMed, Embase, Web of Science, Cochrane Library and CINAHL EBSCOhost databases to identify prospective cohort studies exploring the relationship between ADB and the occurrence of delirium in older hospitalized patients. The primary outcome of the review was the mean ADB scores for the delirium and non-delirium groups, and the secondary outcome was the scores for the subsyndromal and non-delirium groups. The standardized mean difference (SMD) and corresponding 95% confidence intervals (95% CI) were incorporated using a fixed-effect method. Moreover, we performed subgroup analysis according to the admission type, age, the ADB scale type and the ADB classification. Results Nine prospective cohort studies involving 3791 older patients with a median age of 75.1 (71.6–83.9) were included. The ADB score was significantly higher in the delirium group than in the non-delirium group (SMD = 0.21, 95%CI 0.13–0.28). In subgroup analysis, the age subgroup was split into

Abstract Background Fatty liver in dairy cows is a common metabolic disease defined by triglyceride (TG) buildup in the hepatocyte. Clinical diagnosis of fatty liver is usually done by liver biopsy, causing considerable economic losses in the dairy industry owing to the lack of more effective diagnostic methods. Therefore, this study aimed to investigate the potential utility of blood biomarkers for the diagnosis and early warning of fatty liver in dairy cows. Results A total of twenty-four lactating cows within 28 days after parturition were randomly selected as experimental animals and divided into healthy cows (liver biopsy tested, n = 12) and cows with fatty liver (liver biopsy tested, n = 12). Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the macroelements and microelements in the serum of two groups of cows. Compared to healthy cows (C), concentrations of calcium (Ca), potassium (K), magnesium (Mg), strontium (Sr), selenium (Se), manganese (Mn), boron (B) and molybdenum (Mo) were lower and copper (Cu) was higher in fatty liver cows (F). Meanwhile, the observed differences in macroelements and microelements were related to delivery time, with the greatest major disparity between C and F occurring 7 days after delivery. Multivariable analysis was used to test the correlation between nine serum macroelements, microelements and fatty liver. Based on variable importance projection and receiver operating characteristic (ROC) curve analysis, minerals Ca, Se, K, B and Mo were screened as the best diagnostic indicators of fatty liver in postpartum cows. Conclusions Our data suggested that serum levels of Ca, K, Mg, Se, B, Mo, Mn, and Sr were lower in F than in C. The most suitable period for an early-warning identification of fatty liver in cows was 7 days after delivery, and Ca, Se, K, B and Mo were the best diagnostic indicators of fatty liver in postpartum cows.

Abstract Background Due to the complexity of the metabolic pathway network of active ingredients, precise targeted synthesis of any active ingredient on a synthetic network is a huge challenge. Based on a complete analysis of the active ingredient pathway in a species, this goal can be achieved by elucidating the functional differences of each enzyme in the pathway and achieving this goal through different combinations. Lignans are a class of phytoestrogens that are present abundantly in plants and play a role in various physiological activities of plants due to their structural diversity. In addition, lignans offer various medicinal benefits to humans. Despite their value, the low concentration of lignans in plants limits their extraction and utilization. Recently, synthetic biology approaches have been explored for lignan production, but achieving the synthesis of most lignans, especially the more valuable lignan glycosides, across the entire synthetic network remains incomplete. Results By evaluating various gene construction methods and sequences, we determined that the pCDF-Duet-Prx02-PsVAO gene construction was the most effective for the production of (+)-pinoresinol, yielding up to 698.9 mg/L after shake-flask fermentation. Based on the stable production of (+)-pinoresinol, we synthesized downstream metabolites in vivo. By comparing different fermentation methods, including “one-cell, one-pot” and “multicellular one-pot”, we determined that the “multicellular one-pot” method was more effective for producing (+)-lariciresinol, (-)-secoisolariciresinol, (-)-matairesinol, and their glycoside products. The “multicellular one-pot” fermentation yielded 434.08 mg/L of (+)-lariciresinol, 96.81 mg/L of (-)-secoisolariciresinol, and 45.14 mg/L of (-)-matairesinol. Subsequently, ultilizing the strict substrate recognition pecificities of UDP-glycosyltransferase (UGT) incorporating the native uridine diphosphate glucose (UDPG) Module for in vivo synthesis of glycoside products resulted in the following yields: (+)-pinoresinol glucoside: 1.71 mg/L, (+)-lariciresinol-4-O-d-glucopyranoside: 1.3 mg/L, (+)-lariciresinol-4’-O-d-glucopyranoside: 836 µg/L, (-)-secoisolariciresinol monoglucoside: 103.77 µg/L, (-)-matairesinol-4-O-d-glucopyranoside: 86.79 µg/L, and (-)-matairesinol-4’-O-d-glucopyranoside: 74.5 µg/L. Conclusions By using various construction and fermentation methods, we successfully synthesized 10 products of the lignan pathway in Isatis indigotica Fort in Escherichia coli, with eugenol as substrate. Additionally, we obtained a diverse range of lignan products by combining different modules, setting a foundation for future high-yield lignan production.

Introduction: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it significantly increases the risk of cardiovascular complications and morbidity, even with appropriate treatment. Tissue remodeling has been a significant topic, while its systematic transcriptional signature remains unclear in AF. Objectives: Our study aims to systematically investigate the molecular characteristics of AF at the cellular-level. Methods: We conducted single-nuclei RNA-sequencig (snRNA-seq) analysis using nuclei isolated from the left atrial appendage (LAA) of AF patients and sinus rhythm. Pathological staining was performed to validate the key findings of snRNA-seq. Results: A total of 30 cell subtypes were identified among 80, 592 nuclei. Within the LAA of AF, we observed a specific subtype of dedifferentiated cardiomyocytes (CMs) characterized by reduced expression of cardiac contractile proteins (TTN and TRDN) and heightened expression of extracellular-matrix related genes (COL1A2 and FBN1). Transcription factor prediction analysis revealed that gene expression patterns in dedifferentiated CMs were primarily regulated by CEBPG and GISLI. Additionally, we identified a distinct subtype of endothelial progenitor cells (EPCs) demonstrating elevated expression of PROM1 and KDR, a population decreased within the LAA of AF. Epicardial adipocytes disclosed a reduced release of the anti-inflammatory and anti-fibrotic factor PRG4, and an augmented secretion of VEGF signals targeting CMs. Additionally, we noted accumulation of M2-like macrophages and CD8+ T cells with high pro-inflammatory score in LAA of AF. Furthermore, the analysis of intercellular communication revealed specific pathways related to AF, such as inflammation, extracellular matrix, and vascular remodeling signals. Conclusions: This study has discovered the presence of dedifferentiated CMs, a decrease in endothelial progenitor cells, a shift in the secretion profile of adipocytes, and an amplified inflammatory response in AF. These findings could offer crucial insights for future research on AF and serve as valuable references for investigating novel therapeutic approaches for AF.

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvβ3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

The healing of large skin defects remains a significant challenge in clinical settings. The lack of epidermal sources, such as autologous skin grafting, limits full-thickness skin defect repair and leads to excessive scar formation. Skin organoids have the potential to generate a complete skin layer, supporting in-situ skin regeneration in the defect area. In this study, skin organoid spheres, created with human keratinocytes, fibroblasts, and endothelial cells, showed a specific structure with a stromal core surrounded by surface keratinocytes. We selected an appropriate bioink and innovatively combined an extrusion-based bioprinting technique with dual-photo source cross-linking technology to ensure the overall mechanical properties of the 3D bioprinted skin organoid. Moreover, the 3D bioprinted skin organoid was customized to match the size and shape of the wound site, facilitating convenient implantation. When applied to full-thickness skin defects in immunodeficient mice, the 3D bioprinted human-derived skin organoid significantly accelerated wound healing through in-situ regeneration, epithelialization, vascularization, and inhibition of excessive inflammation. The combination of skin organoid and 3D bioprinting technology can overcome the limitations of current skin substitutes, offering a novel treatment strategy to address large-area skin defects.

Axolotls are known for their remarkable regeneration ability. Exploring their transcriptome provides insight into regenerative mechanisms. However, the current annotation of the axolotl transcriptome is limited, leaving the role of unannotated transcripts in regeneration unknown. To discourse this challenge, we exploited long-read sequencing technology, which enables direct observation of full-length RNA transcripts, greatly enhancing the coverage and accuracy of axolotl transcriptome annotation. By utilizing this method, we identified 222 novel gene loci and 4775 novel transcripts, which were quantified using short-read sequencing data. Through the inclusive analysis, we discovered novel homologs, potential functional proteins, noncoding RNAs, and alternative splicing events in key regeneration pathways. In particular, we identified novel transcripts with high protein-coding potential implicated in cell cycle regulation and musculoskeletal development, and regeneration were identified. Interestingly, alternative splice variants were also detected across diverse pathways critical to regeneration. This specifies that these novel transcripts potentially play vital roles underpinning the robust regenerative capacities of axolotls. Single-cell transcriptomic analysis further revealed these isoforms to predominantly exist in axolotl limb chondrocytes and mature tissue cell populations. Overall, the findings significantly advanced consideration of the axolotl transcriptome and provided a new perspective for understanding the mechanisms of regenerative abilities of axolotls.

Background At present, there are few studies on the stability of warfarin anticoagulation therapy. The main evaluation method is SAMe-TT2R2 score, but it has obvious limitations and is not applicable to non-white population. Previous studies have shown that platelet distribution width (PDW) and left atrial diameter (LAD) are closely related to time within therapeutic range (TTR). Whether they can be incorporated into the existing scoring system and improved is worthy of clinical reflection. Objective To explore the predictive value of modified SAMe-T-PDW2-LAD2 score for the percentage of TTR of common international normalized ratio (INR) for the stability of warfarin anticoagulation therapy. Methods A total of 164 patients with persistent nonvalvular atrial fibrillation who were treated with warfarin anticoagulation in Jiujiang NO.1 People's Hospital from January 2021 to June 2023 were selected as the research objects. TTR≥65% was defined as high quality anticoagulation. TTR