Search

Abstract Background Cervical cancer is a major health threat in the female population. Human immunodeficiency virus (HIV)-positive women encounter a higher risk of cervical cancer. It is significant to promote cervical cancer screening attendance among HIV-positive women. Little is known about the awareness, attendance, and attitudes toward cervical cancer screening, as well as the associated factors, among Chinese HIV-positive women. Methods A cross-sectional study was conducted among 411 HIV-positive women attending a large ART clinic in Yunnan, an HIV-endemic province in China. Participants were recruited using the convenient sampling method from January 2019 to August 2020. An interviewer-administered semi-structured questionnaire was utilized to collect information on socio-demographic and behavioral characteristics, clinical characteristics related to HIV infection, awareness, attendance, and attitudes toward cervical cancer screening. Binary logistic regression analyses were used to determine factors associated with awareness, attendance, and attitude toward cervical cancer screening. Results Some 69.8% (287) of the participants were aware of cervical cancer screening, but only 27.7% (114) had attended screening within 3 years. After receiving a brief health education, 72.3% (297) of the participants exhibited a positive attitude toward cervical cancer screening. Participants with a higher education background and longer duration of antiretroviral therapy were more likely to be aware of cervical cancer screening and have up-to-date screening. The up-to-date screening attendance was also influenced by age, smoking status, and health insurance. Single participants were less likely to show a positive attitude toward cervical cancer screening compared married or cohabiting counterparts. The main facilitators to attending cervical cancer screening were health promotion activity and well-organized programs, while the main barriers were high costs of the service and inadequate awareness. Conclusions Although most HIV-positive women attending a large ART clinic in Yunnan were aware of cervical cancer screening, the up-to-date attendance was low. It is crucial to conduct health education and promotion through efficient channels to improve awareness and attendance. The discrepancy between awareness and attendance also emphasized the importance of adopting appropriate screening strategies and powerful health policies that can foster the attendance of cervical cancer screening among HIV-positive women. Efforts should be devoted to constructing a comprehensive healthcare system with high accessibility in China for cervical cancer prevention and management for HIV-positive women.

Abstract Background Inflammatory bowel disease (IBD), a persistent gastrointestinal disease, is featured with impaired gut immunity. Previous studies have demonstrated that tuft cells can regulate the intestinal type 2 immune response by activating downstream ILC2 and Th2 cells and repair gut barrier upon invasion of parasitic helminths, bacteria, protozoans, and enteritis through different chemo-sensing receptors, such as bitter taste receptors. Berberine is a widely used in the treatment of diarrhea in clinic, however the mechanism underlying this effect is not clear. In this study, we aim to explore the relationship between berberine and tuft cells in dextran sulfate sodium (DSS) -induced colitis. Results Our data showed that berberine significantly ameliorated DSS-induced colitis and regulating type 2 innate immune lymphocytes (ILC2) and Th2 immune cells via tuft cells in the gut. Furthermore, the effect of berberine on colitis was partially abolished by U73122, a bitter taste receptor inhibitor, suggesting that bitter taste signalling pathway played an important role in the effect of berberine on relieving colitis. Conclusions Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. Our study reveals the unique pharmacological mechanisms of berberine in the context of colitis, laying the foundation for further clinical applications of this compound.

Background: Cuproptosis is a novel pathway that differs from other forms of cell death and has been confirmed to be applicable for predicting tumor prognosis and clinical treatment response. However, the mechanism underlying the resistance of colorectal cancer (CRC) to cuproptosis at the molecular level has not been elucidated. Methods: Using bioinformatics analysis, the expression of CCAAT/enhancer-binding protein beta (CEBPB) in CRC tissues and its enrichment in biological processes were detected. Quantitative reverse transcription polymerase chain reaction and western blotting (WB) were employed to test the expression of CEBPB in CRC cells. WB was utilized to assess the levels of proteins related to cuproptosis and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. The MTT assay was used to test cell viability. Cell proliferation was assessed by a colony formation assay. Transwell assays were used to measure cell migration and invasion ability. DLAT-aggregate formation was determined by immunofluorescence. Results: CEBPB was highly upregulated in CRC cells to enhance cell viability, proliferation, migration, and invasion. CEBPB was strongly implicated in copper ion homeostasis and the mTOR signaling pathway in CRC. In a CRC cuproptosis cell model, rescue experiments revealed that a PI3K/AKT/mTOR pathway inhibitor attenuated the promoting effect of CEBPB overexpression on the PI3K/AKT/mTOR pathway and rescued the sensitivity of CRC to cuproptosis. Conclusion: This work demonstrated that CEBPB can activate the PI3K/AKT/mTOR signaling pathway, thereby decreasing the sensitivity of CRC to cuproptosis. These data suggested that targeting CEBPB or the PI3K/AKT/mTOR pathway may enhance the sensitivity of CRC patients to cuproptosis, providing a combined therapeutic strategy for cuproptosis-induced therapy.

Abstract Engineered heme proteins exhibit excellent sustainable catalytic carbene transfer reactivities toward olefins for value-added cyclopropanes. However, unactivated and electron-deficient olefins remain challenging in such reactions. To help design efficient heme-inspired biocatalysts for these difficult situations, a systematic quantum chemical mechanistic study was performed to investigate effects of olefin substituents, non-native amino acid axial ligands, and natural and non-natural macrocycles with the widely used ethyl diazoacetate. Results show that electron-deficient substrate ethyl acrylate has a much higher barrier than the electron-rich styrene. For styrene, the predicted barrier trend is consistent with experimentally used heme analogue cofactors, which can significantly reduce barriers. For ethyl acrylate, while the best non-native axial ligand only marginally improves the reactivity versus the native histidine model, a couple of computationally studied macrocycles can dramatically reduce barriers to the level comparable to styrene. These results will facilitate the development of better biocatalysts in this area.

Abstract Distal cholangiocarcinoma is a rare and highly aggressive malignant tumor. The inherent tumor characteristics and growth pattern of cancer cells pose a challenge for diagnosis and treatment. Chemotherapy resistance leads to limited treatment options for patients with advanced cholangiocarcinoma. However, drug resistance studies in cholangiocarcinoma are often limited by the use of preclinical models that do not accurately replicate the essential features of the disease. In this study, we established and characterized a primary multidrug-resistant distal cholangiocarcinoma cell line, CBC3T-6. STR profiling indicated no evidence of cross-contamination. This cell line remains stable during long-term in vitro culture and is characterized by short doubling times and rapid subcutaneous tumor formation in mice. In addition, among the first-line anticancer drugs for cholangiocarcinoma, CBC3T-6 cells showed varying degrees of resistance to gemcitabine, oxaliplatin, cisplatin, and 5-FU. Whole exome sequencing analysis revealed that CBC3T-6 cells contained a variety of potentially pathogenic somatic cell mutations, such as TP53 and KRAS mutations. ABCB1 mutation as a possible therapeutic target for multidrug resistance. In conclusion, CBC3T-6 cells can be used as a useful tool to study the mechanism of cholangiocarcinoma and develop new therapeutic strategies for multidrug resistance.

Abstract Pairing center (PC) on each chromosome of Caenorhabditis elegans is crucial for homolog pairing and initiating synapsis. Within each PC, clusters of 11/12 bp DNA motif recruit one of four paralogous meiosis-specific proteins: ZIM-1, ZIM-2, ZIM-3, or HIM-8. However, the mechanistic basis underlying the specificity of ZIM/HIM-8-PC DNA interaction remains elusive. Here, we describe crystal structures of HIM-8, ZIM-1 and ZIM-2 DNA binding domains (ZF1, ZF2 and CTD) in complex with their cognate PC DNA motifs, respectively. These structures demonstrated the ZF1-2-CTD folds as an integrated structural unit crucial for its DNA binding specificity. Base-specific DNA-contacting residues are exclusively distributed on ZF1-2 and highly conserved. Furthermore, the CTD potentially contributes to the conformational diversity of ZF1-2, imparting binding specificity to distinct PC DNA motifs. These findings shed light on the mechanism governing PC DNA motif recognition by ZIM/HIM-8 proteins, suggesting a co-evolution relationship between PC DNA motifs and ZF1-2-CTD in shaping the specific recognition.

Abstract Background Deep partial-thickness burns have a significant impact on both the physical and mental health of patients. Our previous study demonstrated human Umbilical Cord Mesenchymal stem cells (hUCMSCs) could enhance the healing of severe burns in small animal burn models, such as rats. Furthermore, our team has developed a deep partial-thickness burn model in Bama miniature pigs, which can be utilized for assessing drug efficacy in preclinical trials for wound healing. Therefore, this study further determine the optimal dosage of hUCMSCs in future clinical practice by comparing the efficacy of low-to-high doses of hUCMSCs on deep partial-thickness burn wounds in Bama miniature pigs. Materials and methods The male Bama miniature pigs (N = 8, weight: 23–28 kg and length: 71–75 cm) were used to establish deep partial-thickness burn models, which used a continuous pressure of 1 kg and contact times of 35 s by the invented electronic burn instrument at 100℃ to prepare 10 round burn wounds with diameter of 5 cm according to our previous report. And then, 0 × 10^7, 1 × 10^7, 2 × 10^7, 5 × 10^7 and 1 × 10^8 doses of hUCMSCs were respectively injected into burn wounds of their corresponding groups. After treatment for 7, 14 and 21 days, the burned wound tissues were obtained for histological evaluation, including HE staining for histopathological changes, immunohistochemistry for neutrophil (MPO+) infiltration and microvessel (CD31+) quantity, as well as Masson staining for collagen deposition. The levels of inflammatory factors TNF-α, IL-1β, IL-10 and angiogenesis factors angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), as well as collagen type-I/type-III of the wound tissues were quantified by ELISA. Results All of doses hUCMSCs can significantly increase wound healing rate and shorten healing time of the deep partial-thickness burn pigs in a dose-dependent manner. Furthermore, all of doses hUCMSCs can significantly promote epithelialization and decreased inflammatory reaction of wound, including infiltration of inflammatory cells and levels inflammatory factors. Meanwhile, the amounts of microvessel were increased in all of doses hUCMSCs group than those in the burn group. Furthermore, the collagen structure was disordered and partially necrotized, and ratios of collagen type-I and type-III were significantly decreased in burn group (4:1 in normal skin tissue), and those of all hUCMSCs groups were significantly improved in a dose-dependent manner. In a word, 1 × 10^8 dose of hUCMSCs could regenerate the deep partial-thickness burn wounds most efficaciously compared to other dosages groups and the burn group. Conclusion This regenerative cell therapy study using hUCMSCs demonstrates the best efficacy toward a high dose, that is dose of 1 × 10^8 of hUCMSCs was used as a reference therapeutic dose for treating 20 cm2 deep partial-thickness burns wound in future clinical practice. Graphical abstract

Abstract The absorption of the essential element nitrogen by plants affects various aspects of plant physiological activity, including gene expression, metabolite content and growth. However, the molecular mechanism underlying the potato tuberization response to nitrogen remains unclear. Potato plants were subjected to pot experiments under nitrogen deficiency, normal nitrogen levels and nitrogen sufficiency. A comprehensive analysis of the physiological responses, transcriptomic profiles, and metabolic pathways of potato stolons subjected to nitrogen stress was conducted. Transcriptomic analysis revealed 2756 differentially expressed genes (DEGs) associated with nitrogen stress. Metabolomic analysis identified a total of 600 differentially accumulated metabolites (DAMs). Further correlation analysis of the major DEGs and DAMs revealed that 9 key DEGs were associated with alpha-linolenic acid metabolism, 16 key DEGs with starch and sucrose metabolism, 7 key DEGs with nitrogen metabolism, and 16 key DEGs with ABC transporters. Nitrogen deficiency significantly increased the sucrose, GDP-glucose and L-glutamic acid levels and promoted stolon growth by increasing the expression of AMY (alpha-amylase), BE (1,4-alpha-glucan branching enzyme), SS (starch synthase), SPS (sucrose‒phosphate synthase) and AGPS (glucose‒1-phosphate adenylyltransferase). However, high nitrogen levels had the opposite effect. In addition, high nitrogen levels upregulated EG (endoglucanase), SUS (sucrose synthase) and GDH (glutamate dehydrogenase) and led to significant accumulation of 9-Hydroperoxy-10,12,15-octadecatrienoate (9(S)-HpOTrE), (13 S)-Hydroperoxyoctadeca-9,11,15-trienoate (13 (S)-HpOTrE) and L-glutamine, ultimately affecting the balance between plant growth and defense. Overall, our comprehensive study revealed the co-expressed genes and potential pathways related to potato tuber formation under different nitrogen conditions. These data provide a better understanding needed for improving potato tuber traits at the molecular and metabolic levels.

Abstract With the enrichment of large-scale group decision-making (LSGDM) methods, the decentralized consensus reaching process (CRP) has demonstrated many advantages. However, when the probabilistic linguistic preference relation (PLPR) is utilized in the decentralized CRP, its consistency and readability are hardly to maintain. Besides, the low-cost consensus adjustment and non-cooperative behaviors of subgroups are still not considered simultaneously in the decentralized CRP. In order to solve these problems, this article proposes a decentralized feedback-based consensus model to support CRP in LSGDM based on PLPR with complete readability. First, to maintain the consistency of PLPR throughout the LSGDM process, an additive expected consistency for PLPR is specifically defined. This definition enables the automatic consistency maintenance of PLPR during linear-weight-based clustering, opinion adjustment, and opinion aggregation. Given that the existing consistency adjustment method always destroys the readability of the original PLPR, a definition of complete readability for PLPR, reflected by a reasonable probability distribution of its elements, is proposed. This is followed by a consistency-improving optimization model that considers both the adjustment cost and complete readability. Subsequently, in order to support a more realistic CRP, a decentralized feedback-based minimum cost consensus model is established to improve the group consensus level while addressing the non-cooperative behaviors of subgroups. Furthermore, an illustrative example of the selection of expressway repair plans is presented to testify the practicality of the proposed methods and demonstrate the distinctive characteristics in comparison with the existing approaches.

Abstract Background Calcaneal fractures are the most common type of tarsal fractures. The sustentaculum tali (ST) offers anatomical stability in calcaneal fractures, and recently, ST screws have been widely used in their treatment. This study aimed to investigate the clinical efficacy and value of ST screw fixation via a modified sinus tarsi approach (MSTA) for treating displaced intraarticular calcaneal fractures (DIACFs). Methods This study enrolled 64 patients (64 feet): 32 patients in the calcaneal locking plate combined with the ST screw group (CLP-STS Group) and 32 patients in the simple calcaneal locking plate internal fixation group (CLP Group). The minimum follow-up duration was 18 months. Ankle function was evaluated using VAS, AOFAS, and Short Form-36 scores. Imaging evaluation included the Böhler angle, Gissane angle, length, height, and width of the calcaneus, and the Böhler angle in both groups 1 year after surgery. Results Functional evaluation revealed that postoperative AOFAS and VAS scores in the CLP-STS Group were significantly better than those in the CLP Group. After surgery, the Böhler angle, Gissane angle, and length, height, and width of the calcaneus were significantly corrected compared to the preoperative values; however, the difference in these indicators between the two groups was not significant. Nevertheless, at the 1-year postoperative follow-up, the calcaneal Böhler angle loss in the CLP-STS Group was significantly better than that in the CLP Group. Conclusion Compared to simple calcaneal locking plate internal fixation, combining the plate with the additionally free ST screw can resolve the limited intraoperative exposure of MSTA, reduce postoperative foot pain in patients, and improve clinical efficacy.

Abstract Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge and evade immunity, resulting in breakthrough infections in vaccinated populations. There is an urgent need for the development of vaccines with broad protective effects. In this study, we selected hotspot mutations in the receptor-binding domain (RBD) that contribute to immune escape properties and integrated them into the original RBD protein to obtain a complex RBD protein (cRBD), and we found cRBDs have broad protective effects against SARS-CoV-2 variants. Three cRBDs were designed in our study. Compared with the BA.1 RBD protein, the cRBDs induced the production of higher levels of broader-spectrum neutralizing antibodies, suggesting stronger and broader protective efficacy. In viral challenge experiments, cRBDs were more effective than BA.1 RBD in attenuating lung pathologic injury. Among the three constructs, cRBD3 showed optimal broad-spectrum and protective effects and is a promising candidate for a broad-spectrum SARS-CoV-2 vaccine. In conclusion, immunization with cRBDs triggered immunity against a wide range of variants, including those that emerged after we had completed designing the cRBDs. This study preliminarily explores and validates the feasibility of incorporating hotspot mutations that contribute to immune evasion into the RBD to expand the activity spectrum of antigen-induced antibodies.

Abstract Background Research investigating the potential link between gingival microvascular blood flow and inflammatory status is scarce. This study aims to assess color doppler flow imaging (CDFI) and micro-flow imaging (MFI) as tools for the assessment of gingival papilla blood flow (GPBF) and to examine their diagnostic utility as a noninvasive means of detecting gingival bleeding. Methods CDFI and MFI were used to assess the GPBF grade (0–4) of 140 anterior gingival papilla sites in advanced periodontitis patients. Correlations between GPBF grades and periodontal characteristics were examined, and diagnostic performance as a means of predicting bleeding on probing (BOP) was examined using receiver operating characteristic curves. Results GPBF grades 0 and 1 assessed by the MFI were 14.29% and 15.71% respectively, lower than the 28.57% and 24.29% assessed by the CDFI. In contrast, MFI detected a higher frequency of GPBF grade 2 sites (40.71%) relative to CDFI (22.14%). The CDFI and MFI provided consistent results in 62.14% of the sites, while the MFI demonstrated higher ratings in rest 37.86% of the sites. A significant positive correlation was detected between GPBF grade and the modified gingival index (MGI), bleeding index (BI), BOP, and probing depth (PD). It showed high accuracy for CDFI or MFI to diagnosing BOP with a sensitivity of 80.51% and 96.43% and a specificity of 77.27% and 57.14%, respectively. Area under the receiver operator characteristic curve values when predicting BOP based on the GPBF grade determined using CDFI and MFI approaches 0.887 (95% CI 0.833–0.942) and 0.917 (95% CI 0.862–0.972), respectively, and there were no significant differences between these values (Z = − 1.502, p = 0.133). Conclusions Both MFI and CDFI can be employed for the evaluation of GPBF, and MFI is better suited to detecting mild inflammation. Trial registration ChiCTR2200066021 (Date of registration: 22/11/2022).

Abstract The giant freshwater prawn (Macrobrachium rosenbergii) has many advantages in aquaculture, such as fast growth rate, short breeding cycle and good nutrition, which makes it a freshwater shrimp with high economic value. Herein, high-quality chromosome-level genome of both female and male prawns were obtained by combining Illumina paired-end sequencing, PacBio single molecule sequencing technique and High-through chromosome conformation capture (Hi-C) technologies. In ZZ male prawn, a final contig assembly of 3118.58 Mb with a N50 length of 956,237 bp was obtained. In WW female prawn, a final contig assembly of 3333.31 Mb with a N50 length of 1,143,555 bp was obtained. The assembled genome sequences from prawns were anchored to 59 chromosomes. Moreover, the sex chromosomes including W chromosome and Z chromosome were generated in prawn with the length of 36.23 Mb and 27.33 Mb, respectively. The sequence similarity of Z chromosome and W chromosome reached to 74.90%. The high-quality genome resource will be useful for further molecular breeding and functional genomic research of giant freshwater prawns.

Abstract In this study, nonaxisymmetric endwall contouring technology is employed as a passive control strategy to enhance the stable operating range of a centrifugal compressor with an asymmetric volute. The endwall contouring method is applied to the hub‐side wall of the vaned diffuser within a centrifugal compressor stage. Instead of utilizing a flat hub as the baseline diffuser, various diffuser configurations featuring hub‐side contoured endwalls are explored, with adjustments in the peak radial position and peak height of the convex and concave profiles. Numerical simulations are conducted to evaluate the performance of the centrifugal compressor stage with both the baseline and contoured vaned diffusers. The investigation explores the underlying flow control mechanisms and establishes the effective endwall contouring guidelines. The findings highlight the effectiveness of endwall contouring in enhancing the stable operating range of centrifugal compressors. Notably, a substantial enhancement of 15.1% in the stable operating range is achieved by employing the contoured diffuser with the peak radial position near the vane leading edge (LE) and the peak height at 20% of the vane height. The endwall contoured diffusers reduce the positive LE incidence angles to direct the fluid toward the suction side (SS), and increase the radial velocity near the SS to suppress the hub‐suction corner separations in the diffuser passages near the volute tongue. These improvements collectively contribute to the enhancement of diffuser flow characteristics. Finally, a set of effective endwall contouring guidelines is proposed to guide the endwall contouring design for enhancing the stable operating range of centrifugal compressors.

Vehicle turn-in rate is a critical and widely adopted input for expressway rest area design and operation. With the implementation of expressway ETC gantries, the ERA turn-in rate can be further estimated by measuring the travel speed distribution via ETC gantry data. This paper proposed an adaptive density peak clustering Gaussian mixture model (ADPC-GMM) for ERA turn-in rate estimation. The ADPC algorithm is applied to generate the GMM’s inputs accommodating to the traffic characteristic of ERA expressway segments and GMM would further provide the turn-in rate estimation results. To validate the model precision, the turn-in rate data of four selected ERAs in Sichuan, China, as well as the ETC gantry data of their corresponding expressway sections are obtained. According to the estimation results, the MAE and RMSE are 0.0228 and 0.0267 for the passenger car scenario and 0.0264 and 0.0356 for the commercial truck scenario, respectively. These results are also at the lowest level compared with the results acquired from ordinary GMM, K-Means and DBSCAN algorithms. The proposed method has good applicability for vehicle turn-in rate estimation and can be deployed at different ERAs, especially those ERAs without traffic monitoring.

Abstract Mutation of methylenetetrahydrofolate reductase (MTHFR) C677T leads to the decrease of folate utilization and the impairment of spermatogenesis. This study attempts to investigate the association between MTHFR C677T polymorphisms and nonobstructive oligozoospermia, asthenozoospermia or oligoasthenozoospermia in the Chinese population. The study cohort comprised 189 patients diagnosed with oligozoospermia, asthenozoospermia or oligoasthenozoospermia, and 626 controls based on clinical examinations. The MTHFR c.677 genotype of all subjects was determined by fluorescence staining in situ hybridization and the significance of different genotype frequencies was further analyzed by Chi-square test. The results showed that the frequency of MTHFR 677 CT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 33.3%, 38.3% and 44.0% respectively, whereas it was 47.3% in the control group. The P value of Chi-square test was 0.070, 0.103 and 0.654, respectively. The frequency of MTHFR 677 TT genotype in the oligozoospermia, asthenozoospermia and oligoasthenozoospermia group was 31.1%, 11.7% and 18.0% respectively, while that in the control group was 19.5%. The P value of Chi-square test was 0.061, 0.070 and 0.066, respectively. Collectively, there is a weak association between MTHFR C677T polymorphisms and oligozoospermia, asthenozoospermia or oligoasthenozoospermia within the current Chinese population cohort.

Abstract This study evaluates the clinical significance of nano-carbon suspension in total thyroidectomy with cervical lymph node dissection for papillary thyroid carcinoma (PTC). The objective of this study was to assess the efficacy of nano-carbon suspension in enhancing parathyroid gland preservation, reducing postoperative complications, and improving surgical precision. A retrospective analysis on 219 PTC patients who underwent total thyroidectomy with cervical lymph node dissection between March 2014 and March 2018 was conducted. Patients were divided into two groups: an experimental group (n = 107) that received nano-carbon suspension and a control group (n = 112) that did not. Comparative analyses included demographics, surgical parameters, postoperative calcium and parathyroid hormone (PTH) levels, the number of dissected lymph nodes, and the incidence of complications. Baseline characteristics, including age, sex, and BMI, showed no statistically significant differences between the experimental and control groups. Postoperative calcium levels were significantly more stable in the experimental group, with median levels of 2.22 mmol/L on day 1 versus 2.06 mmol/L in the control group (P

Plant-based foods, a new category of foods made from plant materials with specific processes, have characteristics similar to those of animal-based foods, which meet consumers’ nutritional needs. Plant-based foods have become a research hotspot and key focus in the field of food science, as they help to ensure sustainable food supply, realize efficient and low-carbon utilization of resources, and promote the optimization of residents’ dietary structure and the improvement of nutritional levels. At present, most research on plant-based foods focuses on developing new products, but little attention has been paid to potential food safety risks. In order to provide references and enlightenments for guaranteeing the quality and safety of plant-based foods and promoting the healthy development of the plant-based food industry, this article systematically reviews and summarizes the potential chemical and biological safety risk factors of plant-based foods that are currently available on the market, and proposes possible solutions for the problems.

Abstract The early stages of embryonic development rely on maternal products for proper regulation. However, screening for functional maternal-specific factors is challenging due to the time- and labor-intensive nature of traditional approaches. Here, we combine a computational pipeline and F0 null mutant technology to screen for functional maternal-specific chromatin regulators in zebrafish embryogenesis and identify Mcm3l, Mcm6l, and Npm2a as playing essential roles in DNA replication and cell division. Our results contribute to understanding the molecular mechanisms underlying early embryo development and highlight the importance of maternal-specific chromatin regulators in this critical stage.

Abstract Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.

Mine integrated energy system (MIES) can promote the utilization of derived energy and achieve multi-energy complementation and ecological protection. Now it gradually becomes an important focus for scientific carbon reduction and carbon neutrality. To reduce the impact of uncertain prediction differences on the system during the process of using mine derived energy, a low-carbon economic operation strategy of MIES considering energy supply uncertainty is developed in this paper. Firstly, based on the basic structure of energy flow in MIES, the energy-carbon flow framework of MIES is established for the low-carbon operation requirements. Secondly, considering carbon emission constraints, the low-carbon economic operation optimization model (LEOOM) is built for MIES to minimize operation cost and carbon emission. Finally, multiple uncertainties of the system are modeled and analyzed by using the robust model under the risk aversion strategy of information gap decision theory (IGDT), and a model conversion method is designed to optimize the low-carbon economic operation model. The simulation results under three scenarios demonstrate that compared to the existed economic dispatching models, the proposed model achieves a 30% reduction in carbon emission while the operational cost of MIES only is increased by 2.1%. The model efficiently mitigates the carbon emission of the system, and the proposed uncertain treatment strategy can significantly improve the robustness of obtained operation plans.

Abstract For multi-dimensional high-order nonlinear systems with unstable path quality in parameter and extension terms, we developed a new fast search random tree strategy. First, we established a high-order Lipschitz vector field dynamic system to adapt to high-order systems of multi-degree-of-freedom robots, with the complex obstacle function being one of its key components. Secondly, we designed a classification gap filtering network layer (Classification LSTM) to screen training data models and ensure the global stability of data in path design. Additionally, the visual sensors deployed in the unit area effectively implement the path marking backtracking strategy and dead zone path simplification. Finally, three examples are provided to verify the effectiveness of this design method.

Abstract Both anaesthesiologists and surgeons experience challenges in managing airway stenosis and scar contracture in the face and neck. Herein, we report the case of a 38-year-old woman (BMI 23.1 kg/m2, third-degree burns covering 40% of her body, an American Society of Anaesthesiologists physical status III) with an unusual case of airway constriction. This patient had a predictable difficult airway (mouth opening of 2 cm, bilateral nostril scar hyperplasia, Mallampatti score III, scarring of the head and neck, and severe tracheal stenosis). Tracheal stenosis measuring 5.5 mm in width as observed 8 cm below the glottis, and the bronchoscope could not pass through it. After two failed attempts at laryngeal mask insertion, we decided to instead insert a custom-made tracheal tube under the guidance of a fiberoptic bronchoscope. The operation was successful, and the patient was transferred to the intensive care unit (ICU).

Abstract Recent research has explored the potential of the demethylating drug 5-azacytidine (Aza) as therapy for a range of diseases. However, the therapeutic efficacy of Aza for patients of atherosclerosis remains unclear. This study investigates the therapeutic application of Aza to atherosclerosis in order to elucidate the underlying mechanisms. We generated induced Tregs (iTregs) from CD4+ T cells by using Aza in vitro, and this was followed by the intravenous infusion of iTregs for the treatment of atherosclerosis. The adoptive transfer of Aza-iTreg significantly increased peripheral blood Treg cells, suppressed inflammation, and attenuated atherosclerosis in ApoE−/− mice. Furthermore, we observed a notable demethylation of the Forkhead box P3 (Foxp3)-regulatory T cell-specific demethylated region (TSDR) and an upregulation of Foxp3 expression in the CD4+ T cells in the spleen of the ApoE−/− mice following the transfer of Aza- iTregs. We also demonstrated that Aza converted naive CD4+ T cells into Tregs by DNA methyltransferase 1 (Dnmt1)-mediated Foxp3-TSDR demethylation and the upregulation of Foxp3 expression. Conversely, the overexpression of Dnmt1 in the CD4+ T cells attenuated the Aza-induced Foxp3-TSDR demethylation and upregulation of Foxp3 expression. Our results reveal that Aza converts naive CD4+ T cells into functional Tregs by inhibiting Dnmt1, and the transfer of Aza-iTregs suppresses atherosclerosis in mice.

Abstract Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

Abstract Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

Abstract Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves’ disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts (CBC) monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of CBC may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia.

Background: The aim of this study was to establish and validate a Susceptibility-weighted imaging (SWI)-based predictive model for neonatal intracranial haemorrhage (ICH). Methods: A total of 1190 neonates suspected of ICH after cranial ultrasound screening in a tertiary hospital were retrospectively enrolled. The neonates were randomly divided into a training cohort and a internal validation cohort by a ratio of 7:3. Univariate analysis was used to analyze the correlation between risk factors and ICH, and the prediction model of neonatal ICH was established by multivariate logistic regression based on minimum Akaike information criterion (AIC). The nomogram was externally validated in another tertiary hospital of 91 neonates. The performance of the nomogram was evaluated in terms of discrimination by the area under the curve (AUC), calibration by the calibration curve and clinical net benefit by the decision curve analysis (DCA). Results: Univariate analysis and min AIC-based multivariate logistic regression screened the following variables to establish a predictive model for neonatal ICH: Platelet count (PLT), gestational diabetes, mode of delivery, amniotic fluid contamination, 1-min Apgar score. The AUC was 0.715, 0.711, and 0.700 for the training cohort, internal validation cohort, and external validation cohort, respectively. The calibration curve showed a good correlation between the nomogram prediction and actual observation for ICH. DCA showed the nomogram was clinically useful. Conclusion: We developed and validated an easy-to-use nomogram to predict ICH for neonates. This model could support individualized risk assessment and healthcare.

Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (RPS6) gene, which is dependent in CCA. We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis. Functional investigations have shown that alterations in RPS6 expression, both gain- and loss-of function could affect the proliferation of CCA cells. In xenograft tumor models, RPS6 overexpression enhances tumorigenicity, whereas RPS6 silencing reduces it. Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle, especially DNA replication. Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6. Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing (AS) events, and combined with RNA immunoprecipitation sequencing, revealed that minichromosome maintenance complex component 7 (MCM7) binds to RPS6, which regulates its AS and increases oncogenic activity in CCA. Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer (V-PMO) significantly inhibited the growth of CCA cells, patient-derived organoids, and subcutaneous xenograft tumor. Taken together, the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

Abstract This study elucidated the unique pathological features of tissue healing by magnamosis and revealed the changes in landmark molecule expression levels related to collagen synthesis and tissue hypoxia. Forty-eight male Sprague–Dawley rats were divided into the magnamosis and suture anastomosis groups, and gastrojejunal anastomosis surgery was performed. Rats were dissected at 6, 24, and 48 h and 5, 6, 8, 10, and 12 days postoperatively. Hematoxylin, eosin, and Masson’s trichrome staining were used to evaluate granulation tissue proliferation and collagen synthesis density at the anastomosis site. Immunohistochemistry was used to measure TGF-β1 and HIF-1α expression levels. Magnamosis significantly shortened the operation time, resulting in weaker postoperative abdominal adhesions (P

Abstract 30 min of moderate-intensity aerobic exercise per day is recommended, but the response and adaptation of endothelial function (EF) to this exercise remains controversial. The purpose of this study was to determine the changes in EF in endurance trained and untrained individuals before and after this exercise and to compare the differences between trained and untrained individuals. Twelve endurance-trained male college athletes (trained group) and 12 untrained male college students (untrained group) performed a 30-min run at an intensity of 60% VO2max. Brachial artery flow-mediated dilation (FMD) was measured before exercise, 30 min and 60 min after exercise, and the following morning. Resting diameter and maximum diameter showed large time effects (p

Abstract Three-dimensional Spatial Transcriptomics has revolutionized our understanding of tissue regionalization, organogenesis, and development. However, existing approaches overlook either spatial information or experiment-induced distortions, leading to significant discrepancies between reconstruction results and in vivo cell locations, causing unreliable downstream analysis. To address these challenges, we propose ST-GEARS (Spatial Transcriptomics GEospatial profile recovery system through AnchoRS). By employing innovative Distributive Constraints into the Optimization scheme, ST-GEARS retrieves anchors with exceeding precision that connect closest spots across sections in vivo. Guided by the anchors, it first rigidly aligns sections, next solves and denoises Elastic Fields to counteract distortions. Through mathematically proved Bi-sectional Fields Application, it eventually recovers the original spatial profile. Studying ST-GEARS across number of sections, sectional distances and sequencing platforms, we observed its outstanding performance on tissue, cell, and gene levels. ST-GEARS provides precise and well-explainable ‘gears’ between in vivo situations and in vitro analysis, powerfully fueling potential of biological discoveries.

Abstract Background Follicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows. Results In this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries. Conclusions These findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows.

In the present work, a wall-structured nickel-aluminum bronze (NAB) alloy was fabricated via electron beam directed energy deposition (EB-DED) additive manufacturing with a single-pass multi-layer deposition strategy. A comprehensive comparative analysis of microstructure, mechanical properties, and corrosion resistance was conducted against a conventionally cast NAB alloy. The inherent rapid solidification and cyclic thermal processing of the EB-DED technique profoundly influenced the microstructural evolution of the NAB alloy. The as-deposited NAB alloy exhibited a fine-grained microstructure, devoid of the martensitic β′ phase, accompanied by the spheroidization of partial κIII precipitates, and a homogeneous distribution of alloying elements. These distinctive microstructural attributes synergistically enhanced the strength, hardness, and toughness of the NAB alloy, conferring superior mechanical properties compared to its cast counterpart. Furthermore, the as-deposited alloy demonstrated remarkable corrosion resistance in a 3.5 wt% NaCl solution, significantly outperforming the cast alloy. The underlying mechanisms governing the structure-property relationships were elucidated. This comprehensive investigation provided insights into the unique characteristics and potential applications of EB-DED fabricated NAB alloys, positioning them as promising candidates for high-performance components subjected to severe mechanical and corrosive service conditions.

This research endeavors to address the persistent dissemination of public opinion within social networks, mitigate the propagation of inappropriate content on these platforms, and enhance the overall service quality of social networks. To achieve these objectives, Convolutional Neural Network (CNN) and Long Short-Term Memory (LSTM) techniques are employed in this research to develop a predictive model for anticipating public opinion crises in social network mining. This model furnishes users with a valuable reference for subsequent decisionmaking processes. The initial phase of this research involves the collection of user behavior data from social networks using IoT technologies, serving as the basis for extensive big data analysis and neural network research. Subsequently, a social network text categorization model is constructed by amalgamating the Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM) architecture, elucidating the training procedures of deep learning methodologies within CNN and LSTM networks. The effectiveness of this approach is subsequently validated through comparisons with other deep learning techniques. Based on the obtained results and findings, the CNN-LSTM model demonstrates a noteworthy accuracy rate of 92.19% and an exceptionally low loss value of 0.4075. Of particular significance is the classification accuracy of the CNN-LSTM algorithm within social network datasets, which surpasses that of alternative algorithms, including CNN (by 6.31%), LSTM (by 4.43%), RNN (by 3.51%), Transformer (by 40.29%), and Generative Adversarial Network (GAN) (by 4.49%). This underscores the effectiveness of the CNN-LSTM algorithm in the realm of social network text classification.

The impact of hot rolling finish temperature (HRFT) on the evolution of microstructure, texture, as well as formability—including deep drawability and bendability—of Al–Mg–Si alloy was studied in present work. The obtained results reveal that HRFT has a notable influence on the dynamic softening and dynamic precipitation behaviors during the hot rolling process of the investigated alloy. This leads to the volume fraction and number density of micro-sized Mg2Si particles increase as the increase of HRFT, those of nano-sized particles decrease, and the dislocation density decrease, in the hot-rolled sheets. These microstructural variations persist in the cold-rolled sheets, subsequently affecting the ultimate microstructure, texture, as well as formability of T4P sheets. The deep drawability improves as the HRFT rises, as indicated by the increase in normal anisotropy (r‾) and decrease in planar anisotropy (Δr). This is attributed to the weakening of texture intensity. The bendability, quantified by the minimum hemming factor (Rmin/t), deteriorates as the HRFT rises from 260 °C to 390 °C, attributed to the strengthening of P component along with the weakening of Cube component. Conversely, with the HRFT rises from 390 °C to 420 °C, the bendability improves dramatically due to the significant reduction in the average grain size. A combination of excellent deep drawability and bendability could be obtained by elevating the HRFT to 420 °C, attributed to the combined effect of weakened texture intensity and fine grains.

Stacking faults (SFs) and the interaction between solute atoms and SFs in a Mg–Bi alloy are investigated using aberration-corrected scanning transmission electron microscopy. It is found that abundant I1 SFs are generated after cold rolling and are mainly distributed inside {101¯2} twins. After aging treatment, the formation of single-layer and three-layer Bi atom segregation in the vicinity of I1 fault are clearly observed. Bi segregation also occurs at the 1/6 bounding Frank partial dislocation cores. The segregation behaviors in I1 fault and Frank dislocations are discussed and rationalized using first-principles calculations.

High resolution isotope ratio mass spectrometry (HR-IRMS) is often used to measure the abundance of deuterium to verify the efficiency of isotope isolation of a cryogenic distillation column system. In order to achieve precise quantification of hydrogen isotope abundance by HR-IRMS, a fine tuning procedure was performed by using molecular hydrogen to optimize the source parameters, steering parameters and analyzer parameters. The mass resolution can reach 10 000 after tuning, which is high enough to separate all potential hydrogen and helium isotopes except for 3He+ and T+. The test results of peak center stability, peak top flatness, resolution and sensitivity stability showed that the performance of the mass spectrometer can meet the demand for hydrogen isotope analysis. The inlet pressure should be in the range of 4-33 Pa to obtain stable sensitivity, and the accelerating voltage of the ion source should not be less than 8 V because it is negatively correlated with the production rate of trimmers (H3+, D3+, H2D+ and HD2+ etc.). As the accelerating voltage decreasing, the production rate of trimers increases. Another key factor affecting the production rate of trimers is the inlet pressure, the square of which is proportional to the production rate of trimers. Therefore, optimizing the ion source parameters to obtain higher sensitivity is a better way than increasing the sample inlet pressure. On this basis, the equilibrium hydrogen isotope standards which are essential to obtain the sensitivity of each component of hydrogen isotopes were prepared by a self-made standard gas preparation device, and the sensitivity values of each component were corrected by pure gases and the self-prepared standard with verified compositions. The molecular leak rate for the inlet hole was determined by monitoring the pressure for H2 and D2 as a function of time as the gas leaked out, and the leak rate of the other components could be calculated using the leak rate of H2 or D2 because the leak rate is inversely proportional to the square root of the molar mass. Standard mixtures were analyzed to test precision and trueness of this method. The results showed that the measurement precision is better than 1% for samples with natural deuterium abundance and better than 0.5% for samples with medium to high abundance of deuterium. The measured values are in good agreement with the standard values. Compared to the low resolution mass spectrometry, this method is simple and reliable, does not need to resolve the mass overlap peak, and the accuracy of the measurement does not depend on the degree of hydrogen isotope balance in the sample.

Abstract Ultra-low-power consumption and high-speed integrated switches are highly desirable for future data centers and high-performance optical computers. In this study, we proposed an ultra-low-power consumption silicon electro-optic switch based on photonic crystal nanobeam cavities on a foundry platform. The proposed switch showed an ultra-low static-tuning power of 0.10 mW and a calculated dynamic switching power of 6.34 fJ/bit, with a compact footprint of 18 μm × 200 μm. Additionally, a 136-Gb/s four-level pulse amplitude modulation signal transmission experiment was carried out to verify the capability of the proposed electro-optic switch to support high-speed data transmission. The proposed device has the lowest static-tuning power consumption among silicon electro-optic switches and the highest data transmission rate. The results demonstrate the potential applications of this switch in high-performance optical computers, data center interconnects, optical neural networks, and programmable photonic circuits.

Abstract Macrophage metabolism dysregulation, which is exacerbated by persistent stimulation in infectious and inflammatory diseases, such as diabetic infectious bone defects (DIBD), eventually leads to the failure of bone repair. Here, we have developed an injectable, macrophage-modulated GAPDH-Silence drug delivery system. This microsphere comprises chondroitin sulfate methacrylate (CM) and methacrylated gelatin (GM), while the dimethyl fumarate (DMF)-loaded liposome (D-lip) is encapsulated within the microsphere (CM@GM), named D-lip/CM@GM. Triggered by the over-expressed collagenase in DIBD, the microspheres degrade and release the encapsulated D-lip. D-lip could modulate metabolism by inhibiting GAPDH, which suppresses the over-activation of glycolysis, thus preventing the inflammatory response of macrophages in vitro. While beneficial for macrophages, D-lip/CM@GM is harmful to bacteria. GAPDH, while crucial for glycolysis of staphylococcal species (S. aureus), can be effectively countered by D-lip/CM@GM. We are utilizing existing drugs in innovative ways to target central metabolism for effective eradication of bacteria. In the DIBD model, our results confirmed that the D-lip/CM@GM enhanced bacteria clearance and reprogrammed dysregulated metabolism, thereby significantly improving bone regeneration. In conclusion, this GAPDH-Silence microsphere system may provide a viable strategy to promote diabetic infection bone regeneration.

Abstract Alzheimer’s disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.

Abstract Malignant melanoma represents a particularly aggressive type of skin cancer, originating from the pathological transformation of melanocytes. While conventional interventions such as surgical resection, chemotherapy, and radiation therapy are available, their non-specificity and collateral damage to normal cells has shifted the focus towards immunotherapy as a notable approach. Extracellular vesicles (EVs) are naturally occurring transporters, and are capable of delivering tumor-specific antigens and directly engaging in the immune response. Multiple types of EVs have emerged as promising platforms for melanoma vaccination. The effectiveness of EV-based melanoma vaccines manifests their ability to potentiate the immune response, particularly by activating dendritic cells (DCs) and CD8+ T lymphocytes, through engineering a synergy of antigen presentation and targeted delivery. Here, this review mainly focuses on the construction strategies for EV vaccines from various sources, their effects, and immunological mechanisms in treating melanoma, as well as the shortcomings and future perspectives in this field. These findings will provide novel insights into the innovative exploitation of EV-based vaccines for melanoma immune therapy.