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Abstract The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17α-MHCKO) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17fl/fl and A17α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.

Abstract Background Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis. Methods MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice. Results This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis. Conclusion These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases.

Abstract This study aims to address the issue of high energy consumption in the hydrocyclone separation process. By introducing a novel slotted overflow pipe structure and utilizing experimental and response surface optimization methods, the optimal parameters were determined. The research results indicate that the number of slots, slot angles, and positioning dimensions significantly influence the performance of the hydrocyclone separator. The optimal combination was found to be three layers of slots, a positioning dimension of 5.3 mm, and a slot angle of 58°. In a Φ100mm hydrocyclone separator, validated through multiple experiments, the separation efficiency increased by 0.26% and the pressure drop reduced by 24.88% under a flow rate of 900 ml/s. CFD simulation verified the reduction in internal flow field velocity and pressure drop due to the slotted structure. Therefore, this study provides an effective reference for designing efficient and low-energy hydrocyclone separators.

Abstract Background Chronic stress induces cognitive deficits. There is a well-established connection between the enteric and central nervous systems through the microbiota-gut-brain (MGB) axis. However, the effects of the gut microbiota on cognitive deficits remain unclear. The present study aimed to elucidate the microbiota composition in cognitive deficits and explore its potential in predicting chronic stress-induced cognitive deficits. Methods Mice were randomly divided into control and chronic restraint stress (CRS) groups. The mice subjected to CRS were further divided into cognitive deficit (CRS-CD) and non-cognitive deficit (CRS-NCD) groups using hierarchical cluster analysis of novel object recognition test results. The composition and diversity of the gut microbiota were analyzed. Results After being subjected to chronic restraint distress, the CRS-CD mice travelled shorter movement distances (p = 0.034 vs. CRS-NCD; p

Abstract The endothelial glycocalyx is damaged in postcardiac arrest syndrome (PCAS), but the prognostic value is unknown. We aimed to observe the expression and prognostic value of glycocalyx shedding products, including syndecan-1 (SDC-1), hyaluronan (HA), and heparan sulfate (HS) in PCAS. Data on clinical and 28-day outcomes of seventy-one consecutive patients with out-of-hospital cardiac arrest (OHCA) after the return of spontaneous circulation (ROSC) were collected. SDC-1, HA, and HS were measured on days 0, 1, and 3 after ROSC. Thirty healthy individuals were controls. Glycocalyx shedding was observed in human umbilical vein endothelial cells (HUVECs) stimulated during hypoxia and reoxygenation in vitro. Within 4 h of ROSC, SDC-1 and HA levels, significantly increased. In the 28-day non-survivors, HA levels showed a gradual upward trend, SDC-1 remained at a high level, and HS levels first increased, then decreased. Kaplan–Meier curves and binary logistic regression analysis showed the prognostic value of SDC-1 levels on days 0, 1, and 3, HA levels on days 1 and 3, and HS levels on day 1. Only HS levels on day 1 showed a prognostic value for 28-day neurological outcomes. SDC-1 and HA levels were positively correlated with the no-flow time. In vitro, HUVECs showed shedding of SDC-1 and HS during a prolonged duration of hypoxia. After ROSC, SDC-1, HA, and HS levels may predict the 28-day survival after PCAS, and HS levels are associated with functional outcomes.

Abstract CD320, which is a transmembrane protein responsible for facilitating the absorption of vitamin B12, plays a key role in this process. However, the relationships between CD320 and immune cell infiltration levels remain unclear, with limited studies investigating the diagnostic and prognostic significance of CD320 in hepatocellular carcinoma. We used various databases, including the TIMER, GEPIA, UALCAN and TCGA databases to investigate the expression levels of CD320 in hepatocellular carcinoma. Subsequently, we analyzed the prognosis of hepatocellular carcinoma patients with different expression levels of CD320. Furthermore, we also performed Western blot, immunohistochemistry, and immunofluorescence analyses to validate the results of the database analysis. Finally, the functions of CD320 in hepatocellular carcinoma were also confirmed via relevant cell experiments and angiogenesis assays. We found that CD320 expression was significantly upregulated in tumor vascular endothelial cells. Moreover, the knockdown of CD320 led to a reduction in angiogenesis in endothelial cells. Increased expression of CD320 was also correlated with a poor prognosis in patients with hepatocellular carcinoma, which suggested that CD320 may be a potential prognostic marker. Finally, TIMER analysis demonstrated that the infiltration of six immune cell types was significantly associated with high expression levels of CD320 in hepatocellular carcinoma. Herein, we demonstrated that CD320 may play an important role in angiogenesis in hepatocellular carcinoma. These findings suggested that CD320 may be a potential clinical prognostic marker and immunotherapy target for hepatocellular carcinoma.

BackgroundFibrinogen plays a pivotal role in the inflammatory cascade and is intricately linked to the pathogenesis of sepsis. Nevertheless, its significance as a prognostic marker for sepsis-associated acute kidney injury (SA-AKI) remains uncertain. This study aimed to investigate the association between fibrinogen levels and 28-day mortality with sepsis-associated acute kidney injury.MethodThe fibrinogen levels of patients admitted to the intensive care unit of Beth Israel Deaconess Medical Center between 2008 and 2019 were retrospectively assessed, and those diagnosed with SA-AKI were divided into low, middle and high fibrinogen level groups according to tertiles. Multivariate Cox proportional hazards model was used to assess the 28-day mortality risk of the SA-AKI patients.ResultsA total of 3,479 patients with SA-AKI were included in the study. Fibrinogen demonstrated an independent association with 28-day mortality, yielding a hazard ratio (HR) of 0.961 (95% confidence interval [CI]: 0.923-0.999, P = 0.0471). Notably, a non-linear relationship between fibrinogen levels and 28-day mortality was observed, with the threshold observed at approximately 1.6 g/l. The effect sizes and corresponding CIs below and above this threshold were 0.509 (0.367, 0.707) and 1.011 (0.961, 1.064), respectively. Specifically, the risk of mortality among SA-AKI patients decreased by 49.1% for every 1 g/l increment in fibrinogen, provided that fibrinogen levels were less than 1.6 g/l.ConclusionIn patients with SA-AKI, a non-linear relationship was identified between fibrinogen levels and 28-day mortality. Particularly, when their fibrinogen levels were less than 1.6 g/l, a concomitant decrease in 28-day mortality was observed as fibrinogen levels increased.

ObjectiveTo measure the palatal soft tissue thickness and cortical bone density to determine safe regions for the placement of orthodontic mini-implants and to examine the influence of sex and age on soft tissue thickness and cortical bone density.Materials and methodsCone-beam computed tomography images of 42 patients (22 males and 20 females), including 21 adults and 21 adolescents, were examined in this study. The palatal soft tissue thickness and cortical bone density were measured at the coronal planes between the premolars (P4–5), between the second premolars and first molars (P5–6), and between the first molars and second molars (P6–7).ResultsThe thickness of the soft tissue revealed similar coronal planes, but the bone density varied. The mean thickness was 3.8 mm at 0°–60° and 1.5 mm at 60°–90°. P4–5 had the highest bone density (>600 HU), decreasing toward P6–7 (

The rheological behavior of propellant slurries is crucial for ensuring the feasibility of the 3D printing process, controlling print quality, regulating performance, and simulating predictions. However, there have been relatively few prior studies on the rheological properties of composite solid propellant slurries at low temperatures, which hinders the application of 3D printing propellant technology under extreme temperature conditions. In addition, the use of 3D printing technology to manufacture propellants at low temperatures is advantageous for improving safety. This paper investigates the rheological properties of monodisperse systems with aluminum powder as a solid filler and end-hydroxy polybutadiene (HTPB) as the dispersed phase at low temperatures (−15∼10 °C). It explores the effects of solid content, temperature, and particle size on their rheological properties. Results show that the viscosity of the system in the range of −15∼10 °C increases exponentially with the decrease in temperature, and the viscosity at −15 °C increases by 616.90 % compared with that at 10 °C when the volume fraction (φ) of Al-1 is 35.8 %; the larger size of the particles the larger the viscosity is when the temperature and φ are the same, which is interpretes in terms of interfacial properties between the systems. The low-temperature correction factor is introduced into the Einstein-Roscoe equation to obtain the modified viscosity-volume fraction equation, and the correction factor is 0.0173, as evidenced by its excellent agreement with the experimental data.

Abstract Background The incidence of coronary heart disease (CHD) in youth is rapidly increasing but difficultly recognized in the early stage. Methods and Results In this retrospective study, 194 CHD patients under the age of 45 who previously experienced chest pain symptoms and 170 non‐CHD patients were included and demographic data were collected. Systemic inflammation index (SII) and systemic inflammation response index (SIRI) were increased in young CHD patients (p

Introduction Laparoscopic proximal gastrectomy with double flap technique (LPG-DFT) reconstruction has been used for proximal early gastric cancer in recent years. However, its feasibility and safety remain uncertain, as only a few retrospective studies have contained postoperative complications and long-term survival data. LPG-DFT for proximal early gastric cancer is still in the early stages of research. Large-scale, prospective randomised controlled trials (RCTs) are necessary to assess the value of LPG-DFT for proximal early gastric cancer.Methods and analysis This study is a multicentre, prospective, open-label, RCT that investigates the antireflux effect of LPG-DFT compared with laparoscopic total gastrectomy with Roux-en-Y (LTG-RY) reconstruction for proximal early gastric cancer. A total of 216 eligible patients will be randomly assigned to the LPG-DFT group or the LTG-RY group at a 1:1 ratio using a central, dynamic and stratified block randomisation method, if inclusion criteria are met. General and clinical data will be collected when the patient is enrolled in the study and keep pace with the patient at each stage of his medical and follow-up pathway. The primary endpoint is the proportion of patients with reflux esophagitis (Los Angeles Grade B or more) within 12 months postoperatively. The secondary endpoints included intraoperative outcomes, postoperative recovery, postoperative pain assessment, pathological outcomes, postoperative quality of life, postoperative nutrition status, morbidity and mortality rate, and oncological outcomes (3-year overall survival (OS), 3-year disease-free survival (DFS), 5-year DFS and 5-year OS).Ethics and dissemination The protocol is approved by the Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University ethics committee (registration number: SYSKY-2022-276-02) on 28 September 2022.We will report the positive as well as negative findings in international peer-reviewed journals.Trial registration number NCT05890339.

Abstract Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, “epi-miRNAs”, can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

Abstract Aims Recent studies have indicated an association between intestinal flora and lipids. However, observational studies cannot indicate causality. In this study, we aimed to investigate the potentially causal relationships between the intestinal flora and blood lipids. Methods We performed a bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between intestinal flora and blood lipids. Summary statistics of genome-wide association studies (GWASs) for the 211 intestinal flora and blood lipid traits (n = 5) were obtained from public datasets. Five recognized MR methods were applied to assess the causal relationship with lipids, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. Results The results indicated a potential causal association between 19 intestinal flora and dyslipidemia in humans. Genus Ruminococcaceae, Christensenellaceae, Parasutterella, Terrisporobacter, Parabacteroides, Class Erysipelotrichia, Family Erysipelotrichaceae, and order Erysipelotrichales were associated with higher dyslipidemia, whereas genus Oscillospira, Peptococcus, Ruminococcaceae UCG010, Ruminococcaceae UCG011, Dorea, and Family Desulfovibrionaceae were associated with lower dyslipidemia. After using the Bonferroni method for multiple testing correction, Only Desulfovibrionaceae [Estimate = -0.0418, 95% confidence interval [CI]: 0.9362–0.9826, P = 0.0007] exhibited stable and significant negative associations with ApoB levels. The inverse MR analysis did not find a significant causal effect of lipids on the intestinal flora. Additionally, no significant heterogeneity or horizontal pleiotropy for IVs was observed in the analysis. Conclusion The study suggested a causal relationship between intestinal flora and dyslipidemia. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address the problems in the clinic.

A fault-tolerant quantum computer must decode and correct errors faster than they appear to prevent exponential slowdown due to error correction. The Union-Find (UF) decoder is promising with an average time complexity slightly higher than $O(d^{3})$. We report a distributed version of the UF decoder that exploits parallel computing resources for further speedup. Using a field-programmable gate array (FPGA)-based implementation, we empirically show that this distributed UF decoder has a sublinear average time complexity with regard to $d$, given $O(d^{3})$ parallel computing resources. The decoding time per measurement round decreases as $d$ increases, the first time for a quantum error decoder. The implementation employs a scalable architecture called Helios that organizes parallel computing resources into a hybrid tree-grid structure. Using a Xilinx VCU129 FPGA, we successfully implement $d$ up to 21 with an average decoding time of 11.5 ns per measurement round under 0.1% phenomenological noise and 23.7 ns for $d=17$ under equivalent circuit-level noise. This performance is significantly faster than any existing decoder implementation. Furthermore, we show that Helios can optimize for resource efficiency by decoding $d=51$ on a Xilinx VCU129 FPGA with an average latency of 544 ns per measurement round.

To address the challenges posed by nonlinear tire characteristics in trajectory tracking control of active four-wheel steering (4WS) vehicle or fire-fighting robot, a novel control method is proposed. This method incorporates time-varying corrected cornering stiffness to enhance adaptability. Initially, the impact of friction coefficient and vertical load on tire lateral force nonlinearity is analyzed. Key input features are identified, and a cornering stiffness estimation model is developed using a Back Propagation (BP) neural network. Subsequently, the trajectory tracking state equation is established based on the 2-degree-of-freedom (2-DOF) dynamic model and trajectory tracking error model. An active front-wheel steering (AFS) trajectory tracking sliding mode controller (SMC) is designed, augmented by a Radial Basis Function (RBF) neural network, forming an RBF-SMC AFS controller capable of real-time correction of cornering stiffness. Additionally, an active rear-wheel steering (ARS) controller is designed based on fuzzy control theory, considering the influence of center of gravity lateral deviation on vehicle stability. Finally, Simulation tests under varied speed conditions on icy and dry asphalt surfaces, using the Matlab/Simulink-Carsim co-simulation platform, demonstrate that the proposed method dynamically adjusts front and rear axle cornering stiffness, enhancing trajectory tracking accuracy and maneuvering stability, particularly in high-speed or low-friction road conditions.

To improve the characteristics of traditional model predictive control (MPC) semi-active suspension that cannot achieve the optimal suspension control effect under different conditions, a variable horizon model predictive control (VHMPC) method is devised for magnetorheological semi-active suspension with air springs. Mathematical models are established for the magnetorheological dampers and air springs. Based on the improved hyperbolic tangent model, a forward model is established for the magnetorheological damper. The adaptive fuzzy neural network method is used to establish the inverse model of the magnetorheological damper. The relationship between different road excitation frequencies and the control effect of magnetorheological semi-active suspension with air springs is simulated, and the optimal prediction horizons under different conditions are obtained. The VHMPC method is designed to automatically switch the predictive horizon according to the road surface excitation frequency. The results demonstrate that under mixed conditions, compared with the traditional MPC, the VHMPC can improve the smoothness of the suspension by 2.614% and reduce the positive and negative peaks of the vertical vibration acceleration by 11.849% and 6.938%, respectively. Under variable speed road conditions, VHMPC improved the sprung mass acceleration, dynamic tire deformation, and suspension deflection by 7.191%, 7.936%, and 22.222%, respectively, compared to MPC.

Introduction:P. candolleana Wight et Arn. Is a traditional Chinese herbal medicine used by the Gelao nationality in southwest China, has been historically applied to treat various gastrointestinal disorders. Despite its traditional usage, scientific evidence elucidating its efficacy and mechanisms in treating ulcerative colitis (UC) remains sparse. This study aimed to determine the quality and chemical composition of Pimpinella candolleana and to identify its potential therapeutic targets and mechanisms in acetic acid-induced ulcerative colitis (UC) rats through integrated approaches.Methods: Morphological and microscopic characteristics, thin layer chromatography (TLC) identification, and quantitative analysis of P. candolleana were performed. UPLC-Q-TOF-MS, network pharmacology, and molecular docking were used to identify its chemical composition and predict its related targets in UC. Furthermore, a rat model was established to evaluate the therapeutic effect and potential mechanism of P. candolleana on UC.Results: Microscopic identification revealed irregular and radial arrangement of the xylem in P. candolleana, with a light green cross-section and large medullary cells. UPLC-Q-TOF-MS analysis detected and analyzed 570 metabolites, including flavonoids, coumarins, and terpenoids. Network pharmacology identified 12 effective components and 176 target genes, with 96 common targets for P. candolleana-UC, including quercetin, luteolin, and nobiletin as key anti-inflammatory components. GO and KEGG revealed the potential involvement of their targets in RELA, JUN, TNF, IKBKB, PTGS2, and CHUK, with action pathways such as PI3K-Akt, TNF, IL-17, and apoptosis. Molecular docking demonstrated strong affinity and binding between these key components (quercetin, luteolin, and nobiletin) and the key targets of the pathway, including JUN and TNF. Treatment with P. candolleana improved body weight loss, the disease activity index, and colonic histological damage in UC rats. Pimpinella candolleana also modulated the levels of IL-2 and IL-6 in UC rats, reduced the expression of pro-inflammatory cytokines such as IL-6, MAPK8, TNF-α, CHUK, and IKBKB mRNA, and decreased the expression of TNF, IKBKB, JUN, and CHUK proteins in the colon of UC rats, thereby reducing inflammation and alleviating UC symptoms.Conclusion:P. candolleana exerts its protective effect on UC by reducing the expression of proinflammatory cytokines and inhibiting inflammation, providing scientific evidence for its traditional use in treating gastrointestinal diseases. This study highlights the potential of P. candolleana as a natural therapeutic agent for UC and contributes to the development of novel medicines for UC treatment.

Abstract Background Richter’s syndrome (RS) defines the transformation of chronic lymphocytic leukemia into high-grade lymphoma, which usually involves lymph nodes and bone marrow. Extranodal involvement of the heart is an extremely rare condition. Patients with heart involvement tended to have a low response to chemotherapy and relative poor prognosis. The transformation process of RS is often insidious and nonspecific making it challenging to diagnose. Case presentation A 64-year-old woman wih a history of chronic lymphocytic leukemia (CLL) presented with intermittent chest pain and was diagnosed with non-ST-elevation myocardial infarction (NSTEMI). However, the contrast enhanced echocardiography revealed a large irregular mass, measuring about 75.4 mm × 37.5 mm, located on the lateral and posterior wall of the right ventricle. Biopsy of the cardiac mass and the results revealed diffuse large B-cell lymphoma. Conclusions We present a case of a 64-year-old woman with aggressive diffuse large B-cell lymphoma involving the heart. This case could provide some insights in the diagnosis of cardiac lymphoma.

Abstract Considering the non‐linear characteristics of both the input and output of photovoltaic (PV) modules and quasi‐Z‐source inverters, as well as the unpredictable natural factors such as large disturbances caused by changes in illumination and temperature, an average state model for the PV quasi‐Z‐source inverter is established. This paper uses the output current of photovoltaic module, DC‐link capacitor voltage and its integral as state variables, then an adaptive reaching law with second‐order sliding mode characteristics is designed by combining with power reaching law and variable speed reaching law. By using the sliding mode controller based on the adaptive reaching law to control the stability of the DC‐link voltage of the quasi‐Z‐source inverter and the small capacitor voltage ripple, the photovoltaic system can operate stably at the maximum power point when the temperature and illumination conditions change abruptly, and the grid‐connected effect is improved. Through SIMULINK and RT‐LAB real‐time simulation, the effectiveness of the proposed adaptive sliding mode control strategy is verified when the environment changes, which effectively improves the dynamic response speed and grid‐connected effect of the system, and ensures the global robustness of the grid‐connected system.

A new method of numerical simulating prediction and decontamination effect evaluation for abrasive jet decontamination to radioactively contaminated metal is proposed. Based on the Computational Fluid Dynamics and Discrete Element Model (CFD-DEM) coupled simulation model, the motion patterns and distribution of abrasives can be predicted, and the decontamination effect can be evaluated by image processing and recognition technology. The impact of three key parameters (impact distance, inlet pressure, abrasive mass flow rate) on the decontamination effect is revealed. Moreover, here are experiments of reliability verification to decontamination effect and numerical simulation methods that has been conducted. The results show that: 60Co and other homogeneous solid solution radioactive pollutants can be removed by abrasive jet, and the average removal rate of Co exceeds 80%. It is reliable for the proposed numerical simulation and evaluation method because of the well goodness of fit between predicted value and actual values: The predicted values and actual values of the abrasive distribution diameter are Ф57 and Ф55; the total coverage rate is 26.42% and 23.50%; the average impact velocity is 81.73 m/s and 78.00 m/s. Further analysis shows that the impact distance has a significant impact on the distribution of abrasive particles on the target surface, the coverage rate of the core area increases at first, and then decreases with the increase of the impact distance of the nozzle, which reach a maximum of 14.44% at 300 mm. It is recommended to set the impact distance around 300 mm, because at this time the core area coverage of the abrasive is the largest and the impact velocity is stable at the highest speed of 81.94 m/s. The impact of the nozzle inlet pressure on the decontamination effect mainly affects the impact kinetic energy of the abrasive and has little impact on the distribution. The greater the inlet pressure, the greater the impact kinetic energy, and the stronger the decontamination ability of the abrasive. But in return, the energy consumption is higher, too. For the decontamination of radioactively contaminated metals, it is recommended to set the inlet pressure of the nozzle at around 0.6 MPa. Because most of the Co elements can be removed under this pressure. Increasing the mass and flow of abrasives appropriately can enhance the decontamination effectiveness. The total mass of abrasives per unit decontamination area is suggested to be 50 g because the core area coverage rate of the abrasive is relatively large under this condition; and the nozzle wear extent is acceptable.

Due to improper setting of operating parameters, cigarette machines are subject to a high unqualified production rate. For this reason, in this study, a multiobjective optimisation (MOP) method based on the metaheuristic intelligence optimisation is proposed in this study. First, to eliminate interference parameters, the random forest (RF) is used to analyse the parameter importance of the cigarette machine and select the most important operation parameters for the multiobjective optimisation. Second, an artificial neural network (ANN) optimised by the grey wolf optimiser is designed to establish a mirror model of the cigarette machine to fast calculate the machine output quality factors, including the rod break rate, single cigarette weight, and circumference index. Lastly, an improved multiobjective grey wolf optimisation algorithm is used to optimise these three quality factors simultaneously to obtain the optimal operating parameters of the cigarette machine. A machine swarm (including four cigarette machines) in the real world is used to evaluate the developed optimisation method, and the testing results demonstrate that the proposed multiobjective optimisation method is able to improve the three quality factors by at least 50 %, which greatly reduces the unqualified rate of cigarettes.

Abstract The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029 leads to the identification of a class of dodecapeptides, glidonins, that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus. The N-terminal diversity originates from the wide substrate selectivity of the initiation module. The C-terminal putrescine moiety is introduced by the unusual termination module 13, the condensation domain directly catalyzes the assembly of putrescine into the peptidyl backbone, and other domains are essential for stabilizing the protein structure. Swapping of this module to another two nonribosomal peptide synthetases leads to the addition of a putrescine to the C-terminus of related nonribosomal peptides, improving their hydrophilicity and bioactivity. This study elucidates the mechanism for putrescine addition and provides further insights to generate diverse and improved nonribosomal peptides by introducing a C-terminal putrescine.

Acetobacter syzygii CCTCC M 2022983 was isolated and characterized from Tibetan kefir grains, which is utilized as a functional food with diverse bioactive properties. After 6 days of fermentation by A. syzygii, Acetobacter fermented extract (AFE) showed significantly higher antioxidant, anti-tyrosinase, and anti-melanin effects compared to the unfermented yeast extract (UFY). Western blotting confirmed that AFE reduced melanogenesis-related proteins (MITF, TYR, TRP-1, TRP-2). LC-MS/MS analysis identified 4-hydroxybenzoic acid as abundant in AFE, contributing to its antioxidant capacity. Succinic acid and citric acid emerged as the major compound and a type of mixed inhibitor against mushroom tyrosinase, with IC50 values of 2.943 mM and 1.615 mM, respectively. Fluorescence spectra analysis revealed that these acids caused conformational changes in tyrosinase. Moreover, succinic acid and citric acid prevented L-DOPA from auto-oxidation with IC50 values of 0.355 mM and 0.261 mM, respectively. Molecular docking analysis suggested that these acids interacted with the association of the H and L subunits of tyrosinase, thereby reducing its stability. In B16-F10 cells, succinic and citric acids significantly reduced melanin production in a dose-dependent manner. Thus, succinic acid and citric acid revealed promising potential for applications in the food and medicine industries as melanogenesis inhibitors due to their safety.

Hydrogels are widely used in tissue engineering due to their ability to form three-dimensional (3D) structures that support cellular functions and mimic the extracellular matrix (ECM). Despite their advantages, dextran-based hydrogels lack intrinsic biological activity, limiting their use in this field. Here, we present a strategy for developing bioactive hydrogels through sequential thiol–maleimide bio-functionalization and enzyme-catalyzed crosslinking. The hydrogel network is formed through the reaction of tyramine moieties in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2), allowing for tunable gelation time and stiffness by adjusting H2O2 concentrations. Maleimide groups on the hydrogel backbone enable the coupling of thiol-containing bioactive molecules, such as arginylglycylaspartic acid (RGD) peptides, to enhance biological activity. We examined the effects of hydrogel stiffness and RGD concentration on human mesenchymal stem cells (hMSCs) during differentiation and found that hMSCs encapsulated within these hydrogels exhibited over 88% cell viability on day 1 across all conditions, with a slight reduction to 60–81% by day 14. Furthermore, the hydrogels facilitated adipogenic differentiation, as evidenced by positive Oil Red O staining. These findings demonstrate that DexTA–Mal hydrogels create a biocompatible environment that is conducive to cell viability and differentiation, offering a versatile platform for future tissue engineering applications.

Abstract Regenerative repair of the brain after traumatic brain injury (TBI) remains an extensive clinical challenge, inspiring intensified interest in therapeutic approaches to explore superior repair strategies. Exosome therapy is another research hotspot following stem cell alternative therapy. Prior research verified that exosomes produced by neural stem cells can participate in the physiological and pathological changes associated with TBI and have potential neuroregulatory and repair functions. In comparison with their parental stem cells, exosomes have superior stability and immune tolerance and lower tumorigenic risk. In addition, they can readily penetrate the blood‒brain barrier, which makes their treatment efficiency superior to that of transplanted stem cells. Exosomes secreted by neural stem cells present a promising strategy for the development of novel regenerative therapies. Their tissue regeneration and immunomodulatory potential have made them encouraging candidates for TBI repair. The present review addresses the challenges, applications and potential mechanisms of neural stem cell exosomes in regenerating damaged brains.

The performance of the suspension is a crucial criterion for evaluating both vehicle handling and passenger comfort. To enhance suspension performance, this study proposes the design of a Quantum Genetic Fuzzy Sliding Mode Controller (S-QFSMC) based on the Smith predictor estimator, building upon the foundation of the vehicle magneto-rheological semi-active air suspension. According to the physical model of the vehicle suspension, a mechanical model of a quarter-vehicle magneto-rheological semi-active air suspension with time delay is established. On this basis, a conventional sliding mode controller is designed, and quantum genetic algorithm and fuzzy control principles are employed to optimize the chattering issue associated with sliding mode control. The Smith predictor estimator is utilized to effectively compensate for the time delay in the suspension system. Subsequently, a simulation analysis of the vehicle suspension performance is conducted. The results indicate that, compared to passive suspension control, both the QFSMC controller and the S-QFSMC controller improve the suspension performance, with the S-QFSMC controller exhibiting superior comprehensive improvement. This validates the effectiveness of the designed controllers.

Circular RNAs (circRNAs) are a distinct class of non-coding RNAs that play regulatory roles in the initiation and progression of tumors. With advancements in transcriptome sequencing technology, numerous circRNAs that play significant roles in tumor-related genes have been identified. In this study, we used transcriptome sequencing to analyze the expression levels of circRNAs in normal adjacent tissues, primary colorectal cancer (CRC) tissues, and CRC tissues with liver metastasis. We successfully identified the circRNA hsa_circ_0020134 (circ0020134), which exhibited significantly elevated expression specifically in CRC with liver metastasis. Importantly, high levels of circ0020134 were associated with a poor prognosis among patients. Functional experiments demonstrated that circ0020134 promotes the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, upregulation of circ0020134 was induced by the transcription factor, PAX5, while miR-183-5p acted as a sponge for circ0020134, leading to partial upregulation of PFN2 mRNA and protein levels, thereby further activating the downstream TGF-β/Smad pathway. Additionally, downregulation of circ0020134 inhibited epithelial-mesenchymal transition (EMT) in CRC cells, which could be reversed by miR-183-5p inhibitor treatment. Collectively, our findings confirm that the circ0020134-miR-183-5p-PFN2-TGF-β/Smad axis induces EMT transformation within tumor cells, promoting CRC proliferation and metastasis, thus highlighting its potential as a therapeutic target for patients with CRC liver metastasis.

Abstract Purpose The significance of detecting human herpesvirus 7 (HHV-7) in the lower respiratory tract of patients with severe pneumonia is unclear. This study aims to evaluate the clinical characteristics and prognosis of detecting HHV-7 in the lower respiratory tract of patients with severe pneumonia. Methods Patients with severe pneumonia requiring invasive mechanical ventilation and underwent commercial metagenomic next-generation sequencing (mNGS) testing of bronchoalveolar lavage fluid from January 2019 to March 2023 were enrolled in 12 medical centers. Clinical data of patients were collected retrospectively, and propensity score matching was used for subgroup analysis and mortality assessment. Results In a total number of 721 patients, 45 cases (6.24%) were identified with HHV-7 positive in lower respiratory tract. HHV-7 positive patients were younger (59.2 vs 64.4, p = 0.032) and had a higher rate of co-detection with Cytomegalovirus (42.2% vs 20.7%, p = 0.001) and Epstein–Barr virus (35.6% vs 18.2%, p = 0.008). After propensity score matching for gender, age, SOFA score at ICU admission, and days from ICU admission to mNGS assay, there was no statistically significant difference in the 28-day mortality rate between HHV-7 positive and negative patients (46.2% vs 36.0%, p = 0.395). Multivariate Cox regression analysis adjusting for gender, age, and SOFA score showed that HHV-7 positive was not an independent risk factor for 28-day mortality (HR 1.783, 95%CI 0.936–3.400, p = 0.079). Conclusion HHV-7 was detected in the lungs of 6.24% of patients with severe pneumonia. The presence of HHV-7 in patients with severe pneumonia requiring invasive mechanical ventilation is associated with a younger age and co-detected of Cytomegalovirus and Epstein–Barr virus. While HHV-7 positivity was not found to be an independent risk factor for mortality in this cohort, this result may have been influenced by the relatively small sample size of the study.

Background Foam cells play crucial roles in all phases of atherosclerosis. However, until now, the specific mechanisms by which these foam cells contribute to atherosclerosis remain unclear. We aimed to identify novel foam cell biomarkers and interventional targets for atherosclerosis, characterizing their potential mechanisms in the progression of atherosclerosis. Methods Microarray data of atherosclerosis and foam cells were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expression genes (DEGs) were screened using the “LIMMA” package in R software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) annotation were both carried out. Hub genes were found in Cytoscape after a protein-protein interaction (PPI) enrichment analysis was carried out. Validation of important genes in the GSE41571 dataset, cellular assays, and tissue samples. Results A total of 407 DEGs in atherosclerosis and 219 DEGs in foam cells were identified, and the DEGs in atherosclerosis were mainly involved in cell proliferation and differentiation. CSF1R and PLAUR were identified as common hub genes and validated in GSE41571. In addition, we also found that the expression of CSF1R and PLAUR gradually increased with the accumulation of lipids and disease progression in cell and tissue experiments. Conclusion CSF1R and PLAUR are key hub genes of foam cells and may play an important role in the biological process of atherosclerosis. These results advance our understanding of the mechanism behind atherosclerosis and potential therapeutic targets for future development.

Abstract Background Nonunion is a failure of fracture healing and a major complication after fractures. Ubiquitin-specific protease 1 (USP1) is a deubiquitinase that involved in cell differentiation and cell response to DNA damage. Herein we investigated the expression, function and mechanism of USP1 in nonunion. Methods and results Clinical samples were used to detect the USP1 expression in nonunion. ML323 was selected to inhibit USP1 expression throughout the study. Rat models and mouse embryonic osteoblasts cells (MC3T3-E1) were used to investigate the effects of USP1 inhibition on fracture healing and osteogenesis in vivo and in vitro, respectively. Histological changes were examined by micro-computerized tomography (Micro-CT), hematoxylin & eosin (H&E) staining and Masson staining. Alkaline phosphatase (ALP) activity detection and alizarin red staining were used for osteogenic differentiation observation. The expression of related factors was detected by quantitative real-time PCR, western blot or immunohistochemistry (IHC). It was shown that USP1 was highly expressed in nonunion patients and nonunion rats. USP1 inhibition by ML323 promoted fracture healing in nonunion rats and facilitated the expression of osteogenesis-related factors and the signaling of PI3K/Akt pathway. In addition, USP1 inhibition accelerated osteogenic differentiation and promoting PI3K/Akt signaling in MC3T3-E1 cells. Conclusions USP1 inhibition plays a promotive role in coordinating osteogenic differentiation and fracture healing during nonunion. PI3K/Akt may be the downstream pathway of USP1.

There are various clinical treatments for traumatic brain injury, including surgery, drug therapy, and rehabilitation therapy; however, the therapeutic effects are limited. Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury. In this study, we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (3D-CC-INExos) to improve traumatic brain injury repair and functional recovery after traumatic brain injury in rats. Composite scaffolds comprising collagen, chitosan, and exosomes derived from neural stem cells pretreated with insulin-like growth factor-1 (INExos) continuously released exosomes for 2 weeks. Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model, as assessed by the Morris water maze test and modified neurological severity scores. In addition, immunofluorescence staining and transmission electron microscopy showed that 3D-CC-INExos implantation significantly improved the recovery of damaged nerve tissue in the injured area. In conclusion, this study suggests that transplanted 3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.

Intact endometrium and proper endometrial thickness are the necessary conditions for normal uterine reproductive function. Intrauterine adhesion (IUA) can cause recurrent abortion and infertility, which seriously affects the normal reproductive function of patients. At present, the treatment methods for IUA include surgery elimination and use of estrogen, but there are problems such as poor effectiveness, high rate of recurrence, and still with low pregnancy rate. The specific pathogenesis and developmental mechanism of IUA and the repair mechanism of damaged endometrium are still unclear. Establishing an appropriate animal model is conducive to the research of human IUA in all aspects. Here, we introduced the common rat models of IUA in recent years, including physical and mechanical damage method, chemical damage method, biological damage method and combined damage method, and described its application from the aspects of modeling rate, stability, and pathogenesis of IUA, and discussed the observation indexes to evaluate the success of modeling, in order to provide useful reference for selecting appropriate modeling methods. Generally, the combined model of repeated endometrial damage and infection of pregnant rats may be more suitable for the clinical IUA caused by multiple abortions and infections after curettage.

Abstract Recent years, Burkholderia species have emerged as a new source of natural products (NPs) with increasing attractions. Genome mining suggests the Burkholderia genomes include many natural product biosynthetic gene clusters (BGCs) which are new targets for drug discovery. In order to collect more Burkholderia, here, a strain S-53 was isolated from the soil samples on a mountain area in Changde, P.R. China and verified by comparative genetic analysis to belong to Burkholderia. The complete genome of Burkholderia strain S-53 is 8.2 Mbps in size with an average G + C content of 66.35%. Its taxonomy was both characterized by 16S rRNA- and whole genome-based phylogenetic trees. Bioinformatic prediction in silico revealed it has a total of 15 NP BGCs, some of which may encode unknown products. It is expectable that availability of these BGCs will speed up the identification of new secondary metabolites from Burkholderia and help us understand how sophisticated BGC regulation works.

Abstract While role-playing games and personalized learning have been regarded as effective tools to improve students’ learning, incorporating personalized learning into role-playing games is challenging and approaches are limited to cognitive and motivational variables. Aiming at expanding approaches to incorporate personalization into role-playing games, this study included affective and cognitive variables to develop a personalized role-playing game, guiding by the situational design model. A pilot study was conducted to examine the effectiveness of the game on students’ learning performance and cognitive load. Results showed that personalized role-playing game environment was effective in improving students’ performance, reducing extraneous load, and promoting germane load. This study also found that although decreased extraneous load, could leave students more GL capacity for efficient learning, this would not necessarily lead to performance improvement. Students need to be motivated to invest sufficient germane load to actively process the learning materials and thus, improve performance. The findings have several implications for future research designing personalized educational games aimed to promote efficient learning.

Abstract To optimize the optimal nozzle structure and multiple nozzle arrangement for hydrate jet crushing and to promote the development of solid fluidization extraction technology for shallow unconformity hydrate in China’s oceans, the submerged jet flow field of six commonly used nozzle structures in the downhole in-situ jet crushing process was analyzed on the basis of the solid fluidization extraction process in double-layer pipes, and the effect of the jet hole arrangement on the overflow performance of hydrate slurry in the outer annulus of double-layer pipes was also investigated. It was demonstrated that tapered straight nozzles were preferably selected as the nozzle type for hydrate solid fluidization mining process based on jet core stage length, jet energy dissipation rate, and jet fluid axial velocity. In the meantime, the optimum arrangement of the nozzles was preferred on the basis of the annular pressure drop and the flow resistance coefficient, with the number of single circle not higher than 3 and the axial spacing of the nozzles not lower than 50 mm. This study can provide a theoretical basis for nozzle selection and tool design for the solid fluidization jet crushing process of marine unconformable hydrates.

Iron is essential for bacterial survival, and most bacteria capture iron by producing siderophores. Burkholderiales bacteria produce various types of bioactive secondary metabolites, such as ornibactin and malleobactin siderophores. In this study, the genome analysis of Burkholderiales genomes showed a putative novel siderophore gene cluster crb, which is highly similar to the ornibactin and malleobactin gene clusters but does not have pvdF, a gene encoding a formyltransferase for N-δ‑hydroxy-ornithine formylation. Establishing the bacteriophage recombinase Redγ-Redαβ7029 mediated genome editing system in a non-model Burkholderiales strain Paraburkholderia caribensis CICC 10960 allowed the rapid identification of the products of crb gene cluster, caribactins A-F (1–6). Caribactins contain a special amino acid residue N-δ‑hydroxy-N-δ-acetylornithine (haOrn), which differs from the counterpart N-δ‑hydroxy-N-δ-formylornithine (hfOrn) in ornibactin and malleobactin, owing to the absence of pvdF. Gene inactivation showed that the acetylation of hOrn is catalyzed by CrbK, whose homologs probably not be involved in the biosynthesis of ornibactin and malleobactin, showing possible evolutionary clues of these siderophore biosynthetic pathways from different genera. Caribactins promote biofilm production and enhance swarming and swimming abilities, suggesting that they may play crucial roles in biofilm formation. This study also revealed that recombineering has the capability to mine novel secondary metabolites from non-model Burkholderiales species.

Summary: The liver has long been deemed a tolerogenic organ. We employed high-dimensional mass cytometry and immunohistochemistry to depict the temporal and spatial dynamics of immune cells in the spleen and liver in a murine model of spontaneous liver allograft acceptance. We depicted the immune landscape of spontaneous liver tolerance throughout the rejection and acceptance stages after liver transplantation and highlighted several points of importance. Of note, the CD4+/CD8+ T cell ratio remained low, even in the tolerance phase. Furthermore, a PhenoGraph clustering analysis revealed that exhausted CD8+ T cells were the most dominant metacluster in graft-infiltrating lymphocytes (GILs), which highly expressed the costimulatory molecule CD86. The temporal and spatial dynamics of immune cells revealed by high-dimensional analyses enable a fine-grained analysis of GIL subsets, contribute to new insights for the discovery of immunological mechanisms of liver tolerance, and provide potential ways to achieve clinical operational tolerance after liver transplantation.

BackgroundLiver hepatocellular carcinoma (LIHC) is one of the malignant tumors with high incidence as well as high death, which is ranked as the sixth most common tumor and the third highest mortality worldwide. CD93, a transmembrane protein, has been widely reported to play an important role in different types of diseases, including many types of cancer by mainly functioning in extracellular matrix formation and vascular maturation. However, there are few researches focusing on the role and potential function of CD93 in LIHC.MethodsIn this study, we comprehensively analyzed the relationship between CD93 and LIHC. We not only discovered transcriptional expression of CD93 in LIHC by using the TIMER, GEPIA and UALCAN database, but also performed WB and IHC to verify the protein expression of CD93 in LIHC. Meantime, Kaplan-Meier Plotter Database Analysis were used to assess the prognosis of CD93 in LIHC. After knowing close correlation between CD93 expression and LIHC, there were STRING, GeneMania and GO and KEGG enrichment analyses to find how CD93 functions in LIHC. We further applied CIBERSORT Algorithm to explore the correlation between CD93 and immune cells and evaluate prognostic value of CD93 based on them in LIHC patients.ResultsThe transcriptional and protein expression of CD93 were both obviously increased in LIHC by above methods. There was also a significant and close correlation between the expression of CD93 and the prognosis of LIHC patients by using Kaplan-Meier Analysis, which showed that LIHC patients with elevated expression of CD93 were associated with a predicted poor prognosis. We found that the functions of CD93 in different cancers are mainly related to Insulin like growth factor binding protein 7 Gene (IGFBP7)/CD93 pathway via STRING, GeneMania and functional enrichment analyses. Further, our data obtained from CIBERSORT Algorithm suggested CD93 was also associated with the immune response. There is a close positive correlation between CD93 expression and the infiltration levels of all six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Importantly, CD93 can affect the prognosis of patients with LIHC partially due to immune infiltration.ConclusionOur results demonstrated CD93 may be a candidate predictor of clinical prognosis and immunotherapy response in LIHC.

Abstract Strategies for treating osteoarthritis (OA) have become a research focus because an effective treatment for OA is unavailable. The objective of this study was to explore the effects and underlying mechanisms of glutamine (Gln) in OA. First, the chondrocytes were identified and a standard IL-1β-induced OA model was established. After treatment with Gln or saline, the viability and apoptosis of chondrocytes were evaluated using a CCK-8 assay and flow cytometry analysis, which revealed that Gln can improve the IL-1β-induced OA cells. Meanwhile, Gln can enhance the expression of aggrecan and collagen II, which are protective proteins for articular cartilage. Instead, Gln inhibited the expression of matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13), which can degrade cartilage. To better understand the underlying mechanisms of Gln in IL-1β-induced chondrocytes, the classical OA pathways of JNK and NF-κB were examined at the protein and mRNA levels using western blot and qRT–PCR analyses. We found that JNK and NF-κB were downregulated gradually depending on the Gln dose and protective and destructive factors changed based on changes of JNK and NF-κB. The effects of high-dose Gln were more effective than low-dose. Moreover, Gln was applied to the animal OA model to check the effects in vivo. The results showed that Gln attenuated cartilage degeneration and decreased OARSI scores, which demonstrated that Gln can improve OA. The experiments showed that Gln can benefit mice with OA by inhibiting the JNK and NF-κB signaling pathways.

The transition metal iron plays a crucial role in living cells. However, high levels of iron are potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 de-repress the expression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism.

AimsFew studies on early recurrence (ER) focused on patients with persistent atrial fibrillation (AF). We aimed to investigate the characteristics and clinical significance of ER in patients with persistent AF after catheter ablation (CA).MethodsA total of 348 consecutive patients who underwent first-time CA for persistent and long-standing persistent AF between January 2019 and May 2022 were investigated.ResultsAbout 5/348 (1.44%) patients who failed to convert to sinus rhythm after CA were excluded. A total of 110/343 (32.1%) patients had ER, in which 98 (89.1%) were persistent and 50.9% occurred in the first 24 h after CA. Compared with the patients without ER, those with ER were more likely to have late recurrence (LR) (92.7% vs. 1.7%, P

ObjectiveTo explore the relationship between flavin-containing monooxygenases (FMOs) and peritoneal metastasis (PM) in gastric cancer (GC).Materials and methodsTIMER 2.0 was used to perform pan-cancer analysis and assess the correlation between the expression of FMOs and cancers. A dataset from The Cancer Genome Atlas (TCGA) was used to analyze the correlation between FMOs and clinicopathological features of GC. PM is well established as the most common mode of metastasis in GC. To further analyze the correlation between FMOs and PM of GC, a dataset was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database. The results were validated by immunohistochemistry. The relationship between FMOs and PM of GC was explored, and a novel PM risk signature was constructed by least absolute shrinkage and selection operator (LASSO) regression analysis. The regression model’s validity was tested by multisampling. A nomogram was established based on the model for predicting PM in GC patients. The mechanism of FMOs in GC patients presenting with PM was assessed by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in TCGA and GEO datasets. Finally, the potential relationship between FMOs and immunotherapy was analyzed.ResultsThe pan-cancer analysis in TCGA and GEO datasets showed that FMO1 was upregulated, while FMO2 and FMO4 were downregulated in GC. Moreover, FMO1 and FMO2 correlated positively with the T and N stage of GC in the TCGA dataset. FMO1 and FMO2 expression was a risk factor for GC (hazard ratio: 1.112 and 1.185). The overexpression of FMO1 was significantly correlated with worse disease-free-survival (DFS) and overall survival (OS). However, no relationship was found between FMO2 expression in GC and DFS and OS. PM was highly prevalent among GC patients and typically associated with a worse prognosis. FMO1 was highly expressed in GC with PM. FMO1 and FMO2 were positively correlated with PM in GC. We identified a 12-gene panel for predicting the PM risk signature by LASSO (Area Under Curve (AUC) = 0.948, 95%CI: 0.896–1.000). A 10-gene panel for PM prediction was identified (AUC = 0.932, 95%CI: 0.874–0.990), comprising FMO1 and FMO2. To establish a model for clinical application, a 7-gene panel was established (AUC = 0.927, 95% CI: 0.877–0.977) and successfully validated by multisampling. (AUC = 0.892, 95% CI: 0.878–0.906). GO and KEGG analyses suggest that FMO1 and FMO2 regulate the extracellular matrix and cell adhesion. FMO1 and FMO2 were positively correlated with the immune score of GC, and their expression was associated with the infiltration of immune cells.ConclusionPM in GC is strongly correlated with FMOs. Overall, FMO1 and FMO2 have huge prospects for application as novel diagnostic and therapeutic targets.

Abstract Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients’ poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.