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IntroductionThe adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) has proven clinically beneficial in patients with non-small cell lung cancer refractory to checkpoint blockade immunotherapy, which has prompted interest in TIL-adoptive cell transfer. The transgenic expression of IL15 can promote the expansion, survival, and function of T cells ex vivo and in vivo and enhance their anti-tumor activity. The effect of expressing mIL15 regulated by hypoxia in the tumor microenvironment on the expansion, survival, and stem-like properties of TILs has not been explored.MethodsUsing TILs expanded from the tumor tissues of lung cancer patients, TILs with or without mIL15 expression (TIL-mIL15 or UN-TIL) were generated by lentiviral transduction. To reflect the advantages of mTIL15, the cells were divided into groups with IL2 (TIL-mIL15+IL2) or without IL2 (TIL-mIL15-IL2).ResultsCompared to UN-TIL cells, mIL15 expression had a similar capacity for promoting TIL proliferation and maintaining cell viability. Our experimental findings indicate that, compared to UN-TIL and TIL-mIL15+IL2 cells, the expression of mIL15 in TIL-mIL15-IL2 cells promoted the formation of stem-like TILs (CD8+CD39-CD69-) and led to significant decreases in the proportion and absolute number of terminally differentiated TILs (CD8+CD39+CD69+). RNA-Seq data revealed that in TIL-mIL15-IL2 cells, the expression of genes related to T cell differentiation and effector function, including PRDM1, ID2, EOMES, IFNG, GZMB, and TNF, were significantly decreased, whereas the expression of the memory stem-like T cell marker TCF7 was significantly increased. Furthermore, compared to UN-TIL and TIL-mIL15+IL2 cells, TIL-mIL15-IL2 cells showed significantly lower expression levels of inhibitory receptors LAG3, TIGIT, and TIM3, which was consistent with the RNA-Seq results.DiscussionThis study demonstrates the superior persistence of TIL-mIL15-IL2 cells, which may serve as a novel treatment strategy for lung cancer patients.

IntroductionEmerging evidences suggests that the disrupted branched-chain amino acids (BCAAs) homeostasis and elevated BCAAs promote obesity-related insulin resistance (IR). Exercise improves insulin sensitivity. However, whether BCAAs plays a role in the exercise-attenuated IR remains to be fully investigated.MethodsIn this study, male C57BL/6J mice were induced to become diet-induced obese (DIO) and served as subjects. The initial investigation focused on the impact of exercise on IR and BCAAs. The DIO mice were randomly assigned to either a sedentary group (CON, n = 16) or an exercise group (EX, n = 16). The EX group underwent a 12-week aerobic exercise regimen on a treadmill. After 12-week, plasma BCAAs and branched-chain keto acids (BCKAs) were measured by liquid chromatography-mass spectrometry, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed, and the expression and phosphorylation of BCAAs catabolic proteins, as well as AKT T308 in gastrocnemius muscle and liver tissues, were evaluated using western blotting. Subsequently, the study explored the role of BCAAs in enhancing IR through exercise. Mice were randomly allocated into 4 groups: sedentary group (CON, n = 8), sedentary with BCAAs supplementation group (CON+BCAA, n = 8), exercise group (EX, n = 16), and exercise with BCAAs supplementation group (EX+BCAA, n = 16). The exercise protocol was as above. Mice in the BCAAs supplemented groups received drinking water containing 2% BCAAs. After 12-week, plasma BCAAs and BCKAs were measured, GTT and ITT tests were performed, and the phosphorylation of AKT T308, as well as p70S6K T389 in gastrocnemius muscle and liver, were compared between the EX group and the EX+BCAA group. Additionally, the phosphorylation of AMPKα T172 in both tissues was measured across all four groups.Results12-week aerobic exercise improved insulin sensitivity in DIO mice while inducing BCAAs catabolic protein expression in skeletal muscle and liver, and reducing the plasma BCAAs level. Importantly, BCAAs supplementation elevated the plasma level of BCAAs and counteracted the exercise-attenuated IR. In skeletal muscle and liver tissues, BCAAs supplementation impaired the exercise-improved insulin signaling without enhancing mammalian target of rapamycin activity. AMPK activity was enhanced by aerobic exercise, which was abolished by BCAAs supplementation.ConclusionAerobic exercise attenuated insulin resistance via restoring BCAAs homeostasis and AMPK activity. The impacts of BCAAs intake on the metabolic effects of exercise sheds light on the combined exercise and nutrition intervention strategy for diabetes management.

ObjectiveHearing and functional mobility impairments are recognized as risk factors for cognitive decline in older adults, yet the causal relationship underlying these associations is not well-understood. This study aims to explore whether engagement in social activities mediates the link between hearing or functional mobility impairment and cognitive decline.MethodsThis cross-sectional study was carried out in two cities in Jiangsu Province, Eastern China. Participants self-reported hearing impairment and social activity engagement, whereas functional mobility impairment was assessed using the Timed Up and Go Test (TUGT). Cognitive function was evaluated through the Modified Mini-Mental State Examination (MMSE). Logistic regression analysis explored factors influencing cognitive function, and mediation analysis was conducted to examine the relationship between hearing or functional mobility impairment and cognitive decline.ResultsThe study included 10,217 adults aged 60 and above. Among them, 19.35% reported hearing impairment, while 40.86% failed the Timed Up and Go Test (TUGT). The Modified Mini-Mental State Examination (MMSE) indicated a 30.40% prevalence of cognitive decline. Logistic regression analysis identified significant associations of cognitive function with factors such as gender, age, education level, residency, living arrangement, hyperlipidemia, cerebrovascular disease, alcohol consumption, smoking, Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), social activity, hearing, and functional mobility (p

ObjectiveDepression is a complex affective disorder characterized by high prevalence and severe impact, commonly presenting with cognitive impairment. The objective diagnosis of depression lacks precise standards. This study investigates eye movement characteristics during emotional face recognition task (EFRT) in depressive patients to provide empirical support for objective diagnosis.MethodsWe recruited 43 patients with depression (Depressive patients, DP) from a psychiatric hospital and 44 healthy participants (Healthy Control, HC) online. All participants completed an EFRT comprising 120 trials. Each trial presented a gray screen for 800 ms followed by a stimulus image for judgment. Emotions were categorized as positive, neutral, or negative. Eye movement trajectories were recorded throughout the task. Latency of First Fixation (LFF), Latency of First Fixation for Eye AOI, and Latency of First Fixation for Mouth AOI were used as representative indicators of early attention, Proportion of Eye AOI, and Proportion of Mouth AOI as measures of intermediate attention, Accuracy (ACC) and Reaction Time (RT) as behavioral indicators of late-stage attention. In this study, these metrics were employed to explore the differences between patients with depression and healthy individuals.ResultsCompared to healthy participants, individuals with depression exhibit longer first fixation latencies on the eyes and mouth during the early attention stage of emotional face recognition, indicating an avoidance tendency toward key facial recognition cues. In the mid-to-late attention stages, depressive individuals show an increased fixation ratio on the eyes and a decreased fixation ratio on the mouth, along with lower accuracy and longer response times. These findings suggest that, relative to healthy individuals, individuals with depression have deficits in facial recognition.ConclusionThis study identified distinct attention patterns and cognitive deficits in emotional face recognition among individuals with depression compared to healthy individuals, providing an attention-based approach for exploring potential clinical diagnostic markers for depression.

PurposeWe sought to develop and validate a nomogram for predicting extra-urinary recurrence (EUR) following radical nephroureterectomy (RNU) in patients with upper urinary tract urothelial carcinoma (UTUC).MethodsData from 556 UTUC patients post-RNU at the First Hospital of Jilin University were retrospectively analyzed. These patients were categorized into a training group (n=389) and a validation group (n=167). Variables significantly associated with prognosis were identified using univariate Cox regression and most minor absolute shrinkage and selection operator (LASSO) analysis. These independent predictors were incorporated into the nomogram to estimate extra-urinary recurrence-free survival (EURFS). Validation of the nomogram involved ROC curves, calibration plots, and decision curve analysis (DCA). Patients were stratified into two risk categories based on their nomogram scores to compare EURFS using the Kaplan-Meier method.ResultsEight predictors were identified: T-stage, N-stage, tumor grade, local and nerve invasion, preoperative hemoglobin level, neutrophil-to-lymphocyte ratio (NLR), and creatinine, all proving to be independent predictors of EUR. A nomogram was created based on these eight factors, and using the ROC, calibration curves, and DCA, good prediction results were shown in both the training and validation groups. The training and validation groups also showed reliable predictive performance. In particular, there was a significant difference in survival between the high-risk and low-risk groups (P

IntroductionPrime quality kamaboko (cooked surimi) is produced from Alaska pollock. The main challenge of using cheaper fish fillets, including Barramundi, is achieving similar textures.MethodsCombined with fish gelatin, modified starch by vortex fluidic device was used to enhance the quality of kamaboko made from Barramundi.ResultsModification by a continuous flow vortex fluidic device (VFD) significantly reduces the size of particles of starch relative to conventional homogenization. Blending this VFD-modified starch with fish gelatin resulted in a well-organized cross-linked matrix compared to products manufactured from homogenization modified starch. This led to higher gel strength of the former (1,708.32 g/cm2) relative to the latter (832.56 g/cm2). Mixing different proportions of fish gelatin and VFD-processed starch to make Barramundi kamaboko (5, 10, and 15%), yielded a product with greater chewiness relative to Alaska pollock kamaboko. Sensory evaluation indicated that the 5% product was optimal and the 15% product with the highest chewiness (56.10 N) was the least favorable.DiscussionThese results clearly indicate the potential of VFD processed starch, blended with fish gelatin to enhances the quality of kamaboko.

IntroductionLung cancer is a leading cause of cancer-related deaths, with its incidence continuing to rise. Chromatin remodeling, a crucial process in gene expression regulation, plays a significant role in the development and progression of malignant tumors. However, the role of chromatin regulators (CRs) in lung adenocarcinoma (LUAD) remains underexplored.MethodsThis study developed a chromatin regulator-related signature (CRRS) using a 429-combination machine learning approach to predict survival outcomes in LUAD patients. The CRRS model was validated across multiple independent datasets. We also investigated the impact of CRRS on the immune microenvironment, focusing on immune cell infiltration. To identify potential therapeutic targets, TFF1, a chromatin regulator, was knocked down using siRNA in LUAD cells. We assessed its impact through apoptosis analysis, proliferation assays, and in vivo tumor growth studies. Additional validation was performed using Ki67 expression and TUNEL assays.ResultsThe CRRS accurately predicted survival outcomes and was shown to modulate immune cell infiltration in the tumor microenvironment. High-risk patients demonstrated increased activity in cell cycle regulation and DNA repair pathways, along with distinct mutation profiles and immune responses compared to low-risk patients. TFF1 emerged as a key therapeutic target. Knockdown of TFF1 significantly inhibited LUAD cell proliferation, induced apoptosis, and suppressed in vivo tumor growth. Ki67 and TUNEL assays confirmed the role of TFF1 in regulating tumor growth and cell death.DiscussionThese findings highlight the potential of chromatin regulators in prognostic modeling and immune modulation in LUAD. TFF1 was identified as a promising therapeutic target, suggesting that targeting TFF1 could provide new treatment strategies. Further research is warranted to explore its full potential and therapeutic applicability.

ObjectiveOverweight and obesity are serious public health issues worldwide and significantly impair children’s executive function (EF). However, there is no consensus regarding the benefits of aerobic exercise, on the EF of overweight and obese children. This study systematically evaluated the intervention effects of aerobic exercise on EF and its subcomponents (inhibitory control, working memory, and cognitive flexibility) in overweight and obese children.MethodsWe searched six databases—PubMed, Web of Science, Cochrane Library, Embase, EBSCOhost, and China National Knowledge Infrastructure—until March 17, 2024 for randomized controlled trials examining the effects of aerobic exercise on the EF of overweight and obese children the Cochrane Risk of Bias Assessment Tool. Following heterogeneity testing, RevMan 5.4 and Stata 17.0 were used for meta-analysis and subgroup analysis of the three indicators. The standardized mean difference (SMD) and 95% confidence intervals (CI) were used as statistical measures for effect analysis with the SMD value as the effect size and a p-value of ≤0.05 indicating statistical significance.ResultsEighteen studies involving 1,260 participants were included. Aerobic exercise significantly improved overall EF (SMD = −0.50, 95% CI [−0.68, −0.32], p 25 kg/m2) do not benefit from the intervention, highlighting the need for a specific focus on intervention outcomes in future studies.

BackgroundIt has been previously demonstrated that intestinal barrier damage is one of the underlying mechanisms leading to frailty in non-HIV-infected aging populations. However, there is a paucity of direct evidence which demonstrates the association between intestinal barrier damage and frailty in people living with HIV (PLWH).MethodsThe present study is a retrospective case control study. Participants older than 50 years old were stratified into a frail/pre-frail group (case group) and non-frail group (control group) according to the Fried frailty phenotype. We collected and curated data concerning socio-demographic variables, psychological states and social functioning, and clinical information associated with the identification of biomarkers of intestinal barrier damage, microbial translocation, and levels of inflammatory cytokines of participants.ResultsThe case group had significantly higher levels of Reg-3α (p=0.042) and I-FABP (p=0.045) compared to the control group. We further observed, after adjusting for confounding factors by logistic regression analysis, that I-FABP levels remained significantly higher in the case group compared to the control group (p=0.033). Also, Fried Phenotype scores positively correlated with I-FABP levels (rs=0.21, p=0.01), LPS levels (rs=0.20, p=0.02), and sCD14 levels (rs=0.18, p=0.04). Moreover, the study confirmed both the positive correlation between inflammatory cytokines (IL-6 and IP-10) with frailty in aging PLWH, and between inflammatory cytokines (IL-6, IL-8 and IP-10) with biomarkers of intestinal barrier dysfunction in older PLWH.ConclusionThe present study indicates that the inflammation induced by intestinal barrier damage/dysfunction is likely to contribute to frailty in aging PLWH.

Thermal protection systems (TPSs) are important components of reusable spacecraft, and their assembly quality has a crucial impact on flight safety. Owing to the complex assembly process and variable states of spacecraft thermal protection systems, assembly parameters may vary under different assembly states. Therefore, to obtain assembly parameters accurately and efficiently under different assembly states, in this study, 3D point cloud data and fiber optic sensor data were fused to develop an assembly parameter update method for assembly process state changes. Firstly, based on the measured data of thermal protection components and load-bearing structure, the gap, flush and matching parameters solution model are proposed. Secondly, to address the deformation problem of the load-bearing structure caused by changes in assembly status, a fusion method based on laser scanning and sensor detection was devised to achieve deformation prediction of the assembly structure during the assembly process. Thirdly, based on the assembly parameter solution model and point cloud prediction model, a constraint-based assembly parameter optimisation model was established, and an improved quantum particle swarm optimisation (LQPSO) algorithm was employed to achieve assembly parameter updates oriented toward changes in assembly status. Finally, an experimental system for array-based thermal protection structure simulation was established to validate the proposed method. The results show that the proposed parameter update method can achieve ideal results for different assembly state simulation components.

Soil moisture is a critical factor for vegetation restoration in arid regions. Poorly planned artificial sand-fixing vegetation systems often exacerbate soil moisture depletion, leading to further degradation. In this study, soil moisture content at various depths was continuously monitored from June to October 2023 in four key community plots—Corethrodendron scoparium, Calligonum mongolicum, and Artemisia ordosica, and bare sand—in a 31-year-old revegetated area located on the northeastern edge of the Tengger Desert. We analyzed the distribution and dynamic changes of soil moisture across the different and evaluated its temporal stability. The representative soil moisture depth was determined by using the coefficient of determination (R2) and the Nash-Sutcliffe efficiency (NSE). The results showed significant differences in soil moisture among the four plots. The bare sand plot had the highest soil water storage in the 0-200 cm layer, at 46.37 mm. In contrast, the Corethrodendron scoparium, Calligonum mongolicum, and Artemisia ordosicaa plots had similar soil water storage values ranging from 33.50 to 33.67 mm, indicating that vegetation restoration has increased soil moisture absorption by an average of 27.4%. Analysis using relative difference and Spearman rank correlation methods revealed varying levels of temporal stability in soil moisture across different soil depths and plots. The Corethrodendron scoparium and bare sand plots showed higher temporal stability compared to the Calligonum mongolicum and Artemisia ordosica plots. The representative depths of temporal stability for the four plots were determined to be 100 cm, 150 cm, 20 cm, and 100 cm, respectively.

BackgroundRegulated cell death (RCD) is a genetically controlled form of cell death that plays an important role in organogenesis, tissue remodeling, and pathogenesis of cancers. Transforming growth factor-beta-activation kinase 1 (TAK1) is a member of the serine/threonine protein kinase family, which can respond to internal and external stimuli and participate in inflammatory responses through multiple signaling pathways and cellular processes. In the last two decades, the regulatory roles of TAK1 at the crossroads of multiple RCD pathways, including apoptosis, necroptosis, pyroptosis, and PANoptosis were revealed by 801 articles retrieved from the Web of Science Core Collection database. To analyze global research trends and hotspots concerning the role of TAK1 in RCD, the bibliometric and visualized analysis were applied in the current study.MethodsThe data for this bibliometrics study were retrieved from the Web of Science Core Collection database. The search formula was (TS=(Apoptosis) OR TS=(pyroptosis) OR TS=(Necroptosis) OR TS=(PANoptosis) OR TS=(Autophagy) OR TS=(Ferroptosis) OR TS=(cuproptosis)) AND ((TS=(TAK1)) OR TS=(MAP3K7)). The co-occurrence and co-cited analysis on basic bibliometric parameters were conducted by VOSviewer. The dual-map overlay of journals, citation bursts, keyword timelines, and keyword bursts were analyzed by CiteSpace.ResultsA total of 801 articles from 46 countries have been included in the analysis. The number of publications demonstrates a consistent increase from 1999 to 2024. The primary research institutions driving this field are Osaka University Notably, the Journal of Biological Chemistry stands out as the most popular journal in this domain. These publications collectively involve contributions from 4663 authors, with Jun Tsuji emerging as a prolific author. Jun Tsuji also gains the highest co-citation frequency. Emerging research hotspots are encapsulated by keywords, including apoptosis, NF-κB, inflammation, autophagy, and TNFα.ConclusionThis is the first bibliometric and visualized study to analyze the global trends and hotspots of TAK1 in RCD. Based on the analysis of 801 articles, the results provide a retrospective and comprehensive visualized view of the research hotspots and frontiers of TAK1 at the crossroads of multiple RCD signaling pathways and propose ideas for guiding their future investigations in molecular mechanisms and therapeutic strategies in this field.

Maize is one of the most successful crops in utilizing heterosis which significantly improves maize stresses resistance and yield. Drought is a destructive abiotic stress that significantly reduces crop yield, particularly in maize. Drought stress and re-watering frequently occur during the growth and development of maize; however, the molecular mechanisms of heterosis under drought stress and re-watering have rarely been systematically investigated. Zhengdan7137 and Zhengdan7153 are two maize hybrid varieties with robust heterosis, and separately belongs to the SS×NSS and Reid×Tangsipingtou heterotic groups. 54 transcriptomes of these two hybrids and their parental inbred lines were analyzed under well-watering (WW), water-deficit (WD), and re-watering (RW) conditions using RNA-Seq. In this study, we identified 3,411 conserved drought response genes (CDRGs) and 3,133 conserved re-watering response genes (CRRGs) between Zhengdan7137 and Zhengdan7153. When comparing CDRGs and CRRGs to overdominance and underdominance genes, we identified 303 and 252 conservative drought response overdominance genes (DODGs) and underdominance genes (DUDGs), respectively, and 165 and 267 conservative re-watering response overdominance genes (RODGs) and underdominance genes (RUDGs), respectively. DODGs are involved in stress response-related processes, such as L-phenylalanine metabolism, carbohydrate metabolism, and heat response, whereas DUDGs are associated with glucose metabolism, pentose-phosphate shunt, and starch metabolism. RODGs and RUDGs contribute to the recovery of hybrids from drought stress by upregulating cell propagation and photosynthesis processes, and repressing stress response processes, respectively. It indicated overdominant and underdominant genes conservatively contributed to hybrid heterosis under drought stress. These results deepen our understanding of the molecular mechanisms of drought resistance, uncover conservative molecular mechanisms of heterosis under drought stress and re-watering, and provide potential targets for improving drought resistance in maize.

Monitoring the status of grafts and the occurrence of postoperative complications, such as rejection, is crucial for ensuring the success and long-term survival of organ transplants. Traditional histopathological examination, though effective, is an invasive procedure and poses risks of complications, making frequent use impractical. In recent years, graft-derived cell-free DNA (gd-cfDNA) has emerged as a promising non-invasive biomarker. It not only provides early warnings of rejection and other types of graft injury but also offers important information about the effectiveness of immunosuppressive therapy and prognosis. gd-cfDNA shows potential in the monitoring of organ transplants. The early, real-time information on graft injury provided by gd-cfDNA facilitates timely individualized treatment and improves patient outcomes. However, the progress of research on gd-cfDNA varies across different organs. Therefore, this article will comprehensively review the application and findings of gd-cfDNA in monitoring various solid organs, discussing the advantages, limitations, and some future research directions to aid in its clinical application.

Ports are of great significance in processing cargo containers and facilitating global marine logistics. Nevertheless, the susceptibility of the container shipping network for hazardous cargo is likely to intensify in the event of a significant disruption at a major port, such as adverse weather conditions, inadequate management practices, or unforeseen catastrophes. Such situations require the deployment of port protection emergency response and prevention in advance. This study proposes a digital twin (DT) model that employs extensive and trajectory data within containers to comprehensively analyze the occurrence of hazardous cargo failures within the port storage process. The virtual models of physical entities in the port are created through a data-driven approach, and the behavior of these entities in a port environment with big data is then simulated. A combination of a convolutional neural network (CNN) and a long short-term memory (LSTM) algorithm is employed to provide predictions for the service layer of the DT system. The predicted correlation coefficients of temperature and humidity in the container reach 0.9855 and 0.9181, respectively. The developed system driven by DT models integrated with a CNN and the LSTM algorithm can more effectively assist the safety manager in achieving prevention in port operations. This study enables marine authorities and decision-makers to optimize emergency procedures, thereby reducing the probability of accidents in port operations and logistics.

IntroductionThe massive loss of global glacier mass caused by climate problems has caused concern, while the Earth’s rotation as the most significant form of motion has also been subtly affected. However, the quantitative effects of massive glaciers losing mass on Earth’s rotation have not been revealed.MethodsHerein, the knowledge of moment of inertia and suitable rotational inertia models in classical mechanics is initially utilized to assess the effect of quantitative glaciers losing mass on Earth's rotation.ResultsAfter specific calculations, the putative 200 billion tons of glaciers losing mass bring on an increase of 1.4099×10-4s in Earth’s rotation time in 365 days.DiscussionThis work examines the connection between glaciers losing mass and Earth’s rotation from classical mechanics, thus providing the way for investigations of relationship between climate changes and Earth.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized primarily by persistent synovial inflammation and joint destruction. In recent years, ferroptosis, as a novel form of cell death, has garnered widespread attention due to its critical role in various diseases. This review explores the potential mechanisms of ferroptosis in RA and its relationship with the pathogenesis of RA, systematically analyzing the regulatory role of ferroptosis in synovial cells, chondrocytes, and immune cells. We emphasize the evaluation of ferroptosis-related pathways and their potential as therapeutic targets, including the development and application of inhibitors and activators. Although ferroptosis shows some promise in RA treatment, its dual role and safety issues in clinical application still require in-depth study. Future research should focus on elucidating the specific mechanisms of ferroptosis in RA pathology and developing more effective and safer therapeutic strategies to provide new treatment options for RA patients.

BackgroundGliomas are aggressive brain tumors associated with a poor prognosis. Cancer stem cells (CSCs) play a significant role in tumor recurrence and resistance to therapy. This study aimed to identify and characterize glioma stem cells (GSCs), analyze their interactions with various cell types, and develop a prognostic signature.MethodsSingle-cell RNA sequencing data from 44 primary glioma samples were analyzed to identify GSC populations. Spatial transcriptomics and gene regulatory network analyses were performed to investigate GSC localization and transcription factor activity. CellChat analysis was conducted to infer cell-cell communication patterns. A GSC signature (GSCS) was developed using machine learning algorithms applied to bulk RNA sequencing data from multiple cohorts. In vitro and in vivo experiments were conducted to validate the role of TUBA1C, a key gene within the signature.ResultsA distinct GSC population was identified, characterized by high proliferative potential and an enrichment of E2F1, E2F2, E2F7, and BRCA1 regulons. GSCs exhibited spatial proximity to myeloid-derived suppressor cells (MDSCs). CellChat analysis revealed an active MIF signaling pathway between GSCs and MDSCs. A 26-gene GSCS demonstrated superior performance compared to existing prognostic models. Knockdown of TUBA1C significantly inhibited glioma cell migration, and invasion in vitro, and reduced tumor growth in vivo.ConclusionThis study offers a comprehensive characterization of GSCs and their interactions with MDSCs, while presenting a robust GSCS. The findings offer new insights into glioma biology and identify potential therapeutic targets, particularly TUBA1C, aimed at improving patient outcomes.

BackgroundCurrent treatments and prevention strategies for echinococcosis are inadequate. Recent advancements in molecular vaccine development show promise against Echinococcus granulosus; however, Echinococcus multilocularis remains a challenge. A Multi-epitope Vaccine could potentially induce specific B and T lymphocyte responses, thereby offering protection against Echinococcus multilocularis infection.MethodsThis study aimed to develop a MEV against alveolar echinococcosis. Key epitopes from the Echinococcus multilocularis proteins EmTSP3 and EmTIP were identified using immunoinformatics analyses. These analyses were conducted to assess the MEV feasibility, structural characteristics, molecular docking, molecular dynamics simulations, and immune simulations. The immunogenicity and antigenicity of the vaccine were evaluated through in vitro and in vivo experiments, employing ELISA, Western blotting, FCM, challenge infection experiments, and ELISPOT.ResultsThe effective antigenicity and immunogenicity of MEV were demonstrated through immunoinformatics, as well as in vitro and in vivo experiments. In vitro experiments revealed that MEV increased the secretion of IFN-γ and IL-4 in PBMC and successfully bound to specific antibodies in patient serum. Furthermore, mice immunized with MEV developed a robust immune response, characterized by elevated levels of CD4+ and CD8+ T-cells, increased secretion of IFN-γ and IL-4 by specific Th1 and Th2 cells, and heightened serum antibody levels. Importantly, MEV reduced the weight of cysts by conferring resistance against echinococcosis. These findings suggest that MEV is a promising candidate for the prevention of Echinococcus multilocularis infection.ConclusionA total of 7 CTL, 7 HTL, 5 linear B-cell, and 2 conformational B-cell epitopes were identified. The vaccine has demonstrated effective antigenicity and immunogenicity against AE through molecular docking, immune simulation, molecular dynamics studies, and both in vitro and in vivo experiments. It provides effective protection against Echinococcus multilocularis infection, thereby laying a foundation for further development.

The incidence of Acute myeloid leukemia (AML) increases with advancing age, and the prognosis for elderly patients is significantly poorer compared to younger patients. Although the combination therapy of venetoclax and hypomethylating agents has demonstrated improved prognosis in patients unable to tolerate intensive chemotherapy, there remains a therapeutic blank for those who fail to achieve remission with current treatment regimens. Here, we report the successful clinical utilization of autogenous CLL1 CAR-T therapy combined with hematopoietic stem cell transplantation in a 73-year-old patient diagnosed with refractory AML. The patient achieved morphological complete remission (CR) with incomplete marrow recovery and a slight presence of minimal residual disease (MRD) after receiving CLL1 CAR-T therapy. To further enhance the treatment and promote the recovery of hemopoiesis, we performed bridged allogenic hematopoietic stem cell transplantation (allo-HSCT) 20 days after the infusion of CLL1 CAR-T cells. The patient achieved MRD-negative CR following HSCT treatment. His primary disease maintained a complete remission status during the 11-month follow-up period. The patient encountered grade 2 cytokine release syndrome and grade 4 granulocytopenia subsequent to the infusion of CAR-T cells, while several rounds of infection and graft-versus-host disease were observed following allo-HSCT. Nevertheless, all these concerns were successfully addressed through comprehensive provision of supportive treatments. We have successfully demonstrated a highly effective and safe combination strategy involving CLL1 CAR-T therapy and allo-HSCT, which has exhibited remarkable tolerability and holds great promise even for elderly patients with AML.

Understanding the wave and current conditions of coral reef ecosystems is essential for maintaining their health, as many reef processes are controlled by these hydrodynamic conditions. In this study, high-frequency measurements of tides, waves, and currents were made using acoustic, electromagnetic, and pressure instruments over a 28-d period on the fore-reef and reef flat of a coral reef atoll in the South China Sea. The research revealed wave transformation, tidal and wave modulation of flow, and wave setup conditions for the first time at this typical atoll. Three large wave processes dominated by gravity waves (GWs) are observed in the fore-reef. The GWs are significantly attenuated on the reef flat, whereas infragravity (IG) waves strengthened. The tidal modulation of GWs and IG waves on the reef flat is significant when the incident wave height exceeded 1 m. In the fore-reef, the modulation of progressive tidal waves and large waves leads to relatively stronger upper-layer currents, and weak near-bottom currents are primarily attributed to the dissipation of tidal wave energy by the rough coral terrain. In calm conditions, flow variations on the reef flat are modulated by tides, thereby allowing seawater flow to pass through the reef flat during spring tides. Conversely, during periods with large waves, tidal modulation of flow on the reef flat is less significant, and the cross-reef flow velocity increases with increasing incident wave height. The occurrence of wave setup on the reef flat enhances cross-reef flow towards the lagoon. The wave setup is positively linearly correlated with the incident wave height. The magnitude of wave setup is associated with the distance between the measurement sites on the fore-reef and reef flat.

BackgroundThe impact of micronutrients, including vitamins and minerals, on different kidney diseases has been reported in some observational studies; however, their causal relationship remains uncertain. We aimed to ascertain the causal genetic relationships between micronutrients and different kidney diseases using the Mendelian randomization (MR) method.MethodsInstrumental variables (IVs) for genetically predicting calcium (Ca), iron (Ir), Zinc (Zn), selenium (Se), copper (Cu), vitamin D (Vit D), and vitamin C (Vit C) levels in humans were obtained, and a bidirectional two-sample MR was used to examine potential associations between the levels of these seven micronutrients and the risk of seven different kidney diseases including hypertensive renal disease, diabetic nephropathy, IgA nephropathy, membranous nephropathy, cystic nephropathy, chronic kidney disease (CKD), and chronic tubulo-interstitial nephritis. Five different MR analyses were conducted, with the main method being the inverse variance-weighted (IVW) method. Moreover, sensitivity analyses were performed to assess heterogeneity and potential pleiotropy.ResultsThe IVW method revealed that Ca levels were associated with a decreased risk of hypertensive renal disease (OR = 0.61, 95% CI: 0.40–0.93, p-value = 0.022), and Se levels were associated with a decreased risk of hypertensive renal disease (OR = 0.72, 95% CI: 0.53–0.99, p-value = 0.040), diabetic nephropathy (OR = 0.83, 95% CI: 0.73–0.93, p-value = 0.002), and CKD (OR = 0.87, 95% CI: 0.77–0.99, p-value = 0.028). Conversely, Vit D levels were associated with an increased risk of polycystic kidney disease (OR = 1.76, 95% CI: 1.15–2.69, p-value = 0.0095). In addition, no potential causal relationship was found between vitamin C levels, iron levels, zinc levels, and copper levels and different kidney diseases. Meanwhile, inverse Mendelian randomization showed no potential causal relationship between different chronic kidney diseases and micronutrients. The Cochrane’s Q test, MR-Egger regression, and MR-PRESSO did not suggest heterogeneity and pleiotropy, providing evidence of the validity of the MR estimates.ConclusionOur results indicate a cause-and-effect connection between micronutrients and certain kidney diseases, but additional study is required to provide more conclusive evidence. This research has the potential to assist clinicians in managing the consumption of specific micronutrients among individuals with chronic kidney diseases, as well as in promoting disease prevention among both healthy populations and those who are susceptible to chronic underlying conditions.

BackgroundIntervertebral disc degeneration (IDD) progression involves multiple factors, including loss of nucleus pulposus cells and extracellular matrix as the basic pathological mechanism of degeneration, and is closely related to cellular senescence and immune cell infiltration. The aim of study was to identify critical cellular senescence-related genes and immune cell infiltration characteristics in IDD.MethodsFour datasets, including GSE70362, GSE112216, GSE114169, and GSE150408, were downloaded from the Gene Expression Omnibus database. The senescence-related genes were acquired from the CellAge Database and intersected with differentially expressed genes (DEGs) between IDD and control samples for senescence-related DEGs (SRDEGs). Protein-protein interaction (PPI) network analysis was performed to obtain ten hub SRDEGs. A consensus cluster analysis based on these hub genes was performed to divide the patients into clusters. The functional enrichment, and immune infiltration statuses of the clusters were compared. Weighted gene co-expression network analysis was used to identified key gene modules. The overlapping genes from key modules, DEGs of clusters and hub SRDEGs were intersected to obtain potential biomarkers. To verify the expression of potential biomarkers, quantitative polymerase chain reaction (qPCR) and immunohistochemistry were performed by using human intervertebral disc tissues.ResultsIn the GSE70362 dataset, a total of 364 DEGs were identified, of which 150 were upregulated and 214 were downregulated, and 35 genes were selected as SRDEGs. PPI analysis revealed ten hub SRDEGs and consensus cluster analysis divided the patients into two clusters. Compared to Cluster 2, Cluster 1 was highly enriched in extracellular matrix organization and various metabolic process. The level of Follicular T helper cells in the Cluster 1 was significantly higher than that in the Cluster 2. IGFBP3 and NQO1 were identified as potential biomarkers. The remaining 3 datasets, and the result of qPCR and immunohistochemistry showed that the expression levels of NQO1 and IGFBP3 in the degenerated group were higher than those in the control or treatment groups.ConclusionSenescence-related genes play a key role in the development and occurrence of IDD. IGFBP3 and NQO1 are strongly correlated with immune infiltration in the IDD and could become novel therapeutic targets that prevent the progression of IDD.

Background and aimsThe association between blood pressure (BP) and dementia in older adults remains unclear, prompting this study to investigate the relationship between various BP indicators and dementia in this population.MethodsA cross-sectional survey was conducted in 2019, including 3,599 participants aged 65 years or older. The basic demographic characteristics of participants were collected. BP measurements and neuropsychological assessments were performed. From the systolic BP (SBP) and diastolic BP (DBP) values, mean arterial pressure (MAP), pulse pressure (PP) and blood pressure index (BPI) were calculated. Generalized additive models and logistic regression models were used to analyze the association between BP indicators and dementia.ResultsGeneralized additive models identified a U-shaped relationship between DBP and dementia, which was more significant in males and people 70 years of age and older. The optimal DBP associated with the lowest dementia risk was 85 mmHg. Logistic regression models revealed that compared to the DBP subgroup (80–89 mmHg), participants in the DBP

BackgroundLead exposure levels are closely linked to human health and can cause damage to multiple organ systems, including the blood system and liver. However, due to insufficient evidence, the effects of lead exposure on hematological and biochemical indices have not been fully established.ObjectiveThis study aims to explore the blood lead levels of permanent residents in Jiangxi Province and analyze the factors affecting blood lead levels and the impact of blood lead levels on hematological and biochemical indices.MethodsWe conducted a cross-sectional study including questionnaires, health examinations, and blood sample examinations on 720 randomly selected permanent residents (3–79 years) in Jiangxi Province in 2018. The blood lead levels were measured using inductively coupled plasma mass spectrometry. Routine hematological and biochemical tests were determined by qualified medical institutions using automated hematology analyzers and biochemistry analyzers.ResultsThe geometric mean of blood lead concentration in permanent residents of Jiangxi Province was 20.45 μg/L. Gender, age, annual household income, smoking, and hypertension were the influencing factors for blood lead levels. For each 1 μg/L increase in blood lead, the risks of elevated red blood cell count (from low to high), platelet volume distribution width, alkaline phosphatase (from low to high), and cholesterol increased by 2.4, 1.6, 3.6, and 2.3%, respectively, whereas the risks of elevation of direct bilirubin and total bilirubin both decreased by 1.7%.ConclusionThe blood lead level in permanent residents of Jiangxi Province is higher than the national average. Higher blood lead levels were found in men than in women; blood lead levels were positively correlated with age but negatively correlated with annual household income; smoking and hypertension are risk factors for elevated blood lead; and blood lead levels affect routine hematological and biochemical markers such as red blood cell count, platelet volume distribution width, direct bilirubin, total bilirubin, alkaline phosphatase, and cholesterol.

ObjectiveTo analyze changes in renal function and associated risk factors in patients with bladder cancer undergoing robot-assisted radical cystectomy (RARC) with intracorporeal or extracorporeal urinary diversion (ICUD or ECUD).MethodsClinical-pathological data was extracted from electronic medical records of 266 patients with bladder cancer who underwent RARC at our institution between August 2015 and August 2022. Postoperative renal function was assessed using the estimated glomerular filtration rate (eGFR).ResultPatients were classified into ECUD and ICUD groups based on the surgical approach. Significant differences in eGFR were observed between the two groups at 1, 2, and 3 years postoperatively. Moreover, 112 patients (42.1%) experienced long-term renal function injury. Independent risk factors for long-term renal function injury included the type of surgical approach, ureteroenteric anastomotic strictures, and pathological stage T3 or above. In terms of short-term renal function, 30 cases of acute kidney injury (AKI) were observed, with an incidence rate of 11.3%. No difference in AKI incidence was found between the groups.ConclusionsPostoperative AKI and chronic kidney injury are prevalent complications following RC. This study highlights that pathological stage, ureteroenteric anastomotic strictures, and ECUD significantly impact long-term renal function, but the type of urinary diversion (ileal conduit or orthotopic neobladder) had no effect on renal function, and ICUD was superior in terms of long-term renal injury rate. Therefore, precise preoperative assessment and the selection of appropriate surgical approach are crucial for preserving renal function in patients with bladder cancer.

AimsThis study aims to explore the different transition patterns and capture types during two bipolar pacing tests based on the selective left bundle branch (LBB) capture determined by the continuous pacing and recording technique.MethodsIn total, 67 patients completed two unipolar and two bipolar pacing tests based on selective LBB capture during screwing-in for left bundle branch pacing (LBBP) using the continuous pacing and recording technique. The electrophysiological characteristics and potential mechanisms of different pacing configurations were further evaluated in this study.ResultsWe found six transition patterns and derived seven capture types in two bipolar pacing tests according to the analysis of continuous electrocardiogram and electrogram changes. Compared with the conventional configuration of “Tip−Ring+” bipolar pacing, “Ring−Tip+” testing had a lower threshold for simultaneous capture of the LBB and the left and right ventricular septum myocardium (1.57 vs. 2.84 V at 0.5 ms) and was the only configuration to yield the peculiar “LBBP + right ventricular septum pacing (RVSP)” capture type.ConclusionsIn this study, we observed for the first time that “Ring−Tip+” bipolar pacing allows for a lower clinically applicable pacing threshold for simultaneous capture of the LBB and left and right ventricular septum myocardium, and the peculiar “LBBP + RVSP” capture type. This may be a more advantageous physiological pacing configuration, warranting further investigation and application in the future.Lay summaryBased on the specific selective LBB capture, we first found six transition patterns and derived seven capture types in two bipolar pacing tests due to the different thresholds of the LBB, left ventricular septal myocardial, and right ventricular septal myocardial. Compared with the conventional configuration of “Tip−Ring+” bipolar pacing, “Ring−Tip+” testing had a lower threshold for simultaneous capture of the LBB and the left and right ventricular septum myocardium (1.57 vs. 2.84 V at 0.5 ms) and was the only configuration to yield the peculiar “LBBP + RVSP” capture type. More pacing strategies should be released and investigated to achieve the best physiological pacing according to the individualized electrophysiological characteristics of patients.

ObjectiveExploring the association between common mineral intake and the risk of colorectal cancer (CRC).MethodsWe utilized the multivariate Cox proportional hazards model to assess the association between intake of minerals and the risk of CRC, estimating hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsA total of 101,686 eligible participants were included in the analysis of this study, including 1,100 CRC cases. After adjusting for potential confounders, we found that total zinc intake (HRQ4vs.Q1: 0.79, 95%CI 0.67–0.93; P for trend 0.05).ConclusionOur findings suggested that an appropriate intake of total zinc, iron, copper, selenium and magnesium were associated with lower CRC risk.

Advanced manufacturing research for sustainable battery life cycles is of utmost importance to reach net zero carbon emissions (European Commission, 2023a) as well as several of the United Nations Sustainable Development Goals (UNSDGs), for example: 30% reduction of CO2 emission, 10 million job opportunities and access to electricity for 600 million people (World Economic Forum, 2019). This editorial paper highlights international motivations for pursuing more sustainable manufacturing practices and discusses key research topics in battery manufacturing. Batteries will be central to our sustainable future as generation and storage become key components to on-demand energy supply. Four underlying themes are identified to address industrial needs in this field: 1. Digitalizing and automating production capabilities: data-driven solutions for production quality, smart maintenance, automation, and human factors, 2. Human-centric production: extended reality for operator support and skills development, 3. Circular battery life cycles: circular battery systems supported by service-based and other novel business models, 4. Future topics for battery value chains: increased industrial resilience and transparency with digital product passports, and next-generation battery chemistries. Challenges and opportunities along these themes are highlighted for transforming battery value chains through circularity and more sustainable production, with a particular emphasis on lithium-ion batteries (LIB). The paper concludes with directions for further research to advance a circular and sustainable battery value chain through utilizing the full potential of digitalization realising a cleaner, more energy-efficient society.

Immunoproteasome is a specialized form of proteasome which plays a crucial role in antigen processing and presentation, and enhances immune responses against malignant cells. This review explores the role of immunoproteasome in the anti-tumor immune responses, including immune surveillance and modulation of the tumor microenvironment, as well as its potential as a target for cancer immunotherapy. Furthermore, we have also discussed the therapeutic potential of immunoproteasome inhibitors, strategies to enhance antigen presentation and combination therapies. The ongoing trials and case studies in urology, melanoma, lung, colorectal, and breast cancers have also been summarized. Finally, the challenges facing clinical translation of immunoproteasome-targeted therapies, such as toxicity and resistance mechanisms, and the future research directions have been addressed. This review underscores the significance of targeting the immunoproteasome in combination with other immunotherapies for solid tumors and its potential broader applications in other diseases.

BackgroundCurrently, evidence regarding the causal relationship between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome is limited and inconsistent. Therefore, this study employs Mendelian randomization (MR) methodology to investigate the causal relationship between the two.MethodsThis study selected 110 single-nucleotide polymorphisms (SNPs) of primary immunodeficiency-related genes as instrumental variables (IVs). Genetic associations of primary immunodeficiency-related genes were derived from recent genome-wide association studies (GWAS) data on human plasma protein levels and circulating immune cells. Data on genes associated with varicella-zoster virus reactivation syndrome were obtained from the GWAS Catalog and FINNGEN database, primarily analyzed using inverse variance weighting (IVW) and sensitivity analysis.ResultsThrough MR analysis, we identified 9 primary immunodeficiency-related genes causally associated with herpes zoster and its subsequent neuralgia; determined causal associations of 20 primary immunodeficiency-related genes with three vascular lesions (stroke, cerebral aneurysm, giant cell arteritis); revealed causal associations of 10 primary immunodeficiency-related genes with two ocular diseases (retinopathy, keratitis); additionally, three primary immunodeficiency-related genes each were associated with encephalitis, cranial nerve palsy, and gastrointestinal infections.ConclusionsThis study discovers a certain association between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome, yet further investigations are warranted to explore the specific mechanisms underlying these connections.

IntroductionWith the aging population, the relationship between human health and the ecological environment has gained increasing attention. In China, it is imperative to evaluate the policy effects of the Environmental Protection Tax (EPT) on improving the ecological environment and enhancing the health of middle-aged and older adult people.MethodsThis study, based on data from the China Health and Retirement Longitudinal Study (CHARLS), employs a Difference-in-Differences (DID) model to assess the health effects of the EPT policy.ResultsThe findings indicate that the EPT policy significantly improves the health of middle-aged and older adult individuals and reduces the prevalence of chronic diseases. The EPT policy affects the health of middle-aged and older adult through two main mechanisms: emission reduction and psychological effects. These are evidenced by reductions in PM10 particle concentration and sulfur dioxide emissions, improvements in public sleep quality and memory, and significant changes in environmental awareness and concern.DiscussionHeterogeneity analysis reveals differences across urban and rural areas, age groups, and education levels. Following the implementation of the EPT policy, there are notable improvements in reduction of chronic diseases among rural residents, self-rated health among urban residents, and overall health among the older adult and individuals with a junior high school education or lower. The study’s results confirm the importance of environmental policies in promoting public health, providing a reference for the refinement of the EPT system, and offering insights for environmental pollution control in developing countries.

BackgroundChemicals may lead to acute liver injuries, posing a serious threat to human health. Achieving the precise safety profile of a compound is challenging due to the complex and expensive testing procedures. In silico approaches will aid in identifying the potential risk of drug candidates in the initial stage of drug development and thus mitigating the developmental cost.MethodsIn current studies, QSAR models were developed for hepatotoxicity predictions using the ensemble strategy to integrate machine learning (ML) and deep learning (DL) algorithms using various molecular features. A large dataset of 2588 chemicals and drugs was randomly divided into training (80%) and test (20%) sets, followed by the training of individual base models using diverse machine learning or deep learning based on three different kinds of descriptors and fingerprints. Feature selection approaches were employed to proceed with model optimizations based on the model performance. Hybrid ensemble approaches were further utilized to determine the method with the best performance.ResultsThe voting ensemble classifier emerged as the optimal model, achieving an excellent prediction accuracy of 80.26%, AUC of 82.84%, and recall of over 93% followed by bagging and stacking ensemble classifiers method. The model was further verified by an external test set, internal 10-fold cross-validation, and rigorous benchmark training, exhibiting much better reliability than the published models.ConclusionThe proposed ensemble model offers a dependable assessment with a good performance for the prediction regarding the risk of chemicals and drugs to induce liver damage.

Wave- and current-supported fluid mud on gently sloped continental shelves represents a type of sediment gravity flow capable of rapidly transporting substantial sediment over short periods, significantly contributing to coastal geomorphic evolution. To investigate the dynamics of intertidal fluid mud events, in-situ observations were conducted from May 9 to May 18, 2017, using a seabed tripod system at the lower intertidal flat of the central Jiangsu coast, China. Fluid mud was observed following a medium wind-wave event, with a maximum significant wave height of 0.42 m. The liquefied seabed, loosened by liquefaction, facilitated bed erosion and sediment resuspension. Fluid mud layers, with mean suspended sediment concentrations (SSCs) exceeding 10 g/L, periodically formed during high slack tide, early flood, and late ebb phases. These layers varied in thickness from 4 cm to 20 cm and exhibited strong stratification caused by suspended sediment. Fluid mud disappeared when the bottom turbulence kinetic energy exceeded a threshold of 0.00045 m²/s² due to an increase in current velocity. The downslope movement of intertidal fluid mud was estimated using a theoretical buoyancy-friction model and validated by observed offshore-directed velocity jets at 0.1 m above the seabed during high slack tide phases. Additionally, onshore winds favored fluid mud formation during early flood phases, while offshore winds favored it during late ebb phases. These observations suggest that fluid mud can form on intertidal flats under conditions where tidal flows and winds align, contributing to a deeper understanding of the formation mechanisms of shallow gravity flows and the improvement of sediment transport models.

BackgroundNirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5 days are lacking.MethodsA real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5 days of COVID-19 onset and no Paxlovid treatment during more than 5 days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group.ResultsDuring the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81–33.93) vs. 38.14 (IQR 36.92–40.00), p < 0.001; 31.33 (IQR 26.00–33.47) vs. 38.62 (IQR 35.62–40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found.ConclusionPaxlovid treatment within 10 days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10 days when patients have a high viral load.

Introduction: This study investigates the characteristics of sediment disturbance caused by impeller rotation in reservoirs of inland rivers with high sediment content in China. A scaled experimental model, reflecting typical environmental conditions of inland water reservoirs in Northwest China, was established in Lanzhou, Gansu Province, following the principle of similarity.Methods: The study integrates numerical simulations using Ansys Fluent software and corroborates the findings through hydraulic experiments. Computational Fluid Dynamics (CFD) and the κ–ε Realizable model were employed to simulate the solid-liquid mixing process, which was verified against the experimental model.Results: The results indicate that increasing the impeller velocity from 2 rad/s to 8 rad/s, while submerged at a depth of 1000 mm in the flow field, enhances the rate of bottom sediment suspension. Furthermore, the rate of suspended sediment discharge from the model outlet increased with inflow velocity ranging from 0.1 m/s to 0.8 m/s. A decrease in the impeller’s submersion depth from 600 mm to 1200 mm was found to reduce the maximum disturbance radius affecting the bottom sediment.Discussion: The reliability of the simulation was confirmed by comparing the software results with experimental data. This study provides insights into the mechanisms of sediment-laden flow disturbance in the reservoir areas of inland rivers in China and lays the groundwork for more comprehensive investigations into sediment discharge in these environments.

Metamaterials are artificially created materials or structures with properties not found in nature. They encompass electromagnetic, acoustic, and mechanical metamaterials, which are particularly significant in applied engineering. Mechanical metamaterials exhibit unique mechanical properties such as vanishing shear modulus, negative Poisson’s ratio, negative compressibility, etc. This paper reviews the most commonly used mechanical metamaterials and discusses their applications in the field of applied engineering, specifically in vibration isolation, energy absorption, and vibration reduction. The prospects for future developments in this field are also presented.

Natural fractures are widely developed and distributed in tight sandstone reservoirs in the western Sichuan Basin, China, influenced by complex tectonic movements and diagenetic processes. These natural fractures serve as the main flow channels and important storage spaces in such reservoirs. Understanding their development characteristics and controlling factors determines the positioning and production efficiency of tight gas wells. This paper first explores the types and characteristics of natural fractures in the second member of the Upper Triassic Xujiahe Formation (T3x2) in the western Sichuan Basin through outcrop investigations, core observations, image log interpretations, and thin section analyses. We study the main influencing factors controlling the development and distribution of tectonic shear fractures by combining the characterization of fracture attributes. The results show that the tight sandstone reservoirs in the T3x2 mainly contain tectonic fractures, diagenetic fractures, and overpressure fractures, among which shear fractures in tectonic fractures are the main types. There are four sets of tectonic shear fractures in the study area, oriented in the E-W, N-S, NE-SW, and NW-SE directions. The dip angles of fractures range from 20° to 80°, with an average dip angle of 53°, predominantly consisting of high-angle fractures. The lengths of fractures are mainly within 100 cm, with a mean value of 47.53 cm, and 76.2% of fractures have lengths less than 50 cm. Fracture apertures range from 2.51 to 163.19 μm, with an average of 30.54 μm. The proportion of effective fractures in tectonic shear fractures reaches 85.7%. The development of tectonic shear fractures is primarily influenced by lithology, rock mechanics stratigraphy, diagenetic processes and facies, and faults. Lithology stands as the fundamental factor influencing the degree of fracture development in tight reservoirs. In rocks with the same composition, as the grain size decreases, the degree of fracture development increases. Simultaneously, with the rise in muddy content, fracture development diminishes in siltstone, argillaceous siltstone, silty mudstone, and mudstone. The formation and distribution of fractures are governed by rock mechanics stratigraphy, primarily manifested as a decrease in fracture density with an increase in rock mechanics layer thickness within a certain range. Diagenetic processes affect the abundance of tectonic shear fractures by influencing the mechanical properties of rocks. The stronger the compaction and cementation, the poorer the physical properties, and the higher the brittleness of the rocks, resulting in a greater abundance of tectonic shear fractures. Rocks with strong compaction and robust cementation facies exhibit high brittleness, rendering them more susceptible to fracturing under identical stress conditions. Fractures are highly prevalent in both the hanging wall and footwall of faults. As the distance from the fault increases, the linear density of fractures significantly decreases, owing to the uneven distribution of stress perturbation caused by fault activity.

IntroductionAlmonertinib is an important third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) exhibiting high selectivity to EGFR-sensitizing and T790M-resistant mutations. Almonertinib resistance is a major obstacle in clinical use. Baicalein possesses antitumor properties, but its mechanism of antitumor action against almonertinib-resistant non-small cell lung cancer (NSCLC) remains unelucidated.MethodsCCK-8 assay was used to examine the survival rate of H1975/AR and HCC827/AR cells following treatment for 24 h with different concentrations of baicalein, almonertinib or their combination. The changes in colony formation ability, apoptosis, and intracellular reactive oxygen species (ROS) levels of the treated cells were analyzed using colony formation assay and flow cytometry. Western blotting was performed to detect the changes in protein expressions in the cells. The effects of pre-treatment with NAC on proliferation, apoptosis, and PI3K/Akt signaling pathway were observed in baicalein- and/or almonertinib-treated cells. A nude mouse model bearing subcutaneous HCC827/AR cell xenograft were treated with baicalein (20 mg/kg) or almonertinib (15 mg/kg), and the tumor volume and body mass changes was measured.ResultsBoth baicalein and almonertinib represses the viability of HCC827/AR and H1975/AR cells in a concentration-dependent manner. Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation; triggers apoptosis; causes cleavage of Caspase-3, PARP, and Caspase-9; downregulates the protein expressions of p-PI3K and p-Akt; and significantly inhibits tumor growth in nude mice. Furthermore, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS) and preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction, with partial recovery of the decline of p-PI3K and p-Akt.DiscussionThe combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.

Arsenic (As) contamination of agricultural soils poses a serious threat to crop productivity and food safety. Zinc oxide nanoparticles (ZnONPs) have emerged as a potential amendment for mitigating the adverse effects of As stress in plants. Soybean crop is mostly grown on marginalized land and is known for high accumulation of As in roots than others tissue. Therefore, this study aimed to elucidate the underlying mechanisms of ZnONPs in ameliorating arsenic toxicity in soybean. Our results demonstrated that ZnOB significantly improved the growth performance of soybean plants exposed to arsenic. This improvement was accompanied by a decrease (55%) in As accumulation and an increase in photosynthetic efficiency. ZnOB also modulated hormonal balance, with a significant increase in auxin (149%), abscisic acid (118%), gibberellin (160%) and jasmonic acid content (92%) under As(V) stress assuring that ZnONPs may enhance root growth and development by regulating hormonal signaling. We then conducted a transcriptomic analysis to understand further the molecular mechanisms underlying the NPs-induced As(V) tolerance. This analysis identified genes differentially expressed in response to ZnONPs supplementation, including those involved in auxin, abscisic acid, gibberellin, and jasmonic acid biosynthesis and signaling pathways. Weighted gene co-expression network analysis identified 37 potential hub genes encoding stress responders, transporters, and signal transducers across six modules potentially facilitated the efflux of arsenic from cells, reducing its toxicity. Our study provides valuable insights into the molecular mechanisms associated with metalloid tolerance in soybean and offers new avenues for improving As tolerance in contaminated soils.

The human gut microbiome (GM) impacts various physiological processes and can lead to pathological conditions and even carcinogenesis if homeostasis is disrupted. Recent studies have indicated a connection between the GM and prostatic disease. However, the underlying mechanisms are still unclear. This review aims to provide a summary of the existing information regarding the connection between the GM and various prostatic conditions such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Furthermore, the review aims to identify possible pathogenic mechanisms and suggest potential ways of targeting GM to prevent and treat prostatic disease. Due to the complexity of the mechanism between GM and prostatic diseases, additional research is required to comprehend the association between the two. This will lead to more effective treatment options for prostatic disease.

Introduction: Biocatalysis, particularly through engineered enzymes, presents a cost-effective, efficient, and eco-friendly approach to compound synthesis. We sought to identify ketoreductases capable of synthesizing optically pure alcohols or ketones, essential chiral building blocks for active pharmaceutical ingredients.Methods: Using BioMatchMaker®, an in silico high-throughput platform that allows the identification of wild-type enzyme sequences for a desired chemical transformation, we identified a bacterial SDR ketoreductase from Thermus caliditerrae, Tcalid SDR, that demonstrates favorable reaction efficiency and desired enantiomeric excess.Results: Here we present two crystal structures of the Tcalid SDR in an apo-form at 1.9 Å and NADP-complexed form at 1.7 Å resolution (9FE6 and 9FEB, respectively). This enzyme forms a homotetramer with each subunit containing an N-terminal Rossmann-fold domain. We use computational analysis combined with site-directed mutagenesis and enzymatic characterization to define the substrate-binding pocket. Furthermore, the enzyme retained favorable reactivity and selectivity after incubation at elevated temperature.Conclusion: The enantioselectivity combined with the thermostability of Tcalid SDR makes this enzyme an attractive engineering starting point for biocatalysis applications.

BackgroundThe development of metabolic dysfunction associated steatotic liver disease (MASLD) has been associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. The Composite Dietary Antioxidant Index (CDAI) is a comprehensive score representing an individual intake of various dietary antioxidants, including vitamin A, vitamin C, vitamin E, selenium, zinc, and carotenoids. This study investigated the association between CDAI and MASLD.Materials and methodsClinical and demographic data, as well as ultrasound transient elastography measurements at baseline, were collected from the National Health and Nutrition Examination Survey 2017–2020 (NHANES 2017–2020). The controlled attenuation parameter was utilized to diagnose the presence of hepatic steatosis and to categorize individuals into those with and without MASLD. Liver stiffness was measured by ultrasound transient elastography, and subjects were classified as those with and without advanced liver fibrosis.ResultsThis study included 5,884 adults, of whom 3,433 were diagnosed with MASLD, resulting in a weighted prevalence of 57.3%. After adjusting for covariates, the odds ratios for MASLD were 0.96 (95% CI: 0.82, 1.12) in the second quartile, 0.80 (95% CI: 0.68, 0.95) in the third quartile and 0.60 (95% CI: 0.49, 0.73) in the fourth quartile, respectively. CDAI, however, was not significantly associated with advanced liver fibrosis.ConclusionThese findings suggested that scores on the CDAI were linearly and negatively associated with the prevalence of MASLD in the United States adults.

BackgroundThe aim of this study was to clarify the relationship between expression level of CTLA-4 on CD4+ T cells and sepsis-associated immunosuppression (SAI), and to elucidate the possible mechanism of mTOR pathway mediated autophagic-lysosomal disorder in regulating CTLA-4 expression.MethodsWe enrolled 63 sepsis patients admitted to our ICU between January 1 and June 30, 2023. Peripheral blood mononuclear cells were isolated from the patients within 24 hours of recruitment. Expression levels of mTOR, P62, LC3II, and CTLA-4 on circulating CD4+ T lymphocytes were quantitated using flow cytometry. The association of these markers and relationship between CTLA-4 expression and the incidence of SAI and 28-day mortality were comprehensively analyzed.ResultsCompared with non-immunosuppressed patients with sepsis, patients with SAI had a higher 28-day mortality rate (37.5% vs 13.0%, P=0.039) and higher CTLA-4 mean fluorescence intensity (MFI) on CD4+ T cells (328.7 versus 78.7, P

The escalating prevalence of diabetes has accentuated the significance of addressing the associated diabetic foot problem as a major public health concern. Effectively offloading plantar pressure stands out as a crucial factor in preventing diabetic foot complications. This review comprehensively examines the design, manufacturing, and evaluation strategies employed in the development of diabetic foot insoles. Furthermore, it offers innovative insights and guidance for enhancing their performance and facilitating clinical applications. Insoles designed with total contact customization, utilizing softer and highly absorbent materials, as well as incorporating elliptical porous structures or triply periodic minimal surface structures, prove to be more adept at preventing diabetic foot complications. Fused Deposition Modeling is commonly employed for manufacturing; however, due to limitations in printing complex structures, Selective Laser Sintering is recommended for intricate insole designs. Preceding clinical implementation, in silico and in vitro testing methodologies play a crucial role in thoroughly evaluating the pressure-offloading efficacy of these insoles. Future research directions include advancing inverse design through machine learning, exploring topology optimization for lightweight solutions, integrating flexible sensor configurations, and innovating new skin-like materials tailored for diabetic foot insoles. These endeavors aim to further propel the development and effectiveness of diabetic foot management strategies. Future research avenues should explore inverse design methodologies based on machine learning, topology optimization for lightweight structures, the integration of flexible sensors, and the development of novel skin-like materials specifically tailored for diabetic foot insoles. Advancements in these areas hold promise for further enhancing the effectiveness and applicability of diabetic foot prevention measures.

To ensure the safe operation and dispatching control of a low-voltage distributed photovoltaic (PV) power distribution network (PDN), the load forecasting problem of the PDN is studied in this study. Based on deep learning technology, this paper proposes a robot-assisted load forecasting method for low-voltage distributed photovoltaic power distribution networks using enhanced long short-term memory (LSTM). This method employs the frequency domain decomposition (FDD) to obtain boundary points and incorporates a dense layer following the LSTM layer to better extract data features. The LSTM is used to predict low-frequency and high-frequency components separately, enabling the model to precisely capture the voltage variation patterns across different frequency components, thereby achieving high-precision voltage prediction. By verifying the historical operation data set of a low-voltage distributed PV-PDN in Guangdong Province, experimental results demonstrate that the proposed “FDD+LSTM” model outperforms both recurrent neural network and support vector machine models in terms of prediction accuracy on both time scales of 1 h and 4 h. Precisely forecast the voltage in different seasons and time scales, which has a certain value in promoting the development of the PDN and related technology industry chain.

BackgroundPhysical activity has been shown to have an effect on Carotid plaque (CP) which is a predictor of Cardiovascular disease (CVD). Studies have shown that physical activity can alter the composition of gut microbiota, whether its influence on CP was mediated by gut microbiota has yet to be proved.MethodsWe conducted a case–control study involving 30 CP patients and 31 controls. Logistic regression was used to analyze the association between CP and physical activity. LefSe was used to explore the association between gut microbiota and physical activity as well as CP, and PhyloMed was used to examine the mediating effect of gut microbiota in the association between physical activity and CP.ResultsAfter adjusting for potential confounders, adequate physical activity showed a significant association with a decreased risk of CP (ORadj: 0.25, 95%CI: 0.06, 0.97). CP was associated with enrichment in the order Bacteroidales within the phylum Bacteroidetes and the predominant microbiota in individuals without plaque was the order Clostridiales (LDA scores >3). Individuals with adequate physical activity had a higher abundance of the order Clostridiales, while the order Bacteroidetes was enriched in individuals with inadequate physical activity (LDA scores >3). The PhyloMed revealed a significant mediation effect of gut microbiota in the association between physical activity and CP (p = 0.03).ConclusionAdequate physical activity was significantly associated with a decreased risk of CP, and this association was mediated by an increase in the abundance of gut microbiota in the order Clostridiales.

PurposeRepeated cone-beam CT (CBCT) scans for image-guided radiotherapy (IGRT) increase the health risk of radiation-induced malignancies. Patient-enrolled studies to optimize scan protocols are inadequate. We proposed a virtual clinical trial-based approach to evaluate projection-reduced low-dose CBCT for IGRT.Materials and methodsA total of 71 patients were virtually enrolled with 26 head, 23 thorax and 22 pelvis scans. Projection numbers of full-dose CBCT scans were reduced to 1/2, 1/4, and 1/8 of the original to simulate low-dose scans. Contrast-to-noise ratio (CNR) values in fat and muscle were measured in the full-dose and low-dose images. CBCT images were registered to planning CT to derive 6-degree-of-freedom couch shifts. Registration errors were statistically analyzed with the Wilcoxon paired signed-rank test.ResultsAs projection numbers were reduced, CNR values descended and the magnitude of registration errors increased. The mean CNR values of full-dose and half-dose CBCT were >3.0. For full-dose and low-dose CBCT (i.e. 1/2, 1/4 and 1/8 full-dose), the mean registration errors were< ± 0.4 mm in translational directions (LAT, LNG, VRT) and ±0.2 degree in rotational directions (Pitch, Roll, Yaw); the mean magnitude of registration errors were< 1 mm in translation and< 0.5 degree in rotation. The couch shift differences between full-dose and low-dose CBCT were not statistically significant (p>0.05) in all the directions.ConclusionThe results indicate that while the impact of dose-reduction on CBCT couch shifts is not significant, the impact on CNR values is significant. Further validation on optimizing CBCT imaging dose is required.