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Abstract Background As one of the key features of sleep, sleep duration (SD) has been confirmed to be associated with multiple health outcomes. However, the link between SD and cognitive function (CF) is still not well understood. Methods We employed a combined approach utilizing data from the National Health and Nutrition Examination Survey (NHANES 2011–2014) and Mendelian Randomization (MR) methods to investigate the relationship between SD and CF. In the NHANES cross-sectional analysis, the association between these variables was primarily examined through multivariate linear regression to explore direct correlations and utilized smoothing curve fitting to assess potential nonlinear relationships. To ensure the robustness of our findings, subgroup analyses were also conducted. MR analysis was used to assess the causal relationship between SD and sleeplessness on CF. After excluding confounding factors, univariate and multivariate MR were performed using inverse variance weighting (IVW) as the main analysis method, and sensitivity analysis was performed. Results The results of our cross-sectional study indicate a notable negative association between SD and CF, forming an inverted U-shaped curve with the inflection point occurring at SD = 6 h. This relationship remains consistent and robust across subgroup analyses differentiated by variables such as age, levels of physical activity, and frequency of alcohol intake. In MR analysis, IVW analysis showed no causal relationship between SD and sleeplessness on CF (Both P > 0.05). Conclusion Cross-sectional studies suggest the existence of an inverted U-shaped correlation between SD and CF among the elderly. However, MR analysis did not reveal a causal relationship between SD and CF, which the lack of nonlinear MR analysis may limit. These findings provide evidence from a sleep perspective for optimizing cognitive strategies in older adults.

Abstract Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies. Graphical Abstract

Abstract Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Introduction: Adipogenesis, the process of white adipose tissue expansion, plays a critical role in the development of obesity. Osteoprotegerin (OPG), known for its role in bone metabolism regulation, emerges as a potential regulator in mediating adipogenesis during obesity onset. Objectives: This study aims to elucidate the involvement of OPG in adipogenesis during the early phases of diet-induced obesity and explore its therapeutic potential in obesity management. Methods: Using a diet-induced obesity model, we investigated OPG expression patterns in adipocytes and explored the mechanisms underlying its involvement in adipogenesis. We also assessed the effects of targeted silencing of OPG and recombinant OPG administration on obesity progression and insulin resistance. Additionally, the impact of electroacupuncture treatment on OPG levels and obesity management was evaluated in both animal models and human participants. Results: OPG expression was prominently activated in adipocytes of white adipose tissues during the early phase of diet-induced obesity. Hyperlipidemia induced Cbfa1-dependent OPG transcription, initiating and promoting adipogenesis, leading to cell-size expansion and lipid storage. Intracellular OPG physically bound to RAR and released the PPARɤ/RXR complex, activating adipogenesis-associated gene expression. Targeted silencing of OPG suppressed obesity development, while recombinant OPG administration promoted disease progression and insulin resistance in obese mice. Electroacupuncture treatment suppressed obesity development in an OPG-dependent manner and improved obesity parameters in obese human participants. Conclusion: OPG emerges as a key regulator in mediating adipogenesis during obesity development. Targeting OPG holds promise for the prevention and treatment of obesity, as evidenced by the efficacy of electroacupuncture treatment in modulating OPG levels and managing obesity-related outcomes.

【Objective】The study was carried out to explore the distribution patterns of rhizospheric microbial communities in different resistant pepper varieties, aiming to provide a basis for the targeted optimization of rhizospheric microbial community structure of pepper.【Method】Taking the susceptible pepper variety 'Hailan 99' (HL99) and the resistant variety 'Sanxiaqing' (SSQ) as experimental materials, high-throughput sequencing technology was employed to analyze and compare the effects of susceptible and non-susceptible soil environments on the community diversity, species composition, correlation networks and function of bacteria and fungi in the rhizosphere soil of different disease-resistant pepper plants.【Result】Through high-throughput sequencing, a total of 66 617 operational taxonomic units (OTUs) from soil bacterial samples were obtained, among which the dominant phyla were Proteobacteria and Bacteroidetes, with the relative abundances of approximately 40.1% and 15.3%, respectively. From soil fungal samples, 2 948 OTUs were obtained, among which the dominant phylum was Ascomycota, with an average relative abundance of approximately 47.8%. The rhizospheric microbial community structure and species composition of pepper varieties showed significant differences under different soil conditions. Under susceptible soil conditions, the diversity of bacterial communities in pepper rhizosphere decreased, while the diversity of fungal communities increased. The bacterial OTUs decreased by 6.5%-7.8%, and fungal OTUs increased by 8.8%-9.8%. The relative abundance of Fusarium fungi was significantly higher in the susceptible group (5.0%) compared with that in the resistant group (4.8%), while the relative abundance of beneficial fungi like Mortierella and Trichoderma and beneficial bacteria like Pseudomonas and Bacillus was significantly lower in the susceptible group than that in the resistant group. Overall, under the susceptible soil conditions, the abundance of beneficial rhizosphere fungi and bacteria in the resistant group was higher than that in the susceptible group, contributing to a better soil micro-ecological environment. Based on species abundance tables, the correlation relationships of fungi-fungi, fungi-bacteria and bacteria-bacteria species were calculated respectively at the genus level. The results indicated that the rhizosphere microorganisms of pepper formed a complex ecological network, with high co-occurrence between fungi-fungi and fungi-bacteria (with a positive correlation percentage higher than 50%), suggesting that cooperative relationships outweighed competitive ones. The bacteria-bacteria network structure was more complex, with a positive correlation percentage of about 49.9%.【Conclusion】The rhizospheric microbial community structures of different resistant varieties exhibit significant differences under different soil conditions. The interaction of rhizosphere microorganisms forms a complex microbial ecological network structure. The relative abundance of beneficial fungi and bacteria is higher in the resistant variety than that in the susceptible variety, which suppresses more pathogenic microbes, leading to a healthier soil micro-ecological environment. The key groups identified in this study, including Fusarium, Verticillium, Trichoderma, Bacillus and Pseudomonas, will provide important information for the targeted optimization of rhizospheric microbial community structures and offer crucial theoretical references for the biological control of soil-borne diseases.

Objective To investigate the association between preoperative nutritional scores and moderate-to-severe acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery and the predictive significance of nutritional indices for moderate to severe AKI.Methods This study retrospectively included older patients underwent CABG surgery from the Medical Information Mart for Intensive Care (MIMIC) database. Nutritional scores were calculated by the Geriatric Nutritional Risk Index (GNRI) and the Prognostic Nutritional Index (PNI), respectively. Moderate-to-severe injury was determined by KDIGO criteria. Logistic regression, subgroup analysis, and restricted cubic splines were utilized to investigate the association. The predictive value was also assessed by the area under the curve (AUC), net reclassification index (NRI), and integrated discrimination improvement (IDI).Results A total of 1,007 patients were retrospectively included, of which 100 (9.9%) and 380 (37.7%) had malnutrition calculated by GNRI and PNI scores. The incidence of moderate-to-severe AKI was 524 (52.0%). After adjustment for selected risk factors, worse nutritional scores were associated with a higher incidence of moderate-to-severe AKI (PGNRI

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. Materials and methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. Results CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. Conclusion Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

A new configuration of a 9-degree-of-freedom (DOF) robot has been designed to address the prevalence of balance disorders in patients and the increasing demand for exercise rehabilitation training. This lower-limb end rehabilitation robot can assist patients with repetitive movements to stimulate and rebuild their nervous system and improve their pelvic and muscle motion control abilities. Starting from functional requirements, multiple robot configuration design schemes are proposed, and various performance indicators are comprehensively considered to ultimately select and optimize a 9-DOF redundant series-parallel hybrid robot and complete its kinematic analysis and derivation. This robot consists of a 6-DOF vestibular parallel device and a 3-DOF proprioceptive parallel device in series, which are modular in structure and function while retaining the advantages of the strong load-bearing capacity of series robots and the large workspace of parallel robots. A new structural form is proposed for investigating lower-limb rehabilitation robots.

Abstract Background Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. Methods The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. Results PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. Conclusion This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.

Data center interconnections are cost-sensitive. We propose and demonstrate a cost-effective C-band intensity modulation direct detection (IM/DD) transmitter for extended range (ER) inter-datacenter interconnects utilizing only a 2-bit digital-to-analog converter (DAC). Tomlinson-Harashima precoding (THP) is used in transmitter DSP to compensate for dispersion-induced impairments. Due to the uniform distribution of signal levels after THP encoding, a high-resolution DAC is required to generate electrical signals. The hardware cost of the transmitter can be significantly reduced by compressing the physical number of bits (PNOB) of the DAC to 2 bits. We quantize the signal to 4 levels and utilize up-sampling and noise shaping to greatly reduce the in-band quantization noise. The in-band signal to noise ratio (SNR) can be increased to 23 dB. We experimentally demonstrate a cost-effective 40-Gbaud probabilistic shaping PAM-4 C-band IM/DD transmission over 50-km utilizing only a 2-bit DAC in the transmitter without any optical dispersion compensation. The performance of the proposed scheme is proximate to the common case of using an 8-bit DAC. It has a BER gap of about 2 × 10−3 only when the received optical power (ROP) is higher than −6 dBm.

Abstract Background The growth and development of rice (Oryza sativa L.) are affected by multiple factors, such as ROS homeostasis and utilization of iron. Here, we demonstrate that OsUGE2, a gene encoding a UDP-glucose 4-epimerase, controls growth and development by regulating reactive oxygen species (ROS) and iron (Fe) level in rice. Knockout of this gene resulted in impaired growth, such as dwarf phenotype, weakened root growth and pale yellow leaves. Biochemical analysis showed that loss of function of OsUGE2 significantly altered the proportion and content of UDP-Glucose (UDP-Glc) and UDP-Galactose (UDP-Gal). Cellular observation indicates that the impaired growth may result from decreased cell length. More importantly, RNA-sequencing analysis showed that knockout of OsUGE2 significantly influenced the expression of genes related to oxidoreductase process and iron ion homeostasis. Consistently, the content of ROS and Fe are significantly decreased in OsUGE2 knockout mutant. Furthermore, knockout mutants of OsUGE2 are insensitive to both Fe deficiency and hydrogen peroxide (H2O2) treatment, which further confirmed that OsUGE2 control rice growth possibly through Fe and H2O2 signal. Collectively, these results reveal a new pathway that OsUGE2 could affect growth and development via influencing ROS homeostasis and Fe level in rice.

This study aims to (1) assess the inter-limb asymmetry in hip, knee, and ankle strength and countermovement jump (CMJ) performance among adolescent basketball players and (2) examine the relationship between inter-limb asymmetry and CMJ performance. Moreover, 30 adolescent basketball players (15 boys and 15 girls) aged 14 to 15 years participated in this study. The strength of the lower limb joints was measured using an isokinetic dynamometer at a speed of 60 degrees per second. Three maximal CMJs were performed, and the highest jump was used for the final analysis. The subjects were median-split into high-asymmetry (n = 15) and low-asymmetry (n = 15) groups based on the calculated strength asymmetry scores. The asymmetry scores were calculated using the formula: (dominant–non-dominant)/dominant* 100%. The inter-limb asymmetry data ranged from 12.2% to 21.6%. A Spearman correlation analysis showed that only the inter-limb asymmetry of the ankle plantar flexor was significantly correlated with the CMJ heights (ρ = −0.56, p = 0.001). An independent t-test revealed no significant differences in strength asymmetry between boys and girls (all p > 0.05). The low-asymmetry group demonstrated significantly greater CMJ performance compared to the high-asymmetry group (ES = 1.11, 95% CI = 0.34–1.87, p = 0.007), indicating that inter-limb asymmetry of the ankle plantar flexor has a significant negative impact on CMJ performance. Coaches should focus on enhancing both the strength and symmetry of the ankle joints to improve athletic performance and prevent injuries in sports, where jumping is a common movement.

BackgroundAmid the backdrop of global aging, the increasing prevalence of cognitive decline among the elderly, particularly within the female demographic, represents a considerable public health concern. Physical activity (PA) is recognized as an effective non-pharmacological intervention for mitigating cognitive decline in older adults. However, the relationship between different PA patterns and cognitive function (CF) in elderly women remains unclear.MethodsThis study utilized data from National Health and Nutrition Examination Survey (NHANES) 2011–2014 to investigate the relationships between PA, PA patterns [inactive, Weekend Warrior (WW), and Regular Exercise (RE)], and PA intensity with CF in elderly women. Multivariate regression analysis served as the primary analytical method.ResultsThere was a significant positive correlation between PA and CF among elderly women (β-PA: 0.003, 95% CI: 0.000–0.006, P = 0.03143). Additionally, WW and RE activity patterns were associated with markedly better cognitive performance compared to the inactive group (β-WW: 0.451, 95% CI: 0.216–0.685, P = 0.00017; β-RE: 0.153, 95% CI: 0.085–0.221, P = 0.00001). Furthermore, our results indicate a progressive increase in CF with increasing PA intensity (β-MPA- dominated: 0.16, 95% CI: 0.02–0.09, P = 0.0208; β-VPA-dominated: 0.21, 95% CI: 0.09–0.34, P = 0.0011; β-Total VPA: 0.31, 95% CI: −0.01–0.63, P = 0.0566).ConclusionOur study confirms a positive association between PA and CF in elderly women, with even intermittent but intensive PA models like WW being correlated with improved CF. These findings underscore the significant role that varying intensities and patterns of PA play in promoting cognitive health among older age groups, highlighting the need for adaptable PA strategies in public health initiatives targeting this population.

BackgroundType 2 diabetes mellitus (T2DM) and hearing loss (HL) constitute significant public health challenges worldwide. Recently, the association between T2DM and HL has aroused attention. However, possible residual confounding factors and other biases inherent to observational study designs make this association undetermined. In this study, we performed univariate and multivariable Mendelian Randomization (MR) analysis to elucidate the causal association between T2DM and common hearing disorders that lead to HL.MethodsOur study employed univariate and multivariable MR analyses, with the Inverse Variance Weighted method as the primary approach to assessing the potential causal association between T2DM and hearing disorders. We selected 164 and 9 genetic variants representing T2DM from the NHGRI-EBI and DIAGRAM consortium, respectively. Summary-level data for 10 hearing disorders were obtained from over 500,000 participants in the FinnGen consortium and MRC-IEU. Sensitivity analysis revealed no significant heterogeneity of instrumental variables or pleiotropy was detected.ResultsIn univariate MR analysis, genetically predicted T2DM from both sources was associated with an increased risk of acute suppurative otitis media (ASOM) (In NHGRI-EBI: OR = 1.07, 95% CI: 1.02-1.13, P = 0.012; In DIAGRAM: OR = 1.14, 95% CI: 1.02-1.26, P = 0.016). Multivariable MR analysis, adjusting for genetically predicted sleep duration, alcohol consumption, body mass index, and smoking, either individually or collectively, maintained these associations. Sensitivity analyses confirmed the robustness of the results.ConclusionT2DM was associated with an increased risk of ASOM. Strict glycemic control is essential for the minimization of the effects of T2DM on ASOM.

Abstract Background Chronic Obstructive Pulmonary Disease (COPD) currently ranks as the third leading cause of mortality worldwide, imposing substantial burdens on societal and individual health. Amongst health research tools, walking pace (WP) and hand grip strength (HGS) are cornerstones, extensively associated with diverse health conditions. However, the intricate interplay between these factors and COPD risk remains ambiguous. This study aims to elucidate the causal association of WP, HGS, with COPD risk through a bidirectional Mendelian randomization (MR) approach. Methods Bidirectional MR analysis was performed using Genome-wide association study (GWAS) data of European individuals for WP, HGS, and COPD. Inverse Variance Weighted (IVW) served as the primary MR analysis approach. To supplement the IVW findings, four additional MR methods [MR-Egger, weighted median, maximum likelihood, simple median] were used. To assess heterogeneity and pleiotropy, sensitivity analyses were performed. In addition, multivariate MR (MVMR) analysis was used to assess causality after adjustment for potential confounders. Results IVW method results show a significant negative association between WP and COPD risk in both initial (genome-wide threshold, odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.09–0.51, P = 5.06 × 10− 4) and secondary (locus-wide threshold, OR = 0.27, 95%CI: 0.18–0.41, P = 4.88 × 10− 10) MR analysis. The reverse MR analysis suggested that COPD also diminishes WP. Additionally, a causal risk reduction for COPD with right HGS (OR = 0.74, 95% CI: 0.58–0.94, P = 1.44 × 10− 2) was only found in secondary MR analysis. The outcomes of the four additional MR methods also suggested similar causal relationships, and sensitivity analyses endorsed their robustness. Lastly, the MVMR analysis demonstrated that the WP’s effect on reducing COPD risk persisted independently of potential confounding variables. Conclusion A bidirectional causal relationship exists between typical WP and COPD risk. Conversely, a decrease in right HGS is unidirectionally associated with an increased risk of COPD. The study suggests that WP may serve as a predictive factor for COPD or as a simple evaluative indicator for prognosis.

BackgroundCognitive-Motor Dual Task (CMDT) training has been widely utilized in rehabilitation and sports practice. However, whether CMDT training can better enhance athletes’ cognitive-motor performance compared to traditional single-task (ST) training remains unclear.MethodA systematic review that complied with PRISMA was carried out (Prospero registration number: CRD42023443594). The electronic databases used for the systematic literature search from the beginning through 13 June 2023, included Web of Science, Embase, PubMed, and the Cochrane Library. After obtaining the initial literature, two researchers independently assessed it based on inclusion and exclusion criteria. Finally, the included literature was analyzed to compare the differences between ST training and CMDT training.ResultsAfter screening 2,094 articles, we included 10 acute studies and 7 chronic studies.ConclusionThis systematic review shows that athletes typically show a degradation of performance in CMDT situations as opposed to ST when evaluated transversally. However, this performance decline is notably reduced following longitudinal training in CMDT, indicating the effectiveness of sustained CMDT training in enhancing cognitive-motor performance under dual-task conditions. Our study provides new insights into the application of CMDT in the field of sports training. Practitioners can utilize CMDT to assess athletic skill levels or optimize cognitive-motor performance of athletes, taking into account the specific needs of each sport.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023443594.

Tumor microenvironment contributes to poor prognosis of pancreatic adenocarcinoma (PAAD) patients. Proper regulation could improve survival. Melatonin is an endogenous hormone that delivers multiple bioactivities. Here we showed that pancreatic melatonin level is associated with patients' survival. In PAAD mice models, melatonin supplementation suppressed tumor growth, while blockade of melatonin pathway exacerbated tumor progression. This anti-tumor effect was independent of cytotoxicity but associated with tumor-associated neutrophils (TANs), and TANs depletion reversed effects of melatonin. Melatonin induced TANs infiltration and activation, therefore induced cell apoptosis of PAAD cells. Cytokine arrays revealed that melatonin had minimal impact on neutrophils but induced secretion of Cxcl2 from tumor cells. Knockdown of Cxcl2 in tumor cells abolished neutrophil migration and activation. Melatonin-induced neutrophils presented an N1-like anti-tumor phenotype, with increased neutrophil extracellular traps (NETs) causing tumor cell apoptosis through cell-to-cell contact. Proteomics analysis revealed that this reactive oxygen species (ROS)-mediated inhibition was fueled by fatty acid oxidation (FAO) in neutrophils, while FAO inhibitor abolished the anti-tumor effect. Analysis of PAAD patient specimens revealed that CXCL2 expression was associated with neutrophil infiltration. CXCL2, or TANs, combined with NET marker, can better predict patients’ prognosis. Collectively, we discovered an anti-tumor mechanism of melatonin through recruiting N1-neutrophils and beneficial NET formation.

Background: Osteoarthritis (OA) is one of the most common joint diseases worldwide, imposing a substantial burden on individuals and society. Numerous pieces of evidence suggest that walking pace (WP) can serve as a predictive indicator for the risk of various diseases, and observational studies have also found a potential link between WP and the risk of OA. However, the causal relationship between WP and the risk of OA remains unclear.Methods: We conducted a mendelian randomization (MR) study using data from the European Genome-wide Association Study, which included WP (including 459,915 participants), OA (including 10,083 cases and 40,425 controls), knee OA (including 24,955 cases and 378,169 controls), and hip OA (including 15,704 cases and 378,169 controls). Single nucleotide polymorphisms (SNPs) associated with WP were utilized to infer causal associations with OA and its subtypes. The Inverse Variance Weighted (IVW) technique served as the primary causal analysis method. Three auxiliary MR methods - MR-Egger, weighted median, and maximum likelihood - were used to substantiate the IVW results. Sensitivity analyses were performed to examine heterogeneity and pleiotropy. In addition, multivariate MR (MVMR) analysis was used to assess causality after adjustment for three potential confounders.Results: According to the results of the IVW method, every 1 standard deviation increased in genetic WP corresponds to an 89% reduction in the risk of OA (odds ratio (OR) = 0.11; 95% confidence interval (CI), 0. 06–0.19; p = 1.57 × 10−13), an 83% reduction in the risk of knee OA (OR = 0.17; 95% CI, 0.11–0.28; p = 2.78 × 10−13), and a 76% reduction in the risk of hip OA (OR = 0.24; 95% CI, 0.14–0.43; p = 1.51 × 10−6). These results were confirmed by the three additional MR methods and validated by the sensitivity analysis. Ultimately, the MVMR analysis confirmed that the role of WP in reducing the risk of OA and its subtypes remains consistent regardless of potential confounders.Conclusion: The results of our MR study highlight a significant causal association between WP and the susceptibility to OA, including its knee and hip subtypes. These findings propose that WP could be utilized as a potential prognostic factor for OA risk.

For hundreds of years, the drug discovery and development industry has aimed at identifying single components with a clear mechanism of action as desirable candidates for potential drugs. However, this conventional strategy of drug discovery and development has faced challenges including a low success rate and high development costs. Herein, we critically review state-of-the-art drug discovery and development based on multi-component Chinese medicine formulas. We review the policies and application status of new drugs based on multi-component Chinese medicines in the US, China, and the European Union. Moreover, we illustrate several excellent cases of ongoing applications. Biomedical technologies that may facilitate drug discovery and development based on multi-component Chinese medicine formulas are discussed, including network pharmacology, integrative omics, CRISPR gene editing, and chemometrics. Finally, we discuss potential problems and solutions in pre-clinical and clinical research in drug discovery and development based on multi-component Chinese medicine formulas. We hope that this review will promote discussion of the roles of multi-component Chinese medicine formulas in the discovery and development of new drugs for the treatment of human diseases.

The treatment of patients with balance disorders is an urgent problem to be solved by the medical community. The causes of balance disorders are diverse. An aging population, traffic accidents, stroke, genetic diseases and so on are all possible factors. It has brought great pain and inconvenience to patients and their families. At present, there are two main types of assisted rehabilitation training robots for patients with balance disorders: exoskeleton robots and end robots. The exoskeleton robot is generally installed on the outside of the patient’s body to follow their movement, which can support the weight of the body and provide power support to help the patient train and recover lower limb ability. The use of end robots is usually to secure the patient’s foot to the motion platform and control the pedal to drive the lower limbs to conduct gait training. Such passive training is more suitable for patients with severe disorders. The patient has low awareness of active participation. This paper focuses on research on end rehabilitation training robots for balance disorders. In this paper, a robotic system for rehabilitation training of patients with balance disorders is invented. The robot body is a 9 degree of freedom (DOF) redundant series-parallel hybrid motion platform. Two sets of motion platforms with symmetrical mirror images are used together to simulate different motion modes of the human body and drive the human body to move. Each set of motion platforms is composed of a 6-DOF vestibular parallel device and a 3-DOF proprioception parallel device. It has the advantages of DOF decoupling and fast response, proposing a new structural form for the design of proprioceptive and vestibular simulation platforms. The robot’s functional level can be divided into a vestibular sense module and a proprioception module according to the structure. The two modules can work independently to achieve different functions or work together to achieve complex motion and multisensory fusion. This robot is a redundant mechanism device with 9 DOFs. Through a reasonable distribution of DOF and motion, the robot’s working space can be increased, and the robot’s flexibility and motion performance can be improved. In this paper, a trajectory tracking control algorithm for vestibular and proprioceptive simulation is proposed, which can provide unlimited body sense training for patients within the robot’s limited motion range.

Gastric cancer (GC) is the fifth most common cancer worldwide. Cuproptosis is associated with cell growth and death as well as tumorigenesis. Aiming to lucubrate the potential influence of CRGs in gastric cancer, we acquired datasets of gastric cancer patients from TCGA and GEO. The identification of molecular subtypes with CRGs expression was achieved through unsupervised learning-cluster analysis. To evaluate the application value of subtypes, the K-M survival analysis was conducted to evaluate the clinical prognostic characteristics. Subsequently, we performed Gene Set Variation Analysis (GSVA) and utilized ssGSEA to quantify the extent of immune infiltration. Further, the K-M survival analysis was used to identify the prognosis-related CRGs. Next, signature genes of diagnostic predictive value were screened using the least absolute shrinkage and selection operator (LASSO) algorithm from the expression matrix for TCGA, as well as the signature gene-related subtype was clustered by the “ConsensusClusterPlus” package. Finally, the immunological and drug sensitivity assessments of the signature gene-related subtypes were conducted. A total of 173 CRGs were identified, most of the CRGs undergo copy number variation in gastric cancer. Under different patient subtypes, immune cell levels differed significantly, and the subtype exhibiting high expression of the CRGs had a better prognosis. Furthermore, we selected 34 CRGs that were highly correlated with the prognosis of gastric cancer. By constructing a multivariate Cox proportional-hazards model and a hazard scoring system, we were able to categorize patients into high- and low-risk groups based on their hazard score. K-M analysis demonstrated a significant survival disadvantage in the high-risk group. Based on Lasso regression analysis, we screened 16 signature genes, a multivariate logistic regression model [cutoff: 0.149 (0.000, 0.974), AUC:0.987] and a prognosis network diagram was constructed and their prediction efficiency for gastric cancer prognostic diagnosis was well validated. According to the signature genes, the patients were separated to two signature subtypes. We found that patients with higher CRGs expression and better prognosis had lower levels of immune infiltration. Finally, according to the results of drug susceptibility analysis, docetaxel, 5-Fluorouracil, gemcitabin, and paclitaxel were found to be more sensitive to gastric cancer.

Chili (Capsicum annuum L.) is highly susceptible to soilborne diseases, thereby presenting a significant threat that results in considerable yield losses in chili production. The exploration of genes conferring resistance and the underlying defense mechanisms presents a promising strategy for bolstering plant disease control. In this study, we selected two distinct cultivars, the disease-sensitive ‘Hailan 99’ and the disease-tolerant ‘Sanxiaqing’, to elucidate the molecular basis of their responses to soilborne disease intervention. We conducted a comprehensive analysis of root morphological characteristics and transcriptome profiles under stress conditions. Our findings revealed that, when subjected to soilborne disease intervention, these two cultivars exhibited contrasting root system characteristics and responses, reflecting diverse defense strategies. The disease-resistant cultivar demonstrated superior adaptability, possibly owing to its capacity for swift recognition of pathogen effectors, activation of defense responses, and effective containment of infection at localized sites, thus impeding disease progression. Noteworthy genes such as T459_04053, implicated in effector recognition; MSTRG.26158, MSTRG.30886, and T459_22510, associated with secondary metabolite biosynthesis; and T459_05615, partaking in the autophagy pathway, along with other differentially expressed genes linked to effector recognition, immune activation, and modulation of cell death processes, offer valuable insights into enhancing soilborne disease resistance in chili. Furthermore, these findings contribute to an enhanced understanding of the molecular mechanisms underlying soilborne disease resistance in diverse plant crops.

Dense nonaqueous phase liquid (DNAPL) is one of the main pollution sources of the underground environment. After DNAPL enters the underground environment, the migration and diffusion process has experienced a variety of media, resulting in large-scale and long-term pollution. To better understand the residual and dissolution process of DNAPL in fractures, the visual experiment of DNAPL residual and dissolution in the fracture was carried out using the transparent fracture model made of glass material, and the changes of DNAPL migration morphology and residual distribution in the crack were obtained. The results showed that the migration front of DNAPL in the fracture was finger shaped in the process of displacement of water phase by DNAPL phase, which was consistent with the state in porous media. When the process of water phase displacing DNAPL phase was over, discrete and aggregated DNAPL droplets remained in the fracture. The residual DNAPL was mainly concentrated in the area ranged from 0.3 mm to 0.8 mm. The dissolution rate of DNAPL in the fracture changed from fast to slow, and there was an obvious tailing period. The increased velocity of water phase flow significantly shortened the time of dissolution process. The DNAPL with hydrolysis reaction accounted for only 0.86% on average in the dissolution process. The findings of this study are helpful to the remediation of the underground environment.

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of “seed and soil” suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.

Columnar jointed rock mass (CJRM) formed by intact rock divided by special symmetrical columnar joints is a special type of rock with poor mechanical properties, strong anisotropy, and weak self-supporting ability, severely affecting the excavation safety and stability of underground tunnels. In this study, taking the Baihetan hydropower station as the engineering background, CJRM geological numerical models with different dip angles that combined well with the natural CJRM were generated based on the geological statistical parameters of the engineering site and were verified to have high rationality and accuracy. Tunnel excavation and overloading tests were carried out on these numerical models, and the results showed that the stress and displacement distributions after excavation exhibited strong anisotropic characteristics under different dip angles, and the positions where engineering safety problems are most likely to occur are the side walls, which are prone to stress-structure-controlled failure mode. The self-supporting ability at different dip angles after excavation from weak to strong are 45°, 60°, 75°, 90°, 30°, 0°, and 15°. The safety factors assessed by overloading for CJRM with dip angles of 0–90° degrees were 2.5, 2.6, 2.6, 1.8, 2.1, and 2.2, respectively, providing a valuable reference for the construction safety and support measures of CJRM excavation.

The unique structural characteristics and special symmetry of columnar jointed rock mass result in its complex mechanical properties and strong anisotropy, which seriously affects the safety of engineering construction. To better simulate natural columnar jointed rock mass, a geometric model reconstruction method based on a single-random movement Voronoi diagram of uniform seed points using the feasible geological parameters of horizontal polygon density, irregular factor, dip angle, strike angle, transverse joint spacing, and transverse joint penetration rate is proposed in this paper. Based on this method, numerical simulation of CJRM models with varying strike angles, dip angles, and irregular factors under uniaxial compression were conducted. The results show that the uniaxial compression strengths versus strike angle and dip angle both decrease with the increase in the irregular factor, showing a U-shape and a gentle W-shape, respectively. The strength anisotropy of the strike angle decreases from 1.1057 to 1.0395 with the increase in the irregular factor, indicating relatively isotropy. With the increase int the irregular factor, the strength anisotropy of the dip angle increases from 4.3381 to 6.7953, indicating an increasing strong anisotropy at a high degree, and the effect of the irregular factor on strength behavior has the strongest and weakest impact at the dip angles of 60° and 90°, respectively.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially described to target the respiratory system and now has been reported to infect a variety of cell types, including cardiomyocytes, neurons, hepatocytes, and gut enterocytes. However, it remains unclear whether the virus can directly infect human embryonic stem cells (hESCs) or early embryos. Herein, we sought to investigate this question in a cell-culture system of hESCs. Both the RNA and S protein of SARS-CoV-2 were detected in the infected hESCs and the formation of syncytium was observed. The increased level of subgenomic viral RNA and the presence of dsRNA indicate active replication of SARS-CoV-2 in hESCs. The increase of viral titers in the supernatants revealed virion release, further indicating the successful life cycle of SARS-CoV-2 in hESCs. Remarkably, immunofluorescence microscopy showed that only a small portion of hESCs were infected, which may reflect low expression of SARS-CoV-2 receptors. By setting |log2 (fold change)| > 0.5 as the threshold, a total of 1,566 genes were differentially expressed in SARS-CoV-2-infected hESCs, among which 17 interferon-stimulated genes (ISGs) were significantly upregulated. Altogether, our results provide novel evidence to support the ability of SARS-CoV-2 to infect and replicate in hESCs.

Nowadays, the applications of engineered nanoparticles (ENPs) have been significantly increased, thereby negatively affecting crop production and ultimately contaminating the food chain worldwide. Zinc oxide nanoparticles (ZnO NPs) induced oxidative stress has been clarified in previous studies. But until now, it has not been investigated that how ethylene mediates or participates in ZnO NPs-induced toxicity and related cellular ultrastructural changes in rice seedlings. Here, we reported that 500 mg/L of ZnO NPs reduced the fresh weight (54.75% and 55.64%) and dry weight (40.33% and 47.83%) in shoot and root respectively as compared to control. Furthermore, ZnO NPs (500 mg/L) reduced chlorophyll content (72% Chla, 70% Chlb), induced the stomatal closure and ultrastructural damages by causing oxidative stress in rice seedlings. These cellular damages were significantly increased by exogenous applications of ethylene biosynthesis precursor (ACC) in the presence of ZnO NPs. In contrary, ZnO NPs induced damages on the above-mentioned attributes were reversed through the exogenous supply of ethylene signaling and biosynthesis antagonists such as silver (Ag) and cobalt (Co) respectively. Interestingly, ZnO NPs accelerate ethylene biosynthesis by up-regulating the transcriptome of ethylene biosynthesis responsive genes. The antioxidant enzymes activities and related gene expressions were further increased in ethylene signaling and biosynthesis associated antagonists (Ag and Co) treated seedlings as compared to sole ZnO NPs treatments. In contrary, the above-reported attributes were further decreased by ACC together with ZnO NPs. In a nutshell, ethylene effectively contributes in ZnO NPs induced toxicity and causing ultrastructural and stomatal damage in rice seedlings. Such findings could have potential implications in producing genetic engineered crops, which will be able to tolerate nanoparticles toxicity in the environment.

This paper presents an innovative application of a 6-DOF robot in the field of rehabilitation training. This robot operates in a parallel fashion for lower limb movement, which adopts a new structure that can help patients to carry out a variety of rehabilitation exercises. Traditional parallel robots, such as the Stewart robot, have the characteristics of strong bearing capacity. However, it is difficult to achieve high-speed, high-acceleration and long journey movement. This paper presents a new robot configuration that can address these problems. This paper also conducts an all-around characteristic analysis of this new parallel robot, including kinematics, dynamics and structure, to better study the robot and improve its performance. This paper optimizes an algorithm to make it more suitable for rehabilitation training. Finally, the performance improvements brought by optimization are verified by simulations.

Arabidopsis trichome is specialized structure that develops from epidermal cells, and is an excellent model system for studying various aspects of plant cell development and cell differentiation. Our previous studies have shown that C2H2 zinc finger protein family genes, including GIS, GIS2, GIS3, ZFP5, ZFP6 and ZFP8, play an important role in controlling trichome initiation in Arabidopsis. Here, our novel results showed a C2H2 zinc finger protein, ZFP1, which also plays an important role in trichome initiation in Arabidopsis. ZFP1 over-expression lines display significantly increased trichome number on cauline leaves, lateral branches and main stems in comparison with wild type plants. ZFP1 RNAi lines and loss-of-function mutants showed the opposite phenotype. Furthermore, our study also found that ZFP1 mediates the regulation of trichome initiation by cytokinin signaling. The molecular and genetic analyses reveal that ZFP1 acts upstream of key trichome initiation factors, GL3 and TRY.

BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding single-stranded RNA molecules that inhibit gene expression at post-transcriptional level. Gadd45g (growth arrest and DNA-damage-inducible 45 gamma) is a stress-response protein, which has been implicated in several biological processes, including DNA repair, the cell cycle and cell differentiation. RESULTS: In this work, we found that miR-383 is a negative regulator of Gadd45g. Forced expression of miR-383 decreased the expression of Gadd45g through binding to the 3' untranslated region (3'-UTR), whereas inhibition of miR-383 increased Gadd45g expression. The presence of miR-383 increased the cellular sensitivity to DNA damage in breast cancer cells, which was rescued by ectopic expression of Gadd45g without the 3'-UTR. miR-383 also regulates the expression of Gadd45g in embryonic stem (ES) cells, but not their apoptosis under genotoxic stress. miR-383 was further showed to negatively regulate ES cell differentiation via targeting Gadd45g, which subsequently modulates the pluripotency-associated genes. Taken together, our study demonstrates that miR-383 is a negative regulator of Gadd45g in both tumor cells and ES cells, however, has distinct function in regulating cell apoptosis. miR-383 may be used as antineoplastic agents in cancer chemotherapy. CONCLUSION: We demonstrate for the first time that miR-383 can specifically regulates the expression of Gadd45g by directly targeting to the 3-UTR region of Gadd45g mRNA, a regulatory process conserved in human tumor cells and mouse embryonic stem cells. These two compotents can be potentially used as antineoplastic agents in cancer chemotherapy.

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