Tissue-resident memory CD103+CD8+ T cells in colorectal cancer: its implication as a prognostic and predictive liver metastasis biomarker.

BACKGROUND: Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear. METHODS: Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry. RESULTS: In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects. CONCLUSION: We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.

Engineering d-p Orbital Hybridization in Mo-O Species of Medium-Entropy Metal Oxides as Highly Active and Stable Electrocatalysts toward Ampere-Level Water/Seawater Splitting.

Optimizing the electronic structure of electrocatalysts is of particular importance to enhance the intrinsic activity of active sites in water/seawater. Herein, a series of medium-entropy metal oxides of X(NiMo)O2/NF (X = Mn, Fe, Co, Cu and Zn) is designed via a rapid carbothermal shocking method. Among them, the optimized medium-entropy metal oxide (FeNiMo)O2/NF delivered remarkable HER performance, where the overpotentials as low as 110 and 141 mV are realized at 1000 mA cm-2 (@60 °C) in water and seawater. Meanwhile, medium-entropy metal oxide (FeNiMo)O2/NF only required overpotentials of as low as 330 and 380 mV to drive 1000 mA cm-2 for OER in water and seawater (@60 °C). Theoretical calculations showed that the multiple-metal synergistic effect in medium-entropy metal oxides can effectively enhance the d-p orbital hybridization of Mo─O bond, reduce the energy barrier of H* adsorbed at the Mo sites. Meanwhile, Fe sites in medium-entropy metal oxide can act as the real OER active center, resulting in a good bifunctional activity. In all, this work provides a feasible strategy for the development of highly active and stable medium-entropy metal oxide electrocatalysts for ampere-level water/seawater splitting.

KLF2 enhancer variant rs4808485 increases lupus risk by modulating inflammasome machinery and cellular homoeostasis.

OBJECTIVE: A recent genome-wide association study linked KLF2 as a novel Asian-specific locus for systemic lupus erythematosus (SLE) susceptibility. However, the underlying causal functional variant(s), cognate target gene(s) and genetic mechanisms associated with SLE risk are unknown. METHODS: We used bioinformatics to prioritise likely functional variants and validated the best candidate with diverse experimental techniques, including genome editing. Gene expression was compared between healthy controls (HCs) and patients with SLE with or without lupus nephritis (LN+, LN-). RESULTS: Through bioinformatics and expression quantitative trait locus analyses, we prioritised rs4808485 in active chromatin, predicted to modulate KLF2 expression. Luciferase reporter assays and chromatin immunoprecipitation-qPCR demonstrated differential allele-specific enhancer activity and binding of active histone marks (H3K27ac, H3K4me3 and H3K4me1), Pol II, CTCF, P300 and the transcription factor PARP1. Chromosome conformation capture-qPCR revealed long-range chromatin interactions between rs4808485 and the KLF2 promoter. These were directly validated by CRISPR-based genetic and epigenetic editing in Jurkat and lymphoblastoid cells. Deleting the rs4808485 enhancer in Jurkat (KO) cells disrupted NLRP3 inflammasome machinery by reducing KLF2 and increasing CASPASE1, IL-1ß and GSDMD levels. Knockout cells also exhibited higher proliferation and cell-cycle progression than wild type. RNA-seq validated interplay between KLF2 and inflammasome machinery in HC, LN+ and LN-. CONCLUSIONS: We demonstrate how rs4808485 modulates the inflammasome and cellular homoeostasis through regulating KLF2 expression. This establishes mechanistic connections between rs4808485 and SLE susceptibility.

ERK/CREB and p38 MAPK/MMP14 Signaling Pathway Influences Spermatogenesis through Regulating the Expression of Junctional Proteins in Eriocheir sinensis Testis.

The hemolymph-testis barrier (HTB) is a reproduction barrier in Crustacea, guaranteeing the safe and smooth process of spermatogenesis, which is similar to the blood-testis barrier (BTB) in mammals. The MAPK signaling pathway plays an essential role in spermatogenesis and maintenance of the BTB. However, only a few studies have focused on the influence of MAPK on crustacean reproduction. In the present study, we knocked down and inhibited MAPK in Eriocheir sinensis. Increased defects in spermatogenesis were observed, concurrently with a damaged HTB. Further research revealed that es-MMP14 functions downstream of ERK and p38 MAPK and degrades junctional proteins (Pinin and ZO-1); es-CREB functions in the ERK cascade as a transcription factor of ZO-1. In addition, when es-MMP14 and es-CREB were deleted, the defects in HTB and spermatogenesis aligned with abnormalities in the MAPK. However, JNK impacts the integrity of the HTB by changing the distribution of intercellular junctions. In summary, the MAPK signaling pathway maintains HTB integrity and spermatogenesis through es-MMP14 and es-CREB, which provides insights into the evolution of gene function during barrier evolution.

[Design and analysis of shoulder type exoskeleton stretcher for individual soldier].

For the transportation process of rescuing wounded personnel on naval vessels, a new type of shoulder type exoskeleton stretcher for individual soldier was designed in this paper. The three-dimensional model of the shoulder type exoskeleton stretcher for individual soldier was constructed using three dimensional modeling software. Finite element analysis technique was employed to conduct statics simulation, modal analysis, and transient dynamics analysis on the designed exoskeleton stretcher. The results show that the maximum stress of the exoskeleton stretcher for walking on flat ground is 265.55 MPa, which is lower than the allowable strength of the fabrication material. Furthermore, the overall deformation of the structure is small. Modal analysis reveals that the natural frequency range of the exoskeleton stretcher under different gait conditions is 1.96 Hz to 28.70 Hz, which differs significantly from the swing frequency of 1 Hz during walking. This indicates that the designed structure can effectively avoid resonance. The transient dynamics analysis results show that the maximum deformation and stress of exoskeleton stretcher remain within the safety range, which meets the expected performance requirements. In summary, the shoulder type exoskeleton stretcher for individual soldier designed in this study can solve the problem of requiring more than 2 people to carry for the existing stretcher, especially suitable for narrow spaces of naval vessels. The research results of this paper can provide a new solution for the rescue of wounded personnel on naval vessels.

Optimal dynamic pricing for public transportation considering consumer social learning.

Effective public transportation pricing strategies are critical to reducing traffic congestion and meeting consumer demand for sustainable urban development. In this study, we construct a dynamic game pricing model and a social learning network model for consumers of three modes of public transportation including metro, bus, and pa-transit. In the model, the metro, bus, and pa-transit operators maximize their profits through dynamic pricing optimization, and consumers maximize their utility by adjusting their travel habits through social learning in the social network. The reinforcement learning algorithm is applied to simulate the model, and the results show that: (1) as consumers' perceived sensitivity to different modes of travel increases, the market share and price of each mode of travel adjust accordingly. (2) When taking into account consumers' social learning behavior, the market share of metros remains high, while the market shares of buses and pa-transit are relatively low. (3) As consumers become more sensitive to their perception of each travel mode, operators invest more resources in improving service quality to gain market share, which in turn affects the price of each travel mode. Our results provide decision support for optimal pricing of urban public transportation.

A tree-based corpus annotated with Cyber-Syndrome, symptoms, and acupoints.

Prolonged and over-excessive interaction with cyberspace poses a threat to people's health and leads to the occurrence of Cyber-Syndrome, which covers not only physiological but also psychological disorders. This paper aims to create a tree-shaped gold-standard corpus that annotates the Cyber-Syndrome, clinical manifestations, and acupoints that can alleviate their symptoms or signs, designating this corpus as CS-A. In the CS-A corpus, this paper defines six entities and relations subject to annotation. There are 448 texts to annotate in total manually. After three rounds of updating the annotation guidelines, the inter-annotator agreement (IAA) improved significantly, resulting in a higher IAA score of 86.05%. The purpose of constructing CS-A corpus is to increase the popularity of Cyber-Syndrome and draw attention to its subtle impact on people's health. Meanwhile, annotated corpus promotes the development of natural language processing technology. Some model experiments can be implemented based on this corpus, such as optimizing and improving models for discontinuous entity recognition, nested entity recognition, etc. The CS-A corpus has been uploaded to figshare.

How does street environment affect pedestrian crash risks? A link-level analysis using street view image-based pedestrian exposure measurement.

Street space plays a critical role in pedestrian safety, but the influence of fine-scale street environment features has not been sufficiently understood. To analyze the effect of the street environment at the link level, it is essential to account for the spatial variation of pedestrian exposure across street links, which is challenging due to the lack of detailed pedestrian flow data. To address these issues, this study proposes to extract link-level pedestrian exposure from spatially ubiquitous street view images (SVIs) and investigate the impact of fine-scale street environment on pedestrian crash risks, with a particular focus on pedestrian facilities (e.g., crossing and sidewalk design). Both crash frequency and severity are analyzed at the link level, with the latter incorporating two distinct aggregation metrics: maximum severity and medium severity. Using Hong Kong as a case study, the results show that the link-level pedestrian exposure extracted from SVIs can lead to better model fit than alternative zone-level measurements. Specifically, higher pedestrian exposure is found to increase the total pedestrian crash frequency, while reducing the risk of serious injuries or fatalities, confirming the "safety in numbers" effect for pedestrians. Pedestrian facilities are also shown to influence pedestrian crash frequency and severity in different ways. The presence of crosswalks can increase crash frequency, but denser crosswalk design mitigates this effect. In addition, two-side sidewalks can increase crash frequency, while the absence of sidewalks leads to higher risks of crash severity. These findings highlight the importance of fine-scale street environment and pedestrian facility design for pedestrian safety.

Thymoquinone affects hypoxia-inducible factor-1α expression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways.

BACKGROUND: Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is known for its anti-cancer, anti-inflammatory, anti-fibrosis and antioxidant pharmacological activities. Recent studies on hypoxia-inducible factor-1α (HIF-1α) and PC have shown that HIF-1α affects the occurrence and development of PC in many aspects. In addition, TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α. Therefore, we speculate whether TQ affects HIF-1α expression in PC cells and explore the mechanism. AIM: To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1α expression. METHODS: Cell counting kit-8 assay, Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity, migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial (hTERT-HPNE) cells. Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1α mRNA and protein in PC cells. The effects of TQ on the HIF-1α protein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation. RESULTS: TQ significantly inhibited proliferative activity, migration, and invasion ability and promoted apoptosis of PANC-1 cells; however, no significant effects on hTERT-HPNE cells were observed. TQ significantly reduced the mRNA and protein expression levels of HIF-1α in PANC-1, AsPC-1, and BxPC-3 cells. TQ significantly inhibited the expression of the HIF-1α initial expression pathway (PI3K/AKT/mTOR) related proteins, and promoted the ubiquitination degradation of the HIF-1α protein in PANC-1 cells. TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1α protein but affected the stability of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90, thus promoting its ubiquitination degradation. CONCLUSION: The regulatory mechanism of TQ on HIF-1α protein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90; Secondly, TQ reduced the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.

Efficacy, Safety, and Treatment Burden of Aflibercept 2 mg and Ranibizumab in Retinal Vein Occlusion: A Systematic Review and Meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to provide an updated evidence base for clinical decision-making by comparing the efficacy and safety of aflibercept 2 mg and ranibizumab in treating retinal vein occlusion (RVO). METHODS: A systematic search was conducted using eight databases up to December 2021. Randomized controlled trials (RCTs) and real-world studies (RWSs) comparing aflibercept and ranibizumab in patients with RVO were evaluated. The primary outcomes assessed were efficacy, number of injections administered, and adverse events. RESULTS: Three RCTs (424 patients) and 11 RWSs (1415 patients) were included. For central RVO (CRVO), RCTs demonstrated a comparable efficacy, whereas RWSs showed that mean changes from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were significantly greater with aflibercept compared to ranibizumab; the number of injections of aflibercept was fewer than that of ranibizumab in RCTs, but similar in RWSs. For branch RVO (BRVO), no statistically significant difference in efficacy between the two drugs in RCTs/RWSs was observed, with fewer injections of aflibercept at 12 months in RWSs. The safety profiles of both drugs were similar for both CRVO and BRVO. CONCLUSIONS: For CRVO, aflibercept had similar efficacy and safety profile but with fewer injections versus ranibizumab in RCTs; RWSs showed greater BCVA improvement and CRT reduction with aflibercept than ranibizumab. For BRVO, RCTs showed similar in efficacy, safety, and injection numbers for both drugs, while RWSs demonstrated that aflibercept required fewer injections at 12 months of follow-up. Overall, this study provides updated evidence for clinical decision-making in the treatment of RVO.

Rapid carbothermal shocking fabrication of iron-incorporated molybdenum oxide with heterogeneous spin states for enhanced overall water/seawater splitting.

Molybdenum dioxide (MoO2) has been considered as a promising hydrogen evolution reaction (HER) electrocatalyst. However, the active sites are mainly located at the edges, resulting in few active sites and poor activity in the HER. Herein, we first reported on an efficient strategy to incorporate Fe into MoO2 nanosheets on Ni foam (Fe-MoO2/NF) using a rapid carbothermal shocking method (820 °C for 127 s). Notably, the different spin states between Fe and Mo atoms could lead to rich lattice dislocations in Fe-MoO2/NF, exposing abundant oxygen vacancies and the low-oxidation-state of Mo sites during the rapid Joule heating process. As tested, the catalyst exhibited superior activity with ultralow overpotentials (HER: 17 mV@10 mA cm-2; oxygen evolution reaction (OER): 310 mV@50 mA cm-2) and high OER selectivity in alkaline seawater splitting. Meanwhile, this catalyst was equipped in a home-made anion exchange membrane (AEM) seawater electrolyzer, which achieved a low energy consumption (5.5 kW h m-3). More importantly, Fe-MoO2/NF also coupled very well with a solar-driven electrolytic system and turned out a solar-to-hydrogen (STH) efficiency of 13.5%. Theoretical results also demonstrated that Fe incorporated and abundant oxygen vacancies in MoO2 can distort the distance of the Mo-O bonds and regulate the electronic structure, thus optimizing the binding energy of H*/OOH* adsorption. This method can be extended to other heterogeneous spin states in MoO2-based catalysts (e.g. Ni-MoO2/NF, Co-MoO2/NF) for seawater splitting, and provide a simple, efficient and universal strategy to prepare highly-efficient MoO2-based electrocatalysts.

Genome-wide sequencing reveals geographical variations in the thermal adaptation of an aquaculture species with frequent seedling introductions.

Climate change and human activity are essential factors affecting marine biodiversity and aquaculture, and understanding the impacts of human activities on the genetic structure to increasing high temperatures is crucial for sustainable aquaculture and marine biodiversity conservation. As a commercially important bivalve, the Manila clam Ruditapes philippinarum is widely distributed along the coast of China, and it has been frequently introduced from Fujian Province, China, to other regions for aquaculture. In this study, we collected four populations of Manila clams from different areas to evaluate their thermal tolerance by measuring cardiac performance and genetic variations using whole-genome resequencing. The upper thermal limits of the clams showed high variations within and among populations. Different populations displayed divergent genetic compositions, and the admixed population was partly derived from the Zhangzhou population in Fujian Province, implying a complex genomic landscape under the influence of local genetic sources and human introductions. Multiple single nucleotide polymorphisms (SNPs) were associated with the cardiac functional traits, and some of these SNPs can affect the codon usage and the structural stability of the resulting protein. This study shed light on the importance of establishing long-term ecological and genetic monitoring programs at the local level to enhance resilience to future climate change.

The hemostatic and anti-inflammatory effects of intravenous single-dose of tranexamic acid in double-segment posterior lumbar interbody fusion: a case control study.

This study aims to observe the hemostatic and anti-inflammatory effects of intravenous administration of tranexamic acid (TXA) in dual segment posterior lumbar interbody fusion (PLIF). The data of 53 patients with lumbar disease treated with double-segment PLIF were included in this study. The observation group was received a single-dose intravenous of TXA (1 g/100 mL) 15 min before skin incision after general anesthesia. The control group was not received TXA. The observation indicators included postoperative activated partial prothrombin time (APTT), thrombin time (PT), thrombin time (TT), fibrinogen (FIB), platelets (PLT), and postoperative deep vein thrombosis in the lower limbs, surgical time, intraoperative bleeding volume, postoperative drainage volume, transfusion rate, postoperative hospital stay, red blood cell (RBC), hemoglobin (HB), hematocrit (HCT), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) on the 1st, 4th, 7th, and last tested day after surgery. All patients successfully completed the operation, and there was no deep vein thrombosis after operation. There was no statistically significant difference in postoperative APTT, PT, TT, FIB, PLT, surgical time, and postoperative hospital stay between the two groups (p > 0.05). The intraoperative bleeding volume, postoperative drainage volume, and transfusion rate in the observation group were lower than those in the control group, and the differences were statistically significant (p < 0.05). There was no statistically significant difference in RBC, HB, HCT, CRP, and ESR between the two groups on the 1st, 4th, 7th, and last tested day after surgery (p > 0.05). Intravenous administration of TXA in dual segment PLIF does not affect coagulation function and can reduce bleeding volume, postoperative drainage volume, and transfusion rate. Moreover, it does not affect the postoperative inflammatory response.

Clinical features and prognosis of patients with anti-GBM disease combined with mesangial IgA deposition.

Introduction: Anti-GBM diseases with IgA deposition in the mesangial region are rarely described.The factors influencing renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition are unknown. Methods: We searched the pathological reports of the First Affiliated Hospital of Zhengzhou University from 2015 to 2023 and found that a total of 72 patients with the anti-GBM disease and 25 patients combined with mesangial IgA deposition. We studied the clinical and pathological features, renal prognosis, and the factors affecting renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition. Results: Their median age was 44 years, and their age distribution was unimodal. The proportion of oliguria or anuria in patients with anti-GBM disease combined with mesangial IgA deposition was significantly lower than that in patients with classic anti-GBM disease (13.04 vs. 42.31%, p=0.030). Their 24-hour urinary protein excretion was significantly higher [median:3.25 vs. 1.12g/24h, Interquartile range(IQR):1.032~3.945 vs. 0.63~1.79g/24h, p=0.020], serum creatinine (SCr) level at the initial diagnosis was lower(median:456.0 vs. 825.5µmol/L, IQR:270.0~702.0 vs. 515.8~1231.2µmol/L, p=0.002), peak SCr level was lower (median: 601.0 vs. 907.2µmol/L, IQR: 376.5~937.0 vs. 607.0~1361.2µmol/L, p=0.007), and their serum complement 3(C3) level was higher(median: 1.275 vs. 1.015g/L, IQR:1.097~1.462 vs. 0.850~1.220g/L, p=0.027). They had better renal outcomes during follow-up (p<0.001). After adjustment for hypertension, oliguria or anuria, and crescents%, IgA deposition in the mesangial region was still an independent protective factor (p=0.003) for ESRD in anti-GBM patients. Hypertension (p=0.026) and SCr levels at initial diagnosis (p=0.004) were risk factors for renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition. Discussion: Patients with anti-GBM disease combined with mesangial IgA deposition have less severe renal impairment and better renal prognosis than patients with classic anti-GBM disease.

Nomogram to predict ventilator-associated pneumonia in large vessel occlusion stroke after endovascular treatment: a retrospective study.

Background: Ventilator-Associated Pneumonia (VAP) severely impacts stroke patients' prognosis after endovascular treatment. Hence, this study created a nomogram to predict the occurrence of VAP after endovascular treatment. Methods: The individuals with acute ischemic stroke and large vessel occlusion (AIS-LVO) who received mechanical ventilation and endovascular therapy between July 2020 and August 2023 were included in this retrospective study. The predictive model and nomogram were generated by performing feature selection optimization using the LASSO regression model and multifactor logistic regression analysis and assessed the evaluation, verification and clinical application. Results: A total of 184 individuals (average age 61.85 ± 13.25 years, 73.37% male) were enrolled, and the rate of VAP occurrence was found to be 57.07%. Factors such as the Glasgow Coma Scale (GCS) score, duration of stay in the Intensive Care Unit (ICU), dysphagia, Fazekas scale 2 and admission diastolic blood pressure were found to be associated with the occurrence of VAP in the nomogram that demonstrating a strong discriminatory power with AUC of 0.862 (95% CI, 0.810-0.914), and a favorable clinical net benefit. Conclusion: This nomogram, comprising GCS score, ICU duration, dysphagia, Fazekas scale 2 and admission diastolic blood pressure, can aid clinicians in predicting the identification of high-risk patients for VAP following endovascular treatment in large vessel occlusion stroke.