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Relevance. Aging is anatural biological process of aretrograde nature, during which there is an imbalance of all systems, including the matrix metalloproteinase (MMP) system and tissue inhibitors of matrix metalloproteinases (TIMP). And vascular aging is associated with functional and structural changes primarily in the arterial vasculature with age. Aging may be atrigger factor for pathological changes in the endothelium. The molecular mechanisms underlying the process of vascular endothelial dysfunction include increased expression and activation of matrix metalloproteinases, the concentration of which changes with aging. Numerous studies report the role of MMP-1,–2,–9,–12 in the pathogenesis of premature aging of the endothelium; they initiate cell apoptosis, which contributes to increased permeability, but there are no studies in which all age categories of both men and women were analyzed, not burdened by somatic pathology. This study examines the features of the proteolysis/antiproteolysis system in apparently healthy people of different ages and genders.Materials and Methods.As part of the pilot study, 347 apparently healthy people took part (226 women and 121 men, divided by age, according to the WHO classification), who underwent the first stage of clinical examination at the State Budgetary Institution “Consultative and Diagnostic Center of the Mountains. Yuzhno-­Sakhalinsk”, in which the level of MMP and TIMP in the blood serum was determined by solid-­phase ELISA, ng/ml. Statistical processing of the research results was carried out using the IBM SPSS Statistics Version 25.0 software package.Resultsand Discussion.Changes in the proteolysis/antiproteolysis system were determined in both agroup of men and women of different ages, which can be characterized as not pathological, but close to such. It was found that in men aged 60-74 years, discoordinated work of matrix metalloproteinases and their inhibitors was recorded in the direction of enhancing the profibrosing effect, and in women in the same age category, the exact opposite component was identified—anti-fibrosing.Conclusion.The current development has demonstrated the influence of age and genetic resources on the system of matrix metalloproteinases and their tissue inhibitors, in addition, aspecial age group has been identified—the elderly group, which requires protection of the vascular system in order to monitor the impaired proteolysis/antiproteolysis system.

A novel strategy involving warm rolling and tempering-annealing was introduced to optimize the strength-ductility balance of Fe-10.2Mn-2.2Al-0.41C-0.6 V (wt. %) steel. The V- and κ-carbide particles produced during the tempering are critical for tailoring the austenite characteristics during the subsequent annealing. Austenite that nucleates on Mn-rich κ-carbides inherit their high Mn content and fine grain size. Quantitative calculations suggest that the pinning effect exerted by the V-carbide particles strongly resists grain boundary motion and recrystallization grain growth, further refining the final microstructure. Moreover, the dual nano-sized particles induce abnormal variations in the grain size and fraction of austenite, influencing the deformation mechanisms. In the absence of deformation twins, the fresh martensite develops into “separating walls” to refine the microstructure and further enhances the work hardening in addition to the complex dislocation mobile. Finally, the tempered-annealed sample demonstrated a simultaneous increase in the yield and tensile strengths from 1166 to 1452 MPa and 1507–1727 MPa, but a slight decrease in the total elongation from 18.6% to 16.8% compared to annealed sample, achieving a good strength-ductility balance.

Abstract The locked segment is critical for determining the stability of locked segment-type landslides. Research indicates that the volume expansion point marks the transition from the secondary creep stage to the tertiary creep stage in a landslide’s evolution, and also separates the stable crack growth stage from the unstable crack growth stage in the locked segment. Identifying the volume expansion point is essential for early warning and predicting locked segment-type landslides. A series of instruments (resistance strain gauges, acoustic emission system, piezoelectric acceleration sensors, etc.) were used to conduct physical model tests of the landslide with retaining-wall-like locked segment under external load on the landslide’s trailing edge. The evolution process of this landslide was analyzed through changes in slope shape and stress response characteristics. The experimental results reveal the failure mechanism of the landslide with retaining-wall-like locked segment: the upper part of the landslide thrusts and slides, the middle part squeezes and uplifts, the retaining-wall-like locked segment produces a locking effect, and compression-shear fracture of the retaining-wall-like locked segment leads to landslide failure. Based on the deformation and acoustic emission characteristics of the locked segment, a method for identifying the volume expansion point was established. This point was used as the onset of acceleration point in the inverse velocity method to predict the failure time of the locked segment-type landslides, incorporating the three-stage creep model and Fukumoto’s theory.

Abstract Background LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. Methods Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. Results Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value

Abstract Receptor Expression-Enhancing Protein 3 (REEP3) serves as a pivotal enzyme crucial for endoplasmic reticulum (ER) clearance during mitosis and is implicated in the advancement of diverse malignancies. Nonetheless, the biological role and mechanisms of REEP3 in pancreatic cancer patients, along with its interplay with immune infiltration, remain inadequately elucidated. In this study, we initially analyzed the differential expression of REEP3 between pancreatic cancer tissues and normal pancreas tissues using the Cancer Genome Atlas (TCGA), GTEx and Gene Expression Omnibus (GEO) databases. Subsequently, we utilized Kaplan–Meier analysis, Cox regression and ROC curve to determine the predictive value of REEP3 for the clinical outcomes of pancreatic cancer patients. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), were conducted to explore the potential signaling pathways and biological functions associated with pancreatic cancer. Furthermore, we investigated the PPI network, miRNA, RBP and transcription factor interactions of REEP3 using databases such as GeneMania, STRING, StarBase, KnockTK, ENCODE, Jaspar and hTFtarget. Lastly, the “ssGSEA” algorithm and TIMER database were employed to investigate the correlation between REEP3 expression and immune infiltration as well as immune checkpoints. The expression of REEP3 in pancreatic cancer showed a significantly higher level compared to that in normal tissues. ROC curve analysis indicated that REEP3 holds substantial diagnostic potential for pancreatic cancer patients. Elevated REEP3 expression correlated with unfavorable outcomes in terms of both overall survival and relapse-free survival, establishing it as a notable adverse prognostic marker in pancreatic cancer. Moreover, both univariate and multivariate Cox regression analyses demonstrated that REEP3 maintained an independent association with overall survival. Functional enrichment analyses revealed pathways significantly linked to REEP3, including cytoplasmic translation, wound healing, viral processes, regulation of cellular component size and actin filament organization. Additionally, REEP3 expression displayed a significant positive correlation with CD8+ T cells, B cells, natural killer cells, dendritic cells and macrophages. REEP3 is a potential diagnostic, prognostic marker and immunotherapeutic target for pancreatic cancer.

Abstract Objective Melanoma, with its high degree of malignancy, stands as one of the most dangerous skin cancers and remains the primary cause of death from skin cancer. With studies demonstrating the potential of traditional Chinese medicine to intervene and treat melanoma, we turned our attention to celastrol. Celastrol is a triterpene compound extracted from the traditional Chinese medicine derived from Tripterygium wilfordii. Previous studies have shown that celastrol exerts inhibitory effects on various malignant tumors, including melanoma. Hence, our goal was to clarify the impact of celastrol on cell viability, apoptosis, and cell cycle progression by elucidating its effects on the PI3K/AKT/mTOR pathway. Methods CCK-8 and wound healing assays were used to determine the effect of celastrol on the viability and migration of B16-F10 cells. Changes in cell apoptosis, cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were detected by flow cytometry. PI3K/AKT/mTOR pathway proteins and HIF-α mRNA expression in B16-F10 cells were detected by western blotting and qPCR. Moreover, the addition of a PI3K activator demonstrated that celastrol could inhibit the function of B16-F10 cells via the PI3K/AKT/mTOR pathway. Results Celastrol inhibited the viability and migration of B16-F10 cells. Through the inhibition of the PI3K/AKT/mTOR pathway down-regulates the expression of HIF-α mRNA, thereby causing an increase of ROS in cells and a decrease in the mitochondrial membrane potential to promote cell apoptosis and cell cycle arrest. The inhibitory effect of celastrol on B16-F10 cells was further demonstrated by co-culturing with a PI3K activator. Conclusion Celastrol inhibits the function of B16-F10 cells by inhibiting the PI3K/AKT/mTOR cellular pathway and regulating the expression of downstream HIF-α mRNA.

The transport of atmospheric pollutants plays a pivotal role in regional air pollution, highlighting critical concerns over the unequal health outcomes that arise from such transport. While previous researches predominantly focused on key areas in the battle against air pollution, the intensification of control measures necessitates a national perspective to comprehend the health impacts due to pollution transport. Our study establishes an integrated assessment framework that combine an emission-concentration response surface model with a health impact evaluation model to analyse the nationwide health impacts of PM2.5 and O3 pollution transport across China’s 31 provinces. We found that, interprovincial transport of PM2.5 and O3 contributed to 747,000 and 110,000 deaths respectively in 2017, which amounts to 38% and 48% of deaths caused by total anthropogenic emissions. North, East, and Central China together contribute 82% and 69% to the health impacts caused by regional PM2.5 and O3 transport respectively, and the transport among these three regions is also significant. The analysis of interprovincial health impact transport shows that, for PM2.5, the top contributors are Hebei, Shandong, Henan, Anhui, and Jiangsu, with the most affected being Henan, Shandong, Jiangsu, Hebei, and Guangdong. Regarding O3, Shandong, Hebei, Henan, Jiangsu, and Anhui contribute the most, while Henan, Shandong, Hebei, Jiangsu, and Anhui are the most affected. This study can shed lights on regional control strategies by prioritizing control areas based on the health impact of air pollution transport in China.

Soil nutrients are ubiquitously heterogeneously distributed and such heterogeneity can greatly influence plant and population growth, interspecific competition and community structure and productivity. Despite these impacts, it is still unknown how soil nutrient heterogeneity affects community stability. We conducted a three-year experiment in an alpine meadow on the Qinghai-Tibetan Plateau, involving one homogeneous and six heterogeneous treatments of N, P, and K addition. The heterogeneous treatments varied in patch size, patch contrast, and number of patch types. Community stability in the homogeneous treatment tended to be the highest, likely due to high asynchrony among functional groups. However, such effects varied with patch size, patch contrast and number of patch types. Also, the effects of patch contrast and number of patch types on community stability and asynchrony among functional groups depended on patch size. The grass proportion was significantly affected by soil nutrient heterogeneity, and greater number of patch types increased the grass proportion at the small patch size, but not at the large one. Additionally, species richness, Shannon-Weiner index and Simpson index were greater in high patch contrast compared to the homogeneous treatment, but community evenness was not. These results suggest that soil nutrient heterogeneity can influence community stability by modifying functional group asynchrony and community evenness, rather than biomass proportions or other plant diversity indices. Our findings highlight the importance of incorporating soil nutrient heterogeneity in modeling the responses of alpine ecosystems to continuous nitrogen deposition and climate warming.

Abstract Background Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. Methods This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017–2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018–2021) and another from center 2 (n = 43, 2020–2021), were utilized to assess the signature’s association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. Results Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. Conclusion This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC’s MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Abstract Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.

Abstract Objective Tranexamic acid (TXA) demonstrates therapeutic efficacy in the management of traumatic brain injury (TBI). The objective of this systematic review and meta-analysis was to evaluate the safety and effectiveness of TXA in patients with TBI. Methods The databases, namely PubMed, Embase, Web of Science, and Cochrane Library databases, were systematically searched to retrieve randomized controlled trials (RCTs) investigating the efficacy of TXA for TBI from January 2000 to November 2023. Results The present meta-analysis incorporates ten RCTs. Compared to the placebo group, administration of TXA in patients with TBI resulted in a significant reduction in mortality (P = 0.05), hemorrhage growth (P = 0.03), and volume of hemorrhage growth (P = 0.003). However, no significant impact was observed on neurosurgery outcomes (P = 0.25), seizure occurrence (P = 0.78), or pulmonary embolism incidence (P = 0.52). Conclusion The administration of TXA is significantly associated with reduced mortality and hemorrhage growth in patients suffering from TBI, while the need of neurosurgery, seizures, and incidence of pulmonary embolism remains comparable to that observed with placebo.

Abstract Although zinc‒air batteries (ZABs) are regarded as one of the most prospective energy storage devices, their practical application has been restricted by poor air electrode performance. Herein, we developed a free‐standing air electrode that is fabricated on the basis of a multifunctional three‐dimensional interconnected graphene network. Specifically, a three‐dimensional interconnected graphene network with fast mass and electron transport ability, prepared by catalyzing growth of graphene foam on nickel foam and then filling reduced graphene oxide into the pores of graphene foam, is used to anchor iron phthalocyanine molecules with atomic Fe‒N4 sites for boosting the oxygen reduction during discharging and nanosized FeNi hydroxides for accelerating the oxygen evolution during charging. As a result, the obtained air electrode exhibited an ultra‐small electrocatalytic overpotential of 0.603 V for oxygen reactions, a high peak power density of 220.2 mW cm‒2, and a small and stable charge‒discharge voltage gap of 0.70 V at 10 mA cm‒2 after 1136 cycles. Furthermore, in situ Raman spectroscopy together with theoretical calculations confirmed that phase transformation of FeNi hydroxides takes place from α‐Ni(OH)x to β‐Ni(OH)x to γ‐Ni(3+δ)+OOH for the oxygen evolution reaction and Ni is the active center while Fe enhances the activity of Ni active sites.

This study performs a series of mechanical tests, quasi-static and dynamic, on CuCoCrFeNi high-entropy alloys (HEAs) using an experimental setup to explore the performance of Cu-based HEAs in shaped charges. It derives the parameters for the Johnson–Cook constitutive model through fitting. A static penetration test is conducted with a small cone angle and a thin-walled liner. The outcomes are then compared to simulation data generated by AUTODYN software. They indicated that the CuCoCrFeNi HEA liner can produce a shaped-charge jet that achieves both penetration and reaming effects when driven by explosives. In a C45 steel target, the diameter of the penetration hole is 46.43% of the charge diameter. The experimental findings align closely with the simulations, indicating discrepancies of less than 12.13% in the diameters of the penetration holes and ∼2.56% in penetration depths. Hence, the numerical simulation approach and its parameters can be utilized to investigate the penetration characteristics of Cu-based HEA jets, providing a groundwork for future optimization of HEA-shaped charge designs.