Exploration of the prognostic prediction value of the PANoptosis-based risk score and its correlation with tumor immunity in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common cancer with high mortality worldwide. PANoptosis is a novel inflammatory programmed cell death modality with the characteristics of pyroptosis, apoptosis and necroptosis. It is necessary to explore PANoptosis-related genes in LUAD patients and offer evidence for prognosis prediction and therapeutic strategies. Single-cell RNA sequencing data and RNA expression profiles of LUAD patients from The Cancer Genome Atlas and Gene Expression Omnibus databases are used to screen PANoptosis-related differential genes for the construction of a risk model. Fifteen PANoptosis-related markers with prognostic value were identified by Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. Kaplan-Meier analysis and receiver operating characteristic curve analysis further demonstrated the significant predictive capability. Immune infiltration, Single Nucleotide Variants (SNV) mutations, and clinical drug susceptibility were analyzed. In conclusion, a risk model of 15 PANoptosis-related genes has significant value in prognostic prediction for LUAD and has potential to direct clinical therapeutic strategies during the treatment.

Analysis of the effectiveness of multi-disciplinary team integrated management combined with full-media health education intervention in patients with coronary heart disease and diabetes mellitus.

OBJECTIVE: To study the effect of a multi-disciplinary team (MDT) integrated management combined with all-media health education intervention on patients with coronary heart disease (CHD) and diabetes mellitus (DM). METHODS: Fasting plasma glucose (FPG), systolic blood pressure (SBP), and total cholesterol (TC) were evaluated before and after the intervention. The general self-efficacy scale (GSES) was utilized to assess the self-efficacy. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to evaluate depression and anxiety. The Seattle Angina Questionnaire (SAQ), a CHD-specific functional status and quality of life self-measurement tool, was employed to evaluate the quality of life. RESULTS: After the intervention, the levels of FPG, systolic blood pressure, SAS, SDS, and TC in the three groups all decreased (C>B>A,P<0.05). After the intervention, the self-efficacy scores of all three groups were improved (A>B>C, P < 0.05). After the intervention, the score of quality of life in group A and group B was higher than that in group C, and the score in group A was higher than that in group B (P<0.05). CONCLUSION: MDT integrated management combined with all-media health education intervention can effectively ameliorate blood glucose, blood pressure, and blood lipids of patients with CHD and DM, promote their healthy life, improve their self-efficacy, and improve their negative emotions and quality of life.

p16INK4A flow cytometry of exfoliated cervical cells: Its role in quantitative pathology and clinical diagnosis of squamous intraepithelial lesions.

BACKGROUND: P16INK4A is a surrogate signature compensating for the specificity and/or sensitivity deficiencies of the human papillomavirus (HPV) DNA and Papanicolaou smear (Pap) co-test for detecting high-grade cervical squamous intraepithelial lesions or worse (HSIL+). However, traditional p16INK4A immunostaining is labour intensive and skill demanding, and subjective biases cannot be avoided. Herein, we created a high-throughput, quantitative diagnostic device, p16INK4A flow cytometry (FCM) and assessed its performances in cervical cancer screening and prevention. METHODS: P16INK4A FCM was built upon a novel antibody clone and a series of positive and negative (p16INK4A -knockout) standards. Since 2018, 24 100-women (HPV-positive/-negative, Pap-normal/-abnormal) have been enrolled nationwide for two-tier validation work. In cross-sectional studies, age- and viral genotype-dependent expression of p16INK4A was investigated, and optimal diagnostic parameter cut-offs (using colposcopy and biopsy as a gold standard) were obtained. In cohort studies, the 2-year prognostic values of p16INK4A were investigated with other risk factors by multivariate regression analyses in three cervicopathological conditions: HPV-positive Pap-normal, Pap-abnormal biopsy-negative and biopsy-confirmed LSIL. RESULTS: P16INK4A FCM detected a minimal ratio of 0.01% positive cells. The p16INK4A -positive ratio was 13.9 ± 1.8% among HPV-negative NILM women and peaked at the ages of 40-49 years; after HPV infection, the ratio increased to 15.1 ± 1.6%, varying with the carcinogenesis of the viral genotype. Further increments were found in women with neoplastic lesions (HPV-negative: 17.7 ± 5.0-21.4 ± 7.2%; HPV-positive: 18.0 ± 5.2-20.0 ± 9.9%). Extremely low expression of p16INK4A was observed in women with HSILs. As the HPV-combined double-cut-off-ratio criterion was adopted, a Youden's index of 0.78 was obtained, which was significantly higher than that (0.72) of the HPV and Pap co-test. The p16INK4A -abnormal situation was an independent HSIL+ risk factor for 2-year outcomes in all three cervicopathological conditions investigated (hazard ratios: 4.3-7.2). CONCLUSIONS: FCM-based p16INK4A quantification offers a better choice for conveniently and precisely monitoring the occurrence of HSIL+ and directing risk-stratification-based interventions.

Numerical and Field Investigations of Acoustic Emission Laws of Coal Fracture under Hydro-Mechanical Coupling Loading.

Taking coal under hydro-mechanical coupling as the research object, the discrete element software PFC3D (particle flow code) was used to analyze the relationships among the force, acoustic emission (AE), and energy during coal fracture. Based on the moment tensor (MT) inversion, we revealed the AE event distribution and source type during crack initiation and propagation until the final failure of coal. Meanwhile, we examined the relationships among the stress, number and type of cracks, magnitude, KE, and b value of AE under different water and confining pressures. The results show that the numerical simulation can effectively determine the microscopic damage mechanism of coal under different conditions. Moreover, the rupture type of the numerical simulation is consistent with the field investigations, which verifies the rationality of the simulation. These research results can provide reference for safety production evaluation of water inrush mines.

Research on instability characteristics and precursory effect of coal-rock parting-coal structures.

The slip and instability mechanisms of coal-rock parting-coal structures under uniaxial loading conditions were investigated using experiments and case verification. The slip and the corresponding precursors were described by monitoring the displacement, strain, and acoustic emissions (AEs) of coal and rock parting blocks during testing, and the experimental results were verified by analyzing the microseismic (MS) effects during the working face advancing in a coal seam bifurcation area. The main conclusions were as follows: (1) each slip of the discontinuities sandwiched between coal and rock parting produced shear and tensile cracks, but the shear cracks was dominant; (2) for the instability mode that was characterized by low peak stress, high energy release, and a stable b value of AE, each slip corresponds to a peak frequency of AE, which can reveal the final instability mode; (3) the sudden drop in the fault total area of AE can be regarded as a precursor for the warning fracture or slip instability of a discontinuity; and (4) the MS events in the coal seam bifurcation area were mainly characterized by a wide frequency and high amplitude, especially near the coal bifurcation line, where there were obvious characteristics of low-frequency shear fracture for the MS events. This study is relevant for the early warning of coal-rock dynamic disasters triggered by the slip, fracture, and instability of coal-rock parting compound structures in coal mines.

Physiological and multi-omics responses of Neoporphyra haitanensis to dehydration-rehydration cycles.

BACKGROUND: Seaweeds in the upper intertidal zone experience extreme desiccation during low tide, followed by rapid rehydration during high tide. Porphyra sensu lato are typical upper intertidal seaweeds. Therefore, it is valuable to investigate the adaptive mechanisms of seaweed in response to dehydration-rehydration stress. RESULTS: A reduction in photosynthetic capacity and cell shrinkage were observed when N. haitanensis was dehydrated, and such changes were ameliorated once rehydrated. And the rate and extent of rehydration were affected by the air flow speed, water content before rehydration, and storage temperature and time. Rapid dehydration at high air-flow speed and storage at - 20 °C with water content of 10% caused less damage to N. haitanensis and better-protected cell activity. Moreover, proteomic and metabolomic analyses revealed the abundance members of the differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) mainly involved in antioxidant system and osmotic regulation. The ascorbic acid-glutathione coupled with polyamine antioxidant system was enhanced in the dehydration response of N. haitanensis. The increased soluble sugar content, the accumulated polyols, but hardly changed (iso)floridoside and insignificant amount of sucrose during dehydration indicated that polyols as energetically cheaper organic osmolytes might help resist desiccation. Interestingly, the recovery of DAMs and DEPs upon rehydration was fast. CONCLUSIONS: Our research results revealed that rapid dehydration and storage at - 20 °C were beneficial for recovery of N. haitanensis. And the strategy to resist dehydration was strongly directed toward antioxidant activation and osmotic regulation. This work provided valuable insights into physiological changes and adaptative mechanism in desiccation, which can be applied for seaweed farming.

Cold stress tolerance of the intertidal red alga Neoporphyra haitanensis.

BACKGROUND: Red algae Porphyra sensu lato grow naturally in the unfavorable intertidal environment, in which they are exposed to substantial temperature fluctuations. The strategies of Porphyra to tolerate cold stress are poorly understood. RESULTS: Herein, investigations revealed that chilling and freezing induced alterations in the physiological properties, gene transcriptional profiles and metabolite levels in the economically important red algae species, Neoporphyra haitanensis. Control samples (kept at 20 °C) were compared to chilled thalli (10 and 4 °C) and to thalli under - 4 °C conditions. Chilling stress did not affect the health or photosynthetic efficiency of gametophytes, but freezing conditions resulted in the arrest of growth, death of some cells and a decrease in photosynthetic activity as calculated by Fv/Fm. Transcriptome sequencing analysis revealed that the photosynthetic system was down-regulated along with genes associated with carbon fixation and primary metabolic biosynthesis. Adaptive mechanisms included an increase in unsaturated fatty acids levels to improve membrane fluidity, an increase in floridoside and isofloridoside content to enhance osmotic resistance, and an elevation in levels of some resistance-associated phytohormones (abscisic acid, salicylic acid, and methyl jasmonic acid). These physiochemical alterations occurred together with the upregulation of ribosome biogenesis. CONCLUSIONS: N. haitanensis adopts multiple protective mechanisms to maintain homeostasis of cellular physiology in tolerance to cold stress.

Circ-ATIC Serves as a Sponge of miR-326 to Accelerate Esophageal Squamous Cell Carcinoma Progression by Targeting ID1.

In the previous studies, circular RNA (circRNA) has been shown to be closely related to the occurrence and development of various cancers. However, the role and mechanism of circ-ATIC in the progression of esophageal squamous cell carcinoma (ESCC) is not yet clear. Quantitative real-time PCR was used to detect the expression levels of circ-ATIC, microRNA (miR)-326 and inhibitor of DNA binding 1 (ID1) in tissues (n = 50) and cells. Cell counting kit 8 assay, colony formation assay, flow cytometry, wound-healing assay and transwell assay were performed to measure the proliferation, apoptosis, migration, and invasion of cells. In addition, the oxidative stress of cells was evaluated by detecting the productions of superoxide dismutase and malondialdehyde. Animal studies were implied to explore the role of circ-ATIC in ESCC tumor growth. The relationship between circ-ATIC and miR-326 or ID1 was determined by dual-luciferase reporter assay and RNA immunoprecipitation assay. Additionally, the protein expression of ID1 was examined by western blot assay. Circ-ATIC was found to be upregulated in ESCC tissues and cells. Silenced circ-ATIC suppressed the proliferation, migration, invasion, promoted the apoptosis and oxidative stress of ESCC cells. The tumor growth of ESCC also was inhibited by circ-ATIC knockdown. Furthermore, we found that circ-ATIC could sponge miR-326, and miR-326 could target ID1. The rescue experiments revealed that miR-326 inhibitor could reverse the negative regulation of circ-ATIC silencing on ESCC progression, and ID1 overexpression also inverted the inhibitory effect of miR-326 on ESCC progression. In addition, we confirmed that the expression of ID1 was positively regulated by circ-ATIC. Our study showed that circ-ATIC facilitated the progression of ESCC by regulating the miR-326/ID1 axis, indicating that circ-ATIC might be a target for ESCC treatment.

Insights into the Ancient Adaptation to Intertidal Environments by Red Algae Based on a Genomic and Multiomics Investigation of Neoporphyra haitanensis.

Colonization of land from marine environments was a major transition for biological life on Earth, and intertidal adaptation was a key evolutionary event in the transition from marine- to land-based lifestyles. Multicellular intertidal red algae exhibit the earliest, systematic, and successful adaptation to intertidal environments, with Porphyra sensu lato (Bangiales, Rhodophyta) being a typical example. Here, a chromosome-level 49.67 Mb genome for Neoporphyra haitanensis comprising 9,496 gene loci is described based on metagenome-Hi-C-assisted whole-genome assembly, which allowed the isolation of epiphytic bacterial genome sequences from a seaweed genome for the first time. The compact, function-rich N. haitanensis genome revealed that ancestral lineages of red algae share common horizontal gene transfer events and close relationships with epiphytic bacterial populations. Specifically, the ancestor of N. haitanensis obtained unique lipoxygenase family genes from bacteria for complex chemical defense, carbonic anhydrases for survival in shell-borne conchocelis lifestyle stages, and numerous genes involved in stress tolerance. Combined proteomic, transcriptomic, and metabolomic analyses revealed complex regulation of rapid responses to intertidal dehydration/rehydration cycling within N. haitanensis. These adaptations include rapid regulation of its photosynthetic system, a readily available capacity to utilize ribosomal stores, increased methylation activity to rapidly synthesize proteins, and a strong anti-oxidation system to dissipate excess redox energy upon exposure to air. These novel insights into the unique adaptations of red algae to intertidal lifestyles inform our understanding of adaptations to intertidal ecosystems and the unique evolutionary steps required for intertidal colonization by biological life.

Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway.

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase ß (CaMKKß), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKß inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKß.

Effect of resveratrol on intestinal tight junction proteins and the gut microbiome in high-fat diet-fed insulin resistant mice.

High-fat diet (HFD)-feeding induces changes in the microbiome and increases intestinal permeability by impairing tight junction (TJ) protein function, which may explain the insulin resistance (IR) and associated pathologies. We aimed to determine the effects of resveratrol (RES) on the gut microbiome and intestinal TJ proteins. Results showed that RES administration improved the lipid profile, and ameliorated the endotoxemia, inflammation, intestinal barrier defect and glucose intolerance in the HFD-fed mice. Furthermore, it modified the gut microbial composition, reducing the proportion of Firmicutes and the Firmicutes-to-Bacteroidetes ratio. Moreover, Verrucomicrobia and Akkermansia were much more abundant in the HFD + RES group. RES also significantly reduced the abundance of Bilophila and Ruminococcus. These findings suggest that RES may be useful for the treatment of IR and associated metabolic diseases.

Experimental and field investigations on seismic response of joints and beddings in rocks.

Based on experimental and in-situ tests, the propagation and attenuation rules of seismic wave in the intact and jointed rocks subjected to conventional triaxial loading condition were investigated, especially the influencing effects of joints and beddings on the attenuation. Meanwhile, the frequency-spectrum evolutions during the process of attenuation were analysed in detail. To verify the outcomes obtained from the laboratory, the attenuation characteristics of seismic wave generated by blasting in underground strata were tested, and the attenuation rules by the joints between strata was summarized. Finally, the seismic response of joints and beddings in rocks was revealed. This work put forward some references for early weakening and controlling coal-rock dynamic disasters triggered by seismic wave in coal mines based on the attenuation effect of artificial discontinuity such as joint and bedding.

MicroRNA-124 suppresses proliferation and glycolysis in non-small cell lung cancer cells by targeting AKT-GLUT1/HKII.

Non-small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non-small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non-small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD+/NADH were also detected. These tests were conducted using the normal non-small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate-limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non-small cell lung cancer. AKT inhibition blocks miR-124 silencing-induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2-glucose transporter 1/hexokinase II in non-small cell lung cancer cells.

microRNA-214 Governs Lung Cancer Growth and Metastasis by Targeting Carboxypeptidase-D.

Lung cancer is one of the most malignant cancers with a high metastatic potential. The purpose of this study was to study the role and the underlying mechanism of miR-214 in lung cancer progression. The expression of miR-214 in normal lung and lung cancer tissue was analyzed by quantitative real-time PCR analysis. Furthermore, H1299 cells were infected with miR-214 lentivirus, and the effect of infection on cell viability and migration was analyzed. Carboxypeptidase-D (CPD), as a potential target of miR-214, was characterized in either normal lung or lung cancer tissues. The interaction of CPD expression with the tumor suppressing effect of miR-214 was characterized. We demonstrated that low miR-214 expression is a hallmark of lung cancer, especially high-grade and metastatic cancer. In vitro studies in H1299 cells confirmed that low miR-214 expression is associated with enhanced proliferation and migratory abilities. Similarly, CPD overexpression coincides with high-grade lung cancer and the CPD overexpression could reverse the inhibitory effects of miR-214. miR-214 is a tumor suppressor in lung cancer. miR-214 inhibits lung cancer progression by targeting CPD. The miR-214-CPD axis may be a therapeutic axis for lung cancer patients.