LncRNA AC100826.1 regulated PLCB1 to promote progression in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most common malignant tumor. In the present study, we identified a long non-coding RNA (lncRNA) AC100826.1 (simplify to Lnc1), which was highly expressed in non-small cell lung cancer (NSCLC) tissues compared with the paracancerous tissues. We also observed the critical role of Lnc1 in regulating the metastasis ability of NSCLC cells. METHODS: RNA sequencing was performed to detect differential expression levels of lncRNAs in NSCLC tissues and its paracancerous tissues. Effects of Lnc1 on cell proliferation, invasion, and migration were determined by CCK-8, transwell and scratch assays. The xenograft experiment confirmed the effect of Lnc1 on NSCLC cells proliferation and migration abilities in vivo. RT-qPCR and western blots were performed to determine the expression levels of mRNAs and proteins. RESULTS: The expression level of Lnc1 was related to multiple pathological results, knockdown of Lnc1 can inhibit the proliferation and metastasis abilities of NSCLC cells. silencing phospholipase C, ß1(PLCB1) can reverse the promoting effects of overexpression Lnc1 on NSCLC cells proliferation and migration abilities. In addition, the Rap1 signaling pathway was implicated in the regulation of Lnc1 in NSCLC metastasis. CONCLUSION: Our results suggest that Lnc1 regulated the metastatic ability of NSCLC cells through targeting the PLCB1/Rap1 signal pathway.

Quantitative Prediction of Surface Hardness in Cr12MoV Steel and S136 Steel with Two Magnetic Barkhausen Noise Feature Extraction Methods.

The correlation between magnetic Barkhausen noise (MBN) features and the surface hardness of two types of die steels (Cr12MoV steel and S136 steel in Chinese standards) was investigated in this study. Back-propagation neural network (BP-NN) models were established with MBN magnetic features extracted by different methods as the input nodes to realize the quantitative prediction of surface hardness. The accuracy of the BP-NN model largely depended on the quality of the input features. In the extraction process of magnetic features, simplifying parameter settings and reducing manual intervention could significantly improve the stability of magnetic features. In this study, we proposed a method similar to the magnetic Barkhausen noise hysteresis loop (MBNHL) and extracted features. Compared with traditional MBN feature extraction methods, this method simplifies the steps of parameter setting in the feature extraction process and improves the stability of the features. Finally, a BP-NN model of surface hardness was established and compared with the traditional MBN feature extraction methods. The proposed MBNHL method achieved the advantages of simple parameter setting, less manual intervention, and stability of the extracted parameters at the cost of small accuracy reduction.

Butyrate affects bacterial virulence: a new perspective on preventing enteric bacterial pathogen invasion.

Enteric bacterial pathogens are a major threat to intestinal health. With the widespread use of antibiotics, bacterial resistance has become a problem, and there is an urgent need for a new treatment to reduce dependence on antibiotics. Butyrate can control enteric bacterial pathogens by regulating the expression of their virulence genes, promoting the posttranslational modification of their proteins, maintaining an anaerobic environment, regulating the host immune system and strengthening the intestinal mucosal barrier. Here, this review describes the mechanisms by which butyrate regulates the pathogenicity of enteric bacterial pathogens from various perspectives and discusses the prospects and limitations of butyrate as a new option for the control of pathogenic bacteria.

Lnc AC016727.1/BACH1/HIF-1 α signal loop promotes the progression of non-small cell lung cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been reported to play vital roles in the development and progression of cancer. However, their biological significance and functional mechanisms in non-small cell lung cancer (NSCLC) are mostly unclear. METHODS: We performed RNA-sequencing to predict the differential expression of lncRNAs in clinical NSCLC and paired paracancerous lung tissues. To identify lncRNA expression, quantitative polymerase chain reaction (qPCR) was used. Using both cell and mouse models, We studied lncRNA AC016727.1's function in NSCLC growth and metastasis. Western blot assays, dual luciferase reporter assays, and chromatin immunoprecipitation were used to analyze the functional mechanism of lncRNA AC016727.1. RESULTS: Our larger NSCLC cohorts validated that the lncRNA AC016727.1 was upregulated in 94 paired NSCLC tissues and correlated with poor survival. Functionally, lncRNA AC016727.1 downregulation inhibited NSCLC cell proliferation, aerobic glycolysis, EMT, and migration, inducing apoptosis. Conversely, upregulated lncRNA AC016727.1 expression exhibited the opposite effect, promoting NSCLC cell survival. Importantly, lncRNA AC016727.1 knockdown inhibited lung cancer growth and slowed the progression of lung metastasis in nude mouse models. Mechanistically, lncRNA AC016727.1 upregulated BACH1 target gene expression by acting as a sponge for miR-98-5p, thereby functioning as a competing endogenous RNA. The function of lncRNA AC016727.1 is mediated by the miR-98-5p/BACH1 axis in NSCLC cells. Meanwhile, the transcription factor HIF-1α can bind to the promoter and activate lncRNA AC016727.1 transcription. lncRNA AC016727.1 regulates HIF-1α expression via BACH1 in NSCLC and forms the lncRNA AC016727.1/BACH1/HIF-1α signaling loop under hypoxic conditions. CONCLUSION: Our study reveals a novel lncRNA AC016727.1/BACH1/HIF-1α signaling loop in the progression of NSCLC under hypoxic conditions, suggesting that lncRNA AC016727.1 could act as a useful biomarker for NSCLC and a new therapeutic target.

A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model.

A practical strategy for engineering a trachea-like structure that could be used to repair or replace a damaged or injured trachea is an unmet need. Here, we fabricated bioengineered cartilage (BC) rings from three-dimensionally printed fibers of poly(ɛ-caprolactone) (PCL) and rabbit chondrocytes. The extracellular matrix (ECM) secreted by the chondrocytes combined with the PCL fibers formed a "concrete-rebar structure," with ECM deposited along the PCL fibers, forming a grid similar to that of native cartilage. PCL fiber-hydrogel rings were then fabricated and alternately stacked with BC rings on silicone tubes. This trachea-like structure underwent vascularization after heterotopic transplantation into rabbits for 4 weeks. The vascularized bioengineered trachea-like structure was then orthotopically transplanted by end-to-end anastomosis to native rabbit trachea after a segment of trachea had been resected. The bioengineered trachea-like structure displayed mechanical properties similar to native rabbit trachea and transmural angiogenesis between the rings. The 8-week survival rate in transplanted rabbits was 83.3%, and the respiratory rate of these animals was similar to preoperative levels. This bioengineered trachea-like structure may have potential for treating tracheal stenosis and other tracheal injuries.

Targeting CXCR1 alleviates hyperoxia-induced lung injury through promoting glutamine metabolism.

Although increasing evidence suggests potential iatrogenic injury from supplemental oxygen therapy, significant exposure to hyperoxia in critically ill patients is inevitable. This study shows that hyperoxia causes lung injury in a time- and dose-dependent manner. In addition, prolonged inspiration of oxygen at concentrations higher than 80% is found to cause redox imbalance and impair alveolar microvascular structure. Knockout of C-X-C motif chemokine receptor 1 (Cxcr1) inhibits the release of reactive oxygen species (ROS) from neutrophils and synergistically enhances the ability of endothelial cells to eliminate ROS. We also combine transcriptome, proteome, and metabolome analysis and find that CXCR1 knockdown promotes glutamine metabolism and leads to reduced glutathione by upregulating the expression of malic enzyme 1. This preclinical evidence suggests that a conservative oxygen strategy should be recommended and indicates that targeting CXCR1 has the potential to restore redox homeostasis by reducing oxygen toxicity when inspiratory hyperoxia treatment is necessary.

Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells.

Increasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4+ and CD8+ effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.

High-speed multiparametric imaging through off-resonance tapping AFM with active probe.

Off-resonance tapping (ORT) mode of atomic force microscopy (AFM), based on force-distance curve, is widely concerned due to its advantages of weak tip-sample interaction and concurrent quantitative property mapping. However, the ORT-AFM still has the disadvantage of slow scan speed caused by low modulation frequency. In this paper, we overcome this disadvantage by introducing active probe method. With active probe, the cantilever was directly actuated with the induced strain after applying voltage in the piezoceramic film. In this way, the modulation frequency could be increased to more than an order of magnitude faster than that of traditional ORT, thus improving the scan rate. We demonstrated high-speed multiparametric imaging with the active probe method in ORT-AFM.

Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer.

The perils and promises of inspiratory hyperoxia (IH) in oncology are still controversial, especially for patients with lung cancer. Increasing evidence shows that hyperoxia exposure is relevant to the tumor microenvironment. However, the detailed role of IH on the acid-base homeostasis of lung cancer cells remains unclear. In this study, the effects of 60% oxygen exposure on intra- and extracellular pH were systematically evaluated in H1299 and A549 cells. Our data indicate that hyperoxia exposure reduces intracellular pH, which might be expected to reduce the proliferation, invasion, and epithelial-to-mesenchymal transition of lung cancer cells. RNA sequencing, Western blot, and PCR analysis reveal that monocarboxylate transporter 1 (MCT1) mediates intracellular lactate accumulation and intracellular acidification of H1299 and A549 cells at 60% oxygen exposure. In vivo studies further demonstrate that MCT1 knockdown dramatically reduces lung cancer growth, invasion, and metastasis. The results of luciferase and ChIP-qPCR assays further confirm that MYC is a transcription factor of MCT1, and PCR and Western blot assays confirm that MYC is downregulated under hyperoxic conditions. Collectively, our data reveal that hyperoxia can suppress the MYC/MCT1 axis and cause the accumulation of lactate and intracellular acidification, thereby retarding tumor growth and metastasis.

Propionate reduces the viability of Salmonella enterica Serovar Typhi in macrophages by propionylation of PhoP K102.

Propionate, a major constituent of short chain fatty acids, has recently been reported to be involved in both prokaryotic and eukaryotic lysine propionylation (Kpr). However, the propionylation characteristics of the enteric pathogen Salmonella enterica serovar Typhi (S. Typhi) following invasion of the human gut under the influence of propionate, whether virulence is affected, and the underlying mechanisms are not yet known. In the present study, we report that propionate significantly reduces the viability of S. Typhi in macrophages through intra-macrophage survival assays. We also demonstrate that the concentration of propionate and the propionate metabolic intermediate propionyl coenzyme A can affect the level of modification of PhoP by propionylation, which is tightly linked to intracellular survival. By expressing and purifying PhoP protein in vitro and performing EMSA and protein phosphorylation analyses, We provide evidence that K102 of PhoP is modified by Kpr propionate, which regulates S. Typhi viability in macrophages by decreasing the phosphorylation and DNA-binding ability of PhoP. In conclusion, our study reveals a potential molecular mechanism by which propionate reduces the viability of S. Typhi in macrophages via Kpr.

Micromagnetic and Robust Evaluation of Surface Hardness in Cr12MoV Steel Considering Repeatability of the Instrument.

The combination of multifunctional micromagnetic testing and neural network-based prediction models is a promising way of nondestructive and quantitative measurement of steel surface hardness. Current studies mainly focused on improving the prediction accuracy of intelligent models, but the unavoidable and random uncertainties related to instruments were seldom explored. The robustness of the prediction model considering the repeatability of instruments was seldom discussed. In this work, a self-developed multifunctional micromagnetic instrument was employed to perform the repeatability test with Cr12MoV steel. The repeatability of the instrument in measuring multiple magnetic features under both static and dynamic conditions was evaluated. The magnetic features for establishing the prediction model were selected based on the consideration of both the repeatability of the instrument and the ability of magnetic features in surface hardness evaluation. To improve the robustness of the model in surface hardness prediction, a modelling strategy considering the repeatability of the instrument was proposed. Through removing partial magnetic features with higher mean impact values from input nodes, robust evaluation of surface hardness in Cr12MoV steel was realized with the multifunctional micromagnetic instrument.

PEDF Protects Endothelial Barrier Integrity during Acute Myocardial Infarction via 67LR.

Maintaining the integrity and protecting the stability of tight junctions in endothelial cells is a potential therapeutic strategy against myocardial ischaemia. Laminin receptors (67LR) are highly expressed on endothelial cell membranes and are associated with endothelial barrier function. Herein, we sought to demonstrate the direct effects of pigment epithelial-derived factor (PEDF) on tight junctions between endothelial cells via 67LR during acute myocardial infarction (AMI) and elucidate its underlying mechanisms. We detected that PEDF directly increased the level of the tight junction protein zonula occludens protein 1 (ZO-1) after overexpression in vitro and in vivo using Western blotting. Evans Blue/TTC staining showed that PEDF significantly reduced the size of the infarcted myocardium. Immunofluorescence and the transwell cellular experiments suggested that PEDF significantly upregulated PI3K-AKT permeability and the distribution of ZO-1 between endothelial cells under OGD conditions. Interestingly, PEDF significantly upregulated the phosphorylation levels of PI3K-AKT-mTOR under oxygen and glucose deprivation conditions but had no significant effects on the total protein expression. The protective effect of PEDF on ZO-1 was significantly inhibited following the inhibition of PI3K-AKT-mTOR. The activation of phosphorylation of PI3K-AKT-mTOR by PEDF was blocked after silencing 67LR, as were the protective effects of PEDF on ZO-1. Therefore, we have reason to believe that PEDF increased ZO-1 expression through the 67LR-dependent PI3K-AKT-mTOR signaling pathway, thus maintaining tight junction stability and protecting cardiac function.

Establishment of a risk prediction model for prolonged mechanical ventilation after lung transplantation: a retrospective cohort study.

BACKGROUND: Prolonged mechanical ventilation (PMV), mostly defined as mechanical ventilation > 72 h after lung transplantation with or without tracheostomy, is associated with increased mortality. Nevertheless, the predictive factors of PMV after lung transplant remain unclear. The present study aimed to develop a novel scoring system to identify PMV after lung transplantation. METHODS: A total of 141 patients who underwent lung transplantation were investigated in this study. The patients were divided into PMV and non-prolonged ventilation (NPMV) groups. Univariate and multivariate logistic regression analyses were performed to assess factors associated with PMV. A risk nomogram was then established based on the multivariate analysis, and model performance was further examined regarding its calibration, discrimination, and clinical usefulness. RESULTS: Eight factors were finally identified to be significantly associated with PMV by the multivariate analysis and therefore were included as risk factors in the nomogram as follows: the body mass index (BMI, P = 0.036); primary diagnosis as idiopathic pulmonary fibrosis (IPF, P = 0.038); pulmonary hypertension (PAH, P = 0.034); primary graft dysfunction grading (PGD, P = 0.011) at T0; cold ischemia time (CIT P = 0.012); and three ventilation parameters (peak inspiratory pressure [PIP, P < 0.001], dynamic compliance [Cdyn, P = 0.001], and P/F ratio [P = 0.015]) at T0. The nomogram exhibited superior discrimination ability with an area under the curve of 0.895. Furthermore, both calibration curve and decision-curve analysis indicated satisfactory performance. CONCLUSION: A novel nomogram to predict individual risk of receiving PMV for patients after lung transplantation was established, which may guide preventative measures for tackling this adverse event.

Surface Decarburization Depth Detection in Rods of 60Si2Mn Steel with Magnetic Barkhausen Noise Technique.

Magnetic Barkhausen noise (MBN), sensitive to the microstructure of materials, can be applied in the surface decarburization depth detection of ferromagnetic specimens. However, the effects of core microstructures on the determination results of decarburization depth have not been explored. In this study, MBN was employed to evaluate the magnetic properties of the decarburized 60Si2Mn spring steels with martensitic and pearlitic core microstructures. Spring steel samples were austenitized at different times to generate different decarburization depths. Seven magnetic features were extracted from the MBN butterfly profiles. We used the variation coefficient, linear correlation coefficient, and normalized sensitivity to discuss the influence of the core microstructures on these seven features. The different core microstructures led to a large difference in the ability of MBN features to characterize the decarburization layer depth. However, three features of MBN butterfly profiles demonstrated an approximately linear dependency (linear correlation coefficient > 94%) on surface decarburization depth and monotonically increased with the increase in depth in both core microstructures of spring steels.

The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study.

BACKGROUND: Inflammatory biomarkers in the peripheral blood have been established as predictors for immunotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC). Whether they can also predict major pathological response (MPR) in neoadjuvant setting remains unclear. METHODS: In this multi-center retrospective study, 122 and 92 stage I-IIIB NSCLC patients from six hospitals who received neoadjuvant chemoimmunotherapy followed by surgery were included in the discovery and external validation cohort, respectively. Baseline and on-treatment neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) were calculated and associated with MPR. Furthermore, resected tumor samples from 37 patients were collected for RNA-sequencing to investigate the immune-related tumor microenvironment. RESULTS: In both the discovery and validation cohorts, the on-treatment NLR, dNLR, PLR, and SII levels were significantly lower in the patients with MPR versus non-MPR. On-treatment SII remained an independent predictor of MPR in multivariate logistic regression analysis. The area under the curve (AUC) of on-treatment SII for predicting MPR was 0.75 (95%CI, 0.67-0.84) in the discovery cohort. Moreover, the predictive value was further improved by combining the on-treatment SII and radiological tumor regression data, demonstrating an AUC of 0.82 (95%CI, 0.74-0.90). The predictive accuracy was validated in the external cohort. Compared with the SII-high group, patients with SII-Low were associated with the activated B cell receptor signaling pathway and a higher intratumoral immune cell infiltration level. CONCLUSIONS: On-treatment SII was independently associated with MPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy. Further prospective studies are warranted.

Comprehensive Indicators for Evaluating and Seeking Elasto-Magnetic Parameters for High-Performance Cable Force Monitoring.

The elasto-magnetic method is a promising pathway for cable force monitoring in cable-stayed bridges. Under the action of an externally applied pulsed magnetic field, both the variation in the main flux recorded by the induction coil and the localized surface magnetic field measured by the packaged magnetic sensor are typical signals for observing the elasto-magnetic effect in tensioned cables. However, the performances of the parameters extracted from the two types of elasto-magnetic signals are never strictly compared in the experiment. Meanwhile, comprehensive indicators for evaluating the ability of elasto-magnetic parameters on cable force characterization are seldom discussed. As a result, it is difficult to compare the performances of elasto-magnetic devices developed by different teams, and the pathway of seeking new parameters for cable force monitoring is obstructed. In this study, elasto-magnetic calibration experiments were performed on a cable of seven-wire steel strands to simultaneously measure the variation in the main flux and the localized surface magnetic field. Comprehensive indicators considering sensitivity, hysteresis error, and cable force resolution are proposed to examine the performances of classic elasto-magnetic parameters and new candidate ones. Through comparative study, two new parameters demonstrated outstanding ability for cable force measurement, and they are the minimum amplitude of the induced voltage and the area under the curve between two points of 3 dB height of the voltage measured by a Hall sensor. The latter is recommended for high-performance cable force monitoring from the perspective of simplicity in sensor configuration.

Improvement of surgical techniques for orthotopic single lung transplantation in rats.

Background: Although orthotopic single lung transplantation in rats has long been established, this model is still highly challenging. Therefore, we made several modifications in anesthesia, lung extraction, vascular clamp, and transplantation procedures for this model. Methods: Fifty cases of rat left lung transplantation were performed using traditional procedures and modified surgical techniques, respectively. Two hundred Sprague Dawley male rats, half as donors and half as recipients, were randomized equally to the two groups. The modifications included orotracheal intubation via a video laryngoscope, retrograde perfusion following anterograde perfusion, a Rummel tourniquet for the occlusion of pulmonary vessels, flushing the vessels and cuffs before anastomosis with heparin, and a simple pleural drainage. The surgical time, warm and cold ischemia time, vascular complications, and survival rate on postoperative day seven were compared between the two groups. Results: The modified surgical techniques significantly reduced the surgical duration (35.7 vs. 46.3 min, P<0.01), warm ischemia time (16.3 vs. 28.8 min, P<0.01), and vascular complications (2% vs. 16%, P=0.04). Moreover, the survival rate on postoperative day 7 was higher in the improved surgical techniques group (96% vs. 80%, P=0.03). Conclusions: We described the improvement of surgical techniques for orthotopic single lung transplantation in rats, which could shorten anastomoses time, reduce vascular complications, and improve survival rate.

Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway.

The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day-1) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.

Pigment epithelium-derived factor and its role in microvascular-related diseases.

Microvascular diseases are among the most clinically important diseases, and vascular abnormalities are central in the development of such diseases. Pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, exerts antiangiogenic effects without affecting the structure and function of normal blood vessels. PEDF also has neurotrophic effects, which may be a potential direction for the future treatment of angiogenic diseases with lower side effects. Here, we review (i) the expression levels of PEDF in several important organs and clinically common microvascular diseases and (ii) the effects of its absence and presence on the vasculature and nerves, focusing on both angiogenic and neuroprotective aspects. These effects are both positive and negative, and have the potential to be exploited. Additionally, we summarize and compare various PEDF agents and their possible advantages and disadvantages as therapeutic agents, which, despite most still being in the experimental stage, may provide some new opportunities for future clinical treatments and interventions in PEDF-targeted microvascular diseases.