HDAC3 promotes pulmonary fibrosis by activating NOTCH1 and STAT1 signaling and up-regulating inflammasome components AIM2 and ASC.

BACKGROUND: Pre-clinical studies suggest that pan-inhibitors for histone deacetylases (HDACs) may benefit the treatment of pulmonary fibrosis (PF). However, HDAC3-specific roles or mechanisms during PF development are poorly understood. METHODS: The expression of HDAC3 and the impacts of RGFP966, a selective HDAC3 inhibitor, were examined in a bleomycin-induced PF mouse model and in TGF-ß-challenged MRC-5 cells. H&E and Masson staining were employed to reveal the pathological changes in lung; Western blot to assess expressions of biomarkers related to fibrosis and epithelial-mesenchymal transition (EMT), activations of Notch1 and signal transducer and activator of transcription 1 (STAT1) signaling, and levels of inflammasome components, absent in melanoma 2 (AIM2) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC); ELISA to measure productions of proinflammatory interleukin (IL)-1ß and IL-18; cycloheximide chase assay and coimmunoprecipitation to monitor the protein stability and acetylation of Notch intracellular domain 1 (NICD1) and STAT1, respectively. RESULTS: HDAC3 was induced in in vitro and in vivo PF models, which was associated with elevated expressions of fibrosis-related biomarkers, EMT markers, and pro-inflammatory cytokines, activations of Notch1 and STAT1 signaling, and up-regulated inflammasome components, AIM2 and ASC. All the fibrotic phenotypes were potently inhibited by RGFP966, which boosted the acetylation of NICD1 and STAT1, accelerated the degradation of NICD1, and inhibited STAT1 phosphorylation. Overexpressing NICD1 or STAT1 restored the fibrotic phenotypes suppressed by RGFP966. CONCLUSIONS: HDAC3 promoted EMT, inflammation, and PF development by activating Notch1 and STAT1 signaling. Therefore, targeting HDAC3, Notch1 or STAT1 signaling may ameliorate PF development.

High precision angular displacement measurement based on self-correcting error compensation of three image sensors.

As the feedback link of a numerical control system, the measurement accuracy of absolute angular displacement measurements directly affects the control performance of a numerical control system. In previous research, angular displacement measurements based on dual image sensors can achieve higher measurement performance. However, the elimination of harmonic error by the dual image sensor is still limited. For this reason, this paper proposes an image-type angular displacement measurement method based on self-correction error compensation of three image sensors. First, the mathematical model of harmonic error is established, and the shortcomings of using dual image sensors to compensate the error are analyzed. Then, a high precision angular displacement measurement method based on three image sensors is proposed. Finally, the self-correction error compensation method of three image sensors is applied to the angular displacement measurement system, and the measurement performance is verified. The experimental results show that a measurement accuracy of 1.76'' can be achieved on the circular grating with a diameter of 96 mm. In contrast, the dual image sensor can only achieve a measurement accuracy of 2.88''. It is concluded that the odd number of image sensors can achieve higher measurement accuracy than the even number. This research lays a foundation for the realization of high precision image angular displacement measurement.

High-precision displacement measurement algorithm based on a depth fusion of grating projection pattern.

Displacement measurement based on an image recognition algorithm has more advantages in the field of displacement measurement. Due to the uncertainty of image location, the accuracy of the displacement measurement algorithm studied in the previous stage is limited. To improve the accuracy of image-type displacement measurement, a high-precision displacement measurement algorithm based on depth fusion of the grating projection pattern is proposed. First, a line-scan image sensor and parallel light source are placed on both sides of the calibration grating. The marking pattern on the calibration grating is projected onto the image sensor through illumination of the parallel light source to realize the projection imaging. Then, the centroid algorithm is used to calculate the centroid of each line in the collected image, and the mean value of the centroid group is determined. Finally, a linear function is used to fit multiple centroids to calculate the endpoints of the subdivision region, and the subdivision operation is carried out according to a ratio algorithm. To test the performance of the proposed algorithm, a linear displacement measurement device with a 250 mm range and an angular displacement measurement device with a 100 mm diameter grating are both used for experiments. After testing, the linear measurement accuracy of the proposed algorithm is improved from 4.63 to 1.26 µm, and the angular displacement measurement accuracy is enhanced from 8.87 to 2.88''. The research in this paper provides a theoretical basis for high-performance displacement measurement.

Full Digital Processing System of Photoelectric Encoder.

A photoelectric signal, output by a photoelectric receiver, may detrimentally change after the photoelectric encoder is used for a period of time or when the environment changes; this will directly affect the accuracy of the encoder and lead to fatal errors in the encoder. To maintain its high accuracy, we propose an encoder that can work in a variety of environments and that adopts full digital processing. A signal current that travels from the receiver of a photoelectric encoder is converted into a voltage signal via current limiting resistance. All signals are directly processed in the data processor component of the system. The encoder converts all the signals into its normalized counterpart. Then, the angle of the encoder is calculated using the normalized value. The calculated encoder angle compensates for any error. The final encoder angle is obtained, and the encoder angle is output accordingly. Experiments show that this method can greatly reduce the encoder's volume. This method also reduces the encoder error from 167 arcseconds to 53 arcseconds. The encoder can still maintain a high accuracy during environmental changes, especially in harsh environments where there are higher accuracy requirements.

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC.

BACKGROUND/AIMS: Programmed death ligand1(PD-L1) plays a role in the development and progression of non-small cell lung cancer (NSCLC). This study aimed to identify miRNA(s) that are responsible for regulation of expression of PD-L1 in NSCLC, and to investigate the role of PD-L1 in regulation of the cell cycle in NSCLC. METHODS: We predicted the target miRNA of PD-L1, which was miR-140, using the online tools TargetScan and miBase. In NSCLC cells obtained from clinical specimens, in addition to A549 and NCI-H1650 cell cultures, western blots were used to detect the level of expression of proteins, while real-time PCR was used to determine the level of expression of PD-L1, miR-140, cyclin E, and ß-actin. Transfection with miR-140 mimics, miR-140 inhibitors, and PD-L1 siRNA were conducted using commercial kits. To determine whether miR-140 directly binds PD-L1, a luciferase reporter gene with wild type or mutated PD-L1 was used. Cell viability was measured with the MTT assay, and PI staining was used for cell cycle analysis. RESULTS: We found low expression of miR-140 and high expression of PD-L1 and cyclin E in NSCLC cells. Over-expression of miR-140 suppressed the expression of PD-L1 by directly binding its 3' UTR, and was also associated with decreased expression of cyclin E and inhibition of cellular proliferation in A549 and NCI-H1650 cells. Inhibition of PD-L1, in the absence of manipulations to miR-140, also decreased the expression of cyclin E. CONCLUSION: We conclude that miR-140 directly suppresses PD-L1 and inhibits the miR-140/PD-L1/cyclin E pathway in NSCLC.

Efficient Two-Photon Fluorescent Probe for Nitroreductase Detection and Hypoxia Imaging in Tumor Cells and Tissues.

Hypoxia plays an important role in tumor progression, and the development of efficient methods for monitoring hypoxic degree in living systems is of great biomedical importance. In the solid tumors, the nitroreductase level is directly corresponded with the hypoxic status. Many one-photon excited fluorescent probes have been developed for hypoxia imaging in tumor cells via the detection of nitroreductase level. However, two-photon excited probes are more suitable for bioimaging. In this work, a two-photon probe 1 for nitroreductase detection and hypoxic status monitoring in living tumor cells and tissues was reported for the first time. The detection is based on the fact that the nitro-group of probe 1 could be selectively reduced to an amino-group by nitroreductase in the presence of reduced NADH, following by a 1,6-rearrangement-elimination to release the fluorophore, resulting in the enhancement of fluorescence. The probe exhibited both one-photon and two-photon excited remarkable fluorescence enhancement (∼70-fold) for nitroreductase, which afforded a high sensitivity for nitroreductase, with a detection limit of 20 ng/mL observed. Moreover, the applications of the probe for fluorescent bioimaging of hypoxia in living cells and two-photon bioimaging in tissues were carried out, with tissue-imaging depths of 70-160 µm observed, which demonstrates its practical application in complex biosystems.

Automatic compensation system for eccentricity error of absolute optical encoder.

Eccentric error is a vital part of high-precision optical encoder error. An automatic error compensation system is designed to lower the eccentric error of the encoder. On the periphery of the fan-shaped code path of the traditional encoder disk, a set of radial code paths is drawn. This radial code path is composed of several concentric circles with alternating light and dark lines. The direction of the radial code path is perpendicular to the direction of the fine code path. When the encoder rotates, the eccentricity of the encoder disk is measured by the moiré fringe signal output from the radial code channel. Based on the eccentricity error compensation algorithm, the eccentricity error of the encoder disk is compensated in real time to enhance the accuracy of the encoder. The experimental results of an encoder show that the mean square error of the encoder before the eccentricity error compensation is 21.25 arc seconds, and it is 3.66 arc seconds after compensation by this algorithm. The algorithm can significantly compensate the error caused by the eccentricity of the encoder and greatly improve the accuracy of the encoder.

SGLT-2 inhibitors as novel treatments of multiple organ fibrosis.

Fibrosis, a significant health issue linked to chronic inflammatory diseases, affects various organs and can lead to serious damage and loss of function. Despite the availability of some treatments, their limitations necessitate the development of new therapeutic options. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), known for their glucose-lowering ability, have shown promise in offering protective effects against fibrosis in multiple organs through glucose-independent mechanisms. This review explores the anti-fibrotic potential of SGLT2i across different tissues, providing insights into their underlying mechanisms and highlighting recent research advancements. The evidence positions SGLT2i as a potential future treatments for fibrotic diseases.

Serum Exosomal miRNA-125b and miRNA-451a are Potential Diagnostic Biomarker for Alzheimer's Diseases.

Aim: To explore the diagnostic value of serum-derived exosomal miRNAs and predict the roles of their target genes in Alzheimer's disease (AD) based on the expression of miRNAs in AD patients. Methods: We determined the relative concentration of exosomal miRNAs by High-throughput Second-generation Sequencing and real-time quantitative real-time PCR. Results: 71 AD patients and 71 ND subjects were collected. The study demonstrated that hsa-miR-125b-1-3p, hsa-miR-193a-5p, hsa-miR-378a-3p, hsa-miR-378i and hsa-miR-451a are differentially expressed in the serum-derived exosomes of AD patients compared with healthy subjects. According to ROC analysis, hsa-miR-125b-1-3p has an AUC of 0.765 in the AD group compared to the healthy group with a sensitivity and specificity of 82.1-67.7%, respectively. Enrichment analysis of its target genes showed that they were related to neuroactive ligand-receptor interactions, the PI3K-Akt signaling pathway, the Hippo signaling pathway and nervous system-related pathways. And, hsa-miR-451a had an AUC of 0.728 that differentiated the AD group from the healthy group with a sensitivity and specificity of 67.9% and 72.6%, respectively. Enrichment analysis of its target genes showed a relationship with cytokine-cytokine receptor interactions and the PI3K-Akt signaling pathway. Conclusion: The dysregulation of serum exosomal microRNAs in patients with AD may promote the diagnosis of AD. The target genes of miRNAs may be involved in the occurrence and development of AD through various pathways.

Causal relationship between serum metabolites and idiopathic pulmonary fibrosis: Insights from a two-sample Mendelian randomization study.

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung disease with unclear pathological mechanisms. In this study, we utilized bidirectional Mendelian randomization (MR) to analyze the relationship between serum metabolites and IPF, and conducted metabolic pathway analysis. Aim: To determine the causal relationship between serum metabolites and IPF using MR analysis. Methods: A two-sample MR analysis was conducted to evaluate the causal relationship between 824 serum metabolites and IPF. The inverse variance weighted (IVW) method was used to estimate the causal relationship between exposure and results. Sensitivity analysis was conducted using MR Egger, weighted median, and maximum likelihood to eliminate pleiotropy. Additionally, metabolic pathway analysis was conducted to identify potential metabolic pathways. Results: We identified 12 serum metabolites (6 risks and 6 protective) associated with IPF from 824 metabolites. Among them, 11 were known and 1 was unknown. 1-Eicosatrienoylglycophorophospholine and 1-myristoylglycophorophospholine were bidirectional MR positive factors, with 1-myristoylglycophorophospholine being a risk factor (1.0013, 1.0097) and 1-eicosatrienoylglycophorine being a protective factor (0.9914, 0.9990). The four lipids (1-linoleoylglycerophoethanolamine*, total cholesterol in large high-density lipoprotein [HDL], cholesterol esters in very large HDL, and phospholipids in very large HDL) and one NA metabolite (degree of unsaturation) were included in the known hazardous metabolites. The known protective metabolites included three types of lipids (carnitine, 1-linoleoylglycerophoethanolamine*, and 1-eicosatrienoylglycerophophophorine), one amino acid (hypoxanthine), and two unknown metabolites (the ratio of omega-6 fatty acids to omega-3 fatty acids, and the ratio of photoshopids to total lipids ratio in chylomicrons and extremely large very low-density lipoprotein [VLDL]). Moreover, sn-Glycerol 3-phosphate and 1-Acyl-sn-glycero-3-phosphocline were found to be involved in the pathogenesis of IPF through metabolic pathways such as Glycerolide metabolism and Glycerophospholipid metabolism. Conclusion: Our study identified 6 causal risks and 6 protective serum metabolites associated with IPF. Additionally, 2 metabolites were found to be involved in the pathogenesis of IPF through metabolic pathways, providing a new perspective for further understanding the metabolic pathway and the pathogenesis of IPF.

Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson's Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage.

Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson's disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores' distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD.

An MTH1-targeted nanosystem for enhanced PDT via improving cellular sensitivity to reactive oxygen species.

Herein, we developed a strategy to attack the cancer cell defense system against reactive oxygen species to improve photodynamic therapy efficacy with a Ce6@MSN@MTH1 siRNA nanosystem, which was demonstrated to improve cellular sensitivity to reactive oxygen species through suppressing MTH1 protein in cancer cells.

[Development of safety climate measurement at workplace: validity and reliability assessment].

OBJECTIVE: To develop a measurement of safety climate at workplace and assess its validity and reliability. METHODS: According to the theory of preventive safety culture model, a scale including 7 dimensions of 27 items was developed. 342 workers were selected from among all workers of an artificial board factory and were investigated with the developed scale. Occupational accidents were recorded during the past year. Factor analysis, association validation and inter-item consistency test were applied to assess the scale validity and reliability. RESULTS: After the deletion of 6 items, 21 items composed the safety climate scale, which was loaded on 7 common factors: safety competence and consciousness, safety communication, organizational environment, management support, danger judgment, safety control measure and safety training. The cumulative contribution reached to 70.50%. All item communities (common factor variance) were above 0.6 except one item was 0.595. ANOVA showed that occupational accidents were associated with the safety climate score on total, danger judgment and safety control measure dimension (P < 0.05). There existed significant correlation between the safety climate total score and dimension scores (P < 0.01), the correlation coefficients were 0.700, 0.728, 0.705, 0.703, 0.354, 0.571 and 0.485 respectively. The safety climate scale total Cronbach's alpha coefficient, half-split Spearman-Brown coefficient, theta coefficient and omega coefficient indicated that the safety climate scale had good inter-item consistency among items. CONCLUSION: The measurement of safety climate at workplace is developed. It has good reliability and valid.

A rhodamine-appended water-soluble conjugated polymer: an efficient ratiometric fluorescence sensing platform for intracellular metal-ion probing.

Thewater-soluble CP was conjugatedwith a rhodamine spirolactam for the first time to develop a new FRET-based ratiometric fluorescence sensing platform(CP 1) for intracellular metal-ion probing. CP 1 exhibits excellent water-solubility with twowell-resolved emission peaks, which benefit ratiometric intracellular imaging applications.