SEC: A core hub during cell fate alteration.

Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release, thereby playing pivotal roles in the intricate process of cellular fate modulation. Super elongation complex (SEC), a large assembly comprising diverse protein components, has garnered attention due to its emerging significance in orchestrating physiological and pathological cellular identity changes by regulating the transcription of crucial genes. Consequently, SEC emerges as a noteworthy functional complex capable of modulating cell fate alterations. Therefore, a comprehensive review is warranted to systematically summarize the core roles of SEC in different types of cell fate alterations. This review focuses on elucidating the current understanding of the structural and functional basis of SEC. Additionally, we discuss the intricate regulatory mechanisms governing SEC in various models of cell fate alteration, encompassing both physiological and pathological contexts. Furthermore, leveraging the existing knowledge of SEC, we propose some insightful directions for future research, aiming to enhance our mechanistic and functional comprehension of SEC within the diverse landscape of cell fate alterations.

Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

Iridium(III) complexes decorated with silicane-modified rhodamine: near-infrared light-initiated photosensitizers for efficient deep-tissue penetration photodynamic therapy.

Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(III) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.

Nr5a2 ensures inner cell mass formation in mouse blastocyst.

Recent studies have elucidated Nr5a2's role in activating zygotic genes during early mouse embryonic development. Subsequent research, however, reveals that Nr5a2 is not critical for zygotic genome activation but is vital for the gene program between the 4- and 8-cell stages. A significant gap exists in experimental evidence regarding its function during the first lineage differentiation's pivotal period. In this study, we observed that approximately 20% of embryos developed to the blastocyst stage following Nr5a2 ablation. However, these blastocysts lacked inner cell mass (ICM), highlighting Nr5a2's importance in first lineage differentiation. Mechanistically, using RNA sequencing and CUT&Tag, we found that Nr5a2 transcriptionally regulates ICM-specific genes, such as Oct4, to establish the pluripotent network. Interference with or overexpression of Nr5a2 in single blastomeres of 2-cell embryos can alter the fate of daughter cells. Our results indicate that Nr5a2 works as a doorkeeper to ensure ICM formation in mouse blastocyst.

Sigma-1 receptor regulates the endoplasmic reticulum stress pathway in the protective mechanism of dexmedetomidine against hyperoxia-induced lung injury.

Perioperative hyperoxia therapy is of great significance to save the lives of patients, but little is known about the possible mechanisms that induce hyperoxia-induced acute lung injury (HALI) and the measures for clinical prevention and treatment. In this experiment, the models were established with a feeding chamber with automatic regulation of oxygen concentration. The results showed that with the increase in inhaled oxygen concentration and the prolongation of exposure time, the severity of lung injury also increases significantly, reaching the diagnostic indication of HALI after 48 h of inhaling 95 % oxygen concentration. Subsequently, according to the dynamic changes of apoptosis in lung specimens, and the expression changes in Sig-1R-regulated ER stress pathway proteins (Sig-1R, GRP78, p-PERK, ATF6, IRE1, Caspase-12, ATF4, CHOP, Caspase-3 and p-JNK), it was confirmed that the Sig-1R-regulated ER stress signaling pathway was involved in the occurrence of HALI. To explore the preventive and therapeutic effects of routine clinical medication on HALI during the perioperative period, our research group selected dexmedetomidine (Dex) with lung protection. The experimental results revealed that Dex partially reversed the changes in the expression levels of Sig-1R-regulated ER stress pathway proteins. These results preliminarily confirmed that Dex may inhibit apoptosis induced by high oxygen concentration through the Sig-1R-regulated ER stress signaling pathway, thus playing a protective role in HALI.

Neural networks based on attention architecture are robust to data missingness for early predicting hospital mortality in intensive care unit patients.

Background: Although the machine learning model developed on electronic health records has become a promising method for early predicting hospital mortality, few studies focus on the approaches for handling missing data in electronic health records and evaluate model robustness to data missingness. This study proposes an attention architecture that shows excellent predictive performance and is robust to data missingness. Methods: Two public intensive care unit databases were used for model training and external validation, respectively. Three neural networks (masked attention model, attention model with imputation, attention model with missing indicator) based on the attention architecture were developed, using masked attention mechanism, multiple imputation, and missing indicator to handle missing data, respectively. Model interpretability was analyzed by attention allocations. Extreme gradient boosting, logistic regression with multiple imputation and missing indicator (logistic regression with imputation, logistic regression with missing indicator) were used as baseline models. Model discrimination and calibration were evaluated by area under the receiver operating characteristic curve, area under precision-recall curve, and calibration curve. In addition, model robustness to data missingness in both model training and validation was evaluated by three analyses. Results: In total, 65,623 and 150,753 intensive care unit stays were respectively included in the training set and the test set, with mortality of 10.1% and 8.5%, and overall missing rate of 10.3% and 19.7%. attention model with missing indicator had the highest area under the receiver operating characteristic curve (0.869; 95% CI: 0.865 to 0.873) in external validation; attention model with imputation had the highest area under precision-recall curve (0.497; 95% CI: 0.480-0.513). Masked attention model and attention model with imputation showed better calibration than other models. The three neural networks showed different patterns of attention allocation. In terms of robustness to data missingness, masked attention model and attention model with missing indicator are more robust to missing data in model training; while attention model with imputation is more robust to missing data in model validation. Conclusions: The attention architecture has the potential to become an excellent model architecture for clinical prediction task with data missingness.

Correlation of abnormal brain changes with perinatal factors in very preterm infants based on diffusion tensor imaging.

Background: It remains unclear whether very preterm (VP) infants have the same level of brain structure and function as full-term (FT) infants. In addition, the relationship between potential differences in brain white matter microstructure and network connectivity and specific perinatal factors has not been well characterized. Objective: This study aimed to investigate the existence of potential differences in brain white matter microstructure and network connectivity between VP and FT infants at term-equivalent age (TEA) and examine the potential association of these differences with perinatal factors. Methods: A total of 83 infants were prospectively selected for this study: 43 VP infants (gestational age, or GA: 27-32 weeks) and 40 FT infants (GA: 37-44 weeks). All infants at TEA underwent both conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Significant differences in white matter fractional anisotropy (FA) and mean diffusivity (MD) images between the VP and FT groups were observed using tract-based spatial statistics (TBSS). The fibers were tracked between each pair of regions in the individual space, using the automated anatomical labeling (AAL) atlas. Then, a structural brain network was constructed, where the connection between each pair of nodes was defined by the number of fibers. Network-based statistics (NBS) were used to examine differences in brain network connectivity between the VP and FT groups. Additionally, multivariate linear regression was conducted to investigate potential correlations between fiber bundle numbers and network metrics (global efficiency, local efficiency, and small-worldness) and perinatal factors. Results: Significant differences in FA were observed between the VP and FT groups in several regions. These differences were found to be significantly associated with perinatal factors such as bronchopulmonary dysplasia (BPD), activity, pulse, grimace, appearance, respiratory (APGAR) score, gestational hypertension, and infection. Significant differences in network connectivity were observed between the VP and FT groups. Linear regression results showed significant correlations between maternal years of education, weight, the APGAR score, GA at birth, and network metrics in the VP group. Conclusions: The findings of this study shed light on the influence of perinatal factors on brain development in VP infants. These results may serve as a basis for clinical intervention and treatment to improve the outcome of preterm infants.

Multiparametric Magnetic Resonance Imaging With Comprehensive Assessment of Prostate Volume, Morphology, and Composition Better Reflects the Correlation With International Prostate Symptom Score.

OBJECTIVE: To investigate the application of multiparametric magnetic resonance imaging (mp-MRI) for comprehensive evaluation of the correlation between the characteristics of the transitional zone and the International Prostate Symptom Score (IPSS) in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We retrospectively recruited 210 patients with biopsy-proven BPH who underwent preoperative mp-MRI and were assigned an IPSS. The evaluation indicators included prostate volumetric parameters (total prostate volume [TPV], transition zone volume [TZV], and transition zone index [TZI, TZI=TZV/TPV]), prostate morphological parameters (intravesical prostatic protrusion, and presumed circle area ratio) and prostate compositional parameters (apparent diffusion coefficient [ADC], and mean signal intensity of T2WI [mean-SI-T2WI]). The Pearson (r) correlation coefficient, one-way analysis of variance, and multiple linear regression analysis were used to build a regression model for evaluating the correlation between MRI-derived parameters and IPSS, IPSS-storage symptom, IPSS-voiding symptom. RESULTS: Significant correlations were found between IPSS, IPSS-storage symptom, IPSS-voiding symptom, and prostate MRI-derived parameters, including TPV (r = 0.350; r = 0.466; r = 0.225, P < .001), TZV (r = 0.374; r = 0.492; r = 0.243, P < .001), TZI (r = 0.383; r = 0.313; r = 0.354, P < .001), presumed circle area ratio (r = 0.481; r = 0.356; r = 0.469, P < .001), ADC(r = -0.198; r = -0.053; r = -0.239, P < .05) and mean-SI-T2WI (r = -0.626; r = -0.310; r = -0.687, P < .001), respectively. Based on multiple linear regression analysis, the impact of mean-SI-T2WI and TZI on total IPSS were statistically significant (P < .05), and the regression equation established with the analysis (IPSS= 39.224 + 8.469 ×TZI+ (-0.09)× (mean-SI-T2WI)) was statistically significant (F=104.995, P < .001). CONCLUSION: Mp-MRI could be used to evaluate the volume and morphology of BPH. In particular, mean-SI-T2WI and ADC could be used to describe the internal composition of the prostate. The imaging parameters were effective for evaluating BPH.

Ferulic acid alleviates alveolar epithelial barrier dysfunction in sepsis-induced acute lung injury by activating the Nrf2/HO-1 pathway and inhibiting ferroptosis.

CONTEXT: Ferulic acid (FA) has antioxidative and anti-inflammatory effects, and is a promising drug to treat sepsis. OBJECTIVE: To study the therapeutic effect of FA in sepsis-induced acute lung injury (ALI) and its underlying mechanisms. MATERIALS AND METHODS: The caecal ligation and puncture (CLP) manoeuvre was applied to establish a murine model of sepsis-induced ALI, and female BALB/c mice (6 mice per group) were subjected to 100 mg/kg FA or 0.8 mg/kg ferrostatin-1 (Fer-1, ferroptosis inhibitor) treatment to clarify the role of FA in preserving alveolar epithelial barrier function and inhibiting ferroptosis. Lipopolysaccharide (LPS; 500 ng/mL)-induced cell models were prepared and subjected to FA (0.1 µM), sh-Nrf2, and Fe (Fe-citrate, ferroptosis inducer; 5 M) treatment to study the in vitro effect of FA on LPS-induced alveolar epithelial cell injury and the role of the Nrf2/HO-1 pathway. RESULTS: We found that FA decreased the lung injury score (48% reduction), lung wet/dry weight ratio (33% reduction), and myeloperoxidase activity (58% reduction) in sepsis-induced ALI. Moreover, FA inhibited ferroptosis of alveolar epithelial cells and improved alveolar epithelial barrier dysfunction. The protective role of FA against alveolar epithelial barrier dysfunction could be reversed by the ferroptosis inducer Fe-citrate, suggesting that FA alleviates alveolar epithelial barrier dysfunction by inhibiting ferroptosis. Mechanistically, we found that FA inhibited ferroptosis of alveolar epithelial cells by activating the Nrf2/HO-1 pathway. CONCLUSION: Collectively, our data highlighted the alleviatory role of ferulic acid in sepsis-induced ALI by activating the Nrf2/HO-1 pathway and inhibiting ferroptosis, offering a new basis for sepsis treatment.

A high-speed railway network dataset from train operation records and weather data.

High-speed train operation data are reliable and rich resources in data-driven research. However, the data released by railway companies are poorly organized and not comprehensive enough to be applied directly and effectively. A public high-speed railway network dataset suitable for research is still lacking. To support the research in large-scale complex network, complex dynamic system and intelligent transportation, we develop a high-speed railway network dataset, containing the train operation data in different directions from October 8, 2019 to January 27, 2020, the train delay data of the railway stations, the junction stations data, and the mileage data of adjacent stations. In the dataset, weather, temperature, wind power and major holidays are considered as factors affecting train operation. Potential research values of the dataset include but are not limited to complex dynamic system pattern mining, community detection and discovery, and train delay analysis. Besides, the dataset can be used to solve various railway operation and management problems, such as passenger service network improvement, train real-time dispatching and intelligent driving assistance.

Dissection of the practical soybean breeding pipeline by developing ZDX1, a high-throughput functional array.

KEY MESSAGE: We developed the ZDX1 high-throughput functional soybean array for high accuracy evaluation and selection of both parents and progeny, which can greatly accelerate soybean breeding. Microarray technology facilitates rapid, accurate, and economical genotyping. Here, using resequencing data from 2214 representative soybean accessions, we developed the high-throughput functional array ZDX1, containing 158,959 SNPs, covering 90.92% of soybean genes and sites related to important traits. By application of the array, a total of 817 accessions were genotyped, including three subpopulations of candidate parental lines, parental lines and their progeny from practical breeding. The fixed SNPs were identified in progeny, indicating artificial selection during the breeding process. By identifying functional sites of target traits, novel soybean cyst nematode-resistant progeny and maturity-related novel sources were identified by allele combinations, demonstrating that functional sites provide an efficient method for the rapid screening of desirable traits or gene sources. Notably, we found that the breeding index (BI) was a good indicator for progeny selection. Superior progeny were derived from the combination of distantly related parents, with at least one parent having a higher BI. Furthermore, new combinations based on good performance were proposed for further breeding after excluding redundant and closely related parents. Genomic best linear unbiased prediction (GBLUP) analysis was the best analysis method and achieved the highest accuracy in predicting four traits when comparing SNPs in genic regions rather than whole genomic or intergenic SNPs. The prediction accuracy was improved by 32.1% by using progeny to expand the training population. Collectively, a versatile assay demonstrated that the functional ZDX1 array provided efficient information for the design and optimization of a breeding pipeline for accelerated soybean breeding.

Loss of MBD2 ameliorates LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis.

Apoptosis of alveolar epithelial cells is a critical initial link in the pathogenesis of acute lung injury (ALI), recent studies have revealed that Methyl-CpG binding domain protein 2 (MBD2) was involved in the execution of apoptosis, yet its role in ALI remained unclear. In the present study, we aim to explore the role and mechanism of MBD2 in the pathogenesis of ALI. We have found that MBD2 expression, in parallel to apoptosis, increased in alveolar epithelial cells of mice treated with LPS, knockout of MBD2 reduced apoptosis and protected mice from LPS-induced ALI. In MLE-12 cells, a cell line of murine alveolar epithelial cells, LPS induced MBD2 expression and apoptosis in a dose- and time-dependent manner. Knockdown of MBD2 with shRNA alleviated, while overexpression of MBD2 increased LPS-induced apoptosis. Mechanistically, intracellular zinc level decreased when MLE-12 cells were treated with LPS. MBD2 knockdown restored intracellular zinc level after LPS treatment, and MBD2 overexpression further aggravated LPS-induced intracellular zinc loss. Metal transcription factor 1 (MTF1) is a critical transcription factor in charge of intracellular zinc efflux. LPS treatment induced MTF1 expression both in vivo and in vitro. Inhibition of MTF1 reduced LPS-induced apoptosis in MLE-12 cells. MBD2 could bind to the promoter region of MTF1 and promote MTF1 expression. Collectively, these data indicated that loss of MBD2-ameliorated LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis by upregulating MTF1.

SoySNP618K array: A high-resolution single nucleotide polymorphism platform as a valuable genomic resource for soybean genetics and breeding.

Innovations in genomics have enabled the development of low-cost, high-resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole-genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high-confidence genes. Identity-by-state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome-wide association mapping in combination with reported quantitative trait loci enabled fine-mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research.

Development of a laser scanning projection system with a dual-diameter fitting method and particle swarm optimization.

Laser scanning projection can project outlines of assembled components onto a work surface accurately, which can improve assembly efficiency, and is widely applied in industry manufacturing. In order to achieve accurate calibration and projection, a mathematical model of the calibration process is developed, and the dual-diameter fitting method is proposed to extract the central positions of retroreflective targets. Then, a particle swarm optimization (PSO) algorithm is introduced to solve the coordinate transformation matrix between the world frame and the projector frame, and the optimal parameters of the PSO algorithm are obtained to improve the convergence probability of the transformation matrix solutions. The maximum error of the retroreflective targets' central positions between the calculated and theoretical positions is 1.82×10-6mm through the simulation experiment. Furthermore, a novel laser scanning projection setup and a control system based on LabVIEW are developed. Experiments are actually carried out by scanning six retroreflective targets on a standard workpiece, and the transformation matrix is solved correspondingly. The results indicate that the maximum beam steering angle error between the theoretical and actual values calculated by the abovementioned transformation matrix is 5.215668×10-9 degrees. Finally, the projection accuracy is verified by a standard workpiece with accurate patterns. The experiment results prove that the position error of the developed laser scanning projection system is better than 0.5 mm.

Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence.

Different substance dependences have common effects on reward pathway and molecular adaptations, however little is known regarding their shared genetic factors. We aimed to identify the risk genetic variants that are shared for substance dependence (SD). First, promising genome-wide significant loci were identified from 3296 patients (521 alcoholic/1026 heroin/1749 methamphetamine) vs 2859 healthy controls and independently replicated using 1954 patients vs 1904 controls. Second, the functional effects of promising variants on gene expression, addiction characteristics, brain structure (gray and white matter), and addiction behaviors in addiction animal models (chronic administration and self-administration) were assessed. In addition, we assessed the genetic correlation among the three SDs using LD score regression. We identified and replicated three novel loci that were associated with the common risk of heroin, methamphetamine addiction, and alcoholism: ANKS1B rs2133896 (Pmeta = 3.60 × 10-9), AGBL4 rs147247472 (Pmeta = 3.40 × 10-12), and CTNNA2 rs10196867 (Pmeta = 4.73 × 10-9). Rs2133896 in ANKS1B was associated with ANKS1B gene expression and had effects on gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus in heroin dependence. Overexpression of anks1b gene in the ventral tegmental area decreased addiction vulnerability for heroin and methamphetamine in self-administration rat models. Our findings could shed light on the root cause for substance dependence and will be helpful for the development of cost-effective prevention strategies for general addiction disorders.

Novel efficient lattice-based IBE schemes with CPK for fog computing.

The data security of fog computing is a key problem for the Internet of things. Identity-based encryption (IBE) from lattices is extremely suitable for fog computing. It is able to not only simplify certificate management, but also resist quantum attacks. In this paper, firstly, we construct a novel efficient lattice-based IBE scheme with Combined Public Key (CPK) technique by keeping from consumptive trapdoor generation algorithm and preimage sampling algorithm, which is required by the existing lattice-based IBE schemes based on learning with errors (LWE). In addition, its key storage cost is lower and it is IND-ID-CPA secure in the random oracle model. Furthermore, based on this, an enhanced lattice-based IBE scheme with IND-ID-CCA security is developed by employing strong one-time signature. Our schemes only need O(n3/log n) additions of vectors, while the existing schemes need at least O(n3) of additions and multiplications in Setup and Extract phase.

miR­195 promotes LPS­mediated intestinal epithelial cell apoptosis via targeting SIRT1/eIF2a.

A microarray analysis of an animal model with experimental sepsis induced by caecal ligation and puncture revealed that the level of microRNA­195 (miR­195) was upregulated. However, to the best of our knowledge, the role of miR­195 in sepsis remains unknown. The present study investigated the effect of miR­195 on apoptosis in sepsis and investigated the underlying mechanism. The level of miR­195 was measured in human intestinal epithelial cells following exposure to lipopolysaccharide (LPS). Cell viability and apoptosis were detected using Cell Counting kit­8 and flow cytometry assays. The expression levels of apoptosis­associated proteins were determined using western blot analysis. In addition, a dual­luciferase reporter assay was employed to verify the association between miR­195 and sirtuin 1 (SIRT1). Furthermore, the SIRT1 inhibitor EX527 was applied to further confirm the regulatory network of miR­195/SIRT1 in LPS­induced apoptosis. It was demonstrated that LPS significantly inhibited cell viability and promoted cell apoptosis in NCM460 cells in a dose­dependent manner. In addition, miR­195 was significantly upregulated following LPS treatment. The present results revealed that silencing miR­195 prevented apoptosis and alleviated cell injury in LPS­induced NCM460 cells. Further investigation demonstrated that miR­195 bound directly to and negatively regulated SIRT1. Inhibition of SIRT1 reversed the protective effects of miR­195­silencing on the apoptosis and viability of NCM460 cells. Furthermore, silencing miR­195 prevented endoplasmic reticulum (ER) stress­induced apoptosis via a downregulation of SIRT1 and its downstream effectors, including activating transcription factor 4, C/EBP homologous protein, glucose­regulated protein 78 and growth arrest and DNA­damage protein 34, as well as the phosphorylation of eukaryotic translation initiation factor 2A. In conclusion, the present study revealed a novel mechanism by which miR­195 regulates SIRT1­mediated downstream effectors in ER stress­induced apoptosis in sepsis.

The association between cumulative C-reactive protein and brachial-ankle pulse wave velocity.

BACKGROUND AND AIMS: This study aimed to investigate the association between cumulative C-reactive protein (cumCPR) and arterial stiffness. METHODS: The cross-sectional study included 15,432 participants from the Kailuan Cohort. The participants were divided into four groups according to cumCRP quartiles. The average brachial-ankle pulse wave velocity (baPWV) and detective rate of increased arterial stiffness were compared between exposure groups. Statistical analysis was performed with multiple logistic regression analysis to estimate the association between cumCRP and arterial stiffness by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). The several sensitivity analyses were performed to test the robustness of our findings. RESULTS: The average baPWV increased from 1425.70 cm/s of Q1 group to 1626.48 cm/s of Q4 group. And the detective rate of arterial stiffness increased from 44.7 to 70.1% (P < 0.001). Multiple logistic regression analysis showed that after adjusting the confounding factors, compared to the Q1 group, the Q4 group had 42% (adjusted OR 1.42; 95% CI 1.24-1.63) higher arterial stiffness risk. In addition, 10% (adjusted OR 1.10; 95% CI 1.02-1.18) arterial stiffness risk was increased per 1 standard deviation (SD) of cumCRP after a fully adjusted regression model. CONCLUSION: Higher cumCRP exposure is associated with increased arterial stiffness.

Relationship between pulmonary function and brachial-ankle pulse wave velocity in coal miners in northern China.

BACKGROUND: To investigate the relationship between pulmonary function and brachial-ankle pulse wave velocity (baPWV). METHODS: A cross-sectional study was conducted. A total of 11,388 people with complete pulmonary function test and baPWV data and who participated in both the health examination of the Kailuan Occupational Disease Prevention and Treatment Center in 2014-2016 and the health checkup of the Kailuan Group in 2012 and 2014 were selected as subjects. The study population was divided into four groups by forced vital capacity (FVC) quartiles (group 1: FVC <3.50 L; group 2: 3.50 L ≤ FVC <3.96 L; group 3: 3.96 L ≤ FVC <4.47 L; group 4: FVC ≥4.47 L) and divided into four groups by forced expiratory volume in one second (FEV1) quartile (group 1: FEV1 <3.15 L; group 2: 3.15 L ≤ FVC <3.61 L; group 3: 3.61 L ≤ FVC <4.08 L; group 4: FVC ≥4.08 L). Linear regression analysis and multivariate logistic regression were used to analyze the effects of pulmonary function on baPWV. RESULTS: When grouped by FVC, the baPWV of the first group was significantly higher than the other groups. Similarly, the incidence of arteriosclerosis in the first group was significantly higher than the other groups. When grouped by FEV1, the baPWV of the first group was significantly higher than the other groups. The incidence of arteriosclerosis was also significantly higher in the first group than the other groups. After correcting for other confounding factors using linear regression, it was found that the effects of FVC and FEV1 on the study subject's baPWV were -23.84 and -24.65 L, respectively. Multivariate logistic regression analysis showed that when grouped by FVC quartile, the risk of arteriosclerosis was increased by 34% in group 1 compared with group 4 (OR: 1.34, 95% CI: 1.17-1.52); the risk of arteriosclerosis was increased by 16% in group 2 compared with group 4 (OR: 1.16, 95% CI: 1.03-1.31). When grouped by the FEV1 quartile, the risk of arteriosclerosis was increased by 25% in group 1 compared with group 4 (OR: 1.25, 95% CI: 1.10-1.42). CONCLUSIONS: Decreased pulmonary function is negatively correlated with baPWV and is an independent risk factor for arteriosclerosis.

AMPK alleviates endoplasmic reticulum stress by inducing the ER-chaperone ORP150 via FOXO1 to protect human bronchial cells from apoptosis.

Chronic obstructive pulmonary disease (COPD), is characterized by inflammation of airways accompanied by a progressive destruction of lung parenchyma. This process is initiated in most cases by cigarette smoking. In this study we investigated the role of AMP activated protein kinase (AMPK) in cigarette smoke extract (CSE)-induced airway epithelial cell apoptosis as a consequence of endoplasmic reticulum stress (ER stress). Exposure of human bronchial epithelial cells (HBEpC) to CSE resulted in apoptosis as detected using Annexin V-PI flow cytometry. However, co-treatment with N1-(ß-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly increased cell protection against ER stress-induced apoptosis by upregulating the 150 kDa oxygen-regulated protein (ORP150), which functions as an ER-associated chaperone, with concomitant elevation of FOXO1, a critical transcription factor regulating ORP150 expression. Lentiviral silencing of AMPK or FOXO1 using short hairpin (sh) RNA resulted in a significant decrease of ORP150 and an elevation of CCAAT/enhancer-binding protein-homologous protein (CHOP) resulting in ER stress and apoptosis of HBEpC. Together, our results strongly suggest that AMPK can activate ORP150 through FOXO1 pathway and confer protection against ER stress-induced apoptosis of airway epithelial cells following exposure to CSE. Thus, AMPK may serve as a likely therapeutic target for clinical and sub-clinical interventions in COPD.