Dulaglutide restores endothelial progenitor cell levels in diabetic mice and mitigates high glucose-induced endothelial injury through SIRT1-mediated mitochondrial fission.

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.

Airborne environmentally persistent free radicals (EPFRs) in PM2.5 from combustion sources: Abundance, cytotoxicity and potential exposure risks.

As an emerging atmospheric pollutant, airborne environmentally persistent free radicals (EPFRs) are formed during many combustion processes and pose various adverse health effects. In health-oriented air pollution control, it is vital to evaluate the health effects of atmospheric fine particulate matter (PM2.5) from different emission sources. In this study, various types of combustion-derived PM2.5 were collected on filters in a partial-flow dilution tunnel sampling system from three typical emission sources: coal combustion, biomass burning, and automobile exhaust. Substantial concentrations of EPFRs were determined in PM2.5 samples and associated with significant potential exposure risks. Results from in vitro cytotoxicity and oxidative potential assays suggest that EPFRs may cause substantial generation of reactive oxygen species (ROS) upon inhalation exposure to PM2.5 from anthropogenic combustion sources, especially from automobile exhaust. This study provides important evidence for the source- and concentration-dependent health effects of EPFRs in PM2.5 and motivates further assessments to advance public health-oriented PM2.5 emission control.

Three-dimensional multi-color optical nanoscopy at sub-10-nm resolution based on small-molecule organic probes.

Achieving nanometer-scale resolution remains challenging in expansion microscopy due to photon loss. To address this concern, here we develop a multi-color expansion stimulated emission depletion technique based on small-molecule probes to realize high labeling density and intensity. Our method substantially lowers the barrier to visualizing diverse intracellular proteins and their interactions in three dimensions. It enables us to achieve sub-10-nm resolution in structures such as microfilaments, lysosomes, and mitochondria, providing new insights into cell biology.

Far-field super-resolution chemical microscopy.

Far-field chemical microscopy providing molecular electronic or vibrational fingerprint information opens a new window for the study of three-dimensional biological, material, and chemical systems. Chemical microscopy provides a nondestructive way of chemical identification without exterior labels. However, the diffraction limit of optics hindered it from discovering more details under the resolution limit. Recent development of super-resolution techniques gives enlightenment to open this door behind far-field chemical microscopy. Here, we review recent advances that have pushed the boundary of far-field chemical microscopy in terms of spatial resolution. We further highlight applications in biomedical research, material characterization, environmental study, cultural heritage conservation, and integrated chip inspection.

Fitting stochastic epidemic models to gene genealogies using linear noise approximation.

Phylodynamics is a set of population genetics tools that aim at reconstructing demographic history of a population based on molecular sequences of individuals sampled from the population of interest. One important task in phylodynamics is to estimate changes in (effective) population size. When applied to infectious disease sequences such estimation of population size trajectories can provide information about changes in the number of infections. To model changes in the number of infected individuals, current phylodynamic methods use non-parametric approaches (e.g., Bayesian curve-fitting based on change-point models or Gaussian process priors), parametric approaches (e.g., based on differential equations), and stochastic modeling in conjunction with likelihood-free Bayesian methods. The first class of methods yields results that are hard to interpret epidemiologically. The second class of methods provides estimates of important epidemiological parameters, such as infection and removal/recovery rates, but ignores variation in the dynamics of infectious disease spread. The third class of methods is the most advantageous statistically, but relies on computationally intensive particle filtering techniques that limits its applications. We propose a Bayesian model that combines phylodynamic inference and stochastic epidemic models, and achieves computational tractability by using a linear noise approximation (LNA) - a technique that allows us to approximate probability densities of stochastic epidemic model trajectories. LNA opens the door for using modern Markov chain Monte Carlo tools to approximate the joint posterior distribution of the disease transmission parameters and of high dimensional vectors describing unobserved changes in the stochastic epidemic model compartment sizes (e.g., numbers of infectious and susceptible individuals). In a simulation study, we show that our method can successfully recover parameters of stochastic epidemic models. We apply our estimation technique to Ebola genealogies estimated using viral genetic data from the 2014 epidemic in Sierra Leone and Liberia.

Alternative deep learning method for fast spatial-frequency shift imaging microscopy.

Spatial-frequency shift (SFS) imaging microscopy can break the diffraction limit of fluorescently labeled and label-free samples by transferring the high spatial-frequency information into the passband of microscope. However, the resolution improvement is at the cost of decreasing temporal resolution since dozens of raw SFS images are needed to expand the frequency spectrum. Although some deep learning methods have been proposed to solve this problem, no neural network that is compatible to both labeled and label-free SFS imaging has been proposed. Here, we propose the joint spatial-Fourier channel attention network (JSFCAN), which learns the general connection between the spatial domain and Fourier frequency domain from complex samples. We demonstrate that JSFCAN can achieve a resolution similar to the traditional algorithm using nearly 1/4 raw images and increase the reconstruction speed by two orders of magnitude. Subsequently, we prove that JSFCAN can be applied to both fluorescently labeled and label-free samples without architecture changes. We also demonstrate that compared with the typical spatial domain optimization network U-net, JSFCAN is more robust to deal with deep-SFS images and noisy images. The proposed JSFCAN provides an alternative route for fast SFS imaging reconstruction, enabling future applications for real-time living cell research.

A novel multi-module integrated intrusion detection system for high-dimensional imbalanced data.

The high dimension, complexity, and imbalance of network data are hot issues in the field of intrusion detection. Nowadays, intrusion detection systems face some challenges in improving the accuracy of minority classes detection, detecting unknown attacks, and reducing false alarm rates. To address the above problems, we propose a novel multi-module integrated intrusion detection system, namely GMM-WGAN-IDS. The system consists of three parts, such as feature extraction, imbalance processing, and classification. Firstly, the stacked autoencoder-based feature extraction module (SAE module) is proposed to obtain a deeper representation of the data. Secondly, on the basis of combining the clustering algorithm based on gaussian mixture model and the wasserstein generative adversarial network based on gaussian mixture model, the imbalance processing module (GMM-WGAN) is proposed. Thirdly, the classification module (CNN-LSTM) is designed based on convolutional neural network (CNN) and long short-term memory (LSTM). We evaluate the performance of GMM-WGAN-IDS on the NSL-KDD and UNSW-NB15 datasets, comparing it with other intrusion detection methods. Finally, the experimental results show that our proposed GMM-WGAN-IDS outperforms the state-of-the-art methods and achieves better performance.

Effects of Conventional Rehabilitative and Aerobic Training in Patients with Idiopathic Inflammatory Myopathy.

Objective: To investigate the efficacy of conventional rehabilitation alone and conventional rehabilitation combined with aerobic training on muscle strength and function, health condition, and quality of life for patients with stable idiopathic inflammatory myopathy (IIM). Methods: This is a historical retrospective cohort study, in which the medical records of patients with IIM, who received the combination of conventional rehabilitative therapy and aerobic training (combined training group [CTG]), from February 2015 to December 2017 were reviewed. Patients with IIM who received conventional therapy alone were matched based on their age, gender, and disease activity as the control group (CG). Scores obtained on manual muscle testing of eight designated muscles (MMT8) was the primary outcome measure, and scores on the myositis Functional Index-2 (FI-2), Health Assessment Questionnaire (HAQ), and 36-item Short Form Medical Outcomes Study Questionnaire (SF-36) at 12 weeks during training were the secondary outcomes. Results: Fifty-six patients (28 in the CTG and 28 in the CG) were included in this analysis. Patients in both groups had improved MMT8, FI-2, HAQ, and SF-36 scores after 12 weeks of physical therapy. The CTG had a significantly higher score on the MMT8 and HAQ than the CG in the 12th week. The FI-2 scores were significantly higher in the CTG for the four items (P < 0.05) of hip flexion, step test, heel lift, and toe lift. SF-36 scores of the CTG were also higher than those of the CG for the five items (P < 0.05) of physical functioning, general health, vitality, social functioning, and mental health. Conclusions: Physical exercise training including conventional rehabilitation and aerobic training improved muscle function, health condition, and quality of life. Conventional rehabilitative training combined with aerobic training achieved better improvement compared with conventional rehabilitation training alone.

Mitotically heritable epigenetic modifications of CmMYB6 control anthocyanin biosynthesis in chrysanthemum.

Flower color, which is determined by various chemical pigments, is a vital trait for ornamental plants, in which anthocyanin is a major component. However, the epigenetic regulation of anthocyanin biosynthesis remains poorly understood. During chrysanthemum cultivation, we found a heterochromatic chrysanthemum accession (YP) whose progeny generated by asexual reproduction contained both yellow-flowered (YP-Y) and pink-flowered (YP-P) plants. In this study, we aimed to elucidate the epigenetic mechanisms of different flower colors in the YP plant progeny. Metabolome and transcriptome analyses revealed that the difference in flower color between YP-Y and YP-P was caused by expression variation of the anthocyanin biosynthesis gene CmMYB6. Bisulfite sequencing revealed that methylation at the CmMYB6 promoter, especially in the CHH context, was higher in YP-Y than YP-P. After demethylation of the CmMYB6 promoter using the dCas9-TET1cd system, the flower color returned from yellow to pink. Furthermore, the methylation status of the CmMYB6 promoter was higher in YP-Y over three consecutive generations, indicating that this methylation status was heritable mitotically. Finally, investigation of other chrysanthemum cultivars showed that the methylation of CmMYB6 decreased gradually with the increase in anthocyanin content. These results lay an epigenetic foundation for the improvement of flower color in horticultural plants.

Facile Fabrication of Fluorine-Free, Anti-Icing, and Multifunctional Superhydrophobic Surface on Wood Substrates.

Building superhydrophobic protective layers on the wood substrates is promising in terms of endowing them with multiple functions, including water-repellent, self-cleaning, anti-icing functions. In this study, multifunctional superhydrophobic wood was successfully fabricated by introducing SiO2 sol and superhydrophobic powder (PMHOS). The SiO2 sol was prepared using tetraethoxysilane as a precursor and ethanol was used as the dispersant. The PMHOS was synthesized using poly(methylhydrogen)siloxane (PMHS) and ethanol. As a result, the obtained superhydrophobic wood had a water contact angle (WCA) of 156° and a sliding angle (SA) of 6° at room temperature. The obtained superhydrophobic wood exhibited excellent repellency toward common liquid (milk, soy sauce, juice, and coffee). The superhydrophobic layer on the wood surface also exhibited good durability after a series of mechanical damages, including finger wiping, tape peeling, knife scratching, and sandpaper abrasion. In addition, the obtained superhydrophobic wood showed excellent anti-icing properties.

Hydrophobic Modification of Wood Using Tetramethylcyclotetrasiloxane.

Hydrophobic surfaces have aroused considerable attention because of their extensive potential applications. In this work, we developed a facile strategy for fabricating hydrophobic and anti-fouling surfaces on wood substrates. The modification was accomplished simply by immerging wood into the tetramethylcyclotetrasiloxane (D4H) modifier solution for 5 min. The D4H modified wood was characterized using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscope, and energy dispersive spectrometer. The result shows that the D4H modified wood had good hydrophobicity, and the water contact angle of wood in the radial and cross sections reached 140.1° and 152°. In addition, the obtained hydrophobic wood surface also showed anti-fouling properties, UV resistance and could withstand the tape peel test and finger wiping.

Circ_0058063 promotes progression of thyroid cancer by sponging miR-330-3p/SDC4 axis.

Circular RNA takes a crucial part in carcinogenesis. Circ_0058063 has been found to act as an oncogene in esophageal cancer and bladder cancer, but its role in thyroid cancer (TC) is still under investigation. Therefore, we carried out a study to understand its role in TC and its association with miR-330-3p. The circ_0058063 and miR-330-3p in TC tissues and cells were quantified by quantitative reverse transcription PCR, and cell counting kit-8 and scratch adhesion test were conducted for evaluation of cell proliferation and migration. In addition, a dual luciferase reporter assay and RNA immunoprecipitation assay were conducted for interaction analysis between circ_0058063 and miR-330-3p. Circ_0058063 was upregulated in TC tissues and cells, but miR-330-3p expression showed an opposite trend. Both silencing circ_0058063 and upregulating miR-330-3p can suppress the proliferation and migration of TC cells, upregulate Bax, and downregulate Bcl-2. In addition, circ_0058063 is able to target miR-330-3p that is also able to target syndecan 4 (SDC4). circ_0058063 can act as a carcinogen in cases with TC via the miR-330-3p/SDC4 axis.

High-Refractive-Index Chip with Periodically Fine-Tuning Gratings for Tunable Virtual-Wavevector Spatial Frequency Shift Universal Super-Resolution Imaging.

Continued research in fields such as materials science and biomedicine requires the development of a super-resolution imaging technique with a large field of view (FOV) and deep subwavelength resolution that is compatible with both fluorescent and nonfluorescent samples. Existing on-chip super-resolution methods exclusively focus on either fluorescent or nonfluorescent imaging, and, as such, there is an urgent requirement for a more general technique that is capable of both modes of imaging. In this study, to realize labeled and label-free super-resolution imaging on a single scalable photonic chip, a universal super-resolution imaging method based on the tunable virtual-wavevector spatial frequency shift (TVSFS) principle is introduced. Using this principle, imaging resolution can be improved more than threefold over the diffraction limit of a linear optical system. Here, diffractive units are fabricated on the chip's surface to provide wavevector-variable evanescent wave illumination, enabling tunable spatial frequency shifts in the Fourier space. A large FOV and resolutions of λ/4.7 and λ/7.1 were achieved for label-free and fluorescently labeled samples using a gallium phosphide (GaP) chip. With its large FOV, compatibility with different imaging modes, and monolithic integration, the proposed TVSFS chip may advance fields such as cell engineering, precision industry inspection, and chemical research.

Insight into urban PM2.5 chemical composition and environmentally persistent free radicals attributed human lung epithelial cytotoxicity.

Fine particulate matter (PM2.5) is detrimental to the human respiratory system. However, the toxicity of PM2.5 and its associated potentially harmful species, notably novel pollutants like environmentally persistent free radicals (EPFRs), remains unclear. Therefore, one-year site monitoring and ambient air PM2.5 sampling in the Nanjing urban area was designed to investigate the relationships between chemical compositions (carbon fractions, metallic elements, and water-soluble ions) and EPFRs, and change in cytotoxicity with varying PM2.5 components. Oxidative stress (reactive oxygen species, ROS), inflammatory injury (IL-6 and TNF-α), and membrane injury (LDH) of human lung epithelial cells (A549) induced by PM2.5 were analyzed using in vitro cytotoxicity test. Both the composition and toxicity of PM2.5 from different seasons were compared. The average daily exposure of urban PM2.5 associated EPFRs load in Nanjing were 2.29 × 1011 spin m-3. Their exposure concentration and cytotoxic damage ability were stronger in the cold season than warm. The particle compositions of metals and carbon fractions were significantly positively correlated with EPFRs. The airborne EPFRs, organic carbon (OC), and heavy metal Cu, As, and Pb may pose principal cell damage ability, which is worthy of further study interlinking aerosol pollution and health risks.

Programmed Cell Death Pathways in the Pathogenesis of Idiopathic Inflammatory Myopathies.

Idiopathic inflammatory myopathy (IIM) is a heterogeneous group of acquired, autoimmune muscle diseases characterized by muscle inflammation and extramuscular involvements. Present literatures have revealed that dysregulated cell death in combination with impaired elimination of dead cells contribute to the release of autoantigens, damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and result in immune responses and tissue damages in autoimmune diseases, including IIMs. This review summarizes the roles of various forms of programmed cell death pathways in the pathogenesis of IIMs and provides evidence for potential therapeutic targets.

Prevalence of hyperthyroidism with hypercalcemia in Xindu district and the efficacy of vitamin D3 treatment in these patients: a randomized trial.

BACKGROUND: This trial aimed to analyze the relationship between hyperthyroidism and the morbidity rate of hypercalcemia in the Xindu district, Chengdu, Sichuan province. We observed the level of serum calcium, the bone metabolic and thyroid autoimmune-related antibodies index during vitamin D3 treatment combined with traditional antithyroid drugs (ATD). METHODS: Our research included hyperthyroid patients with a first-time diagnosis of Graves diseases (GD) combined with hypercalcemia on the basis of conventional anti-hyperthyroidism therapy, which were randomized into a vitamin D3 group (vitamin D3, 800-1,200 IU/day) and an ATD group (methimazole, 15-30 mg/day). All hyperthyroidism patients with hypercalcemia were analyzed, and changes in serum calcium (Ca2+), parathyroid hormone (PTH), thyroid function, thyroid autoimmune-related antibodies, and 25-dihydroxyvitamin D (25-OHVit D) levels during treatment of thyrotoxicosis with added vitamin D3 were explored. RESULTS: In total, 184 patients with hyperthyroidism were observed, including 36 (19.57%) patients associated with hypercalcemia, with an age of onset of (56.39±5.80) years old. Twelve (6.52%) of these 36 cases reported digestive symptoms as the first manifestation, and four (2.17%) patients presented with a hypercalcemia crisis as the first manifestation. Serum Ca2+, free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin hormone receptor antibody (TRAb) levels increased in patients with hypercalcemia. Following the addition of vitamin D3 treatment, serum Ca2+, FT3, FT4, and TRAb levels were significantly decreased relative to the ATD group, while the thyroid-stimulating hormone (TSH), PTH, and 25-OHVit D levels were normalized. CONCLUSIONS: Our study highlighted the importance of taking functional digestive disturbance into consideration in hyperthyroidism diagnosis, even in the absence of the typical symptoms. The level of thyroid related antibodies, thyroid function, and bone metabolism in hyperthyroidism patients combined with hypercalcemia could be improved by vitamin D3 adjuvant therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2100047870.

Seasonal and areal variability in PM2.5 poses differential degranulation and pro-inflammatory effects on RBL-2H3 cells.

PM2.5 pollution is a widespread environmental and health problem, particularly in China. Besides leading to well-known diseases in the respiratory system, PM2.5 can also alter immune function to induce or aggravate allergic diseases. To determine whether there are temporal and spatial differences in the allergic responses to PM2.5, monthly samples were collected from four regions (urban, industrial, suburban, and rural areas) through a whole year in Nanjing city, China. Inorganic chemical components (metals and water-soluble ions) of PM2.5 were analyzed, and the rat basophil cells (RBL-2H3) exposed to PM2.5 were assessed through quantitative measures of degranulation (ß-hex and histamine) and pro-inflammation cytokine (IL-4 and TNF-α) expression. The highest levels of ß-hex were measured in winter and spring PM2.5 from urban and industrial areas, or autumn PM2.5 from suburban and rural areas. With respect to histamine, autumn PM2.5 samples were most potent irrespective of the location. Autumn and winter PM2.5 induced higher levels of IL-4 than spring and summer samples. However, spring and autumn PM2.5 caused higher levels of TNF-α. The concentrations of water-soluble ions (NH4+, K+ and Cl-), as well as heavy metals (Pb and Cr), were directly and statistically correlated to the inflammation observed in vitro. In general, the differences between regional and seasonal PM2.5 in stimulating cell degranulation may depend on endotoxin and airborne allergen content of PM2.5. The heavy metals and water-soluble ions in PM2.5 were mostly anthropogenic, which increased the particles' mass-based cellular inflammatory potential, therefore, their health risks, e.g. from vehicular exhaust, coal, and biomass combustion, cannot be ignored.

Relationship between long non-coding RNA PCAT-1 expression and gefitinib resistance in non-small-cell lung cancer cells.

BACKGROUND: Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been used as first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, during treatment, cancer cells often develop resistance to gefitinib, the mechanisms of which are not fully understood. This study was designed to elucidate the expression and role of long non-coding RNA (lncRNA)-PCAT-1, a potential biomarker for drug resistance and a therapeutic target for NSCLC, in gefitinib resistance in NSCLC cells. METHODS: In this study, we verified differential PCAT-1 expression in NSCLC gefitinib-resistant tissues or cells. PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence assays were used to verify the correlation between PCAT-1 and gefitinib sensitivity. A nude mouse tumor-bearing model verified that PCAT-1 can reverse gefitinib resistance in vivo. Then, a PI3K/Akt agonist was used to verify the possible mechanism of PCAT-1 action. RESULTS: PCAT-1 is highly expressed in gefitinib-resistant NSCLC tissues and cells. PCAT-1 knockdown enhanced gefitinib sensitivity and gefitinib-induced apoptosis in H1299/GR cells. PCAT-1 knockdown reduced tumor volume and weight, and reversed acquired gefitinib resistance in vivo. PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation in H1299/GR cells. A PI3K/AKT agonist reversed PCAT-1 knockdown-mediated enhancement of gefitinib sensitivity in H1299/GR cells CONCLUSION: PCAT-1 knockdown improves sensitivity to gefitinib by inhibition of AKT and GSK3 phosphorylation in NSCLC. PCAT-1 is as potential target for improving the clinical efficacy of gefitinib.

Abnormalities of the PRMT1-ADMA-DDAH1 metabolism axis and probucol treatment in diabetic patients and diabetic rats.

BACKGROUND: Symmetrical dimethylarginine (ADMA) endogenously inhibits nitric oxide synthase (NOS) and strongly indicates oxidant stress, whose formation primarily derived from type 1 protein arginine N-methyltransferase (PRMT1) and whose metabolism was governed by type 1 dimethylarginine dimethylaminohydrolase (DDAH1). This study aimed to evaluate participation of the PRMT1-ADMA-DDAH1 metabolism axis in the kidneys of type 2 diabetes model rats and human subjects, and the effect of probucol on this axis and renal function. METHODS: A total of 30 rats were randomly assigned to a normal group (NC, n=10), diabetic group (DM, n=10), and a diabetics under probucol treatment group (PM, n=10). Throughout 8 weeks of probucol treatment, plasma NOS, the malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and catalase (CAT) activity were evaluated by chemical colorimetric approach. ADMA concentration was evaluated with an enzyme-linked immunosorbent assay (ELISA) and analysis of expression of PRMT1 and DDAH1 in kidneys with reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and western blotting were performed. RESULTS: The expression of DDAH1 in the kidney, and the plasma NOS, NO, SOD, and CAT activities in diabetic group were lower, while MDA and the expression of PRMT1 and ADMA were higher in contrast to the control group. In diabetics rats receiving probucol, the expressions of DDAH1 and ADMA were downregulated, whereas that of PRMT1 was upregulated. Probucol inhibited the indexes of oxidative stress and improved the kidney function in both diabetic rats and humans. CONCLUSIONS: We found that the expression of the PRMT1-ADMA-DDAH1 axis was altered in the kidneys of diabetic rats. Moreover, results indicated that probucol therapy regulates expression at both ends of this axis, which may preserve renal function by reducing oxidant stress. Therefore, probucol may partially restore expression of the PRMT1-ADMA-DDAH1 axis in diabetic kidneys, immigrate oxidant stress, and enhance renal function.