PDGFRß-Antagonistic Affibody-Mediated Tumor-Targeted Tumor Necrosis Factor-Alpha for Enhanced Radiotherapy in Lung Cancer.

The morbidity and mortality of lung cancer are still the highest among all malignant tumors. Radiotherapy plays an important role in clinical treatment of lung cancer. However, the effect of radiotherapy is not ideal due to the radiation resistance of tumor tissues. Abnormalities in tumor vascular structure and function affect blood perfusion, and oxygen transport is impeded, making tumor microenvironment hypoxic. Tumor hypoxia is the major cause of radiotherapy resistance. By promoting tumor vessel normalization and enhancing vascular transport function, tumor hypoxia can be relieved to reduce radiotherapy resistance and increase tumor radiotherapy sensitivity. In our previous study, a pericytes-targeted tumor necrosis factor alpha (named Z-TNFα) was first constructed and produced by genetically fusing the platelet-derived growth factor receptor ß (PDGFRß)-antagonistic affibody (ZPDGFRß) to the TNFα, and the Z-TNFα induced normalization of tumor vessels and improved the delivery of doxorubicin, enhancing tumor chemotherapy. In this study, the tumor vessel normalization effect of Z-TNFα in lung cancer was further clarified. Moreover, the tumor hypoxia improvement and radiosensitizing effect of Z-TNFα were emphatically explored in vivo. Inspiringly, Z-TNFα specifically accumulated in Lewis lung carcinoma (LLC) tumor graft and relieved tumor hypoxia as well as inhibited HIF-1α expression. As expected, Z-TNFα significantly increased the effect of radiotherapy in mice bearing LLC tumor graft. In conclusion, these results demonstrated that Z-TNFα is also a promising radiosensitizer for lung cancer radiotherapy.

Triphenyl phosphate interferes with the synthesis of steroid hormones through the PPARγ/CD36 pathway in human trophoblast JEG-3 cells.

Triphenyl phosphate (TPhP), a chemical commonly found in human placenta and breast milk, has been shown to disturb the endocrine system. Our previous study confirmed that TPhP could accumulate in the placenta and interference with placental lipid metabolism and steroid hormone synthesis, as well as induce endoplasmic reticulum (ER) stress through PPARγ in human placental trophoblast JEG-3 cells. However, the molecular mechanism underlying this disruption remains unknown. Our study aimed to identify the role of the PPARγ/CD36 pathway in TPhP-induced steroid hormone disruption. We found that TPhP increased lipid accumulation, total cholesterol, low- and high-density protein cholesterol, progesterone, estradiol, glucocorticoid, and aldosterone levels, and genes related to steroid hormones synthesis, including 3ßHSD1, 17ßHSD1, CYP11A, CYP19, and CYP21. These effects were largely blocked by co-exposure with either a PPARγ antagonist GW9662 or knockdown of CD36 using siRNA (siCD36). Furthermore, an ER stress inhibitor 4-PBA attenuated the effect of TPhP on progesterone and glucocorticoid levels, and siCD36 reduced ER stress-related protein levels induced by TPhP, including BiP, PERK, and CHOP. These findings suggest that ER stress may also play a role in the disruption of steroid hormone synthesis by TPhP. As our study has shed light on the PPARγ/CD36 pathway's involvement in the disturbance of steroid hormone biosynthesis by TPhP in the JEG-3 cells, further investigations of the potential impacts on the placental function and following birth outcome are warranted.

The Accelerated Progression of Atherosclerosis Correlates with Decreased miR-33a and miR-21 and Increased miR-122 and miR-3064-5p in Circulation and the Liver of ApoE-/- Mice with Streptozocin (STZ)-Induced Type 2 Diabetes.

Atherosclerosis is a major risk factor for type 2 diabetes (T2D) mortality. We aim to investigate the changes in miR-21, miR-122, miR-33a and miR-3064-5p in circulation and the liver of ApoE-/- mice with streptozocin (STZ)-induced T2D. Twenty 5-week-old male ApoE-/- mice were randomly assigned to the control (n = 10) and T2D group (n = 10) and intraperitoneally injected with a citrate buffer and streptozotocin (STZ) (40 mg/kg BW) once a day for three consecutive days. The successfully STZ-induced T2D mice (n = 5) and control mice (n = 5) were then fed with a high-fat diet (HFD) for 34 weeks. Compared to the control mice, ApoE-/- mice with STZ-induced T2D had slower (p < 0.05) growth, increased (p < 0.05) total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), decreased (p < 0.05) high-density lipoprotein cholesterol (HDL-C) in serum, reduced (p < 0.05) TC and sterol regulatory element-binding protein-2 (Srebp-2), elevated (p < 0.05) ATP-binding-cassette-transporter-A1 (Abca1) in the liver, aggravated (p < 0.05) atherosclerotic lesions in the aorta, downregulated (p < 0.05) miR-21 and miR-33a, and upregulated (p < 0.05) miR-122 and miR-3064-5p in serum and the liver. In addition, the aortic lesions showed a positive correlation with miR-122 (r = 1.000, p = 0.001) and a negative correlation with miR-21 (r = −1.000, p = 0.001) in ApoE-/- mice with T2D. In conclusion, T2D-accelerated atherosclerosis correlates with a reduction in miR-21 and miR-33a and an elevation in miR-122 and miR-3064-5p in circulation and the liver of ApoE-/- mice.

Efficient microwave-to-optical single-photon conversion with a single flying circular Rydberg atom.

We propose a scheme for converting a microwave (mw) single photon in a mw cavity to a flying optical photon. The conversion is realized by using a flying circular Rydberg atom, which plays a role of the "data bus" as an excellent memory to connect the mw and optical cavities. To link the energy levels of atom in optical domain and mw domain, we use fast decircularization method and three-photon Raman transition method. Thank to these low loss processes and the super long lifetime of circular Rydberg states, this scheme can efficiently convert single mw photons into the optical domain. Based on existing experiments and data, the conversion efficiency is simulated as 60%. The theoretical limit of the conversion efficiency is about 87%.

A novel method for the quantification of anlotinib in human plasma using two-dimensional liquid chromatography.

A simple, efficient, and stable detection method of two-dimensional liquid chromatography (2D-LC) was established and validated to determine anlotinib in the human plasma. The 2D-LC system comprises a first-dimensional column (LC1), an intermediate transfer column, and a second-dimensional column (LC2). With simple protein precipitation treatment, the samples were processed directly for detection. The analysis cycle time was completed within 9.50 min. For the anlotinib concentrations, the calibration curve was linear over the 5.00-320.00 ng/mL range. The intra-day and inter-day precision ranges were 0.77-6.22% and 1.92-4.26%, respectively, for anlotinib concentrations. The recoveries were in the range of 97.85-102.50%. A total of 135 plasma samples from 94 patients were analyzed by our method. The plasma concentrations of patients were in the range of 5.17-106.38 ng/mL, in which the female had a higher plasma concentration (6.44-106.38 ng/mL). The simultaneous application of dexamethasone can increase the anlotinib concentration in the plasma. In our clinical application, we found that the factors that affect the plasma concentration include the time and dose of the medication, gender, and drug interactions. The method appears to be sensitive, precise, selective, and suitable for determining the concentration of anlotinib in the plasma sample.

The relationship between test anxiety and emotion regulation: the mediating effect of psychological resilience.

BACKGROUND: Test anxiety has been widely found in medical students. Emotion regulation and psychological resilience have been identified as key factors contributing to anxiety. However, studies on relationships were limited. This study investigated the links between psychological resilience, emotion regulation, and test anxiety in addition to exploring the differences about socio-demographic factors. METHODS: A sample of 1266 medical students was selected through cross-sectional survey from a medical university in China during 2019. Data were obtained by network technique using designed questionnaire, which assesses the level of test anxiety, emotion regulation and psychological resilience, respectively. RESULTS: Medical students experienced test anxiety at different levels, 33.7% of these were seriously. It revealed significant effects of the gender and academic performance on test anxiety. Results of logistic regression indicated that test anxiety was significantly associated with emotion regulation and psychological resilience (p < 0.01). Psychological resilience played a mediating role on the relationship between emotion regulation and test anxiety. CONCLUSIONS: These findings highlight the importance of psychological resilience and emotion regulation in understanding how psychological resilience relates to test anxiety in medical students. Resilience-training intervention may be developed to support students encountering anxiety during the exam.

New thymol and isothymol derivatives from Eupatorium fortunei and their cytotoxic effects.

Four new thymol derivatives (1-4), one new isothymol derivative (5), together with one known analogue (6) were isolated from the overground parts of Eupatorium fortunei. The structures were elucidated by extensive spectroscopic data analysis, including UV, IR, HR-ESIMS, 1D-, and 2D-NMR data. All compounds were evaluated for their cytotoxic effects against four human cancer cell lines using MTT assay. Compounds 1, 2, and 6 showed cytotoxicities with IC50 values 6.24-11.96 µM against MCF-7, HeLa, A549, and Hep G-2 cell lines.

Cachexia-related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs.

Cancer-associated cachexia (CAC) is a devastating syndrome characterized by progressive losses of adipose tissue and skeletal muscle. CAC-related adipose tissue loss (CAL) occurs early and is associated with a shorter survival time. To explore potential regulatory long noncoding RNAs (lncRNAs) of CAL, RNA microarrays were used to analyze the transcriptomes of white adipose tissue from CAC mice vs. control mice. A set of differentially expressed lncRNAs was identified, and among them was CAAlnc1, which suppressed adipogenesis of C3H10 cells as demonstrated by gain-of-function and loss-of-function experiments. RNA immunoprecipitation and pull-down assays revealed Hu antigen R (HuR) was an important binding partner of CAAlnc1. The interaction between CAAlnc1 and HuR blocked the binding of HuR to adipogenic transcription factor mRNAs and further downregulated the expression of these transcription factors. This study generated a list of CAL-related lncRNAs and provided details of a functional lncRNA which may play an important role in CAL.

U2-related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation.

Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double-stranded DNA breaks and cell death. Furthermore, UPF3A, the RNA surveillance factor, was identified as a splicing target of CHERP and SR140, which bind specifically to the regulated exon4 and modulate UPF3A splicing. UPF3A knockdown recapitulates CHERP/SR140 depletion both in vitro and in mice. Importantly, overexpression of UPF3A significantly rescues proliferation defect of CHERP/SR140-depleted cells. These results confirmed that the effect of CHERP/SR140 in promoting tumorigenesis was partially mediated by UPF3A. Extending these results, upregulation of CHERP/SR140 observed in CRC remarkably parallels increased inclusion of UPF3A exon4. Together, our study clarifies how CHERP/SR140 exert an oncogenic role in CRC development partially through regulating expression of UPF3A variants.

Quantification of the Plasma Concentration of Apatinib by 2-Dimensional Liquid Chromatography.

BACKGROUND: Apatinib is a new oral micromolecular tyrosine kinase inhibitor, which is mainly used as a third-line treatment for chemotherapy-refractory advanced metastatic gastric cancer patients. However, apatinib has shown dose titration and severe adverse reactions in clinical practice. Quantification of plasma concentrations of apatinib may be an effective method to balance the clinical efficacy and adverse reactions. The purpose of this study was to develop and validate a 2-dimensional liquid chromatography method for the measurement of apatinib in plasma. METHODS: The analysis of apatinib was performed using a 2-dimensional high-performance liquid chromatography system. We precipitated the proteins with acetonitrile. The mobile phases consisted of a first-dimensional mobile phase (acetonitrile:methanol:25 mmol·L ammonium phosphate = 25:25:50, V/V/V, pH adjusted to 7.2 using phosphoric acid) and a second-dimensional mobile phase (acetonitrile:10 mmol·L ammonium phosphate = 28:72, vol/vol, pH adjusted to 3.7 using phosphoric acid). The ultraviolet detection wavelength was set at 340 nm. The temperature of the detector cell was 40°C, and the injection volume was 500 µL. RESULTS: The range of calibration curve was 15.27-1491.48 ng/mL. The accuracy and imprecision were within ±2.23% and less than 10.22%, respectively (intraday and interday). The range of recovery was 97.45%-108.92%. The intraday and interday relative SDs (reproducibility) of high-performance liquid chromatography retention times were less than 0.18% and 0.46%, respectively. In the clinical assessment, the dose range of apatinib mesylate for patients with gastric cancer was 250-500 mg every day (2-60 days), resulting in trough plasma concentrations between 272.7 and 727.8 ng/mL. CONCLUSIONS: A simple, convenient, accurate, and robust 2-dimensional liquid chromatography method was developed and verified, which successfully determined the plasma concentrations of apatinib in patients with gastric cancer.

Competition and habitat filtering jointly explain phylogenetic structure of soil bacterial communities across elevational gradients.

The importance of assembly processes in shaping biological communities is poorly understood, especially for microbes. Here, we report on the forces that structure soil bacterial communities along a 2000 m elevational gradient. We characterized the relative importance of habitat filtering and competition on phylogenetic structure and turnover in bacterial communities. Bacterial communities exhibited a phylogenetically clustered pattern and were more clustered with increasing elevation. Biotic factors (i.e., relative abundance of dominant bacterial lineages) appeared to be most important to the degree of clustering, evidencing the role of the competitive ability of entire clades in shaping the communities. Phylogenetic turnover showed the greatest correlation to elevation. After controlling the elevation, biotic factors showed greater correlation to phylogenetic turnover than all the habitat variables (i.e., climate, soil and vegetation). Structural equation modelling also identified that elevation and soil organic matter exerted indirect effects on phylogenetic diversity and turnover by determining the dominance of microbial competitors. Our results suggest that competition among bacterial taxa induced by soil carbon contributes to the phylogenetic pattern across elevational gradient in the Tibetan Plateau. This highlights the importance of considering not only abiotic filtering but also biotic interactions in soil bacterial communities across stressful elevational gradients.

Concentrations and resorption patterns of 13 nutrients in different plant functional types in the karst region of south-western China.

BACKGROUND AND AIMS: Elucidating the stoichiometry and resorption patterns of multiple nutrients is an essential requirement for a holistic understanding of plant nutrition and biogeochemical cycling. However, most studies have focused on nitrogen (N) and phosphorus (P), and largely ignored other nutrients. The current study aimed to determine relationships between resorption patterns and leaf nutrient status for 13 nutrient elements in a karst vegetation region. METHODS: Plant and soil samples were collected from four vegetation types in the karst region of south-western China and divided into eight plant functional types. Samples of newly expanded and recently senesced leaves were analysed to determine concentrations of boron (B), calcium (Ca), copper (Cu), iron (Fe), potassium (K), magnesium (Mg), manganese (Mn), molybdenum (Mo), N, sodium (Na), P, sulphur (S) and zinc (Zn). KEY RESULTS: Nutrient concentrations of the karst plants were lower than those normally found in other regions of China and the rest of the world, and plant growth was mainly limited by P. Overall, four nutrients revealed resorption [N (resorption efficiency 34·6 %), P (48·4 %), K (63·2 %) and Mg (13·2 %)], seven nutrients [B (-16·1 %), Ca (-44·0 %), Cu (-14·5 %), Fe (-205·5 %), Mn (-72·5 %), Mo (-35·6 %) and Zn (-184·3 %)] showed accumulation in senesced leaves and two nutrients (Na and S) showed no resorption or accumulation. Resorption efficiencies of K and Mg and accumulation of B, Ca, Fe and Mn differed among plant functional types, and this strongly affected litter quality. Resorption efficiencies of N, P and K and accumulation of Ca and Zn increased with decreasing concentrations of these nutrients in green leaves. The N:P, N:K and N:Mg ratios in green leaves predicted resorption proficiency for N, K and Mg, respectively. CONCLUSIONS: The results emphasize the fact that nutrient resorption patterns strongly depend on element and plant functional type, which provides new insights into plant nutrient use strategies and nutrient cycling in karst ecosystems.

[Low-density lipoprotein cholesterol target goal attainment rate and related factors in patients with acute coronary syndrome after percutaneous coronary intervention].

OBJECTIVE: To observe the low-density lipoprotein cholesterol (LDL-C) target goal attainment rate and related factors in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: From March 2011 to March 2012, a total of 832 ACS patients were retrospectively evaluated in the Cardiology Department of the First Affiliated Hospital of Dalian Medical University. The target goal attainment rate after PCI was defined as the percentage of patients reaching LDL-C goals recommended by The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias (European guidelines) and Chinese guidelines on prevention and treatment of dyslipidemias in adults and Chinese guidelines on percutaneous coronary artery intervention treatment (Chinese guidelines). Multivariate logistic regression analysis was used to analyze the related factors. RESULTS: According to the European guidelines, the overall LDL-C goal attainment rates at 1 month and 9 months after PCI were 25.2% (210/832) and 22.2% (186/832), respectively. According to the Chinese guidelines, the overall LDL-C goal attainment rates at 1 month and 9 months after PCI were 46.5% (387/832) and 42.3% (352/832), respectively. In accordance with the Chinese guidelines, the multivariate logistic regression analysis showed that gender (females/males, OR = 0.650, 95%CI: 0.442-0.956), age ( ≥ 60 years/<60 years, OR = 0.628, 95%CI:0.464-0.850), hypertension (OR = 0.737, 95%CI: 0.547-0.994), prior myocardial infarction history (OR = 0.696, 95%CI:0.511-0.948), prior PCI history (OR = 0.575, 95%CI: 0.339-0.974) and baseline LDL-C levels ( OR = 0.155, 95%CI: 0.096-0.252) were independent risk factors that affected LDL-C goal attainment at 1 month post PCI. Moreover, the following parameters were the independent risk factors for LDL-C goal attainment at 9 months after PCI: prior myocardial infarction history (OR = 0.706, 95%CI:0.521-0.958), prior PCI history (OR = 0.565, 95%CI:0.334-0.957) and baseline LDL-C levels (OR = 0.176, 95%CI:0.110-0.282). CONCLUSIONS: Currently, the LDL-C control rate is low in patients with ACS after PCI. The cholesterol lowering therapy should be individually strengthened for patients after PCI, especially in female patients, patients with aged ≥ 60 years old, hypertension, prior myocardial infarction history, prior PCI history and higher baseline LDL-C level.

Drug-Coated Balloon for de-novo Coronary Artery Lesions Exceeding 2.5 mm in Diameter: Optical Coherence Tomography Analysis and Clinical Follow-Up.

Objective: To investigate the precise changes in the lumen and lesions, and clinical outcomes after DCB treatment for de-novo coronary lesions exceeding 2.5 mm in diameter through a detailed analysis of OCT. Methods: This is a prospective study including 53 consecutive patients with 55 de-novo coronary lesions, who underwent DCB angioplasty-only between January 2021 and April 2022. Quantitative coronary angiography (QCA) and OCT were performed before percutaneous coronary interventions (PCI), immediately after PCI, and at 6-9 months follow-up after PCI. Target lesion failure (TLF) was the primary endpoint of the present study. Multivariate logistic regression analysis was performed to identify the predictors or risks for late lumen enlargement (LLE). Results: A total of 52 patients were successfully treated with DCB. The median follow-up was 7 months, and the incidence of TLF was 7.5%. After the DCB procedure, 43 patients had their scheduled angiographic and OCT examination. QCA demonstrated that the late lumen loss was -0.79 ± 0.28 mm. OCT demonstrated LLE in 79.1% and dissection healing in 65.1% of lesions. After multivariable logistic analysis, type B dissection (odds ratio [OR] 2.92, 95% confidence interval [CI] 1.34-7.41, p = 0.037) was found to be a predictor of LLE, but lipid plaque (OR 0.09, 95% CI 0.01-0.63, p = 0.015) was a risk of LLE. Conclusion: This is the first and largest prospective study to assess the outcomes of DCB treatment for de-novo coronary lesions exceeding 2.5 mm in diameter and the detection of significant vessel enlargement and dissection healing guide by OCT. DCB could be a novel, safe and effective treatment for de-novo coronary lesions exceeding 2.5 mm in diameter through a detailed analysis of OCT.

Enhancement of antitumor response of staphylococcal enterotoxin C2 mutant 2M-118 by promoting cell-mediated antitumor immunity.

BACKGROUND: Staphylococcal enterotoxin C2 (SEC2) is used as an immunotherapeutic drug in China. However, SEC2 are limited due to its immunosuppressive and toxic effects. A SEC2 2M-118 (H118A/T20L/G22E) mutant generated by site-directed mutagenesis was studied to elucidate the underlying antitumor mechanism. METHODS: The effects of 2M-118 on mouse fibrosarcoma (Meth-A) cells and cytokine responses were tested in vitro using a transwell assay and ELISA, respectively. 2M-118 effect on immune function in tumor-bearing mice was tested. Cytokine levels and antitumor responses were measured using ELISA and flow cytometry, respectively. TUNEL staining and immunohistochemistry were employed to detect the tumor apoptosis and CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor tissue. RESULTS: 2M-118 demonstrated the growth inhibition on tumor cells, increase of cytokines production (IL-2, IFN-γ, and TNF-α) and splenocyte proliferation in vitro. 2M-118 effectively inhibited tumor development and increased lymphocytes and cytokines in a tumor-bearing mouse model. Additionally, 2M-118 regulated the tumormicroenvironment by reducing the number of myeloid-derived suppressor cells (MDSCs), increasing the number of TILs, and inducing tumorcell apoptosis. CONCLUSION: 2M-118 promotes immune function and enhances antitumor response. This indicates that 2M-118 could potentially be developed as a novel anti-tumor drug with-highefficiencyandlowtoxicity.

Neuroprotective mechanism of ribisin A on H2O2-induced PC12 cell injury model.

Ribisin A has been shown to have neurotrophic activity. The aim of this study was to evaluate the neuroprotective effect of ribisin A on injured PC12 cells and elucidate its mechanism. In this project, PC12 cells were induced by H2O2 to establish an injury model. After treatment with ribisin A, the neuroprotective mechanism of ribisin A was investigated by methyl tetrazolium (MTT) assay, Enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, fluorescent probe analysis, and western blot. We found that ribisin A decreased the rate of lactate dehydrogenase (LDH) release, increased cellular superoxide dismutase (SOD) level, decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), Ca2+ expression and reactive oxygen species (ROS). Moreover, ribisin A significantly increased mitochondrial membrane potential (MMP) and inhibited apoptosis of PC12 cells. Meanwhile, ribisin A activated the phosphorylation of ERK1/2 and its downstream molecule CREB by upregulating the expression of Trk A and Trk B, the upstream molecules of the ERK signaling pathway.

Macrophage exosomes mediate palmitic acid-induced metainflammation by transferring miR-3064-5p to target IκBα and activate NF-κB signaling.

INTRODUCTION: High palmitic acid (PA) levels trigger metainflammation, facilitating the onset and progression of chronic metabolic diseases. Recently, exosomes were identified as new inflammation mediators. However, the mechanism by which macrophage exosomes mediate PA-induced inflammation remains unclear. OBJECTIVES: To explore how PA induces metainflammation through macrophage exosomes. METHODS: Exosomes secreted by RAW264.7 mouse macrophages stimulated with PA (ExosPA) or not (Exos) were prepared by ultracentrifugation. The differential miRNAs between ExosPA and Exos were identified by high-throughput sequencing, and their targeted mRNAs and proteins were bioinformatically analyzed and verified by qPCR and western blot. Mouse macrophages and metabolic cells (AML-12 hepatocytes, C2C12 myocytes or 3T3-L1 adipocytes) were treated with ExosPA or Exos. The verified miRNAs and its targeted molecules related to inflammation were analyzed in recipient cells. Furthers, exosomes were prepared from primary peritoneal macrophages isolated from AIN93G diet-fed (Control PM-Exos) or HPD-fed (PA PM-Exos) mice. Control or PA PM-Exos were then tail vein injected (30 µg) into mice (n = 10), once a week for 2 weeks. The verified miRNA and its targets in blood, blood exosomes, and metabolic tissues were detected. Finally, measured the levels of miRNA, inflammatory factors, and fatty acids in the blood of 20 obese/overweight individuals and 20 healthy individuals. RESULTS: ExoPA activate NF-κB signaling and enhance inflammatory enzyme/cytokine production in macrophages and metabolic cells. ExoPA enrich miR-3064-5p and target to inhibit IκBα as verified by exosome inhibitors and miR-3064-5p mimics and inhibitors. HPD elevates exosomal miR-3064-5p, macrophage exosomal miR-3064-5p, and inflammatory cytokine levels in mice circulation. PA PM-Exos from HPD-fed mice triggered inflammation in the circulation and metabolic tissues/organs of chow diet-fed mice. Overweight/obese individuals exhibit increased levels of circulating palmitoleic acid, exosomal miR-3064-5p, and high-sensitivity C-reactive proteins. CONCLUSIONS: Macrophage exosomes transferring miR-3064-5p to target IκBα and activate NF-κB signaling in metabolic cells is a mechanism of PA-induced metainflammation.

Apelin stimulation of the vascular skeletal muscle stem cell niche enhances endogenous repair in dystrophic mice.

Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2-related MD, and collagen VI-related myopathy were associated with inefficient mobilization of MuSCs after tissue damage. Using chemoinformatic analysis, we identified the 13-amino acid form of the peptide hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. Systemic administration of AP-13 using osmotic pumps generated a pro-proliferative EC-rich niche that supported MuSC function through angiocrine factors and markedly improved tissue regeneration and muscle strength in all three dystrophic mouse models. Moreover, EC-specific knockout of the apelin receptor led to regenerative defects that phenocopied key pathological features of MD, including vascular defects, fibrosis, muscle fiber necrosis, impaired MuSC function, and reduced force generation. Together, these studies provide in vivo proof of concept that enhancing endogenous skeletal muscle repair by targeting the vascular niche is a viable therapeutic avenue for MD and characterized AP-13 as a candidate for further study for the systemic treatment of MuSC dysfunction.

Transcriptome analysis of Tetrahymena thermophila response to exposure with dihydroartemisinin.

Dihydroartemisinin (DHA) is a derivative of artemisinin and is toxic to parasites. We used the Tetrahymena thermophila (T. thermophila) as a model to explore DHA toxicity. Results showed that low concentration of DHA (20 µmol/L) promoted cell proliferation, whereas high concentrations of DHA (40-1280 µmol/L) inhibited that. Appearance of nucleus was pycnosis by laser scanning confocal microscope. DHA significantly elevated activities of SOD and GSH-Px (P < 0.01) and MDA was markedly increased at high level but decreased at low level (P < 0.01). Further results of transcriptome in T. thermophila treated with different concentration DHA group (0, 20, 160 µmol/L) showed that differentially expressed genes (DEGs) were involved in oxidation-reduction and metabolism of exogenous substances indicated oxidative stress stimulation. Kyoto Encyclopedia of Genes and Genomes showed that DEGs were involved in the cytochrome P450-mediated metabolism of exogenous substances, glutathione metabolism and ABC transport. Remarkably, DNA replication was significantly enriched in low concentration DHA, energy metabolism related pathways and necrotic process were considerably enriched in high concentration DHA. The results of RT-qPCR of 13 DEGs were the same as that of transcriptome, in which the expression of GST and GPx family genes were significantly altered after exposed to high-DHA group. DHA induced oxidative stress damage through disturbing with energy. However, detoxification pathways in T. thermophila to resist oxidative damage and cell alleviated low concentration DHA stress by regulating antioxidant enzyme. This study provides good practice on pharmacological mechanism of artemisinin-based drugs in antiparasitic.

Biologically Plausible Sparse Temporal Word Representations.

Word representations, usually derived from a large corpus and endowed with rich semantic information, have been widely applied to natural language tasks. Traditional deep language models, on the basis of dense word representations, requires large memory space and computing resource. The brain-inspired neuromorphic computing systems, with the advantages of better biological interpretability and less energy consumption, still have major difficulties in the representation of words in terms of neuronal activities, which has restricted their further application in more complicated downstream language tasks. Comprehensively exploring the diverse neuronal dynamics of both integration and resonance, we probe into three spiking neuron models to post-process the original dense word embeddings, and test the generated sparse temporal codes on several tasks concerning both word-level and sentence-level semantics. The experimental results show that our sparse binary word representations could perform on par with or even better than original word embeddings in capturing semantic information, while requiring less storage. Our methods provide a robust representation foundation of language in terms of neuronal activities, which could potentially be applied to future downstream natural language tasks under neuromorphic computing systems.