MicroRNA-23a-3p promotes macrophage M1 polarization and aggravates lipopolysaccharide-induced acute lung injury by regulating PLK1/STAT1/STAT3 signalling.

Macrophage polarization is an important effector process in acute lung injury (ALI) induced by sepsis. MicroRNAs (miRNAs) have emerged as important players in regulating ALI process. Here, we showed that elevated microRNA-23a-3p (miR-23a-3p) promoted LPS-induced macrophage polarization and ALI in mice, while inhibition of miR-23a-3p led to reduced macrophage response and ameliorated ALI inflammation. Mechanically, miR-23a-3p regulated macrophage M1 polarization through targeting polo-like kinase 1 (PLK1). PLK1 was downregulated in LPS-treated macrophages and ALI mouse lung tissues. Knockdown of PLK1 increased macrophage M1 polarization through promoting STAT1/STAT3 activation, while overexpression of PLK1 reduced macrophage immune response. Collectively, our results reveal a key miRNA regulon that regulates macrophage polarization for LPS-induced immune response.

High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.

Predictive criteria of severe cases in COVID-19 patients of early stage: A retrospective observational study.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) often suffer sudden deterioration of disease around 1-2 weeks after onset. Once the disease progressed to severe phase, clinical prognosis of patients will significantly deteriorate. METHODS: This was a multicenter retrospective study on patients of all adult inpatients (≥18 years old) from Tianyou Hospital (Wuhan, China) and the Fourth Affiliated Hospital, Zhejiang University School of Medicine. All 139 patients had laboratory-confirmed COVID-19 in their early stage, which is defined as within 7 days of clinical symptoms. Univariate and multivariate logistic regression models were used to determine the predictive factors in the early detection of patients who may subsequently develop into severe cases. RESULTS: Multivariable logistic regression analysis showed that the higher level of hypersensitivity C-reactive protein (OR = 4.77, 95% CI:1.92-11.87, P = .001), elevated alanine aminotransferase (OR = 6.87, 95%CI:1.56-30.21, P = .011), and chronic comorbidities (OR = 11.48, 95% CI:4.44-29.66, P < .001) are the determining risk factors for the progression into severe pneumonia in COVID-19 patients. CONCLUSION: Early COVID-19 patients with chronic comorbidities, elevated hs-CRP or elevated ALT are significantly more likely to develop severe pneumonia as the disease progresses. These risk factors may facilitate the early diagnosis of critical patients in clinical practice.

[Effect of Silencing FMOD on Proliferation and Migration of H322 Cells and Its Mechanism].

OBJECTIVE: To investigate the regulation of fibromodulin (FMOD) on proliferation, adhesion and migration of non-small cell lung cancer cell line H322, and discuss its action mechanism. METHODS: H322 cells were randomly divided into control group, small interfering RNA (siRNA) silencing FMOD ( FMOD siRNA) group and control siRNA (Con siRNA) group. FMOD siRNA and Con siRNA were transfected into H322 cells. The cell viability of each group was detected by CCK-8 method. The adhesion ability of cells was detected by fluorescein diacetate (FDA) fluorescent staining. The cell migration ability was detected by Transwell method. Real time-PCR was used to detect the mRNA expressions of Cyclin D1, intercellular adhesion molecule -1 （ICAM-1）, E-cadherin, FMOD, transforming growth factor-ß (TGF-ß), Smad2, Smad3, Smad4 and Smad7 in cells. The protein expressions of Cyclin D1, ICAM-1, E-cadherin, FMOD, TGF-ß1, Smad2, Smad3, Smad4 and Smad7 were detected by Western blot. RESULTS: Compared with the Con siRNA group, the cell viability, cell adhesion and migration ability of the FMOD siRNA group were decreased, and the difference was statistically significant ( P<0.01). There was no significant difference between the control group and the Con siRNA group. Real time-PCR and Western blot results showed that the mRNA and protein expression levels of Cyclin D1, ICAM-1, TGF-ß1, Smad2, Smad3 and Smad4 were decreased in FMOD siRNA group, compared with Con siRNA group, while the mRNA and protein expression levels of E-cadherin and Smad7 are elevated. CONCLUSION: Silencing of the FMOD gene significantly reduces the proliferation, adhesion and migration of H322 cells, which may be conducted by inhibiting the TGF-ß/Smad signaling pathway.

The pathology biopsy represents the "gold standard" for diagnosis: a case report.

A 70-year-old male with previously unknown immunodeficiency presented with multiple pulmonary nodular shadows observed on chest and abdomen radiography. Fungal infection was detected in brushing specimens, bronchial lavage, and transbronchial lung biopsy samples. Through next-generation sequencing (NGS) analysis, the patient was ultimately diagnosed with disseminated Talaromyces marneffei infection. Treatment with voriconazole at a dosage of 200 mg every 12 hours was initiated. However, after three months of treatment, the patient still had enlarged retroperitoneal lymph nodes, and a lymph node aspiration biopsy was performed to further clarify the diagnosis, which ultimately led to the diagnosis of Talaromyces marneffei infection and B-cell non-Hodgkin's lymphoma. The main significance of this study is to emphasize the importance for clinicians to obtain comprehensive specimens from patients presenting with multiple masses in order to ensure accurate clinical diagnosis.

A case study of College English teachers' emotional experiences in the blended teaching context.

The current research on language teacher education has witnessed a surge in studies focusing on teacher emotions due to their recognized importance in teaching. However, limited efforts have been found to investigate the emotions of Chinese College English teachers in the blended teaching context. This qualitative case study aims to uncover the emotional experiences of four Chinese College English teachers and explore the causes of their emotions in the blended teaching context. Data for the study was primarily gathered through interviews and case documents. The findings indicate that teachers in Eastern China experienced more positive emotions than negative emotions in the blended teaching context, while teachers in Western China exhibited the reverse pattern. These emotions were caused by their continuous appraisal of the interaction between their personal goals and various ecological systems. The research findings underscore the crucial role of teacher emotion in blended teaching and provide implications for enhancing blended teaching practices.

A narrative inquiry into the agency of an EFL teacher in Western China.

Despite the increasing interest in teacher agency in the field of language teacher psychology, little attention has been paid to how language teachers enact their agency in an under-resourced environment. To address the research gap, this narrative study explored how a secondary English as a foreign language teacher in Western China enacted his agency for professional development and identified its sources. The findings revealed that this teacher enacted his agency through passionate exploration of adaptive teaching and continuous investment in autonomous learning. His agency was attributed to the interplay of his past experiences, long-term goals, teaching beliefs, and the challenging working environment. Consequently, implications for teacher agency research and practice are discussed.

Consensus of Stochastic Dynamical Multiagent Systems in Directed Networks via PI Protocols.

With the rapid development of swarm intelligence, the consensus of multiagent systems (MASs) has attracted substantial attention due to its broad range of applications in the practical world. Inspired by the considerable gap between control theory and engineering practices, this article is aimed at addressing the mean square consensus problems for stochastic dynamical nonlinear MASs in directed networks by designing proportional-integral (PI) protocols. In light of the general algebraic connectivity, consensus underlying PI protocols for a directed strongly connected network is investigated, and due to the M -matrix approaches, consensus with PI protocols for a directed network containing a spanning tree is studied. By constructing appropriate Lyapunov functions, combining with the stochastic analysis technique and LaSalle's invariant principles, some sufficient conditions are derived under which the stochastic dynamical MASs realize consensus in mean square. Numerical simulations are finally presented to illustrate the validity of the main results.

AT2 Receptor Stimulation Inhibits Vascular Smooth Muscle Cell Senescence Induced by Angiotensin II and Hyperglycemia.

BACKGROUND: Hyperglycemia has been widely reported to induce vascular senescence. We have previously demonstrated that angiotensin II (Ang II) could promote brain vascular smooth muscle cell (VSMC) senescence, and its type 2 (AT2) receptor deletion could enhance VSMC senescence. Therefore, we examined the possible cross-talk between Ang II and hyperglycemia on VSMC senescence, and the roles of AT2 receptor agonist, compound 21 (C21) on it. METHODS: Aortic VSMCs were prepared from adult male mice and stimulated with Ang II and/or high glucose (Glu) and/or C21 and/or an autophagy inhibitor, 3-methyladenine (3-MA), and/or an autophagy agonist, rapamycin (RAP) for the indicated times. Cellular senescence, oxidative stress, and protein expressions were evaluated. RESULTS: Combination treatment with Ang II and Glu synergistically increased the proportion of VSMC senescent area compared with control group and each treatment alone, which was almost completely attenuated by C21 treatment. Moreover, combination treatment induced significant changes in the levels of superoxide anion, the expressions of p21 and pRb, and the ratio of LC3B II/I expression, which were also significantly attenuated by C21 treatment. The proportion of VSMC senescent area and the levels of superoxide anion by combination treatment were increased after 3-MA treatment, and the proportion of senescent area and the expressions of p21 and pRb were decreased after RAP treatment, both of which were further attenuated by C21 treatment. CONCLUSIONS: Ang II and hyperglycemia synergistically promoted VSMC senescence, at least partly through the participation by autophagy, oxidative stress, and p21-pRb pathway, which could be inhibited by C21.

PID Control for Synchronization of Complex Dynamical Networks With Directed Topologies.

Over the past decades, the synchronization of complex networks with directed topologies has received considerable attention owing to its extensive applications in the realistic world. Design of proportional-integral-derivative (PID) control protocols for achieving synchronization with directed networks is known to be a challenging task. The purpose of this paper is to establish a connection between the PID control protocols and synchronization of complex dynamical networks with directed topologies. Based on the classical complex network model, we investigate global synchronization with PD controller of a balanced strongly connected directed network and global synchronization with PI controller of a strongly connected directed network, and a directed network containing a spanning tree, respectively. Several sets of sufficient conditions are established under which the network reaches global synchronization. The simulation examples are presented to verify the efficiency of the theoretical results.

Semiglobal Consensus of a Class of Heterogeneous Multi-Agent Systems With Saturation.

This article addresses the leader-following consensus of a class of multi-agent systems (MASs) subjected to saturation. Unlike previous literature, the followers are with heterogeneous dynamics. To solve this problem, we employ the low-gain feedback technique and the parameterized algebraic Riccati equations to design the controllers. For the fixed and switching network topologies, sufficient conditions are put in place to guarantee the semiglobal stability of the consensus error system. Numerical results are also provided to validate the effectiveness of the control design.

Analysis of lung adenocarcinoma with bone metastasis: a case report.

Lung adenocarcinoma is one of the most common types of lung cancer, and patients with epidermal growth factor receptor (EGFR) mutation-positive can be intervened with EGFR-TKI therapy to achieve longer survival. AURA3 study showed that patients resistant with the first generation of EGFR-TKI and with T790M mutation still received longer progression-free survival (PFS) after treatment with the third generation of EGFR-TKI osimertinib, and osimertinib also had a good effect on brain metastasis. Moreover, the FLAURA study published by the European Society of Medical Oncology (ESMO) in 2019 showed that the first line use of osimertinib could achieve a PFS of 18.9 months. In recent years, researches on lung cancer seem like blooming flowers. The new treatment mode for lung cancer treatment such as anti-angiogenic drugs, immunotherapy programs has satisfactory efficacy either alone or in combination. Notably, patients with lung adenocarcinoma often have single or multiple bone metastasis, which brings great suffering to patients, especially when metastases occurred in the weight-bearing bone. However, there is no solid evidence to prove that chemotherapy, targeted therapy, anti-angiogenic drugs, or immunotherapy have long-term efficacy in bone metastasis of lung adenocarcinoma. The present strategies for bone metastasis of lung cancer include of: palliative care, analgesia, improvement of bone metabolism, local radiotherapy, and radionuclide therapy. However, by far, no medical treatment has a significant advantage in inhibiting the course of bone metastasis in lung cancer at the source. In this case, patient with advanced lung adenocarcinoma and EGFR mutation was resistant with the first generation of EGFR-TKI treatment, and after detection of T790M mutation, we switched to osimertinib for primary disease control, bone metastasis was still obvious, and there was still no obvious effect after pain relief, bone metabolism improvement and local radiotherapy. This case is reported to suggest that further efforts in anti-tumor and palliative treatment in bone metastasis of lung adenocarcinoma are urgently needed.

[Fluorescence study on the interaction of narrow distribution low polymerization degree chitooligosaccharides and human serum albumin].

Chitosan (CTS), a linear binary copolymer of (1-->8)-linked 2-acetamido-2-deoxy-beta-D-glucopyranose (GlcNAc unit) and 2-amino-2-deoxy-beta-D-glucopyranose (GlcNH2 unit), is derived from chitin by alkaline deacetylation. In the present work, the narrow molecular weight distribution chitooligosaccharides were prepared by degraded CTS with a microwave-assisted-cleavage method of metal-coordinating template-absorption catalytic oxidation. Under physiological pH conditions, the interaction of CTS and the narrow distribution chitooligosaccharides with Human serum albumin (HSA) was preliminarily explored by fluorescence spectra. Low molecular weight CTS in different concentration was added into HSA solution respectively, the absorptivity of the HSA solution decreased considerably. This phenomenon indicated that there was an interaction between these six different low molecular weight CTS with HSA, and the smaller the DP of the narrow distribution chitooligosaccharides, the stronger the interaction with HSA. However, the interaction gradually failed in as the DP was less than eight. The interaction almost disappeared when using glucosamine, the final product of degraded CTS, which revealed that there was a scale effect between chain-like CTS molecule and protein biomacromolecule. The results suggest that the strongest interaction binding occurs in CTS with DP approximately =8. Whether the DP increases or decreases, the interaction will weaken.

P27 Promotes TGF-ß-Mediated Pulmonary Fibrosis via Interacting with MTORC2.

Pulmonary fibrosis (PF), a progressive and life-threatening pulmonary disease, is the main pathological basis of interstitial lung disease (ILD) which includes the idiopathic pulmonary fibrosis (IPF). No effective therapeutic strategy for pulmonary fibrosis has been established. TGF-ß signaling has emerged as the vital regulator of PF; however, the detailed molecular mechanisms of TGF-ß in PF were uncertain. In the present study, we proved that inhibition of MTORC2 suppresses the expression of P27 in MRC5 and HLF cells. And in bleomycin-induced PF model, the expression of α-SMA and P27 was upregulated. Moreover, TGF-ß application increased the level of α-SMA, vimentin, and P27 in MRC5 and HLF cells. Furthermore, P27 overexpression advanced the cell cycle process and promoted the proliferation of MRC5 and HLF cells. Finally, the rescue experiment showed that MTORC2 knockdown reversed P27 overexpression-induced cell cycle acceleration and proliferation. Thus, our results suggest that P27 is involved in TGF-ß-mediated PF, which was regulated by MTORC2, providing a novel insight into the development of PF.

Correction: Increased Levels of Plasma Soluble Sema4D in Patients with Heart Failure.

[This corrects the article DOI: 10.1371/journal.pone.0064265.].

[Synthesis of sulfur-contained D(+)-glucosamine metal complexes and interaction with DNA and serum albumin].

Four sulfur-contained D(+)-glucosamine metal complexes were synthesized (M-GLUS, M = Co, Cu, Ni and Zn)and characterized by elementary analysis, molar conductance, and proton nuclear magnetic resonance. The yield of the complex was about 70%, and it dissolved easily in water. The ligand coordinates with metalions mainly between sulphur and metalions, the coordination molar ratio of the ligand to metalion was 2 : 1, and the molar conductivity indicated that all the complexes are nonelectrolyte. The mechanism of the interaction between metal complexes and calf thymus (ct) DNA in Tris buffer (pH = 7. 08), was studied by ultraviolet absorption and fluorescence spectroscopy. The results from varied experiments showed that the intensity of the maximal absorption peaks increased with gradual addition of metal complexes, but the metalions can decrease the maximal absorption and the ligand has no effect on it. Meanwhile, metal complexes could remarkably quench the emission intensity of the DNA-EB system, and the metal complexes could be bound to ct DNA. The quenching mechanism was discussed by Stern-Volmer's equation, the figure showed that it is influenced by static quenching and dynamic quenching, so the partial interaction of the complexes and ct DNA was the major mode. Under physiological pH condition, this study was designed to examine the effect of complexes on human serum albumin and bovine serum albumin by fluorescence. The binding constants and sites of the interaction with SA were analyzed by the Scatchard's equation, the results indicated that there was a strong interaction between the four metal complexes and serum albumin and the binding force was Co-GLUS > Zn-GLUS > Cu-GLUS > Cu-GLUS, and the binding site is only one.

[An experimental study of expression of angiotension converting enzyme 2 in myocardium and effect of telmisartan treatment in pressure-overloaded rats].

OBJECTIVE: To study the effect of hypertension and telmisartan treatment on the protein and gene expression of cardiac angiotensin-converting enzyme 2 (ACE2) in pressure-overloaded rats. METHODS: Coarctation of suprarenal abdominal aorta was reproduced in 8 week-old male Sprague-Dawley (SD) rats and then randomized into 4 groups, including a sham group (n=15), a suprarenal aortic coarctation group (model group, n=12), a suprarenal aortic coarctation with low-dose Telmisartan treatment group (low-dose group, 2 mgxkg(-1)xd(-1), n=11) and a suprarenal aortic coarctation with high-dose Telmisartan treatment group(high-dose group, 10 mgxkg(-1)xd(-1), n=13). Telmisartan or equivalent amount of normal saline was gavaged 24 hours before the operation and once every day afterwards for 3 weeks. At the end of 3 weeks, the concentrations of angiotensin (AngII) in plasma and myocardium were measured by radioimmunoassay. Changes in both protein quantity and gene expressions of both ACE2 and ACE were determined by Western blotting analysis and reverse transcription-polymerase chain reaction (RT-PCR) technique, respectively. RESULTS: Suprarenal abdominal aortic coarctation induced a significant increase in the plasma and myocardium AngII concentration [plasma: (495.1+/-55.6) ng/L vs. (269.2+/-39.5)ng/L, myocardium: (103.6+/-23.7) ng/g vs. (49.5+/-13.5) ng/g, both P<0.01] and expressions of gene and protein of ACE (P<0.01) and ACE2 (P<0.05). Telmisartan further increased the concentration of AngII in plasma and myocardium in a dose-dependent manner [plasma: (702.2+/-40.6) ng/L vs. (612.6+/-35.5) ng/L, myocardium (211.5+/-21.5) ng/g vs. (189.6+/-43.6) ng/g, both P<0.05], and induced a dose-dependent increase in both protein and gene expression of ACE2 (protein 1.16+/-0.06 vs. 0.79+/-0.04, gene 0.54+/-0.08 vs. 0.41+/-0.04, both P<0.05). Expression of ACE2 protein in low-dose and high-dose groups was increased by 1.0 and 1.58 folds respectively, and gene was increased by 1.3 and 1.6 folds (all P<0.05). The expression of ACE protein and gene in model group increased significantly (protein: 2.10+/-1.07 vs. 1.02+/-0.05, gene: 1.93+/-0.09 vs. 0.26+/-0.09, both P<0.01). Telmisartan had no significant effect on ACE gene and protein expressions (both P>0.05). CONCLUSION: Suprarenal abdominal aortic coarctation induced a significant increases of ACE and ACE2 gene and protein expressions. Telmisartan induces a dose-dependent increases of cardiac ACE2 gene and protein expression,which may be the mechanism of its therapeutic effects.

[Study on up-regulation of the expression of angiotensin-converting enzyme-2 in human umbilical vein endothelial cells by telmisartan].

OBJECTIVE: To investigate the effect of telmisartan on the protein and gene expression of angiotensin-converting enzyme-2 (ACE2) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were treated with various concentrations of telmisartan (10(-7), 10(-6) and 10(-5) mol/L) for 24 hours. In a time-control experiment, HUVECs were treated with telmisartan at the final concentration of 10(-6) mol/L for 6, 12 and 24 hours, respectively. In another experiment, HUVECs were treated with PD123319 (10(-6) mol/L) only or combined with same final concentration of telmisartan for 12 hours, respectively. Changes in both protein and gene expression of ACE2 were determined with Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) technique, respectively. RESULTS: Telmisartan induced a concentration and time dependent increase in both protein and gene expression of ACE2 (P<0.05 or P<0.01). Compared with control group, treatment of HUVECs with telmisartan at the concentration of 10(-7), 10(-6) and 10(-5) mol/L stimulated 1.5-, 2.7- and 4.6-fold increase in the ACE2 protein expression, as well as 1.2-, 2.3- and 4.5-fold increase in its gene expression, respectively. After treatment of HUVECs with telmisartan for 6, 12, and 24 hours at the concentration of 10(-6) mol/L, the ACE2 protein expression increased 1.6-, 2.7- and 4.2-fold, and its gene expression increased 1.3-, 2.3- and 4.0-fold, respectively. Compared with control and telmisartan groups, PD123319 had no effect on both protein and gene expression of ACE2 (P>0.05). CONCLUSION: Telmisartan up-regulates the protein and gene expression of ACE2 in HUVECs in a concentration and time dependent manner. This effect may be mediated via its specific pathway.

P-th moment and almost sure stability of stochastic switched nonlinear systems.

This paper mainly tends to utilize [Formula: see text]-type function to investigate p-th moment and almost sure stability for a class of stochastic switched nonlinear systems. Based on the multiple Lyapunov functions approach, some sufficient conditions are derived to check the stability criteria of stochastic switched nonlinear systems. One numerical example is provided to demonstrate the effectiveness of the proposed results.