Author Correction: Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling.

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Nicotine restores olfactory function by activation of prok2R/Akt/FoxO3a axis in Parkinson's disease.

BACKGROUND: Olfactory dysfunction occurs frequently in Parkinson's disease (PD). In this study, we aimed to explore the potential biomarkers and underlying molecular pathways of nicotine for the treatment of olfactory dysfunction in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: MPTP was introduced into C57BL/6 male mice to generate a PD model. Regarding in vivo experiments, we performed behavioral tests to estimate the protective effects of nicotine in MPTP-induced PD mice. RNA sequencing and traditional molecular methods were used to identify molecules, pathways, and biological processes in the olfactory bulb of PD mouse models. Then, in vitro experiments were conducted to evaluate whether nicotine can activate the prok2R/Akt/FoxO3a signaling pathway in both HEK293T cell lines and primary olfactory neurons treated with 1-methyl-4-phenylpyridinium (MPP+). Next, prok2R overexpression (prok2R+) and knockdown (prok2R-) were introduced with lentivirus, and the Akt/FoxO3a signaling pathway was further explored. Finally, the damaging effects of MPP+ were evaluated in prok2R overexpression (prok2R+) HEK293T cell lines. RESULTS: Nicotine intervention significantly alleviated olfactory and motor dysfunctions in mice with PD. The prok2R/Akt/FoxO3a signaling pathway was activated after nicotine treatment. Consequently, apoptosis of olfactory sensory neurons was significantly reduced. Furthermore, prok2R+ and prok2R- HEK293T cell lines exhibited upregulation and downregulation of the Akt/FoxO3a signaling pathway, respectively. Additionally, prok2R+ HEK293T cells were resistant to MPP+-induced apoptosis. CONCLUSIONS: This study showed the effectiveness and underlying mechanisms of nicotine in improving hyposmia in PD mice. These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activated prok2R/Akt/FoxO3a axis. These results explained the potential protective functions of nicotine in PD patients.

GBP2 inhibits pathological angiogenesis in the retina via the AKT/mTOR/VEGFA axis.

Pathological retinal angiogenesis is not only the hallmark of retinopathies, but also a major cause of blindness. Guanylate binding protein 2 (GBP2) has been reported to be associated with retinal diseases such as diabetic retinopathy and hypoxic retinopathy. However, GBP2-mediated pathological retinal angiogenesis remains largely unknown. The present study aimed to investigate the role of GBP2 in pathological retinal angiogenesis and its underlying molecular mechanism. In this study, we established oxygen-induced retinopathy (OIR) mice model for in vivo study and hypoxia-induced angiogenesis in ARPE-19 cells for in vitro study. We demonstrated that GBP2 expression was markedly downregulated in the retina of mice with OIR and ARPE-19 cells treated with hypoxia, which was associated with pathological retinal angiogenesis. The regulatory mechanism of GBP2 in ARPE-19 cells was studied by GBP2 silencing and overexpression. The regulatory mechanism of GBP2 in the retina was investigated by overexpressing GBP2 in the retina of OIR mice. Mechanistically, GBP2 downregulated the expression and secretion of vascular endothelial growth factor (VEGFA) in ARPE-19 cells and retina of OIR mice. Interestingly, overexpression of GBP2 significantly inhibited neovascularization in OIR mice, conditioned medium of GBP2 overexpressing ARPE-19 cells inhibited angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, we confirmed that GBP2 downregulated VEGFA expression and angiogenesis by inhibiting the AKT/mTOR signaling pathway. Taken together, we concluded that GBP2 inhibited pathological retinal angiogenesis via the AKT/mTOR/VEGFA axis, thereby suggesting that GBP2 may be a therapeutic target for pathological retinal angiogenesis.

MCPIP1 promotes cell proliferation, migration and angiogenesis of glioma via VEGFA-mediated ERK pathway.

Glioma is the most common primary malignant intracranial tumor in the population, and is often associated with abundant angiogenesis. However, how angiogenesis is regulated during glioma progression is still poorly understood. Data mining of cancer patient database shows that MCPIP1 is positively correlated with VEGFA expression and negatively with survival. In this study, we report that overexpressed MCPIP1 in glioma cells is a boost of angiogenesis. Mechanistically, MCPIP1 upregulates the expression of VEGFA in glioma, and promote the secretion of VEGFA to the surroundings, which could stimulate angiogenesis through ERK pathway. Blocking VEGFA expression and secretion inhibited MCPIP1-mediated angiogenesis and glioma progression in vitro and xenograft models. Collectively, these results identify a critical role for MCPIP1 in angiogenesis and glioma progression by regulating the VEGFA-mediated ERK pathway, suggesting that targeting MCPIP1 may be a potential glioma-selective therapeutic strategy.

Chemokine (C-C motif) receptor 2 is associated with the pathological grade and inflammatory response in IgAN children.

BACKGROUND: Chemokine (C-C motif) receptor 2 (CCR2) is involved in important physiological and pathological processes, such as inflammation and autoimmune diseases. Abnormal immune and inflammatory responses play a critical role in the development and progression of IgA nephritis (IgAN). However, the role of CCR2 in IgAN is unknown. METHODS: Fifteen IgAN children who were diagnosed by kidney biopsy provided kidney biopsy tissue, blood and urine samples, and age-matched healthy control subjects (blood donators n = 12; tissue donators n = 8) were included. Immunohistochemical analysis was used to detect the expression of CCR2, MCP-1, IL-6, IL-17, and TNF-α in the kidney tissues. Relative optical density (OD) was calculated by Image J software, and the correlation between CCR2 expression and pathological grade in IgAN children was analyzed. RESULTS: The expression of CCR2 significantly increased in mesangial cells of children with IgAN compared to that in control group (P < 0.001), especially in IgAN patients with Lee's grade III to IV (P < 0.001). Interestingly, CCR2 expression was positively correlated with Lee's grade (r = 0.9152, P = 0.0001) in IgAN children. The expression levels of inflammatory factors were markedly increased in IgAN children, and importantly CCR2 expression was positively correlated with it's expression level. CONCLUSIONS: The results suggest that CCR2 signaling might be involved in pathological process and inflammatory responses of children IgAN, and could potentially be an intervention target in children IgAN.

Schizophrenia patients with a metabolically abnormal obese phenotype have milder negative symptoms.

BACKGROUND: Schizophrenia patients with a metabolically abnormal obese (MAO) phenotype have been shown poor cardiovascular outcomes, but the characteristics of their current psychiatric symptoms have not been characterized. This study mainly explored the psychiatric symptoms of schizophrenia patients with the MAO phenotype. METHODS: A total of 329 patients with schizophrenia and 175 sex- and age-matched people without schizophrenia from Anhui Province in China were enrolled. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the mental symptoms of the schizophrenia patients. The MAO phenotype was defined as meeting 1-4 metabolic syndrome criteria (excluding waist circumference) and having a body mass index (BMI) ≥ 28 kg/m2. And, metabolically healthy normal-weight (MHNW) phenotype was defined as meeting 0 criteria for metabolic syndrome and 18.5 ≤ BMI < 24 kg/m2. RESULTS: Overall, 15.8% of the schizophrenia patients and 9.1% of the control group were consistent with the MAO phenotype, and the prevalence of MAO in the schizophrenia group was higher than that in the control group. Among the patients with schizophrenia, the MAO group had lower negative factor, cognitive factor and total PANSS scores than the MHNW group. However, when confounding factors were controlled, only the negative factor remained lower significantly. CONCLUSION: We found that schizophrenia patients with the MAO phenotype had reduced negative symptoms, which may indicate an internal mechanism linking metabolic disorders and negative symptoms. TRIAL REGISTRATION: This study was registered in the China Clinical Trial Registration Center (No. chiCTR 1,800,017,044 ).

A higher body mass index in Chinese inpatients with chronic schizophrenia is associated with elevated plasma orexin-A levels and fewer negative symptoms.

Objective: Orexin-A is involved in numerous physiological functions, such as feeding behavior and energy balance. Yet, the associations among the orexin system, weight changes and the clinical symptoms of schizophrenia patients remain uncertain, especially in inpatients with chronic schizophrenia (CS). The purpose of this study was to investigate the relationship between the orexin-A levels, body mass index (BMI) and clinical symptoms of CS inpatients.Methods: Altogether, 324 inpatients were enrolled in our study. The clinical symptoms of all inpatients were measured using a 30-item Positive and Negative Syndrome Scale (PANSS), and then we calculated the BMI of each subject and tested the orexin-A levels by ELISA methods.Results: The orexin-A levels of the CS inpatients in the obesity group (1.24 ± 1.45 ng/ml, n = 52) were significantly higher than those in the non-overweight group (0.85 ± 1.18 ng/ml, n = 176) and the overweight group (0.97 ± 1.15 ng/ml, n = 96). Spearman's correlation analysis showed that higher BMIs were associated with higher plasma orexin-A levels and fewer negative symptoms. Furthermore, the multiple regression analysis indicated that the orexin-A level could be a contributor to BMI (F = 30.21, p < 0.001). However, there was no correlation between plasma orexin-A concentrations and clinical symptoms in our research.Conclusion: A higher plasma orexin-A level may be a factor influencing the BMI of inpatients with CS, and fewer negative symptoms seem to be correlated with higher BMI, but the causality among BMI, orexin-A and clinical symptoms of schizophrenia requires further clinical research.

IgA1 isolated from Henoch-Schönlein purpura children promotes proliferation of human mesangial cells in vitro.

Previous studies show that the proliferation of human mesangial cells (HMCs) played a significant part in the pathogenesis of Henoch-Schönlein purpura nephritis (HSPN). The aim of this study was to explore the proliferation of HMCs induced by IgA1 isolated from the sera of HSP patients. HMCs were cultured in three different types of media, including IgA1 from patients with HSP (HSP IgA1 group), healthy children (healthy IgA1 group) and medium (control group). The proliferation of HMCs incubated with IgA1 was determined by cell counting kit-8 assay and bromodeoxyuridine incorporation. The expression of ERK1/2 and phosphatidylinositol 3 kinase/protein kinase B/mammalian targets of the rapamycin (PI3K/AKt/mTOR) signals and transferrin receptor (TfR/CD71) was detected with the methods of immunoblotting. The results indicated that the proliferation of HMCs significantly increased in the HSP IgA1 group compared with that in the control group or the healthy IgA1 group (P < 0.001). Moreover, we found that IgA1 isolated from HSP patients activated ERK and PI3K/AKt/mTOR signals, and markedly increased TfR/CD71 expression in HMCs. These effects induced by IgA1 isolated from patients with HSP were inhibited by human TfR polyclonal antibody (hTfR pAb) and soluble human transferrin receptor (sTfR), indicating that IgA1-induced HMC proliferation and ERK1/2 and PI3K/AKt/mTOR activation were dependent on TfR/CD71 engagement. Altogether, these data suggested that TfR/CD71 overexpression and ERK1/2 and PI3K/AKt/mTOR activation were engaged in HMC proliferation induced by IgA1 from HSP patients, which might be related to the mesangial injury of HSPN.

Association of Bone Morphogenetic Protein (BMP)/Smad Signaling Pathway with Fracture Healing and Osteogenic Ability in Senile Osteoporotic Fracture in Humans and Rats.

BACKGROUND To investigate the effect of the BMP/Smad signaling pathway on fracture healing and osteogenic ability in senile osteoporotic fracture on humans and rats. MATERIAL AND METHODS Sixty-two patients and well-matched normal controls were enrolled for clinical observation. A rat model of senile osteoporotic fracture was established. Serum BMP2 and Smad4 levels, as well as alkaline phosphatase (ALP) activity, were detected by ELISA. Fracture healing was observed by X-ray radiography and bone formation was analyzed by micro-CT. RESULTS Serum BMP2 and Smad4 levels in patients with senile osteoporotic fracture were significantly lower than those in normal controls (all P<0.01). BMP2 was highly positively correlated with Smad4 in patients with senile osteoporotic fracture (r=0.738). Compared with patients with low serum BMP2 and Smad4 levels, visual analog scale scores decreased, bone mineral density (BMD) increased, and duration of fracture healing was shortened in patients with high levels (all P<0.05). Compared with the Model group, serum BMP2 and Smad4 levels increased, fracture healing was improved, BMD, trabecular bone volume (TBV), tissue volume (TV), bone volume fraction (BV/TV), mean trabecular thickness (Tb. Th), and mean number of trabecular bone (Tb. N) were increased, and ALP activity increased in the BMP2 overexpression group (all P<0.05), while each index in the NC group showed no statistical difference relative to rats in the Model group (all P>0.05). CONCLUSIONS BMP2 overexpression can promote fracture healing and osteogenic ability in senile osteoporotic fractures through activating the BMP/Smad signaling pathway.

Henoch-Schönlein purpura with acute pancreatitis: analysis of 13 cases.

BACKGROUND: Henoch-Schönlein purpura is a common small vessel vasculitis in children. Acute pancreatitis rarely presents as a complication of Henoch-Schönlein purpura and has not been well characterized. METHODS: We retrospectively reviewed 13 cases of Henoch-Schönlein purpura with acute pancreatitis among 3212 patients who attended our hospital between January 2003 and June 2016 and analyzed their clinical characteristics, laboratory findings, imaging findings, treatment and overall prognosis. RESULTS: All patients had abdominal manifestations, including significant abdominal pain (13/13), vomiting (9/13), abdominal distension (3/13) and melena (6/13). Serum amylase level significantly increased in all patients, and urine amylase was increased in 7 cases (7/10). However, increased urine lapse was only noted in 2 cases (2/5), and diffuse swelling of the pancreas was seen in 2 cases (2/13) by abdominal ultrasonography. Although all patients had typical skin purpura (13/13), 5 patients (5/13) with acute pancreatitis initially experienced acute abdominal pain in clinical onset of Henoch-Schönlein purpura. Glucocorticoid therapy was effective in alleviating abdominal symptoms of Henoch-Schönlein purpura patients with acute pancreatitis. All patients were in good general condition without any abdominal complications 6-12 months after discharge. CONCLUSIONS: Acute pancreatitis is rarely observed in Henoch-Schönlein purpura children and has no specific clinical features that differentiate it from abdominal manifestations of Henoch-Schönlein purpura. Therefore, in Henoch-Schönlein purpura patients with severe abdominal pain, serum amylase levels should be assessed to confirm the diagnosis of acute pancreatitis. Early diagnose of Henoch-Schönlein purpura with acute pancreatitis and treatment timely was very important for good clinical outcomes.

Ethanol-induced damage to the developing spinal cord: The involvement of CCR2 signaling.

Ethanol exposure during development causes fetal alcohol spectrum disorders (FASD). A large body of evidence shows that ethanol produces multiple abnormalities in the developing central nervous system (CNS), such as smaller brain size, reduced volume of cerebral white matter, permanent loss of neurons, and alterations in synaptogenesis and myelinogenesis. The effects of ethanol on the developing spinal cord, however, receive little attention and remain unclear. We used a third trimester equivalent mouse model to investigate the effect of ethanol on the developing spinal cord. Ethanol caused apoptosis and neurodegeneration in the dorsal horn neurons of mice of early postnatal days, which was accompanied by glial activation, macrophage infiltration, and increased expression of CCR2, a receptor for monocyte chemoattractant protein 1 (MCP-1). Ethanol-induced neuronal death during development resulted in permanent loss of spinal cord neurons in adult mice. Ethanol stimulated endoplasmic reticulum (ER) stress and oxidative stress, and activated glycogen synthase kinase 3ß (GSK3ß) and c-Jun N-terminal kinase (JNK) pathways. Knocking out MCP-1 or CCR2 made mice resistant to ethanol-induced apoptosis, ER stress, glial activation, and activation of GSK3ß and JNK. CCR2 knock out offered much better protection against ethanol-induced damage to the spinal cord. Thus, developmental ethanol exposure caused permanent loss of spinal cord neurons and CCR2 signaling played an important role in ethanol neurotoxicity.

ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis.

BACKGROUND: Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence. METHODS: We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in response to alcohol exposure in breast cancer cells overexpressing ErbB2/HER2. RESULTS AND DISCUSSION: Chronic alcohol exposure increased breast cancer stem cell-like CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice. Alcohol exposure caused a drastic increase in CSC population and mammosphere formation in breast cancer cells overexpressing ErbB2/HER2. Alcohol exposure stimulated the phosphorylation of p38γ MAPK (p-p38γ) which was co-localized with phosphorylated ErbB2 and CSCs in the mammary tumor tissues. In vitro results confirmed that alcohol activated ErbB2/HER2 and selectively increased p-p38γ MAPK as well as the interaction between p38γ MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38α/ß MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38γ MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin ß1- and alcohol-stimulated p-p38γ MAPK and its association with SAP97. More importantly, p38γ MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2. CONCLUSIONS: p38γ MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38γ MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness.

Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation.

Alcohol abuse increases the risk for pancreatitis. The pattern of alcohol drinking may impact its effect. We tested a hypothesis that chronic ethanol consumption in combination with binge exposure imposes more severe damage to the pancreas. C57BL/6 mice were divided into four groups: control, chronic ethanol exposure, binge ethanol exposure and chronic plus binge ethanol exposure. For the control group, mice were fed with a liquid diet for two weeks. For the chronic ethanol exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks. In the binge ethanol exposure group, mice were treated with ethanol by gavage (5g/kg, 25% ethanol w/v) daily for 3days. For the chronic plus binge exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks and exposed to ethanol by gavage during the last 3days. Chronic and binge exposure alone caused minimal pancreatic injury. However, chronic plus binge ethanol exposure induced significant apoptotic cell death. Chronic plus binge ethanol exposure altered the levels of alpha-amylase, glucose and insulin. Chronic plus binge ethanol exposure caused pancreatic inflammation which was shown by the macrophages infiltration and the increase of cytokines and chemokines. Chronic plus binge ethanol exposure increased the expression of ADH1 and CYP2E1. It also induced endoplasmic reticulum stress which was demonstrated by the unfolded protein response. In addition, chronic plus binge ethanol exposure increased protein oxidation and lipid peroxidation, indicating oxidative stress. Therefore, chronic plus binge ethanol exposure is more detrimental to the pancreas.

Facts and Hopes on Chimeric Cytokine Agents for Cancer Immunotherapy.

Cytokines are key mediators of immune responses that can modulate the antitumor activity of immune cells. Cytokines have been explored as a promising cancer immunotherapy. However, there are several challenges to cytokine therapy, especially a lack of tumor targeting, resulting in high toxicity and limited efficacy. To overcome these limitations, novel approaches have been developed to engineer cytokines with improved properties, such as chimeric cytokines. Chimeric cytokines are fusion proteins that combine different cytokine domains or link cytokines to antibodies (immunocytokines) or other molecules that can target specific receptors or cells. Chimeric cytokines can enhance the selectivity and stability of cytokines, leading to reduced toxicity and improved efficacy. In this review, we focus on two promising cytokines, IL2 and IL15, and summarize the current advances and challenges of chimeric cytokine design and application for cancer immunotherapy. Most of the current approaches focus on increasing the potency of cytokines, but another important goal is to reduce toxicity. Cytokine engineering is promising for cancer immunotherapy as it can enhance tumor targeting while minimizing adverse effects.

Bacteria-derived nanovesicles enhance tumour vaccination by trained immunity.

Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1ß secretion. The elevated interleukin-1ß increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.

Spontaneous transformation of cynomolgus mesenchymal stem cells in vitro: further confirmation by short tandem repeat analysis.

It remains a highly debatable issue whether mesenchymal stem cells (MSCs) can undergo spontaneous transformation in culture. Recently, two groups retracted their previous publications due to the finding that the claimed transformed cells are actually contaminating cancer cells, which calls for a more stringent identification of transformed cells in the field. In this study, we continued with our previous finding of spontaneous transformation of cynomolgus MSCs and provided further evidence using short tandem repeat analysis that the transformed mesenchymal stem cells were indeed derived from cynomolgus MSCs.

AZGP1 as a potential biomarker of IgA vasculitis with nephritis in a children­based urinary proteomics study by diaPASEF.

The present study aimed to screen for potential biomarkers in the urine of immunoglobulin A vasculitis with nephritis (IgAVN) using parallel accumulation­serial fragmentation combined with data­independent acquisition (diaPASEF) proteomic approach. Urine proteomes of eight children with IgAVN and eight healthy children were identified by diaPASEF and all differential proteins were analyzed by Gene Ontology and Kyoto Encyclopedia of Gene and Genome. Then, the specific biomarkers of urine samples from 10 children with IgAVN, 10 children with IgAV and 10 healthy children were verified by ELISA. The present study screened 254 differential proteins from the experiment, including 190 upregulated proteins and 64 downregulated proteins. The results of the ELISA showed that the concentration of urinary zinc­alpha­2­glycoprotein (AZGP1) in children with IgAVN was significantly higher compared with that in children with IgAV and healthy children. The present study provided the potential clinical application of AZGP1 as a helpful biomarker and a potential indicator for early diagnosis of the occurrence of IgAVN.

Seawater Corrosion Resistance of Duplex Stainless Steel and the Axial Compressive Stiffness of Its Reinforced Concrete Columns.

In order to explore the corrosion resistance of duplex stainless steel under seawater corrosion and the compressive stiffness of its reinforced concrete columns, this study first performed seawater corrosion resistance tests on HRB400 ordinary steel rebar and S32205 duplex stainless steel rebar. The effect of the corrosion product film on the corrosion behavior was investigated through polarization curve tests and electrochemical impedance spectroscopy tests. The results showed that the corrosion rate of S32205 duplex stainless steel in a seawater environment was approximately 1/15 that of the HRB400 ordinary steel rebar. The anodic polarization curve of duplex stainless steel rebars exhibited a greater slope than that of carbon steel rebars. In the simulated seawater environment, the corrosion rate of these two kinds of steel bars showed different trends. The corrosion rate of ordinary steel bar HRB400 first decreased and then increased, while that of duplex stainless steel S2205 increased steadily. Furthermore, 18 short concrete columns reinforced with ordinary and duplex stainless steel rebars were subjected to the axial compression test and stiffness analysis; the stiffness of the short columns was calculated from the test data. The theoretical values agreed with the test values, with a stiffness calculation error of less than 5%.

Clinical and preclinical evaluation of miR-144-5p as a key target for major depressive disorder.

BACKGROUND: Neuronal abnormalities are closely associated with major depressive disorder (MDD). Available evidence suggests a role for microRNAs (miRNAs) in regulating the expression of genes involved in MDD. Hence, miRNAs that can be potential therapeutic targets need to be identified. METHODS: A mouse model of chronic unpredictable stress (CUS) was used to evaluate the function of miRNAs in MDD. miR-144-5p was screened from the hippocampi of CUS mice based on sequencing results. Adenovirus-associated vectors were used to overexpress or knockdown miR-144-5p in mice. BpV(pic) and LY294002 were used to determine the relationship between miR-144-5p target genes PTEN and TLR4 in neuronal impairment caused by miR-144-5p deficiency. Western blotting, immunofluorescence, ELISA immunosorbent assay, and Golgi staining were used to detect neuronal abnormalities. Serum samples from healthy individuals and patients with MDD were used to detect miR-144-5p levels in the serum and serum exosomes using qRT-PCR. RESULTS: miR-144-5p expression was significantly decreased within the hippocampal dentate gyrus (DG) of CUS mice. Upregulation of miR-144-5p in the DG ameliorated depression-like behavior in CUS mice and attenuated neuronal abnormalities by directly targeting PTEN and TLR4 expression. Furthermore, miR-144-5p knockdown in normal mice led to depression-like behavior via inducing neuronal abnormalities, including abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation. miR-144-5p deficiency-mediated neuronal impairment was mediated by PI3K/Akt/FoxO1 signaling. Furthermore, miR-144-5p levels were downregulated in the sera of patients with MDD and associated with depressive symptoms. Consistently, serum exosome-derived miR-144-5p levels were decreased in patients with MDD. CONCLUSION: miR-144-5p plays a vital role in regulating neuronal abnormalities in depression. Our findings provide translational evidence that miR-144-5p is a new potential therapeutic target for MDD.