[High expression of ATP5A1 in gastric carcinoma is correlated with a poor prognosis and enhanced glucose metabolism in tumor cells].

OBJECTIVE: To analyze the expression level of ATP5A1 in gastric carcinoma and its influence on the prognosis of the patients and glucose metabolism in the tumor cells. METHODS: We retrospectively analyzed the data of 115 patients undergoing radical resection of gastric carcinoma in our hospital from February, 2013 to November, 2016. ATP5A1 expression in the surgical specimens were detected using immunohistochemistry, and the long-term prognosis of the patients with high (n=58) and low ATP5A1 expression (n=57) were analyzed. In gastric carcinoma MGC803 cells, the effects of lentivirus-mediated ATP5A1 knockdown or overexpression on glucose metabolism were investigated. We also observed the growth and glucose metabolism of xenografts derived from MGC803 cells with ATP5A1 knockdown or overexpression in nude mice. RESULTS: ATP5A1 was significantly overexpressed in gastric carcinoma tissues in close correlation with blood CEA and CA19-9 levels, pathological grade, T stage and N stage (P < 0.05). ATP5A1 overexpression was an independent risk factor for a significantly lowered 5-year survival rate of patients with gastric carcinoma (P < 0.05). ROC curve analysis demonstrated the predictive value of high ATP5A1 expression for the patients'prognosis (P < 0.001). In MGC803 cells, ATP5A1 overexpression significantly upregulated cellular glucose uptake and lactate production and increased the protein levels of HK2, PFK1, and LDHA (P < 0.05), while ATP5A1 knockdown produced the opposite changes (P < 0.05). In the tumor-bearing mice, overexpression of ATP5A1 increased glucose metabolism of the tumor cells and promoted tumor growth (P < 0.05). Overexpression of ATP5A1 promoted the expressions of p-JNK and p-JUN in MGC803 cells (P < 0.05), and the JNK inhibitor SP600125 significantly inhibited the enhancement of cellular glucose metabolism induced by ATP5A1 overexpression (P < 0.05). CONCLUSION: High ATP5A1 expression in gastric cancer is associated a poor long-term prognosis of the patients, and its effect is mediated at least partly by promoting glucose metabolism of the cells through the JNK/JUN pathway.

[High expression of CPNE3 correlates with poor long-term prognosis of gastric cancer by inhibiting cell apoptosis via activating PI3K/AKT signaling].

OBJECTIVE: To explore the correlation of CPNE3 expression with long-term prognosis of patients with gastric cancer (GC) and the possible mechanism. METHODS: We retrospectively collected the data of 104 GC patients undergoing radical surgery in our hospital from February, 2013 to October, 2017. TCGA database and immunohistochemistry were used to analyze CPNE3 expression level in GC tissues and its effects on tumor progression and long-term prognosis of the patients. GO analysis was performed to predict the biological role of CPNE3 in GC. We also conducted cell experiments with MGC803 cells and observed the effects of CPNE3 knockdown, CPNE3 overexpression and LY294002 (a PI3K/AKT inhibitor) treatment on cell apoptosis and cellular expressions of apoptotic proteins using flow cytometry and Western blotting. RESULTS: TCGA analysis and immunohistochemistry both showed high expressions of CPNE3 in GC (P < 0.05). The patients with high CPNE3 expressions had a reduced 5-year survival (P < 0.01), and a high CPNE3 expression, CEA level≥5 µg/L, CA19-9 level ≥37 kU/L, T3-T4 stage, and N2-N3 stage were all independent risk factors for a lowered 5-year survival rate after surgery. The sensitivity and specificity of CPNE3 for predicting 5-year mortality was 79.59% and 74.55%, respectively (P < 0.05). GO analysis predicted that CPNE3 negatively regulated GC cell apoptosis. In MGC803 cells, CPNE3 knockdown significantly increased cell apoptosis, enhanced Bax and Cleaved Caspase-3 expressions and decreased Bcl-2 expression, while CPNE3 overexpression produced the opposite results (P < 0.05). The cellular expressions of p-PI3K and p-AKT were significantly decreased following CPNE3 knockdown and increased following CPNE3 overexpression (P < 0.05). Treatment with LY294002 obviously attenuated the inhibitory effect of CPNE3 overexpression on apoptosis of MGC803 cells (P < 0.05). CONCLUSION: CPNE3 is highly expressed in GC tissues and affects the long-term prognosis of the patients possibly by inhibiting GC cell apoptosis through activation of PI3K/AKT signaling.

[Current status and perspectives of obstetrics in China: an insight from evidence-based medicine].

Nationwide epidemiological data on pregnancy and childbirth was lacking in China during the last decades. Since the establishment of the national data monitoring network and the booming of regional epidemiological studies, more information has emerged. The results and suggestions from the China Labor and Delivery Survey are crucial for improving current clinical practices. Researches that are conducted based on national data monitoring network and hospital-based medical history system, and multicenter clinical trials will provide plenty of useful evidences. These high-quality evidences would further improve clinical practice and development of obstetrics in China.

A nomogram integrating ferroptosis-and immune-related biomarker for prediction of prognosis and diagnosis in kidney renal clear cell carcinoma.

OBJECTIVE: Approximately 60% of patients with kidney renal clear cell carcinoma (KIRC) die within the first 2-3 years. The prognosis for patients with KIRC and its metastases is poor. Ferroptosis and providing immunity are novel treatment targets for several cancers, including KIRC. Therefore, it is important to identify suitable ferroptosis- and immune-related signatures to predict the prognosis and diagnosis of patients with KIRC. MATERIALS AND METHODS: The corresponding data of patients with KIRC were obtained from the Cancer Genome Atlas. Univariate and multivariate Cox regression analyses were used to screen candidate biomarkers in patients with KIRC. RESULTS: We found that four FI-DEGs (BID, MET, LTB4R, and HMOX1) were independently associated with the overall survival of patients with KIRC. The prognosis and diagnosis model constructed using these four biomarkers could predict the outcome of KIRC, as measured by the receiver operating characteristic analyses. CONCLUSIONS: We identified 4 FI-DEGs that could be used as biomarkers in patients with KIRC. The present study not only contributes to understanding the roles of ferroptosis and immunity in the development of KIRC, but also to the diagnosis and prognosis of KIRC, although it remains to be further studied.

What is an appropriate caesarean delivery rate for China: a multicentre survey.

OBJECTIVE: To assess the current status of caesarean delivery (CD) in China, propose reference CD rates for China overall, and by regions, investigate the main indications for CDs and identify possible areas for safe reduction. DESIGN: A multicentre cross-sectional study. SETTING: A total of 94 hospitals across 23 provinces in China. POPULATION: A total of 73 977 randomly selected deliveries. METHODS: We used a modified Robson classification to characterise CDs in subgroups and by regions, and the World Health Organization (WHO) C-Model to calculate reference CD rates. MAIN OUTCOME MEASURES: CD rates in China. RESULTS: In 2015-2016, the overall CD rate in China was 38.9% (95% CI 38.6-39.3%). Considering the obstetric characteristics of the population, the multivariable model-based reference CD rate was estimated at 28.5% (95% CI 28.3-28.8%). Accordingly, an absolute reduction of 10.4% (or 26.7% relative reduction) may be considered. The CD rate varied substantially by region. Previous CD was the most common indication in all regions, accounting for 38.2% of all CDs, followed by maternal request (9.8%), labour dystocia (8.3%), fetal distress (7.7%) and malpresentation (7.6%). Overall, 12.7% of women had prelabour CDs, contributing to 32.8% of the total CDs. CONCLUSIONS: Nearly 39% of births were delivered by caesarean in China but a reduction of this rate by a quarter may be considered attainable. Repeat CD contributed more than one-third of the total CDs. Given the large variation in maternal characteristics, region-specific or even hospital-specific reference CD rates are needed for precision management of CD. TWEETABLE ABSTRACT: The caesarean rate in 2015-2016 in China was 38.9%, whereas the reference rate was 28.5%.

Second-trimester abdominal circumference discordance and adverse perinatal outcomes in monochorionic twins.

OBJECTIVE: The perinatal outcomes in second-trimester abdominal circumference (AC) discordant twins are yet to be established. The aim of this study was to ascertain perinatal risks associated with second-trimester AC discordance in monochorionic (MC) twins. METHOD: We conducted a retrospective study of all MC twin pregnancies over a 7-year period. Intertwin AC discordance at 14-26 gestational weeks was analyzed in relation to Doppler abnormalities, obstetric complications, and perinatal adverse outcomes. RESULTS: A total of 246 MC twin pregnancies were included in the analysis. The smaller twins of second-trimester AC discordant pairs were at increased prevalence of abnormal umbilical artery flow (50% versus 24%, p < .001) and low positive A wave of ductus venous flow (24% versus 9%, p = .002). The second-trimester AC discordant twins were at increased risk of oligohydramnios in smaller twin (OR = 2.44, 95% CI = 1.37-4.32, p < .01), cardiomegaly in larger twin (OR = 2.95, 95% CI = 1.01-8.60, p < .05), birth weight of either twin below the 10th percentile for gestational age (OR = 5.56, 95% CI = 2.67-11.59, p < .001), birth weight discordance > 25% (OR = 9.41, 95% CI = 4.46-19.87, p < .001), IUFD (OR = 3.26, 95% CI = 1.76-6.05, p < .001), and severe neonatal morbidity (OR = 1.83, 95% CI = 1.03-3.26, p < .05). The intact survival rate in discordant and concordant twin pairs was 70% and 89%, respectively (p < .001). CONCLUSIONS: Early and increase fetal surveillance of the second-trimester AC discordant twins should be utilized to establish perinatal risks, thus allowing prenatal care to improve.

[Application of adaptive technology-based speech recognition system in 600 pathological grossing process].

Objective: To establish a speech recognition system based on adaptive technology and to evaluate its value in pathological grossing processes. Methods: A total of 600 tissue specimens were collected at the Zhejiang Provincial People's Hospital affiliated to Hangzhou Medical College between October 1, 2020 and December 31, 2020. A speech recognition system based on adaptive technology was used in the pathological grossing processes, and the pathological examination reports were generated and extracted. Results: The speech recognition system based on adaptive technology showed a good recognition rate (overall recognition rate = 77.87%) and helped achieve rapid input and output of pathological examination data. Conclusions: The speech recognition system can reduce the labor costs, improve the work efficiency of pathologists and increase the quality of medical services, which may be valuable for building next-generation smart hospitals.

Arbuscular mycorrhizal fungus alleviates alfalfa leaf spots caused by Phoma medicaginis revealed by RNA-seq analysis.

AIMS: One of the major limitations to the production of alfalfa (Medicago sativa) is the fungus Phoma medicaginis, which infects alfalfa and causes leaf spots. This study aims to understand alfalfa's response to P. medicaginis infection, the colonization of arbuscular mycorrhizal fungus (AMF) and the effect of AMF on plant-pathogen interactions. METHODS AND RESULTS: Transcriptome analysis (RNA-seq) was used to identify differentially expressed genes (DEGs) in alfalfa infected by P. medicaginis and colonized by AMF Rhizophagus intraradices. AMF ameliorated the effects of P. medicaginis infection on alfalfa by reducing leaf spot incidence and disease index by 39·48 and 56·18% respectively. Inoculation with pathogen and AMF induced the activity of defence pathways, including peroxidase (POD), polyphenol oxidase activities and jasmonic acid (JA), salicylic acid concentration. Plants showed differential expression of P. medicaginis resistance-related genes, including genes belonging to pathogenesis-related (PR) proteins, chitinase activity, flavonoid biosynthesis, phenylpropanoid biosynthesis, glutathione metabolism, phenylalanine metabolism and photosynthesis. Inoculation with AMF led to changes in the expression of genes involved in PR proteins, chitinase activity, phenylalanine metabolism and photosynthesis. CONCLUSION: The physiological and transcriptional changes caused by P. medicaginis infection in non-mycorrhizal and mycorrhizal alfalfa provides crucial information for understanding AMF's association with pathogenic systems. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed that AMF alleviated alfalfa leaf spots demonstrating that AMF can serve as a biocontrol strategy for alfalfa disease management.

Stillbirths in China: a nationwide survey.

OBJECTIVE: To estimate a stillbirth rate at 24 or more gestational weeks in 2015-2016 and to explore potentially preventable causes in China. DESIGN: A multi-centre cross-sectional study. SETTING: Ninety-six hospitals distributed in 24 (of 34) provinces in China. POPULATION: A total of 75 132 births at 24 completed weeks of gestation or more. METHODS: COX Proportional Hazard Models were performed to examine risk factors for antepartum and intrapartum stillbirths. Population attributable risk percentage was calculated for major risk factors. Correspondence analysis was used to explore region-specific risk factors for stillbirths. MAIN OUTCOME MEASURES: Stillbirth rate and risk factors for stillbirth. RESULTS: A total of 75 132 births including 949 stillbirths were used for the final analysis, giving a weighted stillbirth rate of 13.2 per 1000 births (95% CI 7.9-18.5). Small for gestational age (SGA) and pre-eclampsia/eclampsia increased antepartum stillbirths by 26.2% and 11.7%, respectively. Fetal anomalies increased antepartum and intrapartum stillbirths by 17.9% and 7.4%, respectively. Overall, 31.4% of all stillbirths were potentially preventable. Advanced maternal age, pre-pregnant obesity, chronic hypertension and diabetes mellitus were important risk factors in East China; low education and SGA were major risk factors in Northwest, Southwest, Northeast and South China; and pre-eclampsia/eclampsia and intrapartum complications were significant risk factors in Central China. CONCLUSIONS: The prevalence of stillbirth was 13.2 per 1000 births in China in 2015-2016. Nearly one-third of all stillbirths may be preventable. Strategies based on regional characteristics should be considered to reduce further the burden of stillbirths in China. TWEETABLE ABSTRACT: The stillbirth rate was 13.2 per 1000 births in China in 2015-2016 and nearly one-third of all stillbirths may be preventable.

Dual inoculation of alfalfa (Medicago sativa L.) with Funnelliformis mosseae and Sinorhizobium medicae can reduce Fusarium wilt.

AIMS: This study was designed to evaluate the biocontrol of the arbuscular mycorrhizal fungus (AMF) Funnelliformis mosseae and the rhizobium Sinorhizobium medicae on alfalfa (Medicago sativa) wilt caused by Fusarium oxysporum, a severe soil-borne fungal pathogen. METHODS AND RESULTS: The effects of co-inoculation of F. mosseae and S. medicae on alfalfa growth, nitrogen, phosphorus uptake and wilt caused by F. oxysporum were tested. Plant defence-related chemicals were measured to reveal the biochemical mechanism by which alfalfa responds to pathogen infection and how it is regulated by AMF and rhizobium. Pathogen infection caused typical yellowing of alfalfa leaflets and significantly reduced plant AMF colonization. AMF or rhizobium alone and the co-inoculation reduced the plant disease index by 83·2, 48·4 and 81·8% respectively. Inoculation with AMF or rhizobium alone increased the dry weight of alfalfa by more than 13 and 3 times respectively; it also increased plant chlorophyll content by 65·6 and 16·6% respectively. Co-inoculation of AMF and rhizobium induced the plant to accumulate more disease-related antioxidant enzymes, plant hydrolase and plant hormones, such as superoxide dismutase, ß-1,3-glucanase, chitinase, and phenylalanine ammonialyase, abscisic acid, ethylene and H2 O2 , under pathogen stress. CONCLUSIONS: Co-inoculation with F. mosseae and S. medicae offered complementarily improved alfalfa nutrient uptake and growth, which increased plant health. The co-inoculation of AMF and rhizobium regulated plant physiological and biochemical processes and induced plants to produce defence-related compounds, thus decreasing the severity of disease. The simultaneous application of F. mosseae and S. medicae is a potential biocontrol strategy to increase the systemic defence responses of alfalfa to Fusarium wilt. SIGNIFICANCE AND IMPACT OF THE STUDY: This research showed that complex plant-pathogen interactions are affected by rhizobium and AMF, providing insight into plant-microbiome interactions in the rhizosphere as well as the application of the microbiome in agriculture production.

Reconstruction of Vehicle-pedestrian Collision Road Traffic Accidents Based on PC-Crash Software.

ABSTRACT: Objective To discuss the application value of vehicle-pedestrian collision road traffic accidents reconstruction based on PC-Crash software in forensic identification. Methods A case of vehicle-pedestrian collision was chosen based on a tachograph, then PC-Crash software was applied to construct a vehicle-pedestrian collision model, and reconstruct the vehicle-pedestrian collision road traffic accident. Finally, the process of vehicle-pedestrian collision was reproduced. Results In accident reconstruction, when the car speed was lower than 50km/h, the landing point of the pedestrian after collision was in the front of the car. When the car speed was higher than 50 km/h, after collision, the pedestrian flipped towards the car roof and landed behind the car. With the increase of vehicle speed, throwing distance of the pedestrian increased continuously. When the vehicle collision speed reached 60 km/h, the experimental results in this case were basically consistent with the actual situation of the case. Head acceleration of the pedestrian was at the maximum （1 655.70 m/s2） at 0.080 s. Chest acceleration of the pedestrian increased from 597.63 m/s2 to the peak 675.52 m/s2 at 0.055-0.060 s. Tibia acceleration of the pedestrian increased from 759.26 m/s2 to the first peak 1 367.06 m/s2, then reached the maximum speed （1 718.19 m/s2） at 1.225 s. Conclusion The process of vehicle-pedestrian collision road traffic accidents can be reconstructed based on PC-Crash software under a situation of limited conditions, and can further clarify the speed of the vehicle, the location and degree of human body injury as well as the mechanism of damage of the pedestrian in the accident. Therefore, PC-Crash software has a certain practical value in forensic identification of road traffic accidents.

Factors Influencing Rust (Melampsora apocyni) Intensity on Cultivated and Wild Apocynum venetum in Altay Prefecture, China.

Rust (Melampsora apocyni) on Apocynum venetum is the major constraint to the commercial development of this medicinal herb. To determine the factors influencing rust intensity (maximum disease index [DImax]), rust was investigated from 2011 to 2015 in both cultivated and wild A. venetum plants. Partial least squares path modeling (PLS-PM) was used to analyze the paths and extent of the factors related to pathogen, environment, and host that affect rust intensity. DImax exhibited considerable variations across years and study sites, with variations linked to various factors fostering disease development. PLS-PM explained 80.0 and 70.1% of variations in DImax in cultivated and wild plants, respectively. Precipitation was the key factor determining DImax in both cultivated and wild plants (path coefficient [PC] = 0.313 and 0.544, respectively). In addition, the topsoil water content in cultivated plants and the total vegetation coverage in wild plants were also critical determinants of DImax via their effects on the microclimatic factor (contribution coefficients [CC] = 0.681 and 0.989, respectively; PC = 0.831 and 0.231, respectively). In both cultivated and wild plants, host factors were mainly dominated by A. venetum density (CC = 0.989 and 0.894, respectively), and their effect on DImax via the microclimatic factor (PC = 0.841 and 0.862, respectively) exceeded that via the inoculum factor (PC = 0.705 and 0.130, respectively). However, the indirect effects led to DImax variation, while the dilution effect on host (CC = 0.154) from weed in wild plants led to the indirect effect size in wild plants of 0.200, which was lower than -0.699 in cultivated plants.

Unveiling the Superconducting Mechanism of Ba_{0.51}K_{0.49}BiO_{3}.

The mechanism of high superconducting transition temperatures (T_{c}) in bismuthates remains under debate despite more than 30 years of extensive research. Our angle-resolved photoemission spectroscopy studies on Ba_{0.51}K_{0.49}BiO_{3} reveal an unexpectedly 34% larger bandwidth than in conventional density functional theory calculations. This can be reproduced by calculations that fully account for long-range Coulomb interactions-the first direct demonstration of bandwidth expansion due to the Fock exchange term, a long-accepted and yet uncorroborated fundamental effect in many body physics.Furthermore, we observe an isotropic superconducting gap with 2Δ_{0}/k_{B}T_{c}=3.51±0.05, and strong electron-phonon interactions with a coupling constant λ∼1.3±0.2. These findings solve a long-standing mystery-Ba_{0.51}K_{0.49}BiO_{3} is an extraordinary Bardeen-Cooper-Schrieffer superconductor, where long-range Coulomb interactions expand the bandwidth, enhance electron-phonon coupling, and generate the high T_{c}. Such effects will also be critical for finding new superconductors.

Expression of APOB, ADFP and FATP1 and their correlation with fat deposition in Yunnan's top six famous chicken breeds.

1. Adipose differentiation related protein (ADFP), fatty acid transport protein 1 (FATP1) and apolipoprotein B (APOB) are suspected to play an important role in determining intramuscular fat and in overall meat quality. 2. Yunnan's top six famous chicken breeds (the Daweishan Mini, Yanjin Black-bone, Chahua, Wuding, Wuliangshan Black-bone and Piao chicken) are known for the high quality of their meat, but little is known about their expression of these three genes. 3. The present study aimed to examine the ADFP, FATP1 and APOB genes in different tissues of these six breeds at different development stages. The subcutaneous fat from the back midline and front, abdominal fat, liver and muscle tissue was sampled at 28, 49, 70, 91 and 112 days. The expression of ADFP, FATP1 and APOB was measured by real-time PCR. 4. The results showed that the expression of the three genes differed depending on age, tissue types and breeds. However, the expression of the three genes correlated with fat traits. In conclusion, the expression of the ADFP, FATP1 and APOB genes is associated with the fat traits of Yunnan's top six chicken breeds. These results could help with molecular marker screening and marker-assisted breeding to improve the quality of poultry for meat production.

[Research Progress of Traffic Accident Reconstruction Technology Based on PC-Crash Software].

With the development of the computer simulation technology and the digital simulation technology, the traditional calculation method has been gradually replaced by the digital method to deal the road traffic accident scene and analyse the process. The PC-Crash software simulation system can reconstruct the traffic accidents within 32 vehicles, and the accuracy of reconstruction has been fully verified, which is widely used by the transport police department and the accreditation agency. In this paper, the research of road traffic accident reconstruction using PC-Crash software is reviewed, and the application of road traffic accident reconstruction technology based on PC-Crash software and some existing problems in forensic practice are discussed, which provides reference for the research and identification of road traffic accident simulation and reconstruction and theoretical basis for accident treatment.

Effects of Δ(9)-tetrahydrocannabinol (THC) on human amniotic epithelial cell proliferation and migration.

BACKGROUND: The deleterious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) is able to cross the placenta barrier and cause alterations in fetal growth, low birth weight and preterm labor. However, the effects of THC on the human placenta amnion are still unknown. METHODS: The distributions of CB1R and CB2R in human amnion tissues were observed by immunohistochemistry (IHC). Human amniotic epithelial cell proliferation and migration in response to THC treatment were measured by MTS and transwell assays, respectively. The PCR array was performed to study the key regulators involved in the cell migration. The protein levels of CB1R, CB2R in amnion tissues and MMP2, MMP9 in cells were detected by western blotting. Small interfering RNAs (siRNAs) were used to knockdown MMP2 and MMP9 in WISH cells. RESULTS: Our results indicated that both CB1R and CB2R primarily identified in the epithelial layer of human placental amnion tissue. The CB1R expression in the amnion tissue was higher in the preterm group than normal control. High-dose of THC (30uM, but not 20 and 10uM) significantly inhibited (p<0.01) human amniotic epithelial cell lines (WISH) proliferation. Meanwhile, THC at both 10uM and 20uM (p<0.05) significantly suppressed cells migration in both WISH and primary human amniotic epithelial cells. The PCR array data and siRNA experiments demonstrated that MMP2/9 were tightly involved in the regulation of THC-inhibited cell migration in WISH cells. CONCLUSION: These results suggested that THC inhibited the migration of human amniotic epithelial cell through the regulation of MMP2 and MMP9, which in turn altered the development of the amnion during the gestation and partially resulted in preterm labor and other adverse pregnancy outcomes.

Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses.

The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.

CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer.

The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33+ MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33+ MDSCs (P<0.01). Subsequently, we demonstrated that CD45+CD33+CD11b+HLA-DR- MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45+CD33+CD11b+HLA-DR- MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.