Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar.

Scroll compressors are popularly applied in air-conditioning systems. The conventional fabrication process causes gas and shrinkage porosity in the scroll. In this paper, the electromagnetic stirring (EMS)-based semisolid multicavity squeeze casting (SMSC) process is proposed for effectively manufacturing wrought aluminum alloy scrolls. Insulation temperature, squeeze pressure, and the treatment of the micromorphology and mechanical properties of the scroll were investigated experimentally. It was found that reducing the insulation temperature can decrease the grain size, increase the shape factor, and improve mechanical properties. The minimum grain size was found as 111 ± 3 μm at the insulation temperature of 595 °C. The maximum tensile strength, yield strength, and hardness were observed as 386 ± 8 MPa, 228 ± 5 MPa, and 117 ± 5 HV, respectively, at the squeeze pressure of 100 MPa. The tensile strength and hardness of the scroll could be improved, and the elongation was reduced by the T6 heat treatment. The optimal process parameters are recommended at an insulation temperature in the range of 595-600 °C and a squeeze pressure of 100 MPa. Under the optimal process parameters, scroll casting was completely filled, and there was no obvious shrinkage defect observed inside. Its microstructure is composed of fine and spherical grains.

Research has shown that green tea catechins may influence the activity of drug metabolizing enzymes and drug transporters. We examined whether epigallocatechin-3-gallate (EGCG) affected the pharmacokinetics and pharmacodynamics of bisoprolol in rats.

Major depressive disorder (MDD) is one of the most debilitating and severe mental diseases globally. Increasing evidence has shown that epigenetics is critical for understanding brain function and brain disorders, including MDD. N-acetyltransferase 10 (NAT10), acting on histones, mRNA and other substrates, has been reported to be involved in epigenetic events, including histone acetylation and mRNA modifications. NAT10 is highly expressed in the brain. However, the potential effects of NAT10 on MDD are still unknown. Here, we exploited chronic mild stress (CMS) to induce anxiety- and depression-like behaviors in mice and found that the expression of NAT10 in the mouse hippocampus was upregulated after CMS treatment. Inhibition of NAT10 by pharmacological methods produced anxiolytic- and antidepressant-like effects. Neuron-specific overexpression of NAT10 in the hippocampus resulted in anxiety- and depression-like behaviors, accompanied by higher SIRT1 protein levels, and lower dendritic spine densities. Overall, it was found that elevation of NAT10 in hippocampal neurons is involved in the occurrence of anxiety- and depression-like behaviors, suggesting that NAT10 could be a potential new target for developing anxiolytics and antidepressants.

Atherosclerosis (AS) remains the leading cause of mortality throughout the world, and vascular endothelial cell dysfunction is one of the key events leading to this pathology. In recent years, there has been an increased interest in the role of circulating RNAs in various diseases; these noncoding RNAs can regulate gene products by acting as microRNA (miR) sponges. Furthermore, it has been shown that foam cells exhibit high expression levels of hsa_circ_0005699 (circ_0005699); however, to the best of our knowledge, no previous study has investigated the role of circ_0005699 in the regulation of vascular endothelial function. The present study employed human umbilical vein endothelial cells (HUVECs), which have been widely used to study vascular endothelial cell function. In addition, apolipoprotein E (ApoE)-deficient mice were used, which have been shown to rapidly develop AS and are widely used as a model of this disease. Cellular and biochemical techniques were performed, including gene transfection and short hairpin RNA-mediated gene silencing for cell transfection, luciferase reporter gene assay to confirm predicted genes, Cell Counting Kit-8 assay and flow cytometry to assess cell viability and apoptosis, and reverse transcription-quantitative PCR and western blotting for detection of mRNA and protein expression. In the present study, the expression levels of circ_0005699 were increased by oxidized low-density lipoprotein in a time- and dose-dependent manner in HUVECs; this was also associated with increased apoptosis of these cells. In addition, the expression levels of circ_0005699 were elevated, along with increased levels of inflammatory cytokines, in ApoE-deficient mice. An RNA pull-down assay indicated that circ_0005699 can bind miR-450b-5p to decrease its expression, whereas silencing of circ_0005699 resulted in increased expression of miR-450b-5p. In addition, the online bioinformatics tool starBase predicted NFKB1 as a target gene of miR-450b-5p, which was further confirmed by the luciferase reporter gene assay. Notably, knockdown of circ_0005699 resulted in the increased survival of HUVECs, which was associated with decreased protein expression levels of NFKB1 and inflammatory cytokines. By contrast, the effects of circ-0005699 silencing on survival were reversed by miR-450b-5p inhibition or NFKB1 overexpression. In conclusion, knockdown of circ_0005699 may ameliorate endothelial cell injury through regulation of the miR-450b-5P/NFKB1 signaling axis.

To develop a novel method for predicting neonatal respiratory morbidity (NRM) by ultrasound-based radiomics technology. In this retrospective study, 430 high-throughput features per fetal-lung image were extracted from 295 fetal lung ultrasound images (four-chamber view) in 295 single pregnancies. Images had been obtained between 28+3 and 37+6 weeks of gestation within 72 h before delivery. A machine-learning model built by RUSBoost (Random under-sampling with AdaBoost) architecture was created using 20 radiomics features extracted from the images and 2 clinical features (gestational age and pregnancy complications) to predict the possibility of NRM. Of the 295 standard fetal lung ultrasound images included, 210 in the training set and 85 in the testing set. The overall performance of the neonatal respiratory morbidity prediction model achieved AUC of 0.88 (95% CI 0.83-0.92) in the training set and 0.83 (95% CI 0.79-0.97) in the testing set, sensitivity of 84.31% (95% CI 79.06-89.44%) in the training set and 77.78% (95% CI 68.30-87.43%) in the testing set, specificity of 81.13% (95% CI 78.16-84.07%) in the training set and 82.09% (95% CI 77.65-86.62%) in the testing set, and accuracy of 81.90% (95% CI 79.34-84.41%) in the training set and 81.18% (95% CI 77.33-85.12%) in the testing set. Ultrasound-based radiomics technology can be used to predict NRM. The results of this study may provide a novel method for non-invasive approaches for the prenatal prediction of NRM.

Fluoxetine is used to improve cognition, exercise ability, depression, and neurological functions in patients with cerebral ischemic stroke. Circular RNAs (circRNAs) play important regulatory roles in multiple diseases. However, studies regarding the fluoxetine-mediated circRNA-microRNA-messenger RNA (mRNA) axis have not been conducted. This study is aim to investigate the functions of fluoxetine and identification of fluoxetine-mediated circRNAs and mRNAs in cerebral ischemic stroke. The middle cerebral artery occlusion (MCAO) rat models were successfully established at fisrt, and then rats were intraperitoneally injected with 10-mg/kg fluoxetine hydrochloride for 14 d. Afterward, the cerebral infarction area was evaluated using triphenyltetrazolium chloride staining. High-throughput sequencing was adopted to screen the differential circRNAs and mRNAs. The candidate circRNAs, mRNAs, and potential microRNAs were verified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addtion, microRNA and circRNA binding was verified using the dual-luciferase reporter assay. Results revealed that fluoxetine markedly diminished the cerebral infarction area in rats after MCAO. The circRNAs and mRNAs were differentially expressed, which includes 879 circRNAs and 815 mRNAs between sham and MCAO groups, respectively, and 958 circRNAs and 838 mRNAs between MCAO and fluoxetine groups, respectively. In which, circMap2k1 and Pidd1 expression was significantly increased in the MCAO group but suppressed after fluoxetine treatment. Moreover, circMap2k1 directly binds with miR-135b-5p. Taken together, we verified that fluoxetine could improve brain injury after cerebral ischemic stroke. Moreover, the circMap2k1/miR-135b-5p/Pidd1 axis is potentially involved in cerebral ischemic stroke.

Mesenteric lymph nodes (MLNs) are central in immune anatomy. MLNs are associated with the composition of gut microbiota, affecting the central system and immune system. Gut microbiota was found to differ among individuals of different social hierarchies. Nowadays, excision of MLNs is more frequently involved in gastrointestinal surgery; however, the potential side effects of excision of MLNs on social dominance are still unknown.

In recent years, deep learning has seen remarkable progress in many fields, especially with many excellent pre-training models emerged in Natural Language Processing(NLP). However, these pre-training models can not be used directly in music generation tasks due to the different representations between music symbols and text. Compared with the traditional presentation method of music melody that only includes the pitch relationship between single notes, the text-like representation method proposed in this paper contains more melody information, including pitch, rhythm and pauses, which expresses the melody in a form similar to text and makes it possible to use existing pre-training models in symbolic melody generation. In this paper, based on the generative pre-training-2(GPT-2) text generation model and transfer learning we propose MT-GPT-2(music textual GPT-2) model that is used in music melody generation. Then, a symbolic music evaluation method(MEM) is proposed through the combination of mathematical statistics, music theory knowledge and signal processing methods, which is more objective than the manual evaluation method. Based on this evaluation method and music theories, the music generation model in this paper are compared with other models (such as long short-term memory (LSTM) model,Leak-GAN model and Music SketchNet). The results show that the melody generated by the proposed model is closer to real music.

Mixed lineage kinase like protein (MLKL) is a key mediator of necroptosis. While previous studies highlighted the important role of MLKL as one of the central regulators of brain damage against acute ischemic neuronal injury, how the activation of MLKL mediates brain injuries and cell death remains unclear, especially in astrocytes. In a transient middle cerebral artery occlusion (tMCAO) rat model in vivo, and an oxygen-glucose deprivation and reoxygenation (OGD/Re) injury model in both primary cultured astrocytes and human astrocytes, we show that necrosulfonamide (NSA), a MLKL specific inhibitor, reduces infarction volume and improves neurological deficits in tMCAO-treated rats. In addition, NSA treatment, as well as RIP1K inhibitor Nec-1 or RIP3K inhibitor GSK-872 treatment, decreases the OGD/Re-induced leakage of LDH in both primary cultured astrocytes and human astrocytes. NSA treatment also reduces the number of propidium iodide (PI)-positive cells, and prevents the upregulation of necroptotic biomarkers such as MLKL/p-MLKL, RIP3K/p-RIP3K, and RIP1K/p-RIP1K in ischemic penumbra of cerebral cortex in tMCAO-treated rats or in OGD/Re-treated human astrocytes. Importantly, NSA treatment blocks both the nucleus and nuclear envelope localization of MLKL/p-MLKL and RIP3K/p-RIP3K in ischemic cerebral cortex induced by tMCAO. Similarly, Co-immunoprecipitation assay shows that NSA treatment decreases tMCAO- or OGD/Re- induced increased combination of MLKL and RIP3K in nuclear envelope of ischemic penumbra of cerebral cortex or of primary cultured astrocytes, respectively. RIP3K inhibitor GSK-872 also reduces tMCAO-induced increased combination of MLKL and RIP3K in nuclear envelope of ischemic penumbra of cerebral cortex. These data suggest NSA exerts protective effects against focal ischemia/reperfusion injury via inhibiting astrocytic necroptosis through preventing the upregulation of necroptotic kinases as well as blocking both the nucleus and nuclear envelope co-localization of p-MLKL and p-RIP3K. The translocation of p-MLKL, along with p-RIP3K, to the nuclear envelope and the nucleus may play a crucial role in MLKL-mediated necroptosis under ischemic conditions.

Despite the use of clinical trials to provide gold-standard evidence of cancer treatment and intervention effectiveness, racial/ethnic minorities are frequently underrepresented participants. Our objective was to evaluate racial/ethnic differences in knowledge and attitudes towards clinical trials among U.S. cancer survivors.

Several epidemiological studies have previously investigated the association between the TP53 codon 72 polymorphism and oral squamous cell carcinoma (OSCC) susceptibility; however, current results are inconsistent. We therefore performed this meta-analysis to thoroughly investigate any association among Asian patients.

Classification of breast ultrasound (BUS) images is an important step in the computer-aided diagnosis (CAD) system for breast cancer. In this paper, a novel phase-based texture descriptor is proposed for efficient and robust classifiers to discriminate benign and malignant tumors in BUS images.

MicroRNA-150 (miR-150) was revealed to be an attractive prognostic biomarker in recent studies. However, the prognostic significance of miR-150 expression in cancer remains inconclusive. The aim of this study was to summarize the global predicting role of miR-150 in survival in patients with various carcinomas.

High risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. ING4 is one member of the inhibitor of growth (ING) family of type II tumor suppressors and it has been shown to be involved in regulating p53 function. However, the effect and mechanism of HPV16 E6 on ING4 function remain elusive. In this study, we report HPV16 E6 combines with ING4 in vivo and in vitro. The ING4 induced p53 acetylation and its combining with p53 were attenuated by HPV16 E6 independent of p53 degradation. The enhancing function of ING4 on p53 mediated apoptosis was diminished when HPV16 E6 existed. These findings reveal that ING4 may be a common target of oncogenic viruses for driving host cell carcinogenesis.

The Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential latent antigens for Epstein-Barr virus (EBV)-induced immortalization of primary human B lymphocytes in vitro, has been implicated in regulating cell proliferation and anti-apoptosis via interaction with several cellular and viral factors. Gemin3 (also named DDX20 or DP103) is a member of DEAD RNA helicase family which exhibits diverse cellular functions including DNA transcription, recombination and repair, and RNA metabolism. Gemin3 was initially identified as a binding partner to EBNA2 and EBNA3C. However, the mechanism by which EBNA3C regulates Gemin3 function remains unclear. Here, we report that EBNA3C directly interacts with Gemin3 through its C-terminal domains. This interaction results in increased stability of Gemin3 and its accumulation in both B lymphoma cells and EBV transformed lymphoblastoid cell lines (LCLs). Moreover, EBNA3C promotes formation of a complex with p53 and Gemin3 which blocks the DNA-binding affinity of p53. Small hairpin RNA based knockdown of Gemin3 in B lymphoma or LCL cells remarkably attenuates the ability of EBNA3C to inhibit the transcription activity of p53 on its downstream genes p21 and Bax, as well as apoptosis. These findings provide the first evidence that Gemin3 may be a common target of oncogenic viruses for driving cell proliferation and anti-apoptotic activities.

Plants have evolved sophisticated systems to cope with adverse environmental conditions such as cold, drought, and salinity. Although a number of stress response networks have been proposed, the role of plant apoplast in plant stress response has been ignored. To investigate the role of apoplastic proteins in the salt stress response, 10-day old rice plants were treated with 200mM NaCl for 1, 6 or 12h, and the soluble apoplast proteins of rice shoot stems were extracted for differential analysis, compared with untreated controls, by 2-D DIGE saturation labeling techniques. One hundred twenty-two significantly changed spots were identified by LC-MS/MS, and 117 spots representing 69 proteins have been identified. Of these proteins, 37 are apoplastic proteins according to the bioinformatic analysis. These proteins are mainly involved in the processes of carbohydrate metabolism, oxido-reduction, and protein processing and degradation. According to their functional categories and cluster analysis, a stress response model of apoplastic proteins has been proposed. These data indicate that the apoplast is important in plant stress signal reception and response.

The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis, and finally treatment failure. Our research goal is to determine and block the mechanisms of platinum resistance. Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin. These include ATM, p53, and Chk2. The increased Chk2 phosphorylation is modulated by p53 in a wild-type p53 model. Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient) cells doubled the amount of Chk2 phosphorylation 48 hours after cisplatin treatment. p53 knockdown by specific siRNA greatly reduced Chk2 phosphorylation. We conclude that wild-type p53, in response to cisplatin stimulation, plays a role in the upstream regulation of Chk2 phosphorylation at Thr-68. Cells without normal p53 function survive via an alternative pathway in response to the exogenous influence of cisplatin. We strongly suggest that it is very important to include the p53 mutational status in any p53 involved studies due to the functional differentiation of wt p53 and p53 mutant. Inhibition of Chk2 pathway with a Chk2 inhibitor (C3742) increased cisplatin efficacy, especially those with defective p53. Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy.

Due to severe presence of speckle noise, poor image contrast and irregular lesion shape, it is challenging to build a fully automatic detection and classification system for breast ultrasonic images. In this paper, a novel and effective computer-aided method including generation of a region of interest (ROI), segmentation and classification of breast tumor is proposed without any manual intervention. By incorporating local features of texture and position, a ROI is firstly detected using a self-organizing map neural network. Then a modified Normalized Cut approach considering the weighted neighborhood gray values is proposed to partition the ROI into clusters and get the initial boundary. In addition, a regional-fitting active contour model is used to adjust the few inaccurate initial boundaries for the final segmentation. Finally, three textures and five morphologic features are extracted from each breast tumor; whereby a highly efficient Affinity Propagation clustering is used to fulfill the malignancy and benign classification for an existing database without any training process. The proposed system is validated by 132 cases (67 benignancies and 65 malignancies) with its performance compared to traditional methods such as level set segmentation, artificial neural network classifiers, and so forth. Experiment results show that the proposed system, which needs no training procedure or manual interference, performs best in detection and classification of ultrasonic breast tumors, while having the lowest computation complexity.

Whether adenosine offers cardioprotective effects when used as an adjunctive therapy for patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) remains controversial.To evaluate, via meta-analysis, the efficacy of adenosine in patients with AMI undergoing PCI.Randomized controlled trials (RCTs) published in Medline, Embase, and the Cochrane Central Register of Controlled Trials.RCTs of patients with AMI undergoing primary PCI, comparing adenosine treatment and placebo groups and reporting mortality, thrombolysis in myocardial infarction (TIMI) flow grade, myocardial blush grade (MBG), re-infarction, left-ventricular ejection fraction (LVEF), ST-segment elevation resolution (STR), recurrent angina, or heart failure (HF).Risk of bias was assessed by the Cochrane guidelines and publication bias by Egger's test. For studies reported in multiple publications, the most complete publication was used. Arms using different dosing schedules were merged. Mean differences (MDs) or risk ratios (RRs) were determined.Data were extracted from 15 RCTs involving 1736 patients. Compared with placebo, adenosine therapy was associated with fewer occurrences of heart failure (RR: 0.65, 95% confidence interval [CI]: 0.43-0.97, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.03) and no-reflow (TIMI flow grade <3, RR: 0.62, 95% CI: 0.45-0.85, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.003; MBG[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0-1, RR: 0.81; 95% CI: 0.67-0.98, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.03), more occurrences of STR (RR: 1.19, 95% CI: 1.07-1.31, P[REPLACEMENT CHARACTER]<[REPLACEMENT CHARACTER]0.00001), but no overall improvement of LVEF (MD: 2.29, 95% CI: -0.09 to 4.67, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.06). Adenosine improved LVEF in the intravenous subgroup and the regular-dose intracoronary (IC) subgroup (0.24-2.25[REPLACEMENT CHARACTER]mg) compared with placebo (MD: 2.68, 95% CI: 0.66-4.70, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.009). Adenosine was associated with a poorer LVEF in the high-dose (4-6[REPLACEMENT CHARACTER]mg) IC subgroup (MD: -2.40; 95% CI: -4.72 to -0.09, P[REPLACEMENT CHARACTER]=[REPLACEMENT CHARACTER]0.04). There was no significant evidence that adenosine reduced rates of all-cause mortality, cardiovascular mortality or re-infarction after PCI.Adenosine dosage and administration routes, baseline profiles, and endpoints differed among included RCTs. Performance, publication, and reporting biases remain possible.Adenosine therapy appears to improve several outcomes in patients with AMI after PCI, but there is no evidence that adenosine can reduce mortality rates.