Abstract To reveal complex causes of aircraft events, this paper aims to mine association rules between the trigger probability and relative strength via a modified Apriori algorithm. Clustering is ...adopted for data preprocessing and TF–IDF value calculation. Causative item sets of aircraft events are obtained based on the accident causation 2–4 model and are coded to establish code indicators. By avoiding the use of statistical methodologies to resolve not-a-number (NaN) values for altering the interrelations among causes, an enhancement in the Apriori algorithm is proposed by considering frequent items. By extracting frequent patterns, in this paper, all the association rules that satisfy three perspectives (support, confidence and lift) are determined by constantly generating and pruning candidate item sets. A network graph is used to visualize the association rules between different unsafe events and all types of causes. Finally, 9835 representative pieces of data, including general unsafe events, general incidents and serious incidents from the Southwest Air Traffic Management Bureau, are selected for analysis. The results show that improper energy allocation, poor conflict resolution ability, inadequate onsite management duties, adoption of a luck mentality, and occurrence of controller oversight are highly correlated with general unsafe events, and failure to rectify incorrect recitation is notably correlated with general incidents, while inadequate manual promotion, lack of conflict judgement and insufficient safety management are strongly correlated with serious incidents. This study quantitatively reveals the potential patterns and characteristics of mutual interactions among various types of historical aircraft events and highlights directions for controllable prevention and prediction of aircraft events.
Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the ...development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a
) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMD
(markers of pyroptosis) were greater in livers of Hspa12a
mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMD
generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients.
Tetrandrine is well known to act as a calcium channel blocker. It is a potential candidate for a tumor chemotherapy drug without toxicity. Tetrandrine inhibits cancer cell proliferation and induces ...cell death through apoptosis and autophagy. As cancer patients usually experience complications with sarcopenia or muscle injury, we thus assessed the effects of tetrandrine on skeletal muscle cells. We report in this study that a low dose of tetrandrine (less than 5 μM) does not affect the proliferation of C2C12 myoblasts, but significantly inhibits myogenic differentiation. Consistently, tetrandrine inhibited muscle regeneration after BaCl2-induced injury. Mechanistic experiments showed that tetrandrine decreased the p-mTOR level and increased the levels of LC3 and SQSTM1/p62 during differentiation. Ad-mRFP-GFP-LC3B transfection experiments revealed that the lysosomal quenching of GFP signals was suppressed by tetrandrine. Furthermore, the levels of DNM1L/Drp1, PPARGA1 and cytochrome C (Cyto C), as well as caspase 3 activation and ROS production, were decreased following tetrandrine administration, indicating that the mitochondrial network signaling was inhibited. Our results indicate that tetrandrine has dual effects on autophagic flux in myoblasts during differentiation, activation in the early stage and blockade in the late stage. The ultimate blocking of autophagic flux by tetrandrine led to the disruption of mitochondria remodeling and inhibition of myogenic differentiation. The inhibitory effects of tetrandrine on skeletal muscle differentiation may limit its application in advanced cancer patients. Thus, great attention should be paid to the clinical use of tetrandrine for cancer therapy.
Introduction
Allergic rhinitis (AR) is frequently known as a chronic respiratory disease with a global high prevalence. The pivotal roles of histone deacetylase 4 (HDAC4) in multiple human diseases ...have been underlined by numerous studies. Nevertheless, whether HDAC4 is implicated in AR remains to be elaborated. The objective of the current study is to clarify the impacts of HDAC4 on AR.
Methods
First, human nasal epithelial cells (hNECs) were pretreated by interleukin‐13 (IL‐13). HDAC4 expression in hNECs with the presence or absence of IL‐13 treatment was tested by quantitative reverse‐transcription polymerase chain reaction (RT‐qPCR) and western blot. Following, after HDAC4 was depleted, levels of histamine, Immunoglobulin E (IgE) and inflammatory factors were analyzed by ELISA assay. Then, Mucin‐5AC (MUC5AC) expression was examined through RT‐qPCR, western blot, and IF assay. Western blot was to analyze the expression of sirtuin 1 (SIRT1)/nuclear factor‐kappaB (NF‐κB) signaling‐related proteins. After IL‐13‐induced hNECs were cotransfected with HDAC4 interference plasmids and SIRT1 inhibitor EX527, the functional experiments above were conducted again.
Results
The experimental data in this study presented that HDAC4 expression was increased in IL‐13‐induced hNECs. Silencing of HDAC4 cut down the levels of histamine, IgE and inflammatory factors and the expression of MUC5AC. Additionally, knockdown of HDAC4 led to the activation of SIRT1/NF‐κB signaling. Further, the downregulated levels of histamine, IgE and inflammatory factors and the expression of MUC5AC imposed by HDAC4 interference were all reversed by EX527.
Conclusions
In short, HDAC4 inhibition activated SIRT1/NF‐κB signaling to mitigate inflammatory response and mucus production in IL‐13‐treated nasal epithelial cells in AR.
Allergic rhinitis (AR) is frequently known as a chronic respiratory disease with global high prevalence. The pivotal roles of histone deacetylase 4 (HDAC4) in multiple human diseases have been underlined by numerous studies. Our paper is the first to explore the role of HDAC4 in AR and the mechanism involved. We concluded that HDAC4 inhibition activated SIRT1/NF‐κB signaling to mitigate inflammatory response and mucus production in interleukin‐13‐treated nasal epithelial cells in AR.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress the expression of their target genes post-transcriptionally. MiRNAs participate in the regulation of a variety of biological ...processes, including development and diseases. However, the functional role and molecular mechanism by which miRNAs regulate skeletal muscle development and differentiation are not fully understood. In this report, we identified miR-23a as a key regulator of skeletal muscle differentiation. Using bioinformatics analyses, miR-23a is predicted to target multiple adult fast myosin heavy chain (Myh) genes, including Myh 1, 2 and 4. Luciferase reporter assays show that miR-23a directly targets the 3′ untranslated regions (UTRs) of these mRNAs. Interestingly, the expression level of mature miR-23a is inversely correlated with myogenic progression in mouse skeletal muscle. Both gain- and loss-of-function studies using C2C12 myoblasts demonstrate that miR-23a inhibits myogenic differentiation. These findings therefore reveal a novel role of miR-23a in regulating myogenic differentiation via inhibiting the expression of fast myosin heavy chain isoforms.
The location of Low-Altitude Flight Service Station (LAFSS) is a comprehensive decision work, and it is also a multi-objective optimization problem (MOOP) with constraints. As a swarm intelligence ...search algorithm for solving constrained MOOP, the Immune Algorithm (IA) retains the excellent characteristics of genetic algorithm. Using some characteristic information or knowledge of the problem selectively and purposefully, the degradation phenomenon in the optimization process can be suppressed and the global optimum can be achieved. However, due to the large range involved in the low-altitude transition flight, the geographical characteristics, economic level and service requirements among the candidate stations in the corridor are quite different, and the operational safety and service efficiency are interrelated and conflict with each other. And all objectives cannot be optimal. Therefore, this article proposes a Modified Immune Algorithm (MIA) with two-layer response to solve the constrained multi-objective location mathematical model of LAFSS. The first layer uses the demand track as the cell membrane positioning pattern recognition service response distance to trigger the innate immunity to achieve the basic requirements of security service coverage. In the second layer, the expansion and upgrading of adjacent candidate sites are compared to the pathogen's effector, and the adaptive immunity is directly or indirectly triggered again through the cloning, mutation and reproduction between candidate sites to realize the multi-objective equilibrium of the scheme. Taking 486,000 km
of Sichuan Province as an example, MIA for LAFSS is simulated by the MATLAB platform. Based on the Spring open source application framework of Java platform, the cesiumjs map data is called through easyui, and the visualization of site selection scheme is presented with the terrain data of Map World as the background. The experimental results show that, compared with dynamic programming and ordinary immunization, the immune trigger mode of double response and the improved algorithm of operation parameter combination designed by the Taguchi experiment, the total economic cost of location selection is reduced by 26.4%, the service response time is reduced by 25%, the repeat coverage rate is reduced by 29.5% and the effective service area is increased by 17.5%. The security risk, service efficiency and location cost are balanced. The present work is to provide an effective location method for the layout number and location of local transfer flight service stations. For complex scenes with larger scale of low-altitude flight supply and demand and larger terrain changes in the region, the above research methods can be used to effectively split and reduce the dimension.
Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of ...autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.
is a popular edible fungus for its tasty flavour and can be used as a dietary supplement for its functional substances. This study was conducted to evaluate the potential health benefits of
...polysaccharides (SAFP) on water immersion and restraint stress (WIRS)-induced gastric ulcer in rats. The results indicated that SAFP could decrease myeloperoxidase (MPO) activity and plasma corticosterone levels, as well as enhance Prostaglandin E2 (PGE2) and Nitrate/nitrite (NOx) concentration in rats. Furthermore, SAFP significantly attenuated the stress damage, inflammation, pathological changes and gastric mucosal lesion in rats. Moreover, high-throughput pyrosequencing of 16S rRNA suggested that SAFP modulated the dysbiosis of gut microbiota by enhancing the relative abundance of probiotics, decreasing WIRS-triggered bacteria proliferation. In summary, these results provided the evidence that SAFP exerted a beneficial effect on a WIRS-induced gastric ulcer via blocking the TLR4 signaling pathway and activating the Nrf2 signaling pathway. Notably, SAFP could modulate the WIRS-induced dysbiosis of gut microbiota. Thus, SAFP might be explored as a natural gastric mucosal protective agent in the prevention of gastric ulcers and other related diseases in the food and pharmaceutical industries.
Chronic subdural hematomas (CSDHs) are one of the most common neurosurgical conditions. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and ...placement of subdural closed-system drainage. The drainage is generally removed after 48 h, which can be described as fixed-time drainage strategy. According to literature, the recurrence rate is 5-33% with this strategy. In our retrospective study, postoperative hematoma volume was found to significantly increase the risk of recurrence. Based on these results, an exhaustive drainage strategy is conducted to minimize postoperative hematoma volume and achieve a low recurrence rate and good outcomes.
This is a prospective, multicenter, open-label, blinded endpoint randomized controlled trial designed to include 304 participants over the age of 18-90 years presenting with a symptomatic CSDH verified on cranial computed tomography or magnetic resonance imaging. Participants will be randomly allocated to perform exhaustive drainage (treatment group) or fixed-time drainage (control group) after a one-burr hole craniostomy. The primary endpoint will be recurrence indicating a reoperation within 6 months.
This study will validate the effect and safety of exhaustive drainage after one-burr hole craniostomy in reducing recurrence rates and provide critical information to improve CSDH surgical management.
Clinicaltrials.gov, NCT04573387. Registered on October 5, 2020.
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