Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing ß-catenin.

The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family, has been shown to function as an oncogene in various human cancers. However, the function of PSMD14 in glioma and the underlying mechanism remain unclear. In this study, our findings reveal a dramatic upregulation of PSMD14 in GBMs, which is associated with poor survival outcomes. Knocking down PSMD14 is associated with decreased proliferation and invasion of GBM cells in vitro and inhibited tumor growth in a xenograft mouse model. Mechanistically, PSMD14 directly interacts with ß-catenin, leading to a decrease in the K48-linked ubiquitination of ß-catenin and subsequent ß-catenin stabilization. Increased ß-catenin expression significantly reverses the inhibitory effects of PSMD14 knockdown on the migration, invasion, and tumor growth of GBM cells. Moreover, we observed a significant correlation between PSMD14 and ß-catenin expression in human GBM samples. In summary, our results reveal that PSMD14 is a crucial deubiquitinase that is responsible for stabilizing the ß-catenin protein, highlighting its potential for use as a therapeutic target for GBM.

Function and inhibition of P38 MAP kinase signaling: Targeting multiple inflammation diseases.

Inflammation is a natural host defense mechanism that protects the body from pathogenic microorganisms. A growing body of research suggests that inflammation is a key factor in triggering other diseases (lung injury, rheumatoid arthritis, etc.). However, there is no consensus on the complex mechanism of inflammatory response, which may include enzyme activation, mediator release, and tissue repair. In recent years, p38 MAPK, a member of the MAPKs family, has attracted much attention as a central target for the treatment of inflammatory diseases. However, many p38 MAPK inhibitors attempting to obtain marketing approval have failed at the clinical trial stage due to selectivity and/or toxicity issues. In this paper, we discuss the mechanism of p38 MAPK in regulating inflammatory response and its key role in major inflammatory diseases and summarize the synthetic or natural products targeting p38 MAPK to improve the inflammatory response in the last five years, which will provide ideas for the development of novel clinical anti-inflammatory drugs based on p38 MAPK inhibitors.

The Effects of Crystalline Admixture on the Self-Healing Performance and Mechanical Properties of Mortar with Internally Added Superabsorbent Polymer.

Crystalline admixture (CA) can be incorporated into concrete to achieve self-healing of concrete cracks. In this study, both CA and superabsorbent polymer (SAP) were used as self-healing agents to investigate the effects of CA on the self-healing performance and mechanical properties of mortar with internally added SAP at different self-healing ages. The healing effect of cracks in mortar is assessed by crack observation and impermeability. The structure and composition of the filler in the cracks were analyzed by microscopic experiment. The experimental results indicate that CA enhances the healing of cracks in mortar specimens. The chemical reactions of CA primarily contribute to significantly improving the early-age crack-healing ability of the specimens, and the water absorption and expansion ability as well as the internal curing effect of SAP also facilitate the crack-healing process. Increasing the CA content leads to an increase in the Ca/Si ratio of C-S-H, causing a transition from a layered structure to a more compact needle-like structure. When 4% CA was added to the mortar, it resulted in an adequate formation of needle-like C-S-H structures, which eventually penetrate and fill the pits formed by SAP, compensating for the strength loss caused by SAP.

RAS-targeted cancer therapy: Advances in drugging specific mutations.

Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on different RAS allelic mutations or even different cancers with KRASG12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RAS mutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RAS mutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors.

Seismic Signal Analysis Based on Variational Mode Decomposition and Hilbert Transform for Ground Intrusion Activity Classification.

The identification of ground intrusion is a key and important technology in the national public security field. In this paper, a novel variational mode decomposition (VMD) and Hilbert transform (HT) is proposed for the classification of seismic signals generated by ground intrusion activities using a seismic sensing system. Firstly, the representative seismic data, including bicycles, vehicles, footsteps, excavations, and environmental noises, were collected through the designed experiment. Secondly, each original datum is decomposed through VMD and five Band-limited intrinsic mode functions (BIMF) are obtained, respectively, which will be used to generate a corresponding marginal spectrum that can reflect the actual frequency component of the signal accurately by HT. Then, three features related to the marginal spectrum, including marginal spectrum energy, marginal spectrum entropy, and marginal spectrum dominant frequency, are extracted for the analysis of the multi-classification using the support vector machine (SVM) classifier with the LIBSVM library. For the sake of testing and verifying the effectiveness of the proposed variational mode decomposition and Hilbert transform (VMD-HT) technique, the evaluation indicators including accuracy, precision, recall, and F1-Score are used and the results are compared with the time domain, frequency domain, ensemble empirical mode decomposition (EEMD), and empirical wavelet transform (EWT) combined with the HT analysis method. The performance of the VMD-HT method for ground intrusion activity classification provides an average value of 99.50%, 98.76%, 98.76%, and 98.75% for the four evaluation indicators, which are higher than all the other contrasted methods.

Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an evolutionarily conserved protein kinase and the most studied member of the Dual-specificity tyrosine-regulated kinase (DYRK) family. It has been shown that it participates in the development of plenty of diseases, and both the low or high expression of DYRK1A protein could lead to disorder. Thus, DYRK1A is recognized as a key target for the therapy for these diseases, and the studies on natural or synthetic DYRK1A inhibitors have become more and more popular. Here, we provide a comprehensive review for DYRK1A from the structure and function of DYRK1A, the roles of DYRK1A in various types of diseases, including diabetes mellitus, neurodegenerative diseases, and kinds of cancers, and the studies of its natural and synthetic inhibitors.

H-2 increases oxidative stress resistance through DAF-16/FOXO pathways in Caenorhabditis elegans: A new approach to vitiligo treatment.

Oxidative stress disrupts the homeostasis of the redox state in cells and induces apoptosis. Prolonged oxidative stress can impair the normal function of cells, tissues, and organs and lead to the development of several diseases. H-2 was synthesized by derivatising N-Alkylamides (NAAs) from Anacyclus pyrethrum (L.) DC, which is commonly used in the treatment of vitiligo in Uyghurs. The antioxidant activity and potential molecular mechanisms of H-2 were investigated using Caenorhabditis elegans (C. elegans) and mouse melanoma cell B16-F10 models. The in vivo anti-vitiligo activity of H-2 was studied using C57BL/6 mice. The results showed that H-2 could increase the survival time of nematodes under oxidative stress, promote the nuclear localization of DAF-16, and enhance the expression of Superoxide Dismutase 3 (SOD-3) in nematodes thereby activating the antioxidant enzyme system. H-2 could affect the survival rate of age-1 and akt-1 mutants under oxidative stress. H-2 could reverse the oxidative stress damage by reducing the reactive oxygen species (ROS) content in the Hydrogen peroxide (H2O2) -induced oxidative stress damage model of mouse melanoma cells B16-F10. In addition, it was also able to increase the number of melanocytes in the hair follicles of vitiligo model mice and improve the phenomenon of skin damage in mice. In conclusion, our findings suggest that H-2 can alleviate oxidative stress damage in C. elegans and B16-F10, which may be associated with oxidative stress, suppression of antioxidant defences, and transcription factors DAF-16/FOXO, providing beneficial evidence for the application of H-2 in the vitiligo treatment.

Zinc Laurate Protects against Intestinal Barrier Dysfunction and Inflammation Induced by ETEC in a Mice Model.

Enterotoxigenic Escherichia coli (ETEC) infection is one of the most common bacterial causes of diarrhea in children and young farm animals. Medium-chain fatty acids (MCFAs) have been widely used for their antibacterial and immune functions. However, there is limited information regarding the role of MCFAs chelated with Zn in diarrhea induced by ETEC infection. Here, zinc laurate (ZnLa) was used to evaluate its protective effect in a mice diarrhea model induced by ETEC. A total of 45 ICR-weaned female mice were randomly assigned to marginal zinc deficiency (dZn), dZn, and ETEC infection groups (dZn+ETEC); ETEC infection was co-treated with a low, middle, or high dose of ZnLa (ZnLa LOW+ETEC, ZnLa MID+ETEC, and ZnLa HIGH+ETEC), respectively, to explore the effect and its mechanism of ZnLa on diarrhea and intestinal health of mice challenged with ETEC. To further compare the antibacterial efficiency of ZnLa and ZnSO4 in mice with ETEC infection, a total of 36 ICR-weaned female mice were randomly divided into ZnLa, ZnLa+ETEC, ZnSO4, and ZnSO4 and ETEC infection groups (ZnSO4+ETEC); moreover, the growth curve of ETEC also compared ZnLa and ZnSO4 in vitro. Mice pretreated with ZnLa were effectively guarded against body weight losses and increases in diarrhea scores induced by ETEC. ZnLa pretreatment also prevented intestinal barrier damage and ion transport in mice challenged with ETEC, as evidenced by the fact that the intestinal villus height and the ratio of villus height and crypt depth, tight junction protein, and Na+ absorption were higher, whereas intestinal permeability and anion secretion were lower in mice pretreated with ZnLa. In addition, ZnLa conferred effective protection against ETEC-induced intestinal inflammatory responses, as the increases in protein and mRNAs of proinflammatory cytokines were prevented in serum and jejunum, which was likely associated with the TLR4/MYD88/NF-κB signaling pathway. The increase in ETEC shedding and virulence-related gene expression was prevented in mice with ZnLa pretreatment. Finally, the growth of ETEC and virulence-related gene expression were lower in the ZnLa group than in ZnSO4 with an equal concentration of zinc. These findings suggest that ZnLa is a promising prevention strategy to remedy ETEC infection.

Synthesis of Novel Pinocembrin Amino Acid Derivatives and Their Antiaging Effect on Caenorhabditis elegans via the Modulating DAF-16/FOXO.

PURPOSE: Pinocembrin is a dihydroflavonoid, which is widely found in several plant species. Although pinocembrin has good pharmacological activity, it has poor water solubility and low bioavailability. Therefore, we have modified the structure of pinocembrin with a combination of different amino acids to solve this problem. Moreover, the effect of the antiaging activity of them has not been explored. We aim to investigate the effect of pinocembrin and its amino acid derivatives on the aging of Caenorhabditis elegans. METHODS: Pinocembrin was spliced with different amino acids in order to obtain their corresponding derivatives. The preliminary research of pinocembrin and its amino acid derivatives on antiaging effect was studied by using the C. elegans model. Among all the compounds, the one shows the best antiaging effect was then studied on antiaging mechanism. The protective effect on nematodes under emergency conditions was explained by detecting the ROS content and sod-3p::GFP fusion protein expression in nematodes; the possible anti-aging mechanism of nematodes was determined by DAF-16 nuclear localization experiment and the survival curve of transgenic nematodes model under stress conditions. RESULTS: Pb-3 showed the best effect on increasing tolerance to thermal and oxidative stress and reduce the accumulation of lipofuscin. In the assay of C. elegans, pb-3 reduced intracellular ROS accumulation. Application of pb-3 to the transgenic mutant TJ356 induced the translocation of the transcription factor DAF-16 from the cytosol to the nucleus, and modulated the expression of SOD-3 (downstream genes of daf-16), which regulates longevity in C. elegans. Moreover, pb-3 did not prolong the lifespan of daf-16, age-1, daf-2 and hsp16.2 mutants, suggesting that these genetic pathways are involved in mediating the antiaging effects of pb-3. CONCLUSION: The antioxidant and antiaging properties of pb-3 may involve in the DAF-16/FOXO transcription process. Pinocembrin amino acid derivatives might be a novel agent for antiaging therapy.

The association between acromial anatomy and articular-sided partial thickness of rotator cuff tears.

BACKGROUND: Acromial anatomy has been found to be correlated with degenerative full-thickness rotator cuff tears in current studies. However, research on the relationship between acromial anatomy and articular-sided partial thickness of rotator cuff tears (PTRCTs) is still lacking. The purpose of this study was to evaluate whether these imaging graphic parameters exhibit any association between acromial anatomy and degenerative articular-sided PTRCTs. METHODS: Between January 2016 and December 2018, a total of 91 patients without a history of trauma underwent arthroscopy as an articular-sided PTRCT group. In the control group, with age- and sex-matched patients, we selected 91 consecutive outpatient patients who underwent shoulder magnetic resonance imaging (MRI) because of shoulder pain and an MRI diagnosis of only synovial hyperplasia and effusion. MRI was used to measure the acromial type, acromiohumeral distance (AHD), lateral acromial angle (LAA), acromion index (AI), and critical shoulder angle (CSA) by 2 independent observers. RESULTS: The acromion type, AHD and LAA showed no difference between degenerative articular-sided PTRCTs and controls (P = 0.532, 0.277, and 0.108, respectively). AI and CSA were significantly higher in degenerative articular-sided PTRCTs (P = 0.002 and 0.003, respectively). A good correlation was found between AI and CSA to measurement(Pearson correlation coefficient = 0.631). CONCLUSIONS: Our study revealed that higher AI and CSA were found in degenerative articular-sided PTRCTs. Acromial anatomy with a large acromial extension was associated with the occurrence of degenerative articular-sided PTRCTs.

Effects of glycyrrhizin on the growth cycle and ATPase activity of PRRSV-2-infected MARC-145 cells.

Porcine reproductive and respiratory syndrome (PRRS) is a viral infectious disease caused by the porcine reproductive and respiratory syndrome virus (PRRSV) and is devastating the swine industry. MARC-145 cells, an African green monkey kidney cell line, are sensitive to PRRSV-2, and are often used for in vitro studies on PRRSV-2. Preliminary research has shown that glycyrrhizin, an important active component extracted from traditional Chinese medicinal licorice, significantly inhibits the proliferation of PRRSV-2 in MARC-145 cells; however, the in-depth molecular mechanism remains unclear. By determining the cell growth cycle, this study found that PRRSV-2 infection first increased the content of G1-phase MARC-145 cells and then decreased the content of G1-phase cells. Moreover, glycyrrhizin affected the role of PRRSV-2 in regulating the cell cycle. Furthermore, PRRSV-2 had the highest proliferation titer in G0/G1-phase MARC-145 cells, and glycyrrhizin reduced the content of PRRSV-2 in synchronized MARC-145 cells. According to the results of ATPase detection, PRRSV-2 infection weakened the Na+/K+-ATPase and Ca2+/Mg2+-ATPase activities in MARC-145 cells, while glycyrrhizin significantly enhanced their activities in PRRSV-2-infected MARC-145 cells. The above results provide theoretical support toward clarifying the mechanism by which glycyrrhizin inhibits the proliferation of PRRSV-2 in MARC-145 cells. Moreover, these results offer references for the development and use of glycyrrhizin and the clinical treatment of PRRSV-2 infection.

A preliminary study on the neurotoxic mechanism of harmine in Caenorhabditis elegans.

Harmine is a beta-carboline and harmala alkaloid with extensive bioactivities. However, its toxicity, especially in neural system, is not systematically assessed and the toxic mechanism is not yet clear. Using Caenorhabditis elegans (C. elegans) as a model system, we found that harmine exhibited dosage dependent (0, 5, 10, 20, 40, 80, 160, and 320 µmol/L) toxic effect, such as growth inhibition, egg laying defects, shortened life span and increased mortality. Although harmine did not result in obvious structural alterations in neurite or death of neurons, it did show direct acetylcholinesterase inhibition activity. Further, we found that harmine treatment decreased worm pharyngeal pump rate and lowered the content of nitric oxide (NO) in worm body, implying foraging disorders, which is an indicator of acetylcholinergic neuron activity inhibition. Besides, network pharmacology and molecular docking reveals that acetylcholinesterase is one of the major neural toxicity targets as well. Above all, harmine can directly inhibit the activity of acetylcholinesterase, leading to excessive accumulation of acetylcholine, which may be one of the harmine neurotoxicity mechanisms.

Benchmarking of several material constitutive models for tribology, wear, and other mechanical deformation simulations of Ti6Al4V.

Use of an alpha-beta (multiphase HCP-BCC) titanium alloy, Ti6Al4V, is ubiquitous in a wide range of engineering applications. The previous decade of finite element analysis research on various titanium alloys for numerous biomedical applications especially in the field of orthopedics has led to the development of more than half a dozen material constitutive models, with no comparison available between them. Part of this problem stems from the complexity of developing a vectorised user-defined material subroutine (VUMAT) and the different conditions (strain rate, temperature and composition of material) in which these models are experimentally informed. This paper examines the extant literature to review these models and provides quantitative benchmarking against the tabulated material model and a power law model of Ti6Al4V taking the test case of a uniaxial tensile and cutting simulation.

The role of arthroscopic release of gluteal muscle contracture in improving patellofemoral instability.

BACKGROUND: Gluteal muscle contracture (GMC) is a notable problem in some developing countries and includes features such as a snapping sound of the hip, abnormal gait, and unusual posture when patients squat with the knees together. Arthroscopic release can not only resolve symptoms, as previously reported, but can also greatly improve accompanying patellofemoral instability. This study was conducted to evaluate the effect of arthroscopic release of GMC on patellofemoral instability and its underlying mechanism. METHODS: A total of nearly 500 patients who underwent arthroscopic release of GMC over 2.5 years were filtered, and 54 patients were enrolled in the study. The selected research subjects all had combined patellofemoral instability preoperatively. The Lysholm scores and CT scans of the knee were evaluated pre- and postoperatively. RESULTS: The mean follow-up time was 12.2 months. All of the surveyed patients had satisfactory clinical outcomes for hip snapping sounds and abnormal gait. In addition, a significant difference (p < 0.05) was observed between pre- and postoperative Lysholm scores, along with significant knee pain relief. Furthermore, the changes in CT scan parameters were significant as well. The average patellar tilt angle (PTA), patellofemoral index (PFI), and lateral patellar displacement (LPD) were obviously decreased (p < 0.05) after the release. Conversely, the mean lateral patellofemoral angle (LPFA) showed a clear difference (p < 0.05) between preoperative and postoperative CT examinations. CONCLUSIONS: Arthroscopic release of GMC can reduce the tilt and lateral shift of the patella and enhance its stability due to the release of the iliotibial band.

Arthroscopic knotless single-row repair preserving full footprint versus tear completion repair for partial articular-sided rotator cuff tear.

BACKGROUND: The comparison of clinical outcomes of arthroscopic footprint-preserving knotless single-row repair with the tear completion repair technique for articular-sided partial-thickness rotator cuff tears (PTRCTs) remains unclear. METHODS: A total of 68 patients diagnosed with articular-sided PTRCTs who underwent rotator cuff repair between December 2014 and June 2015 were included. Of the 68 patients, 30 received footprint-preserving knotless single-row repair (group 1) and 38 received the tear completion repair technique (group 2). Preoperative and postoperative assessments were compared. RESULTS: Both groups had significantly improved American Shoulder and Elbow Surgeons (ASES) scores (group 1: 48.2 preoperatively to 81.9 postoperatively, p < 0.001; group 2: 47.1 preoperatively to 84.9 postoperatively, p < 0.001) and visual analog scale (VAS) pain score (group 1: 6.0 preoperatively to 0.93 postoperatively, p < 0.001; group 2: 6.1 preoperatively to 1.1 postoperatively, p < 0.001), showing that the two procedures significantly improved postoperative shoulder function. No significant differences were shown in ASES score or VAS pain score between the two groups ( p > 0.05). The mean operation time was significantly shorter in group 1 with an average of 48.1 min than in group 2 with an average of 60.4 min ( p < 0.001). CONCLUSIONS: Footprint-preserving knotless single-row repair obtains similar clinical results compared to tear completion repair in the treatment of articular-sided PTRCTs. Footprint-preserving knotless single-row repair may be a convenient choice for the treatment of articular-sided PTRCTs. Randomized controlled studies are needed to investigate whether the footprint-preserving knotless single-row repair yields better long-term outcomes through the protection of the bursal cuff and restoration of the healthy footprint.

Noise exposure of residential areas along LRT lines in a mountainous city.

Light rapid transit (LRT) has been widely used in a number of Chinese cities in recent years. Different from plain cities, the urban areas in mountainous cities are featured with dense road networks and high density of buildings. The noise impact of urban LRT could be more complex and significant due to the special morphological conditions in mountainous cities. This paper aims to investigate the noise exposure of residential areas along LRT lines in a typical mountainous city, namely Chongqing in Southwest China, through a series of field measurements and questionnaire surveys. Eight typical spatial configurations were classified to represent the relationships between LRT lines and urban mountainous environment. Both the outdoor and indoor acoustic environment of residential areas along LRT lines largely exceeded the national standards by up to 15dBA, with dominant at low frequencies. The LRT noises tend to be more dominant on the 'below track' and 'passing through' rather than 'above track' areas or 'facing towards' locations. Good agreements were achieved between acoustic measurements and subjective evaluations from the local residents. Residents in the noisier areas tend to be more annoyed and influenced by the LRT noise, and 63.2% of interviewed residents once were awakened by the LRT noise. Among various urban noise sources, LRT noise resulted in the largest percentages of highly annoyed residents (30.9%), and acoustic environment was identified by 42.2% of the participants as the most urgent environmental factor to be improved. The preferred control strategies for LRT noise are possible but limited in practice. Moreover, noise sensitivity and age might significantly affect LRT noise annoyance and impact, whereas window glazing and residence time have no significant influence.

[The evolution of adaptive immunity system of Agnathan vertebrates].

All along peoples pay extensive attention on the origin and evolution of adaptive immunity system. Agnathans, taking lamprey as the representative, are generally thought at the edge of evolving the adaptive immunity system. Therefore, it is very significantly important to further study the mechanism of adaptive immunity of agnathans for revealing the origin and evolution of adaptive immunity system. Previous studies indicated that agnathans shared some characters of adaptive immunity with higher vertebrates. In addition, a few researchers also found that some genes are homologous in the structure or function with the immunologically relevant genes of higher vertebrates. In this article, we have summarized some recent research progresses about the mechanism of adaptive immunity system of agnathans. The aim of this paper is to provide valuable clues for further studying of the origin and evolution of the adaptive immunity system of vertebrate.