HSP90ß prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53.

Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90ß (HSP90ß) plays a fundamental role in suppressing cataractogenesis. HSP90ß is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90ß is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90ß silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90ß can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90ß silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90ß and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90ß is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.

The Role of Self-Esteem in Protecting Against Cyber-Victimization and Gaming Disorder Symptoms Among Adolescents: A Temporal Dynamics Analysis.

Previous literature has suggested that victimization is linked to low self-esteem and increases the symptoms of gaming disorder. However, little is known about the intra-individual processes, and the temporal dynamics of cyber-victimization, self-esteem, and gaming disorder symptoms. To address this gap, a three-year longitudinal study was performed using data collected at six different time points from 4206 Chinese adolescents (aged 12-17 years; 50.4% boys). Results of random intercept cross-lagged panel models (RI-CLPMs) indicated that at the within-person level, the fluctuation in self-esteem weakly predicted late cyber-victimization, and the fluctuation of cyber-victimization also weakly predicted late self-esteem. Additionally, the current study identified an interactive effect between self-esteem and gaming disorder symptoms at the within-person level. Fluctuations in self-esteem negatively predicted late gaming disorder symptoms, and vice versa. However, when combining the three variables (i.e., cyber-victimization, self-esteem, and gaming disorder symptoms) into one RI-CLPM, the results did not support the mediation of self-esteem in the relationship between cyber-victimization and gaming disorder symptoms at the within-person level. Moreover, fluctuations in self-esteem negatively predicted late gaming disorder symptoms and cyber-victimization at the within-person level in the RI-CLPM. These findings emphasize the protective role of self-esteem developed against cyber-victimization and gaming disorder symptoms among adolescents.

Longitudinal Relationships Between School Climate, Academic Achievement, and Gaming Disorder Symptoms Among Chinese Adolescents.

Despite growing concerns regarding the development of gaming disorder symptoms among adolescents, the longitudinal relationship between school factors and gaming disorder symptoms remains far from being fully understood. This two-year longitudinal study examined the relationship between school climate perceptions, academic achievement, and gaming disorder symptoms among three distinct demographic cohorts: preadolescents (n = 1513; 46.9% girls, Mage = 10.64 years, SD = 0.56), early adolescents (n = 1771; 48.3% girls, Mage = 13.54 years, SD = 0.70), and late adolescents (n = 2385; 50.1% girls, Mage = 16.41 years, SD = 0.59). A four-wave study was conducted (six months apart) using random intercept cross-lagged panel models (RI-CLPMs) to separate the within-person (state level) from the between-person (trait level) effects. The results obtained from the RI-CLPMs indicated that fluctuations in school climate perceptions negatively predicted subsequent changes in gaming disorder symptoms among preadolescents at the within-person level, but not among early and late adolescents. Fluctuations relating to gaming disorder symptoms also negatively predicted subsequent changes regarding academic achievement in late adolescents, but not in preadolescents and early adolescents. The effect of school-related factors on gaming disorder symptoms varies across different developmental stages. While preadolescents may represent a particularly susceptible subgroup for gaming disorder in terms of being predicted by their school environment, late adolescents appear to be more vulnerable to predictors of gaming disorder symptoms. The current study also discusses the implications of school-wide programs aimed at improving school climate and preventing the development of gaming disorder symptoms during key developmental periods.

High leukocyte mitochondrial DNA copy number contributes to poor prognosis in breast cancer patients.

BACKGROUND: Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA copy number (mtDNAcn) and prognosis of several malignancies in a cancer-specific manner. However, whether leukocyte mtDNAcn can predict the clinical outcome of breast cancer (BC) patients has not been well investigated. METHODS: The mtDNA copy number of peripheral blood leukocytes from 661 BC patients was measured using a Multiplex AccuCopy™Kit based on a multiplex fluorescence competitive PCR principle. Kaplan-Meier curves and Cox proportional hazards regression model were applied to investigate the association of mtDNAcn with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer special survival (BCSS), and overall survival (OS) of patients. The possible mtDNAcn-environment interactions were also evaluated by the Cox proportional hazard regression models. RESULTS: BC patients with higher leukocyte mtDNA-CN exhibited a significantly worse iDFS than those with lower leukocyte mtDNAcn (5-year iDFS: fully-adjusted model: HR = 1.433[95%CI 1.038-1.978], P = 0.028). Interaction analyses showed that mtDNAcn was significantly associated with hormone receptor status (adjusted p for interaction: 5-year BCSS: 0.028, 5-year OS: 0.022), so further analysis was mainly in the HR subgroup. Multivariate Cox regression analysis demonstrated that mtDNAcn was an independent prognostic factor for both BCSS and OS in HR-positive patients (HR+: 5-year BCSS: adjusted HR (aHR) = 2.340[95% CI 1.163-4.708], P = 0.017 and 5-year OS: aHR = 2.446 [95% CI 1.218-4.913], P = 0.011). CONCLUSIONS: For the first time, our study demonstrated that leukocyte mtDNA copy number might influence the outcome of early-stage breast cancer patients depending on intrinsic tumor subtypes in Chinese women.

Violent video game exposure and bullying perpetration among Chinese adolescents: The moderating role of belief in a just world.

Exposure to violent video games is associated with aggressive behaviors among adolescents. However, not all adolescents who play violent video games demonstrate bullying behaviors. Based on the General Aggression Model (GAM), this cross-sectional study examined the interactive effect of individuals (i.e., belief in a just world [BJW]) and situational factors (i.e., violent video game exposure [VVGE]) on bullying perpetration. Using a representative sample of 4250 adolescents from five secondary schools in Southwest China (54.4% males, Mage = 15.14, SD = 1.5 years old), we examined the moderating role of BJW in the relationship between VVGE and bullying perpetration. The results suggest that VVGE is significantly and positively associated with bullying perpetration. Moreover, after controlling for covariates, general and personal BJW interact with the situational variable (i.e., VVGE) to predict bullying perpetration among Chinese adolescents. The positive effect of VVGE on bullying perpetration is lower among adolescents with high general and personal BJW than among adolescents with low BJW. The findings support the GAM theory and highlight the buffering role of BJW in the effect of VVGE on bullying perpetration.

Mir-485-5p on the Morphology and Function of Cardiovascular System.

Cardiovascular disease is a global problem that seriously endangers human health and life. At present, hypertension is considered to be a polygenic disease caused by the interaction of environmental factors and genetic factors. Various environmental factors have been proved to promote the occurrence and development of cardiovascular disease. MicroRNA (miR), as an essential gene regulatory factor in vivo, has been confirmed to participate in the regulation of many cell pathways, and its abnormal expression is closely related to a variety of human diseases. MiR-485-5p is located at 7q22.1, which has been proved to play an essential role in the tumor and cardiovascular system. Therefore, this paper discussed the mechanism of miR-485-5p on the morphology and function of the cardiovascular system. It is believed that miR-485-5p will impact the morphology and function of the cardiovascular system. Therefore, in the current study, 1655 unrelated patients with cardiovascular system diseases were simulated and analyzed based on the above background. A double luciferase reporter gene detection system verified the combination of miRNAs target recognition. The results showed that miR-485-5p significantly inhibited the luciferase activity of pGL-miR-wt but had no effect on pGL6-miR-mut. The lack of miR-485-5p can promote the activation of cardiac fibroblasts. The findings of this study can provide a new understanding and direction for the study of cardiovascular system morphology and function.

The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway.

BACKGROUND: Uric acid (UA) transporters mediate the uptake and outflow of UA, and are greatly involved in the control of UA concentrations. Glucose transporter 9 (GLUT9), one of the UA transporters, has been confirmed to be expressed in human umbilical vein endothelial cells (HUVECs). This study aimed to characterize GLUT9's effect on intracellular UA accumulation in HUVECs in a high-UA environment and to explore the mechanism of cellular dysfunction. METHODS AND RESULTS: HUVECs were treated with UA to establish a model of cellular dysfunction. Then, UA uptake, GLUT9 expression and endothelial nitric oxide synthase (eNOS) and reactive oxygen species (ROS) amounts were measured. UA uptake was concentration- and time-dependent, and UA treatment significantly reduced nitric oxide (NO) levels and eNOS activity. UA also upregulated pro-inflammatory molecules and GLUT9, and increased intracellular ROS amounts in HUVECs. GLUT9 knockdown reduced UA uptake and ROS content, but antioxidant treatment did not reduce GLUT9 expression. To assess the function of JAK2/STAT3 signaling, HUVECs were treated with UA, and the phosphorylation levels of JAK2, STAT3, IL-6 and SOCS3 were increased by a high concentration of UA. In addition, GLUT9 knockdown reduced the phosphorylation of JAK2/STAT3 intermediates and increased p-eNOS amounts. CONCLUSIONS: GLUT9 mediated the effects of high UA levels on HUVECs by increasing the cellular uptake of UA, activating JAK2/STAT3 signaling, and reduced the production of active eNOS and NO in HUVECs.

Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes.

Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53-heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.

Comparison of PPI and combined treatment in the treatment of recurrent laryngeal contact granuloma.

OBJECTIVE: To compare the therapeutic effect of PPI and combined treatment in the treatment of patients with recurrent laryngeal contact granuloma. METHODS: The clinical data of 299 patients with recurrent laryngeal contact granuloma treated with PPI or combined treatment (PPI with glucocorticoid injection into granuloma by the thyroglossal approach) from February 2013 to June 2019 were analyzed retrospectively. Patients were divided into two subgroups: PPI and combined treatment. The cure rates, recurrence rates and cure time of the two subgroups were compared and analyzed separately. Than we can get the optimal treatment of the two treatment in the treatment of recurrent patients. RESULTS: In recurrent patients, the cure rate (81.20%) and recurrence rate (3%) of combined treatment were superior to those of PPI (57.58%) and recurrence rate (12.12%); (P < 0.05). The cure time of PPI was longer than that of combination therapy (P < 0.001). CONCLUSION: The therapeutic effect of combined treatment is better than that of PPI in patients with recurrence. At the same time, combined treatment is an effective treatment for recurrent granuloma and can be used as a first-line treatment for recurrent laryngeal contact granuloma.

Short-term outcome of transcutaneous glucocorticoid injection for laryngeal contact granuloma in females.

OBJECTIVE: To evaluate the short-term efficacy of transcutaneous glucocorticoid injection for laryngeal contact granuloma in females. METHODS: A total of 14 female patients with laryngeal contact granuloma treated in our outpatient department from November 2017 to January 2020 were included in the study. Inspiratory-phase laryngoscopy images were collected before treatment and 1 month after each injection, and the lesion size was measured and evaluated with ImageJ software. RESULTS: Two patients achieved complete remission after one injection, with a percent reduction of 100%. After two injections, 4 patients achieved complete remission, with a percent reduction ranging from 96% to 100%. After 3 injections, 4 patients achieved complete remission (including one patient with bilateral lesions), and the percent reduction ranged from 95% to 100%. Three patients achieved incomplete remission, with a percent reduction of 46%, 55%, and 81%, respectively. In one case, there was no remission, and the granuloma increased in size after treatment. CONCLUSION: In women with laryngeal contact granuloma, transcutaneous glucocorticoid injection therapy can quickly resolve the granuloma in a short period.

Novel CTNND2-TERT fusion in a spindle cell liposarcoma.

Soft tissue tumors can be categorized molecularly into two categories: tumors which are known to have recurrent molecular alterations and tumors which do not have consistent recurrent molecular alterations or translocations. These "nontranslocation" associated sarcomas are clinically more aggressive than their more stable counterparts. However, recent advances in RNA sequencing have discovered recurrent novel fusions within the latter group, namely TERT-TRIO fusions. Furthermore, a recent report discovered this fusion in a spindle cell liposarcoma. Our case describes a novel fusion of CTNND2, a neighbor gene of TRIO, and TERT in a spindle cell liposarcoma, and provides further evidence that spindle cell liposarcoma should be a distinct entity from dedifferentiated liposarcoma.

Current Situation of Methamphetamine Abuse and Related Research Progress.

Drug problem is a major social and public security problem in the world. Drug abuse poses a great threat to economic development, social stability and public health. In recent years, synthetic drugs represented by methamphetamine have surpassed traditional drugs such as morphine, heroin, ketamine and become one of the most abused drugs in the world. In order to solve the problem of drug abuse, it is of great theoretical value and practical significance to carry out all-round and multi-level scientific research on drug-related issues. Based on the current situation of drug abuse, this article reviews research progresses on the epidemiology of methamphetamine abuse, the monitoring technology, the basic researches on toxicity damage, the withdrawal drug screening, the related clinical comorbidity and the testing technologies, comprehensively presenting the development trend of methamphetamine abuse related issues.

Light-controllable metasurface for microwave wavefront manipulation.

Applying multiple physical fields to artificial manipulate electromagnetic waves is a highly stirring research. In this paper, we creatively combine light control with microwave scattering, realizing an optically coding metasurface for beam deflection based on anomalous reflection. A photoresistor and a voltage-driven module are connected to control each row of PIN-diode-loaded unit cells, endowing the reflection phase of the elements with a strong dependence on light. Owing to the high sensitivity of photoresistor, the digital element state "0" or "1" can be switched effectively via light variation sensed by the photoresistor. By modulating the light signal, the arrangement of digital elements can be reprogrammed, generating the specific scattering field. Therefore, the electromagnetic field can be determined by the spatial distribution of light, which induces the connect with the optical information and microwave field. The simulated and experimental results demonstrate the feasibility of our design. This light-steering approach provides a dimension for electromagnetic wave modulation.

A valuable and affordable handheld ultrasound in combating COVID-19.

The handheld ultrasound demonstrates clinical and economic value in combating COVID-19 based on interviews with frontline ultrasound physician and cardiologist as well as a national expert in medical ultrasound.

Tamoxifen inhibits fibroblast proliferation and prevents epidural fibrosis by regulating the AKT pathway in rats.

Many factors contribute to epidural fibrosis after lumbar laminectomy, particularly the excessive proliferation of fibroblasts. Many studies have shown that tamoxifen (TAM) inhibits fibroblast proliferation and reduces fibrosis, but the detailed effect and mechanism of TAM on preventing epidural fibrosis are unknown. To investigate the effect of TAM on fibroblast proliferation and epidural fibrosis, fibroblasts were cultured and treated with different concentrations of TAM. Cell Counting Kit-8(CCK-8) detection, cell cycle analysis and western blot analysis were used to detect the roles of TAM in regulating fibroblast proliferation. Lumbar laminectomies were performed in rats, and various concentrations of TAM were administered by gavage. Histological and immunohistochemical analyses were used to evaluate the effects of TAM on preventing epidural fibrosis. CCK-8 detection showed that TAM could inhibit fibroblast viability; western blot analysis showed that TAM could decrease the expression of proliferative proteins p-AKT and cyclinD1 and increase the expression of antiproliferative proteins P21 and P27. Histological analysis showed that TAM could reduce epidural fibrosis. Immunohistochemical analysis showed that the p-ATK expression in epidural scar tissue was decreased after TAM treatment. The present study demonstrated that TAM could inhibit fibroblast proliferation and prevent epidural fibrosis, potentially through the regulation of the AKT pathway.

Amentoflavone Inhibits Osteoclastogenesis and Wear Debris-Induced Osteolysis via Suppressing NF-κB and MAPKs Signaling Pathways.

Wear debris-induced osteolysis is one of the major reasons for subsequent aseptic loosening after cementless hip arthroplasty. Increasing evidence suggests that receptor activator of nuclear factor kappa-B (NF-κB) ligand-mediated osteoclastogenesis and osteolysis are responsible for wear debris-induced aseptic loosening. In the present study, we explored the effect of amentoflavone (AMF) on inhibiting osteoclast generation and wear debris-induced osteolysis in vitro and in vivo. Twenty-four male C57BL/J6 mice were randomly divided into four groups: a sham group and groups with titanium wear debris treatment followed by intraperitoneal injection of various concentrations of AMF (0, 20, and 40 mg/kg/day). The micro computed tomography scanning and histological analysis were performed. Bone marrow-derived macrophages were cultured to investigate the effect of AMF on osteoclast generation and function. The results showed that AMF suppressed osteoclastogenesis, F-actin ring formation, and bone absorption without cytotoxicity. AMF prevented titanium wear debris-induced osteolysis in mice. AMF suppressed the relative proteins of NF-κB and mitogen-activated protein kinase (MAPKs) signaling pathways. Thus, the present study suggests that AMF derived from plants could inhibit osteoclastogenesis and titanium wear debris-induced osteolysis via suppressing NF-κB and MAPKs signaling pathways.

Signaling molecule methylglyoxal ameliorates cadmium injury in wheat (Triticum aestivum L) by a coordinated induction of glutathione pool and glyoxalase system.

Methylglyoxal (MG) now is found to be an emerging signaling molecule. It can relieve the toxicity of cadmium (Cd), however its alleviating mechanism still remains unknown. In this study, compared with the Cd-stressed seedlings without MG treatment, MG treatment could stimulate the activities of glutathione reductase (GR) and gamma-glutamylcysteine synthetase (γ-ECS) in Cd-stressed wheat seedlings, which in turn induced an increase of reduced glutathione (GSH). Adversely, the activated enzymes related to GSH biosynthesis and increased GSH were weakened by N-acetyl-L-cysteine (NAC, MG scavenger), 2,4-dihydroxy-benzylamine (DHBA) and 1,3-bischloroethyl-nitrosourea (BCNU, both are specific inhibitors of GR), buthionine sulfoximine (BSO, a specific inhibitors of GSH biosynthesis), and N-ethylmaleimide (NEM, GSH scavenger), respectively. In addition, MG increased the activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) in Cd-treated seedlings, followed by declining an increase in endogenous MG as comparision to Cd-stressed seedlings alone. On the contrary, the increased glyoxalase activity and decreased endogenous MG level were reversed by NAC and specific inhibitors of Gly I (isoascorbate, IAS; squaric acid, SA). Furthermore, MG alleviated an increase in hydrogen peroxide (H2O2) and malondialdehyde (MDA) in Cd-treated wheat seedlings. These results indicated that MG could alleviate Cd toxicity and improve the growth of Cd-stressed wheat seedlings by a coordinated induction of glutathione pool and glyoxalase system.

Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells.

Mitofusin 2 (Mfn2) is a dynamin-like protein anchored in the outer mitochondrial membrane that plays a crucial role in ensuring optimal mitochondrial morphological homeostasis. It has been shown that reduced expression of Mfn2 is associated with insulin resistance, but the mechanism is still unclear. We investigated whether Mfn2 deficiency leads to impaired insulin sensitivity via elevated oxidative stress. L6 skeletal muscle cells were treated with palmitate and Mfn2 expression was repressed by transfection with antisense Mfn2. Levels of antioxidant enzymes, reactive oxygen species (ROS), the phosphorylation of c-Jun N-terminal Kinase (JNK) and nuclear factor-κB (NF-κB) and the mitochondrial membrane potential (Δψm) were measured. The results showed palmitate-induced insulin resistance of skeletal muscle cells was accompanied by Mfn2 repression. Meanwhile, the cells had decreased Δψm and activity of antioxidant enzymes which could increase production of ROS, phosphorylation of JNK and NF-κB. When Mfn2 was up-regulated in palmitate-treated cells, oxidative stress and insulin resistance was alleviated. Furthermore, knock-down of Mfn2 in control cells enhanced oxidative stress. Mfn2 deficiency led to increased superoxide concentration and activation of JNK as well as NF-κB associated with insulin signaling. In conclusion, Mfn2 is a potent repressor for oxidative stress and regulation of Mfn2 expression may prove to be a potential method to circumvent insulin resistance.

Mediating Effect of Life Satisfaction on the Relationship between Hope and Internalizing/Externalizing Behaviors among Chinese Adolescents.

This study aimed to examine the mediating effect of life satisfaction in the relationship between hope and internalizing/externalizing behaviors among a sample of 1170 Chinese adolescents (mean age = 14.80 ± 1.76 years, 46.24% boys). Through the use of structural equation modeling (SEM), the study revealed a negative association between hope and internalizing/externalizing behaviors. Furthermore, the findings indicated that life satisfaction partially mediated the relationship between hope and internalizing/externalizing behaviors. The findings highlight the significance of hope and life satisfaction as protective factors in reducing internalizing/externalizing behaviors among adolescents. These results also contribute to the existing research on the role of hope and emphasize the importance of fostering hope and enhancing life satisfaction in prevention and intervention programs targeting adolescent internalizing/externalizing behaviors.

Discovery of a mitochondrial G-quadruplex targeted fluorescent ligand via a slight variation on the near-infrared heptamethine cyanine scaffold.

The heptamethine cyanine dyes are one kind of promising near-infrared (NIR) compounds, holding great potential in both diagnostic and therapeutic regions. Remolding such structures to realize detection of unclarified biotargets or interfering with them seems to be important in the field of chemical biology. In this study, we developed a fluorescent ligand (IR1) targeting mitochondrial G-quadruplexes (mitoG4s) by a slight variation on the typical NIR scaffold (IR780). This ligand could be applied for sensing mitoG4s by fluorescence, making it different from the unmodified dye whose fluorescence was quenched by mitoG4s. Then, IR1 was demonstrated to accumulate in the mitochondria through a mitochondrial membrane potential (MMP) dependent manner. Some of IR1 then bound to mitoG4s, causing mtDNA loss and mitochondrial dysfunction, which thereby triggered PANoptosis, including apoptosis, autophagy and pyroptosis. To the best of our knowledge, IR1 was the first NIR fluorescent ligand with emission centered at above 800 nm for mitoG4s, and the first example causing PANoptosis among the reported mitoG4-targeted ligands.