Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis.

BACKGROUND: Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear. METHODS: We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson's correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins. RESULTS: Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro. CONCLUSIONS: This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.

The dysfunction of CD8+ T cells triggered by endometriotic stromal cells promotes the immune survival of endometriosis.

Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.

Use of Various UVC Photofunctionalization Times to Modify Surface Characteristics and Enhance the Biologic Activity of SLA Titanium.

PURPOSE: To evaluate the effect of ultraviolet-C light (UVC) photofunctionalization treatment time on the biologic activity of airborne particle-abraded and acid-etched (SLA) titanium surfaces and to analyze its physical and chemical mechanisms. MATERIALS AND METHODS: SLA titanium was treated with UVC light for different lengths of time (10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 24 hours), and then changes to its surface characteristics were evaluated via electron microscope scanning, X-ray photoelectron spectroscopy (XPS), water contact angle measurement, and zeta potential measurement. The effect of UVC photofunctionalization on the biologic processes of SLA titanium surfaces was assessed by analyzing the bovine serum albumin adsorption, adhesion, proliferation, morphology, and alkaline phosphatase activity of MG-63 cells. RESULTS: UVC irradiation did not change the topography of SLA titanium surfaces. As treatment times increased, the water contact angle decreased from 120 degrees to 0 degrees, and the hydrocarbon content decreased. Zeta potential testing showed increased surface potential of photofunctionalized titanium. In vitro testing showed that cell adhesion, proliferation, morphology, and alkaline phosphate (ALP) activity on titanium surfaces were significantly improved by UVC photofunctionalization. CONCLUSIONS: UVC photofunctionalization can improve the biologic activity of SLA titanium surfaces by removing hydrocarbons and increasing the surface potential of titanium.

Analysis of clinical correlation between pelvic organ prolapse and HR-HPV infection.

OBJECTIVE: To explore the influence of pelvic organ prolapse (POP) on the risk of high-risk human papilloma virus (HR-HPV) infection. MATERIALS AND METHODS: Retrospective analysis of the HR-HPV infection results of 1183 patients with POP who were treated at the First Affiliated Hospital of Chongqing Medical University, Liangping District People's Hospital affiliated to Chongqing Medical University, and the 13th People's Hospital of Chongqing between October 2018 and October 2021. Patients without POP who underwent HR-HPV examination at the same time were selected as the control group, and the HR-PV infection rate was compared between the two groups. Patients diagnosed with POP were stratified to analyse whether age, menopausal status, degree of POP, location of POP and duration of POP were associated with HR-HPV infection. RESULTS: The rate of HR-HPV infection was lower for patients with POP compared with patients without POP over the same time period. The highest rate of infection was seen in patients aged 60-69 years (14.7%) and the lowest rate (7.5%) was seen in patients aged 50-59 years; differences between age groups were significant. The rate of HR-HPV infection in postmenopausal patients with POP was slightly higher than that in non-menopausal patients with POP, but the difference was not significant. No significant differences in the rate of HR-HPV infection were associated with location of POP, duration of POP or degree of POP. CONCLUSION: POP does not increase the risk of HR-HPV infection.

Application and investigation of thrombopoiesis-stimulating agents in the treatment of thrombocytopenia.

Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)-MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.

A multifunctional nanoparticle for efferocytosis and pro-resolving-mediated endometriosis therapy.

Endometriosis is an inflammation-dependent disorder characterized by the abnormal growth of endometrium-like lesions. In recent years, there is a great deal of interest in the development of anti-inflammatory therapy. Herein, an acid-sensitive calcium carbonate nanoparticle (CaNP) incorporated BML-111 (BML@CaNP) was prepared. BML@CaNP acted as a Ca2+ nanomodulator for efferocytosis (macrophages engulf apoptotic cells). Specifically, BML@CaNP induced the apoptosis of endometriotic stromal cells and enhanced the efferocytosis of macrophages. In addition, the particle can also deliver BML to the ectopic lesion for resolving the inflammatory response. In vivo BML@CaNP effectively suppressed lesion growth in endometriosis mice model, which could be attributed to the enhancing efferocytosis of cells and the lower levels of inflammatory factors in peritoneal fluid. In addition, these nanoparticles did not show side effects. In all, we provide a new anti-inflammatory strategy by both enhancing efferocytosis and resolving inflammation for the treatment of endometriosis.

Public Health Risk Assessment and Prevention Based on Big Data.

In order to improve the ability of public health risk assessment in the context of community collaborative prevention and control, a mathematical model of public health risk assessment in the context of community collaborative prevention and control based on the integration and balanced allocation of big data features in the prevention horizon is proposed. The constraint parameter model of public health risk assessment under the background of community collaborative prevention and control is constructed, the method of dynamic feature analysis of joint prevention and control is adopted to realize the dynamic risk point detection of public health risk assessment data and the integration of constraint mechanism related feature points, and the fuzzy dynamic statistical feature matching method is adopted to carry out the adaptive dynamic statistics and resource balanced allocation analysis of public health risk assessment set under the background of community collaborative prevention and control. A public health risk parameter fusion model is established under the background of community collaborative prevention and control, the methods of balanced resource allocation and joint management and control are combined to realize balanced scheduling and prevention area block matching in the process of dynamic parameter estimation of public health risk evaluation data under the background of community collaborative prevention and control, the correlation distribution of public health risk under the background of community collaborative prevention and control is taken as the cost function, and balanced allocation is realized according to the statistical information sampling results of public health risk evaluation data under the background of community collaborative prevention and control. Combined with differential clustering analysis, the data clustering and attribute merging of public health risk assessment under the background of community collaborative prevention and control are realized, and the mathematical modeling optimization of public health risk assessment under the background of community collaborative prevention and control is realized. The simulation results show that this method has good adaptability, high degree of parameter fusion, and strong ability of matching risk prevention areas and balancing resource allocation in the context of community collaborative prevention and control.

Robust unsupervised Tursiops aduncus whistle-event detection using gammatone multi-channel Savitzky-Golay based whistle enhancement.

Detecting whistle events is essential when studying the population density and behavior of cetaceans. After eight months of passive acoustic monitoring in Xiamen, we obtained long calls from two Tursiops aduncus individuals. In this paper, we propose an algorithm with an unbiased gammatone multi-channel Savitzky-Golay for smoothing dynamic continuous background noise and interference from long click trains. The algorithm uses the method of least squares to perform a local polynomial regression on the time-frequency representation of multi-frequency resolution call measurements, which can effectively retain the whistle profiles while filtering out noise and interference. We prove that it is better at separating out whistles and has lower computational complexity than other smoothing methods. In order to further extract whistle features in enhanced spectrograms, we also propose a set of multi-scale and multi-directional moving filter banks for various whistle durations and contour shapes. The final binary adaptive decisions at frame level for whistle events are obtained from the histograms of multi-scale and multi-directional spectrograms. Finally, we explore the entire data set and find that the proposed scheme achieves the highest frame-level F1-scores when detecting T. aduncus whistles than the baseline schemes, with an improvement of more than 6%.

Improvement in Osseointegration of Titanium Dental Implants After Exposure to Ultraviolet-C Light for Varied Durations: An Experimental Study in Beagle Dogs.

PURPOSE: Ultraviolet-mediated photofunctionalization is a valid technology for enhancing the osseointegration of titanium implants. However, there is no consensus on the effective exposure time to ultraviolet light. The objective of this study was to evaluate the effect of different exposure times of ultraviolet-C (UVC) light on aged titanium implants and explore the optimal treatment duration of UVC photofunctionalization for osseointegration in an animal model. METHODS: Eight male beagle dogs (n = 48) were divided into a control group (n = 12) and 3 experimental groups (n = 12/12/12) which received 4-week-old implants without UVC treatment (C) or treated with UVC for 1/6 hour, 1/2 hour, and 1 hour (UVC-1/6 hour, UVC-1/2 hour, UVC-1 hour) immediately before placement. All the implants were placed 12 weeks after mandibular premolars extraction. Four dogs were euthanized after 4 and 12 weeks of healing, respectively. The marginal bone level and implant stability quotient were measured at implant placement and after sacrifice. Subsequently, micro-CT and histomorphometric analyses were performed following block harvesting. RESULTS: No significant difference in marginal bone loss between the UVC-untreated and UVC-treated groups was found at 4 or 12 weeks. At 4 weeks, significantly higher BV/TV and bone-implant contact were observed in the UVC groups than in the C group, irrespective of the UVC-photofunctionalization duration (BV/TV: UVC-1/6 hour 0.48 ± 0.11, UVC-1/2 hour 0.50 ± 0.06, and UVC-1 hour 0.47 ± 0.08, C 0.34 ± 0.04; bone-implant contact : UVC-1/6 hour 84.30 ± 5.02%, UVC-1/2 hour 85.82 ± 5.05%, and UVC-1 hour 84.98 ± 3.86%, C 71.69 ± 3.52%. P < .05), whereas, no significant difference was observed among the UVC groups. At 12 weeks, there were no significant differences between the C group and UVC groups. After 4 and 12 weeks of healing, no significant difference in implant stability quotient values was observed between the C group and UVC groups. CONCLUSIONS: UVC photofunctionalization improved the early osseointegration of aged titanium implants. However, the effect was not dependent on the UVC-light duration within the range from 1/6 hour to 1 hour.

Research progress on enhancing biological activity of titanium implants by chairside ultraviolet photofunctionalization / 口腔疾病防治

@#Excellent mechanical properties and biocompatibility resulted in titanium and titanium alloys being widely used in the medical field. However, the biological activity of atitanium surface will gradually fade with increasing exposure time, which affects its final osseointegration. As an effective surface modification method, ultraviolet (UV) photofunctionalization does not change the surface morphology of implants and is a suitable surface treatment for many brands of implants. This article summarizes the research progress on the effect of UV photofunctionalization technology on the characteristics of titanium surfaces, biological activity and implant osseointegration, as well as its current clinical applications. Studies have shown that the superhydrophilicity of the titanium surface and improved biological activity endowed by UV photofunctionalization can accelerate and enhance bone formation, resulting in a higher success rate of implant surgery. Therefore, UV photofunctionalization has great potential for clinical chairside applications.

Automated classification of tursiops aduncus whistles based on a depth-wise separable convolutional neural network and data augmentation.

Whistle classification plays an essential role in studying the habitat and social behaviours of cetaceans. We obtained six categories of sweep whistles of two Tursiops aduncus individual signals using the passive acoustic mornitoring technique over a period of eight months in the Xiamen area. First, we propose a depthwise separable convolutional neural network for whistle classification. The proposed model adopts the depthwise convolution combined with the followed point-by-point convolution instead of the conventional convolution. As a result, it brings a better classification performance in sample sets with relatively independent features between different channels. Meanwhile, it leads to less computational complexity and fewer model parameters. Second, in order to solve the problem of an imbalance in the number of samples under each whistle category, we propose a random series method with five audio augmentation algorithms. The generalization ability of the trained model was improved by using an opening probability for each algorithm and the random selection of each augmentation factor within specific ranges. Finally, we explore the effect of the proposed augmentation method on the performance of our proposed architecture and find that it enhances the accuracy up to 98.53% for the classification of Tursiops aduncus whistles.

Bacterial Blight Induced Shifts in Endophytic Microbiome of Rice Leaves and the Enrichment of Specific Bacterial Strains With Pathogen Antagonism.

The endophytic microbiome plays an important role in plant health and pathogenesis. However, little is known about its relationship with bacterial blight (BB) of rice caused by Xanthomonas oryzae pv. oryzae (Xoo). The current study compared the community compositional structure of the endophytic microbiota in healthy and BB symptomatic leaves of rice through a metabarcoding approach, which revealed BB induced a decrease in the alpha-diversity of the fungal communities and an increase in the bacterial communities. BB-diseased rice leaves were enriched with saprophytic fungi that are capable of decomposing plant cell walls (e.g. Khuskia spp. and Leptosphaerulina spp.), while healthy rice leaves were found to be significantly more abundant with plant pathogens or mycotoxin-producing fungi (e.g. Fusarium, Magnaporthe, and Aspergillus). The endophytic bacterial communities of BB-diseased leaves were significantly enriched with Pantoea, Pseudomonas, and Curtobacterium, strains. Pantoea sp. isolates from BB leaves are identified as promising candidates for the biocontrol of BB for their ability to inhibit in vitro growth of Xoo, suppress the development of rice BB disease, and possess multiple PGP characteristics. Our study revealed BB-induced complexed changes in the endophytic fungal and bacterial communities of rice leaves and demonstrated that BB-associated enrichment of some endophytic bacterial taxa, e.g. Pantoea sp. isolates, may play important roles in suppressing the development of BB disease in rice.

Oleoylethanolamide Increases Glycogen Synthesis and Inhibits Hepatic Gluconeogenesis via the LKB1/AMPK Pathway in Type 2 Diabetic Model.

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor α (PPARα) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPARα-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPARα was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor α-independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways.

Depression and Insomnia Are Closely Associated with Thyroid Hormone Levels in Chronic Hepatitis B.

BACKGROUND Depression and insomnia in chronic hepatitis B (CHB) patients affect the quality of life, disease diagnosis, and mortality. CHB patients are more likely to have psychological disorders, but the underlying mechanisms have not been elucidated. This study investigated the incidence of depression in patients with CHB and sought to identify risk factors for depression and insomnia in these patients, focusing on changes in liver function and thyroid hormone levels. MATERIAL AND METHODS This cross-sectional cohort study used the Hamilton Depression Scale and Athens Insomnia Scale to assess the depressive and insomnia states, respectively, of 209 CHB patients. Liver function, thyroid hormone levels, hepatitis B surface antigen, hepatitis B e-antigen, and hepatitis B virus-deoxyribonucleic acid load were evaluated. Liver cirrhosis was assessed by imaging (color Doppler ultrasound and computed tomography). A multivariate logistic regression model was used to analyze the correlation among various factors and depression and insomnia. RESULTS Subclinical and clinical depressive states were found in 23.9% and 5.3% and subclinical and clinical insomnia in 11% and 35.4% of patients, respectively. Depression and insomnia severity were significantly correlated with low FT3 (<3.5 mol/L). The odds ratios of low FT3 for subclinical and clinical depression and clinical insomnia were 3.07 (95% confidence interval (CI), 1.248-7.568), 7.85 (95% CI, 1.839-33.547), and 3.91 (95% CI, 1.417-10.789), respectively. CONCLUSIONS CHB patients are prone to depression and insomnia. FT3 reduction may be a risk factor for depression and insomnia. In clinical settings, more attention needs to be paid to the mental state of patients with FT3 reduction.

Comparison between laparoscopic and endoscopic resections for gastric submucosal tumors.

BACKGROUND/AIMS: Open resection/laparoscopic resection (LR) is the traditional treatment of gastric submucosal tumor (G-SMT). The endoscopic resection (ER) technology provides good results for G-SMT treatment but lacks sufficient evidence-based evidence. This retrospective study aimed to compare the clinical efficacy of ER [endoscopic submucosal dissection (ESD), endoscopic submucosal excavation (ESE), and endoscopic full-thickness resection (EFR)] and LR [laparoscopic wedge resection (LWR) and laparoscopic subtotal gastrectomy (LSG)] for G-SMT. PATIENTS AND METHODS: From January 2013 to January 2017, data of patients with G-SMT with tumor diameter <5 cm were collected from the database of The Affiliated Hospital of Qingdao University and classified based on surgical methods. Demographics, tumor characteristics, surgical outcomes, complications and tumor recurrence were recorded and compared. RESULTS: Overall, 275 patients with G-SMT were enrolled: 152 underwent ER (ESD, n = 65; ESE, n = 23; EFR, n = 61) and 123 underwent LR (LWR, n = 93; LSG, n = 30). Age, sex, R0 resection rate, tumor location, type, recurrence and complications were not statistically significant (P > 0.05). The ER group had a significantly higher percentage of intraluminal tumor (94.1% vs 62.4%) and smaller tumor size (1.8 ± 0.8 vs 3.4 ± 1.2 cm) than the LR group. The ER group had less muscular tumors than the LR group (54.6% vs 70.7%). The ER group had no serosal tumor. The ER group had shorter hospitalization time, postoperative hospital stay and diet recovery time. The LR group had shorter operation time, less cost and less blood loss. CONCLUSION: ER and LR are safe and effective treatments for SMT. For small intraluminally growing SMT, ER is better than LR.

[Investigations on cordycepin production by solid culture of Cordyceps militaris].

An efficient method to produce cordycepin by solid culture using Cordyceps militaris was investigated in this study. Firstly, the changes of cordycepin during various growing periods of solid culture using 5 strains of C. militaris were detected, the best strain and optimal growing period for cordycepin production were determined. Then, by experiments of quadratic rotation-orthogonal combination design and orthogonal design, the medium composition and growth conditions for high yield of cordycepin were optimized. With the optimized method to produce cordycepin, the content of cordycepin in the medium was increased to 0.60%, which was nearly 2 times higher than the highest yield reported.