In transcription antitermination by Qλ, NusA induces refolding of Qλ to form a nozzle that extends the RNA polymerase RNA-exit channel.

Lambdoid bacteriophage Q proteins are transcription antipausing and antitermination factors that enable RNA polymerase (RNAP) to read through pause and termination sites. Q proteins load onto RNAP engaged in promoter-proximal pausing at a Q binding element (QBE) and adjacent sigma-dependent pause element to yield a Q-loading complex, and they translocate with RNAP as a pausing-deficient, termination-deficient Q-loaded complex. In previous work, we showed that the Q protein of bacteriophage 21 (Q21) functions by forming a nozzle that narrows and extends the RNAP RNA-exit channel, preventing formation of pause and termination RNA hairpins. Here, we report atomic structures of four states on the pathway of antitermination by the Q protein of bacteriophage λ (Qλ), a Q protein that shows no sequence similarity to Q21 and that, unlike Q21, requires the transcription elongation factor NusA for efficient antipausing and antitermination. We report structures of Qλ, the Qλ-QBE complex, the NusA-free pre-engaged Qλ-loading complex, and the NusA-containing engaged Qλ-loading complex. The results show that Qλ, like Q21, forms a nozzle that narrows and extends the RNAP RNA-exit channel, preventing formation of RNA hairpins. However, the results show that Qλ has no three-dimensional structural similarity to Q21, employs a different mechanism of QBE recognition than Q21, and employs a more complex process for loading onto RNAP than Q21, involving recruitment of Qλ to form a pre-engaged loading complex, followed by NusA-facilitated refolding of Qλ to form an engaged loading complex. The results establish that Qλ and Q21 are not structural homologs and are solely functional analogs.

Structural and mechanistic basis of σ-dependent transcriptional pausing.

In σ-dependent transcriptional pausing, the transcription initiation factor σ, translocating with RNA polymerase (RNAP), makes sequence-specific protein­DNA interactions with a promoter-like sequence element in the transcribed region, inducing pausing. It has been proposed that, in σ-dependent pausing, the RNAP active center can access off-pathway "backtracked" states that are substrates for the transcript-cleavage factors of the Gre family and on-pathway "scrunched" states that mediate pause escape. Here, using site-specific protein­DNA photocrosslinking to define positions of the RNAP trailing and leading edges and of σ relative to DNA at the λPR' promoter, we show directly that σ-dependent pausing in the absence of GreB in vitro predominantly involves a state backtracked by 2­4 bp, and σ-dependent pausing in the presence of GreB in vitro and in vivo predominantly involves a state scrunched by 2­3 bp. Analogous experiments with a library of 47 (∼16,000) transcribed-region sequences show that the state scrunched by 2­3 bp­and only that state­is associated with the consensus sequence, T−3N−2Y−1G+1, (where −1 corresponds to the position of the RNA 3' end), which is identical to the consensus for pausing in initial transcription and which is related to the consensus for pausing in transcription elongation. Experiments with heteroduplex templates show that sequence information at position T−3 resides in the DNA nontemplate strand. A cryoelectron microscopy structure of a complex engaged in σ-dependent pausing reveals positions of DNA scrunching on the DNA nontemplate and template strands and suggests that position T−3 of the consensus sequence exerts its effects by facilitating scrunching.

Fast response electrically controlled liquid crystal lens array for high resolution 2D/3D switchable display.

A fast response electrically controlled liquid crystal (LC) lens array is revealed. In order to realize the fast response, a double LC layer structure is adopted. The fabricated LC lens array has a small pitch of 310µm and LC layer with a thickness of 50µm. Experimental results show that the focal length of the LC lens array can be continuously adjusted by low driving voltage (∼6.5Vrms), and the shortest focal length is 0.5mm. The switching between 2D display and 3D display is realized by controlling the voltage off and on state of the LC lens array. Experimental result shows that the 2D/3D switchable display has a fast response time of 16ms. The short pitch LC lens array is expected to be used in high-resolution 2D/3D switchable display.

Structural basis of Q-dependent antitermination.

Lambdoid bacteriophage Q protein mediates the switch from middle to late bacteriophage gene expression by enabling RNA polymerase (RNAP) to read through transcription terminators preceding bacteriophage late genes. Q loads onto RNAP engaged in promoter-proximal pausing at a Q binding element (QBE) and adjacent sigma-dependent pause element (SDPE) to yield a Q-loading complex, and Q subsequently translocates with RNAP as a pausing-deficient, termination-deficient Q-loaded complex. Here, we report high-resolution structures of 4 states on the pathway of antitermination by Q from bacteriophage 21 (Q21): Q21, the Q21-QBE complex, the Q21-loading complex, and the Q21-loaded complex. The results show that Q21 forms a torus, a "nozzle," that narrows and extends the RNAP RNA-exit channel, extruding topologically linked single-stranded RNA and preventing the formation of pause and terminator hairpins.

Mechanism of Small Molecules Inhibiting Activator Protein-1 DNA Binding Probed with Induced Fit Docking and Metadynamics Simulations.

Transcription factor activator protein-1 (AP-1) binds to cognate DNA and regulates gene expression. In recent decades, small-molecule inhibitors have been developed for therapeutic applications that block AP-1 binding to DNA. However, the mechanism by which small molecules inhibit AP-1-DNA binding remains elusive. Here, computational studies identified a drug-binding site on the AP-1 Fos/Jun apo structure. Induced fit docking of known inhibitors, together with metadynamics simulations to identify the most plausible binding pose, showed a consensus mode of AP-1/inhibitor interaction. The in silico binding mode of the inhibitors suggests a mechanism of AP-1-DNA binding inhibition, where the inhibitors block the base-contacting residues, preclude access of DNA, and prohibit conformational changes of AP-1 upon DNA binding.

Activator Protein-1: redox switch controlling structure and DNA-binding.

The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-binding regions in both FosB and JunD even in absence DNA. However, while JunD is competent to bind DNA, the FosB bZIP domain must undergo a large conformational rearrangement that is controlled by a 'redox switch' centered on an inter-molecular disulfide bond. Solution studies confirm that FosB/JunD cannot undergo structural transition and bind DNA when the redox-switch is in the 'OFF' state, and show that the mid-point redox potential of the redox switch affords it sensitivity to cellular redox homeostasis. The molecular and structural studies presented here thus reveal the mechanism underlying redox-regulation of AP-1 Fos/Jun transcription factors and provide structural insight for therapeutic interventions targeting AP-1 proteins.

D-dimer testing for safe exclusion and risk stratification in patients with acute pulmonary embolism in primary care.

BACKGROUND: Safe exclusion and risk stratification are currently recommended for the initial management of patients with acute pulmonary embolism (APE). The aim of this study was to assess the safe exclusion and risk stratification value of D-dimer (DD) for APE when tested at the beginning of admission. MATERIALS AND METHODS: All consecutive Chinese APE patients and controls were recruited from January 2010 to December 2012. All measurements of serum indexes were made in duplicate and blinded to the patients' status. All the 40 patients with the first episode of APE were confirmed by multi-detector computed tomographic pulmonary angiography. The plasma prothrombin time (PT), activated partial thromboplastin time, thrombin time, fibrinogen, and DD levels were measured within 24 h of admission. We used the Mann-Whitney U-test to determine the differences between groups and drew receiver operator characteristic curve to evaluate the indexes' value in the APE screening. RESULTS: The PT and DD in the APE group were significantly higher than those in the disease control group (P < 0.05). Taking PT and DD as the useful screening tests for APE and AUC was 0.765 and 0.822, respectively. DD yielded the higher screening efficiency, with DD >1820 µg/L as cut-off value, the sensitivity, specificity, positive and negative predictive value was 82.5%, 75.2%, 56.9%, and 91.6%, respectively. CONCLUSION: The patients with APE showed significant higher DD levels compared with disease controls, suggesting a negative qualitative DD test result can safely and efficiently exclude APE in primary care.

Suggestions to ameliorate the inequity in urban/rural allocation of healthcare resources in China.

The imbalance in the allocation in healthcare resources between urban and rural areas has become a main focus of the recent medical reforms adopted in China. However, systematic analysis has identified wide differences in the allocation of healthcare resources between urban and rural areas, including healthcare expenditures and the number of healthcare facilities, available beds, and personnel. Therefore, the aim of this report was to identify ethical considerations in current governmental policies to rectify existing problems in the distribution of healthcare resources. Our findings indicate that the inequality in the distribution of healthcare resources does not adhere to ethical standards and the policies are flawed because they give rise to differences in the availability of medical care to urban and rural communities. To optimize the allocation of medical healthcare resources, countermeasures are proposed to formulate policies to urge the flow of public healthcare resources to rural areas, strengthen the responsibilities of both governmental and public financial investments, increase the construction of public healthcare facilities in rural areas, promote the quality of healthcare resources, adjust resource allocations to rural public healthcare facilities, and improve resource utilization efficiency by establishing two-way referral mechanisms.

Can hospital promotional activities be more ethical?

At present, there exist a lot of violations of medical ethics in advertising and promotional activities, which have been infringing the rights of patients. Therefore, the ethical criteria should be established as soon as possible to regulate the hospital promotional activities, to regain the trust of people.

Mechanochemical Synthesis of Cross-Linked Chitosan and Its Application as Adsorbent for Removal of Per- and Polyfluoroalkyl Substances from Simulated Electroplating Wastewater.

Chitosan is a promising adsorbent for removing a wide range of pollutants from wastewater. However, its practical application is hindered by instability in acidic environments, which significantly impairs its adsorption capacity and limits its utilization in water purification. While cross-linking can enhance the acid stability of chitosan, current solvent-based methods are often costly and environmentally unfriendly. In this study, a solvent-free mechanochemical process was developed using high-energy ball milling to cross-link chitosan with various polyanionic linkers, including dextran sulfate (DS), poly[4-styrenesulfonic acid-co-maleic acid] (PSSM), and tripolyphosphate (TPP). The mechanochemically cross-linked (MCCL) chitosan products exhibited superior adsorption capacity and stability in acidic solutions compared to pristine chitosan. Chitosan cross-linked with DS (Cht-DS) showed the highest Reactive Red 2 (RR2) adsorption capacity, reaching 1559 mg·g-1 at pH 3, followed by Cht-PSSM (1352 mg·g-1) and Cht-TPP (1074 mg·g-1). The stability of MCCL chitosan was visually confirmed by the negligible mass loss of Cht-DS and Cht-PSSM tablets in pH 3 solution, unlike the complete dissolution of the pristine chitosan tablet. The MCCL significantly increased the microhardness of chitosan, with the order Cht-DS > Cht-PSSM > Cht-TPP, consistent with the RR2 adsorption capacity. When tested on simulated rinsing wastewater from chromium electroplating, Cht-DS effectively removed Cr(VI) (98.75% removal) and three per- and polyfluoroalkyl substances (87.40-95.87% removal), following pseudo-second-order adsorption kinetics. This study demonstrates the potential of the cost-effective and scalable MCCL approach to produce chitosan-based adsorbents with enhanced stability, mechanical strength, and adsorption performance for treating highly acidic industrial wastewater containing a mixture of toxic pollutants.

JQ1 attenuates contrast-induced acute kidney injury through the upregulation of autophagy and inhibition of inflammation.

PURPOSE: Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired AKI. However, there is a paucity of efficacious interventions for the management of CI-AKI. Here, we aim to investigate the effects of JQ1 in CI-AKI and provide theoretical data and a  foundation for  novel ideas for the clinical treatment of CI-AKI. METHODS: In this study, we performed in vivo and in vitro experiments with mice and HK2 cells injury models respectively. The levels of serum creatinine (Cr) and blood urea nitrogen (BUN) were determined by an automatic analyzer for the measurements of renal function. The viability of HK-2 cells was analyzed using the Cell Counting Kit-8 (CCK-8) kit. Additionally, the kidney changes in the mice were detected using histopathology (H&E) and immunofluorescent staining. The mRNA and protein expressions were assessed using Quantitative real-time PCR and western blot, respectively. Autophagy and apoptosis was analyzed by Transmission electron microscopy (TEM) and TUNEL assay respectively. RESULTS: The results demonstrated that JQ1 exhibited potency of attenuating CI-AKI in mouse and HK2 cells. JQ1 increased the expression levels of Atg5, Atg7 and LC3B-II, and decreased the protein levels of p62 in the kidney and HK-2 cells. However, the combined use of JQ1 with chloroquine reversed the effects of JQ1. JQ1 also inhibited the inflammatory cells and downregulated the expression of some inflammatory cytokines (IL-6, IL-1ß, TNF-α, and IFN-γ). CONCLUSION: JQ1 protects against CI-AKI by promoting autophagy and inhibiting inflammation and JQ1 may be a promising therapeutic strategy for CI-AKI.

Air quality and health benefits for different heating decarbonization pathways in China.

The urgent need for decarbonization in China's heating system, comprised of approximately one hundred thousand boilers, is imperative to meet climate and clean air objectives. To formulate national and regional strategies, we developed an integrated model framework that combines a facility-level emission inventory, the Community Multiscale Air Quality (CMAQ) model, and the Global Exposure Mortality Model (GEMM). We then explore the air quality and health benefits of alternative heating decarbonization pathways, including the retirement of coal-fired industrial boilers (CFIBs) for replacement with grid-bound heat supply systems, coal-to-gas conversion, and coal-to-biomass conversion. The gas replacement pathway shows the greatest potential for reducing PM2.5 concentration by 2.8 (2.3-3.4) µg/m3 by 2060, avoiding 23,100 (19,600-26,500) premature deaths. In comparison, the biomass replacement pathway offers slightly lower environmental and health benefits, but is likely to reduce costs by approximately two-thirds. Provincially, optimal pathways vary - Xinjiang, Sichuan, and Chongqing favor coal-to-gas conversion, while Shandong, Henan, Hebei, Inner Mongolia, and Shanxi show promise in CFIBs retirement. Henan leads in environmental and health benefits. Liaoning, Heilongjiang, and Jilin, rich in biomass resources, present opportunities for coal-to-biomass conversion.

A meta­ and bioinformatics analysis of maspin expression levels influencing the prognosis of patients with breast cancer.

Maspin is a serine protease inhibitor that is encoded by the human SERPINB5 gene. As a tumor inhibitor, it can inhibit the growth of tumor cells, increase adhesion between tumor cells and inhibit tumor angiogenesis. In the present study, a meta- and bioinformatics analysis was performed through the PubMed and China National Knowledge Infrastructure databases including entries added until up to March 20, 2023. It was found that compared with normal breast tissue, maspin expression was downregulated in breast cancer tissue. Maspin expression was negatively associated with lymph node metastasis. According to Kaplan-Meier plotter, it was found that lower maspin expression was negatively associated with the overall and distant metastasis-free survival rate of patients with estrogen receptor-positive, luminal A and grade 2 breast cancer. High expression of maspin was also positively associated with the relapse-free survival rate of patients of the luminal A subtype. Low maspin expression was positively associated with the post-progression and distant metastasis-free survival rate of the progesterone receptor-negative subtype. According to the GEPIA database, SERPINB5 mRNA expression was higher in normal than breast cancer tissues and negatively correlated with the TNM stage. High expression of maspin was also positively associated with the overall survival rate. In the UALCAN database, it was found that the mRNA and promoter methylation levels of SERPINB5 were higher in normal than in breast cancer tissues. These findings suggest that the expression of maspin may serve as a potential marker to indicate the occurrence, subsequent progression and even prognosis of breast cancer.

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer.

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

[Expression of peroxiredoxin I in the rats exposed to silica].

OBJECTIVE: To evaluate the change in protein expression of peroxiredoxin I (Prx I) during pulmonary fibrosis among rats exposed to silica dust and to investigate the role of Prx I in pulmonary fibrosis. METHODS: Ninety male Wistar rats were randomly divided into control group (n = 60) and experimental group (n = 30). The control group received intratracheal perfusion of saline (1 ml), while the experimental group received intratracheal perfusion of suspension of silica dust (50 mg/ml) to establish a rat model of silicosis. At 1, 2, 3, 4, 6, or 8 weeks after treatment, 10 rats in control group and 5 rats in experimental group were sacrificed. The lung tissues were collected for conventional pathological observation. The protein expression of Prx I at each time point was measured by immunohistochemistry and Western blot. RESULTS: Among the rats exposed to silica dust, Prx I was seen in the form of brown particles that were mainly distributed in the alveolar septa and the cytoplasm of alveolar epithelial cells, macrophages, vascular endothelial cells, and smooth muscle cells around the blood vessels and tracheae. The control group showed weak protein expression of Prx I, and the experimental group had significantly higher protein expression of Prx I than the control group at all time points (P < 0.05). In the experimental group, the protein expression of Prx I was upregulated significantly at 1 and 2 weeks and decreased at 3∼8 weeks. CONCLUSION: The change in protein expression of Prx I may be one of the important causes of the onset and development of pulmonary fibrosis in rats exposed to free silica.

[Closed-loop blood transfusion management system based on PDA].

A closed-loop transfusion management system is constructed that covers blood preservation, transportation, transfer, distribution of blood, distribution, clinical blood specimen collection and blood transfusion process, which can monitor the implementation of doctor's advice, view the transport process of blood and blood samples, and record blood transfusion and adverse reaction information. These measurements can play a good effect in reduction of manual records and handover links in blood transfusion management, enhance the blood bank management, guarantee safely using blood, and realize the goal of real-time monitoring and closed-loop management.

Mechanochemically sulfidated zero-valent iron as persulfate activation catalyst in permeable reactive barriers for groundwater remediation - A feasibility study.

The technology of permeable reactive barriers is reliable and economically effective to prevent the spread of pollutants in groundwaters. Yet, it is efficacious only with easily reducible chemicals such as heavy metals and halogenated organics. In the present study, sulfidated zero-valent iron solventless synthesized by ball-milling is proposed as a possible barrier filling for activation of persulfate to achieve sound removal of reduction-resistant organic pollutants (the herbicide atrazine was used as a model pollutant). Preliminary batch experiments demonstrated rapid degradation of atrazine. Continuous experiments executed in columns proved the superior efficiency of sulfidated iron as a persulfate activator, compared to zero-valent iron, in terms of removal of both atrazine and byproducts. Optimal atrazine removal in the column was achieved with 10% sulfidated iron packing, and 9 mM persulfate at a hydraulic residence time of 6.02 h. Under such conditions, the estimated bed length of the reactive barrier for 99% atrazine removal was 8.69 cm. The morphology and surface-active species in the column demonstrated that activation of persulfate mainly occurred at the inlet of the column until the complete usage of the active species. Batch experiments with coexisting ions suggested that they have a minor influence on atrazine removal percentage, while Mg2+, Ca2+, CO2- and HCO- had a significant impact on the kinetics of the process. However, analogous column experiments demonstrated that the coexisting ions have a negative influence on both atrazine and its byproducts. The results obtained in this study corroborate the potential application of persulfate-enhanced permeable reactive barriers for in situ removal of atrazine from underground water.

Evaluation of Pharmacokinetics and Safety with Bioequivalence of Ibuprofen Sustained-Release Capsules of Two Formulations, in Chinese Healthy Volunteers: Bioequivalence Study.

Purpose: Ibuprofen is the first of the nonsteroidal anti-inflammatory drug (NSAID) to be used in the clinic. Our aim was to explore the pharmacokinetics (PK), bioequivalence, food effect, and safety of oral ibuprofen sustained-release capsules by two sponsors in healthy volunteers (HVs). Methods: Two separate randomized, open-label, single-dose, crossover-design studies were conducted: a fasting study (n = 24) and a fed study (n = 24). In each study, HVs were 1:1 divided into two groups (T-R and R-T) and received 0.3-g/capsule ibuprofen with a 3-day washout. The plasma was collected for up to 24 hours at the time point after dosing on Day 1/Day 4. The plasma concentrations of ibuprofen were measured using an HPLC-MS/MS method, and PK parameters were determined by noncompartmental methods. Results: Forty-eight healthy volunteers were enrolled. In fasting subjects, the maximum plasma concentration (Cmax, mean ± SD) was 14.86±3.19 µg/mL at 5.0 (4.0, 7.0) hours (median [min, max]) for sponsor T, and 13.88±2.60 µg/mL at 4.5 (3.0, 8.0) hours for sponsor R. In fed subjects, Cmax was 21.31±4.08 µg/mL at 5.6 (4.3, 10.0) hours for sponsor T, and 19.77±3.36 µg/mL at 6.0 (2.0, 8.0) hours for sponsor R. All 90% confidence intervals (CIs) for Cmax, AUC0-t, and AUC0-∞ were within the bioequivalence bounds (80-125%) both fasting and fed studies. Conclusion: Ibuprofen is well tolerated and has a favorable safety profile. In both fasting and fed study, there were no serious AEs, or AEs leading to withdrawal. Bioequivalence is achieved under fasting and fed conditions, supporting the demonstration of biosimilarity.

High Expression of SMO and GLI1 Genes with Poor Prognosis in Malignant Mesothelioma.

Background: To investigate the value of SMO and GLI1 genes in the hedgehog pathway in malignant mesothelioma specimens. Further study on the expression and prognosis of SMO and GLI1 in malignant mesothelioma tissues and the relationship between the two and the molecular mechanisms of mesothelioma immunity and to further investigate the prognostic value of mesothelioma expression. Materials and Methods: Immunohistochemistry and RT-qPCR were applied to detect the expression of SMO and GLI1 proteins and mRNA in biopsy specimens and plasma cavity effusion specimens from malignant mesothelioma (n = 130) and benign mesothelial tissues (n = 50) and to analyze the clinicopathological significance and survival risk factors of SMO and GLI1 protein expression in mesothelioma. The mechanisms of mesothelioma cell expression and immune cell infiltration were investigated using bioinformatics methods. Results: SMO and GLI1 in mesothelioma tissues detected high concordance between the diagnostic results of mesothelioma biopsy specimens and plasma cavity effusion specimens. The expression levels of SMO and GLI1 protein and mRNA in mesothelioma tissues were higher than those in benign mesothelioma tissues. The expression levels of SMO and GLI1 protein were correlated with the age, site, and asbestos exposure history of patients with mesothelioma. The expression levels of SMO and GLI1 protein were correlated with the expressions of ki67 and p53 (P < 0.05). SMO and GLI1 gene expression levels were negatively correlated with good prognosis in mesothelioma patients (P < 0.05). Cox proportional risk model indicated that protein expressions of invasion, lymph node metastasis, distant metastasis, staging, and genes were independent prognostic factors of mesothelioma. The GEPIA database showed the overall survival rate and the disease-free survival rate of mesothelioma patients in the high SMO and GLI1 expression groups; the UALCAN database analysis showed lower SMO expression levels in mesothelioma patients with more pronounced TP53 mutations (P = 0.001); GLI1 gene expression levels were strongly correlated with lymph node metastasis in mesothelioma patients (P = 0.009). Timer database analysis showed that the mechanism of immune cell infiltration was closely related to SMO and GLI1 expression. The degree of immune cell infiltration was strongly correlated with the prognosis of mesothelioma patients (P < 0.05). Conclusion: The expression levels of both SMO and GLI1 proteins were higher than those of normal mesothelial tissues, and the mRNA expression levels also changed in the same direction. SMO and GLI1 gene expressions in mesothelioma were negatively correlated with age, site of occurrence, and history of asbestos exposure. Positive expression of SMO and GLI1 was negatively correlated with patient survival. The Cox proportional risk model showed that gender, history of asbestos exposure, site of occurrence, SMO, and GLI1 were independent prognostic factors for mesothelioma. The mechanism of immune cell infiltration in mesothelioma is closely related to the gene expression of both and the survival prognosis of mesothelioma patients.

Evaluation of ferritin and TfR level in plasma neural-derived exosomes as potential markers of Parkinson's disease.

Introduction: Early diagnosis of Parkinson's disease (PD) remains challenging. It has been suggested that abnormal brain iron metabolism leads to excessive iron accumulation in PD, although the mechanism of iron deposition is not yet fully understood. Ferritin and transferrin receptor (TfR) are involved in iron metabolism, and the exosome pathway is one mechanism by which ferritin is transported and regulated. While the blood of healthy animals contains a plentiful supply of TfR-positive exosomes, no studies have examined ferritin and TfR in plasma neural-derived exosomes. Methods: Plasma exosomes were obtained from 43 patients with PD and 34 healthy controls. Neural-derived exosomes were isolated with anti-human L1CAM antibody immunoabsorption. Transmission electron microscopy and western blotting were used to identify the exosomes. ELISAs were used to quantify ferritin and TfR levels in plasma neural-derived exosomes of patients with PD and controls. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of ferritin and TfR. Independent predictors of the disease were identified using logistic regression models. Results: Neural-derived exosomes exhibited the typical exosomal morphology and expressed the specific exosome marker CD63. Ferritin and TfR levels in plasma neural-derived exosomes were significantly higher in patients with PD than controls (406.46 ± 241.86 vs. 245.62 ± 165.47 ng/µg, P = 0.001 and 1728.94 ± 766.71 vs. 1153.92 ± 539.30 ng/µg, P < 0.001, respectively). There were significant positive correlations between ferritin and TfR levels in plasma neural-derived exosomes in control group, PD group and all the individuals (rs = 0.744, 0.700, and 0.752, respectively). The level of TfR was independently associated with the disease (adjusted odds ratio 1.002; 95% CI 1.000-1.003). ROC performances of ferritin, TfR, and their combination were moderate (0.730, 0.812, and 0.808, respectively). However, no relationship was found between the biomarkers and disease progression. Conclusion: It is hypothesized that ferritin and TfR in plasma neural-derived exosomes may be potential biomarkers for PD, and that they may participate in the mechanism of excessive iron deposition in PD.