Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

A cost-effectiveness analysis of lung cancer screening with low-dose computed tomography and a polygenic risk score.

INTRODUCTION: Several studies have proved that Polygenic Risk Score (PRS) is a potential candidate for realizing precision screening. The effectiveness of low-dose computed tomography (LDCT) screening for lung cancer has been proved to reduce lung cancer specific and overall mortality, but the cost-effectiveness of diverse screening strategies remained unclear. METHODS: The comparative cost-effectiveness analysis used a Markov state-transition model to assess the potential effect and costs of the screening strategies incorporating PRS or not. A hypothetical cohort of 300,000 heavy smokers entered the study at age 50-74 years and were followed up until death or age 79 years. The model was run with a cycle length of 1 year. All the transition probabilities were validated and the performance value of PRS was extracted from published literature. A societal perspective was adopted and cost parameters were derived from databases of local medical insurance bureau. Sensitivity analyses and scenario analyses were conducted. RESULTS: The strategy incorporating PRS was estimated to obtain an ICER of CNY 156,691.93 to CNY 221,741.84 per QALY gained compared with non-screening with the initial start age range across 50-74 years. The strategy that screened using LDCT alone from 70-74 years annually could obtain an ICER of CNY 80,880.85 per QALY gained, which was the most cost-effective strategy. The introduction of PRS as an extra eligible criteria was associated with making strategies cost-saving but also lose the capability of gaining more LYs compared with LDCT screening alone. CONCLUSION: The PRS-based conjunctive screening strategy for lung cancer screening in China was not cost-effective using the willingness-to-pay threshold of 1 time Gross Domestic Product (GDP) per capita, and the optimal screening strategy for lung cancer still remains to be LDCT screening for now. Further optimization of the screening modality can be useful to consider adoption of PRS and prospective evaluation remains a research priority.

Ferumoxytol-Enhanced 5D Multiphase Steady-State Imaging Using Rotating Cartesian K-Space With Low-Rank Reconstruction for Pediatric Congenital Heart Disease.

BACKGROUND: The rotating Cartesian k-space multiphase steady-state imaging with contrast (ROCK-MUSIC) pulse sequence enables acquisition of whole-heart, cardiac phase-resolved images in pediatric congenital heart disease (CHD) without reliance on the ventilator gating signal. Multidimensional reconstruction with low rank tensor (LRT) has shown promise for resolving complex cardiorespiratory motion. PURPOSE: To enhance ROCK-MUSIC by resolving cardiorespiratory phases using LRT reconstruction and to enable semi-automatic hyperparameter tuning by developing an image quality scoring model. STUDY TYPE: Retrospective. POPULATION: Thirty patients (45% female, age 2 days to 6.7 years) with CHD. FIELD STRENGTH/SEQUENCE: 3-T, four-dimensional (4D) spoiled gradient recalled echo sequence. ASSESSMENT: Eigenvector-based iTerative Self-consistent Parallel Imaging Reconstruction (ESPIRiT) served as the reference comparison for LRT reconstruction. A 4-point Likert scale was used for cardiac and vascular image quality scoring based on cardiac chamber definition, lumen signal uniformity, vascular margin clarity, and motion artifact. Ejection fraction and ventricular volumes were assessed in 16 patients. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and edge sharpness were computed. STATISTICAL TESTS: Intraclass correlation coefficients, Wilcoxon signed-rank test, Bland-Altman. A P-value <0.05 was considered statistically significant. RESULTS: Relative to ESPIRiT, LRT images received significantly higher cardiac (2.81 ± 0.57 vs. 3.19 ± 0.54) and vascular (2.81 ± 0.60 vs. 3.36 ± 0.53) image quality scores. Image quality scoring with semi-automated hyperparameter tuning showed strong correlations (R2 = 0.748) among image quality, SNR, and septal sharpness. Comparison of ejection fraction and volumetry derived from ESPIRiT, and LRT showed no significant systematic difference (P = 0.32). DATA CONCLUSION: Integration of low-rank reconstruction with ROCK-MUSIC acquisition may be feasible, and semi-automatic hyperparameter tuning could be effective for generating cardiorespiratory resolved images. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Partial Discharge Fault Diagnosis in Power Transformers Based on SGMD Approximate Entropy and Optimized BILSTM.

Partial discharge (PD) fault diagnosis is of great importance for ensuring the safe and stable operation of power transformers. To address the issues of low accuracy in traditional PD fault diagnostic methods, this paper proposes a novel method for the power transformer PD fault diagnosis. It incorporates the approximate entropy (ApEn) of symplectic geometry mode decomposition (SGMD) into the optimized bidirectional long short-term memory (BILSTM) neural network. This method extracts dominant PD features employing SGMD and ApEn. Meanwhile, it improves the diagnostic accuracy with the optimized BILSTM by introducing the golden jackal optimization (GJO). Simulation studies evaluate the performance of FFT, EMD, VMD, and SGMD. The results show that SGMD-ApEn outperforms other methods in extracting dominant PD features. Experimental results verify the effectiveness and superiority of the proposed method by comparing different traditional methods. The proposed method improves PD fault recognition accuracy and provides a diagnostic rate of 98.6%, with lower noise sensitivity.

Special transcriptome landscape and molecular prognostic signature of non-smoking head and neck cancer patients.

As a well-known behavioral risk factor for human health, smoking is involved in carcinogenesis, tumor progression, and therapeutic interventions of head and neck squamous cell carcinoma (HNSCC). The stratification of disease subtypes according to tobacco use is expressively needed for HNSCC precision therapy. High-throughput transcriptome profiling by RNA sequencing (RNA-seq) from The Cancer Genome Atlas (TCGA) was collected and collated for differential expression analysis and pathway enrichment analysis to characterize the molecular landscape for non-smoking HNSCC patients. Molecular prognostic signatures specific to non-smoking HNSCC patients were identified by the least absolute shrinkage and selection operator (LASSO) analysis and were then verified via internal and external validation cohorts. While proceeding to immune cell infiltration and after drug sensitivity analysis was further carried out, a proprietary nomogram was finally developed for their respective clinical applications. In what it relates to the non-smoking cohort, the enrichment analysis pointed to human papillomavirus (HPV) infection and PI3K-Akt signaling pathway, with the prognostic signature consisting of another ten prognostic genes (COL22A1, ADIPOQ, RAG1, GREM1, APBA2, SPINK9, SPP1, ARMC4, C6, and F2RL2). These signatures showed to be independent factors, and the related nomograms were, thus, constructed for their further and respective clinical applications. While the molecular landscapes and proprietary prognostic signature were characterized based on non-smoking HNSCC patients, a clinical nomogram was constructed to provide better HNSCC patient classification and guide treatment for non-smoking HNSCC patients. Nonetheless, there are still significant challenges in the recognition, diagnosis, treatment, and understanding of the potentially efficient mechanisms of HNSCC with no tobacco use.

Helical Self-Assembly and Fe3+ Detection of V-Shaped AIE-Active Chiral Tetraphenylbutadiene-Based Polyamides.

Chiral aggregation-induced emission (AIE) molecules have drawn attention for their helical self-assembly and special optical properties. The helical self-assembly of AIE-active chiral non-linear main-chain polymers can produce some desired optical features. In this work, a series of V-shaped chiral AIE-active polyamides P1-C3, P1-C6, P1-C12 and linear P2-C3, P2-C6, bearing n-propyl/hexyl/dodecyl side-chains, based on tetraphenylbutadiene (TPB), were prepared. All target main-chain polymers exhibit distinct AIE characteristics. The polymer P1-C6 with moderate length alkyl chains shows better AIE properties. The V-shaped main-chains and the chiral induction of (1R,2R)-(+)-1,2-cyclohexanediamine in each repeating unit promote the polymer chains display helical conformation, and multiple helical polymer chains induce nano-fibers helicity when the polymer chains aggregate and self-assemble in THF/H2 O mixtures. Simultaneously, the helical conformation polymer chains and helical nano-fibers cause P1-C6 produce strong circular dichroism (CD) signals with positive Cotton effect. Moreover, P1-C6 could also occur fluorescence quenching response to Fe3+ selectively with a low detection limit of 3.48 µmol/L.

C Allele of the PPARδ+294T>C Polymorphism Confers a Higher Risk of Hypercholesterolemia, but not Obesity and Insulin Resistance: A Systematic Review and Meta-Analysis.

The relationships of the PPARα Leu162Val and PPARδ+294 T>C polymorphisms with metabolic indexes have been reported to be inconsistent and even contradictory. The meta-analysis was conducted to clarify the relationships between the two variants and the indexes of obesity, insulin resistance, and blood lipids. PubMed, Google Scholar, Embase, and Cochrane Library were searched for eligible studies. Standardized mean difference with 95% confidence interval was calculated to estimate the differences in the metabolic indexes between the genotypes of the Leu162Val and+294 T>C polymorphisms. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. Forty-one studies (44 585 subjects) and 33 studies (23 018 subjects) were identified in the analyses for the Leu162Val and+294 T>C polymorphisms, respectively. C allele carriers of the+294 T>C polymorphism had significantly higher levels of total cholesterol and low-density lipoprotein cholesterol than TT homozygotes in the whole population. Notably, C allele carriers of the+294 T>C polymorphism had significantly higher levels of triglycerides and total cholesterol in East Asians, but lower levels of triglycerides in West Asians than TT homozygotes. Regarding the Leu162Val polymorphism, it was found that Val allele carriers had significantly higher levels of blood glucose than Leu/Leu homozygotes only in European Caucasians. The meta-analysis demonstrates that C allele of the+294 T>C polymorphism in PPARδ gene confers a higher risk of hypercholesterolemia, which may partly explain the relationship between this variant and coronary artery disease.

Proteomic characterization and comparison of milk fat globule membrane proteins of Saanen goat milk from 3 habitats in China using SWATH-MS technique.

Saanen goats are among the major dairy goats in China. In present study, variation of milk fat globule membrane proteins profile of Saanen goat milk caused by geographic location was investigated using sequential window acquisition of all theoretical fragment ions data-independent acquisition mass spectrometry based proteomic approach. A total of 1,001 proteins were quantified in goat milk collected from 3 habitats of China [Guangdong (GD); Inner Mongolia (IM); Shannxi (SX)]. Most of the proteins were found to act cellular process of biological process, cell of cellular component, binding of molecular function after Gene Ontology annotation and metabolic of pathway indicated by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Differentially expressed proteins (DEP) for GD versus IM, GD versus SX, IM versus SX were identified to be 81, 91, and 44, respectively. Gene Ontology enrichment analysis showed that the greatest DEP for 3 groups (GD vs. IM, GD vs. SX, IM vs. SX) were cellular process, cellular process and organonitrogen compound biosynthetic process/immune system process for biological process. For cellular component, the largest number of DEP for 3 comparison groups were organelle, organelle and organelle/intracellular. For molecular function, DEP of the 3 comparison groups were expressed most in structural molecule activity, binding and anion binding, respectively. Pathways with the majority of DEP were ribosome, systemic lupus erythematosus and primary immunodeficiency/systemic lupus erythematosus/amoebiasis/PI3K-Akt signaling pathway for GD versus IM, GD versus SX and IM versus SX, severally. Protein-protein interaction network analysis showed that DEP interacted most were 40S ribosomal protein S5, fibronectin and Cytochrome b-c1 complex subunit 2, mitochondrial for GD versus IM, GD versus SX and IM versus SX, separately. Data may give useful information for goat milk selection and milk authenticity in China.

Adapting to the world: The determination and plasticity of T follicular helper cells.

Antibodies are crucial in host defenses as well as in allergic diseases. T follicular helper (TFH) cells play essential roles in germinal center reactions by facilitating B-cell differentiation and immunoglobulin affinity maturation and isotype switching. Although TFH cells have a unique gene transcription program and regulatory network, recently there has been increasing evidence of TFH cell plasticity, with some TFH cells expressing genes typically related to other types of effector T cells associated with different types of Ig subclasses and in the context of different pathogen infections and health conditions. Here, we review the plasticity of TFH cells in various types of immune responses. We also point out the important implications of TFH plasticity in understanding and treating human diseases, including allergy.

Maize Genotypes Sensitive and Tolerant to Low Phosphorus Levels Exhibit Different Transcriptome Profiles under Talaromyces purpurogenus Symbiosis and Low-Phosphorous Stress.

Talaromyces purpurogenus, an endophytic fungus, exhibits beneficial effects on plants during plant-fungus interactions. However, the molecular mechanisms underlying plants' responses to T. purpurogenus under low-phosphorous (P) stress are not fully understood. In this study, we investigated the transcriptomic changes in maize with low-P-sensitive (31778) and -tolerant (CCM454) genotypes under low-P stress and its symbiotic interaction with T. purpurogenus. Its colonization enhanced plant growth and facilitated P uptake, particularly in 31778. Transcriptome sequencing revealed that 135 DEGs from CCM454 and 389 from 31778 were identified, and that only 6 DEGs were common. This suggested that CCM454 and 31778 exhibited distinct molecular responses to T. purpurogenus inoculation. GO and KEGG analysis revealed that DEGs in 31778 were associated with nicotianamine biosynthesis, organic acid metabolic process, inorganic anion transport, biosynthesis of various secondary metabolites and nitrogen metabolism. In CCM454, DEGs were associated with anthocyanin biosynthesis, diterpenoid biosynthesis and metabolic process. After T. purpurogenus inoculation, the genes associated with phosphate transporter, phosphatase, peroxidase and high-affinity nitrate transporter were upregulated in 31778, whereas AP2-EREBP-transcription factors were detected at significantly higher levels in CCM454. This study provided insights on the molecular mechanisms underlying plant-endophytic fungus symbiosis and low-P stress in maize with low-P-sensitive and -tolerant genotypes.

Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3',3'-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.

Docetaxel liposomes for lung targeted delivery: development and evaluation.

Docetaxel (DTX) is an artificial semi-synthetic second-generation taxane anti-tumor drug, which is suitable for the treatment of various cancers such as lung cancer. The route of administration of DTX formulations has been extended to oral, intravenous, and rectal, with few studies on pulmonary administration being reported. Here, we had developed DTX liposomes (DTX-lips) for pulmonary inhalation administration. The particle size of the preparation was 125 nm, the encapsulation efficiency was 94.4 ± 0.14%, and the drug loading capacity was 1.26 ± 0.01%. It had good stability. The fine particle fraction with aerodynamic diameter less than 6.4 µm accounts for 64.63 ± 0.12%, showed excellent aerosolization performance. DTX-lips were slow to release in simulated lung fluid. The fluorescence distribution experimented in mice and tissues showed that the fluorescence of the inhaled liposome group was mainly distributed in the lung, and the retention time was significantly prolonged as compared with those of the other two groups. No significant fluorescence was observed in other tissues, which was conducive to the full effect of the drug in the lung tissue. DTX-lips had no damage to respiratory system and whole body. These results indicated that the inhaled DTX-lips had good lung targeting, reduced accumulation in other organs, and improved the safety and effectiveness of the drug.

[Yigong Powder regulates CXCL12/CXCR4 signaling to reduce glutamate release and prevent cognitive decline in mouse model of aging].

This study aims to explore the effect of preventive administration of Yigong Powder on the learning and memory abilities of the mouse model of aging induced by D-galactose and decipher the underlying mechanism, so as to provide a basis for the application of Yigong Powder in the prevention and treatment of cognitive decline. Forty KM mice were randomized into control, model, donepezil(1.5 mg·kg~(-1)), and high-dose(7.5 g·kg~(-1)) and low-dose(3.75 g·kg~(-1)) Yigong Powder groups. The mice in other groups except the control group were injected with D-galactose(200 g·kg~(-1)) at the back of the neck for the modeling of aging. At the same time, the mice were administrated with corresponding drugs by gavage for one month. Morris water maze was used to examine the learning and memory abilities of the mice. Hematoxylin-eosin staining was employed to observe the pathological and morphological changes of the hippocampus. The immunofluorescence assay was employed to detect the expression of ionized calcium-binding adapter molecule 1(IBA1), glial fibrillary acidic protein(GFAP), chemokine C-X-C-motif ligand 12(CXCL12), chemokine C-X-C-motif receptor 4(CXCR4) in the hippocampus and observe the positional relationship between IBA1, GFAP, and CXCR4. Western blot was employed to determine the protein levels of extracellular regulated kinase(ERK), p-ERK, and tumor necrosis factor receptor 1(TNFR1). Enzyme-linked immunosorbent assay was employed to measure the levels of glutamate and tumor necrosis factor(TNF-α) in the brain tissue and the level of TNF-α in the serum and spleen. Yigong Powder significantly shortened the escape latency, increased the times crossing platforms, and prolonged the cumulative time in quadrants of the aging mice. It alleviated the nerve cell disarrangement, increased intercellular space, and cell degeneration or death in the hippocampus and reduced the pathology score of the damaged nerve. Moreover, Yigong Powder reduced the positive area of IBA1 and GFAP, reduced the levels of TNF-α in the brain tissue, serum, and spleen, and decreased spleen index. Furthermore, Yigong Powder decreased the average fluorescence intensity of CXCL12 and CXCR4, reduced CXCR4-positive astrocytes and microglia, down-regulated the protein levels of p-ERK/ERK and TNFR1, and lowered the level of glutamate in the brain tissue. This study showed that the preventive administration of Yigong Powder can ameliorate the learning and memory decline of the D-galactose-induced aging mice by regulating the immune function of the spleen and the CXCL12/CXCR4 signaling in the brain to reduce glutamate release. However, the mechanism of Yigong San in preventing and treating dementia via regulating spleen and stomach function remains to be studied.

The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity.

Current therapies for treating heterogeneous cancers such as head and neck squamous cell carcinoma (HNSCC) are non-selective and are administered independent of response biomarkers. Therapy resistance subsequently emerges, resulting in increased cellular proliferation that is associated with loss of differentiation. Whether a cancer cell differentiation potential can dictate therapy responsiveness is still currently unknown. A multi-omic approach integrating whole-genome and whole-transcriptome sequencing with drug sensitivity was employed in a HNSCC mouse model, primary patients' data, and human cell lines to assess the potential of functional differentiation in predicting therapy response. Interestingly, a subset of HNSCC with effective GRHL3-dependent differentiation was the most sensitive to inhibitors of PI3K/mTOR, c-Myc, and STAT3 signaling. Furthermore, we identified the GRHL3-differentiation target gene Filaggrin (FLG) as a response biomarker and more importantly, stratified HNSCC subsets as treatment resistant based on their FLG mutational profile. The loss of FLG in sensitive HNSCC resulted in a dramatic resistance to targeted therapies while the GRHL3-FLG signature predicted a favorable patient prognosis. This study provides evidence for a functional GRHL3-FLG tumor-specific differentiation axis that regulates targeted therapy response in HNSCC and establishes a rationale for clinical investigation of differentiation-paired targeted therapy in heterogeneous cancers.

Level-specific associations of urinary antimony with cognitive function in US older adults from the National Health and Nutrition Examination Survey 2011-2014.

BACKGROUND: We have looked at antimony (Sb) as a new neurotoxin which causes neuronal apoptosis in animal studies. At the population level, however, there is no direct evidence for a relationship between Sb exposure and cognitive performance. METHOD: The study comprehensively assessed the correlation between urinary antimony levels and cognitive test scores in 631 creatinine-corrected older persons using data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. RESULTS: Using logistic regression, the study looked at the prevalence of cognitive impairment at different levels of urine antimony concentrations and found that, after controlling for covariates, higher doses of urinary antimony were positively associated with cognitive function compared to controls, odds ratio (ORs) with 95% confidence interval (CI) were 0.409 (0.185-0.906) and 0.402 (0.186-0.871) respectively. Restricted cubic spline curves showed a non-linear and dose-specific correlation between urinary antimony and cognitive performance, with lower doses associated with better cognitive performance, while higher doses may be associated with cognitive impairment. CONCLUSIONS: Our data provide evidence for a correlation between Sb and cognitive function at the population level, although the specific mechanisms need to be investigated further.

Comparative analysis of caseins in Saanen goat milk from 3 different regions of China using quantitative proteomics.

A quantitative proteomic technique based on data-independent acquisition (DIA) was used to analyze differentially expressed caseins of Saanen goat milk samples collected from 3 regions in China (Guangdong, GD; Inner Mongolia, IM; Shaanxi, SX). A total of 345 proteins were quantified in each sample. Gene Ontology (GO) analysis showed that proteins were mainly involved in cellular process and cell and binding functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that proteins were mainly involved in metabolic pathways. Differentially expressed proteins (DEP) between goat milk from 3 comparison groups composed of paired regions were compared and analyzed. The number of DEP was 114, 69, and 79 for GD versus IM, GD versus SX, and IM versus SX, respectively. The GO enrichment analysis of the 3 comparison groups showed that differences were mainly related to the regulation of biological quality, biological regulation, and response to stimulus in terms of biological process; extracellular region for cellular component; and binding function for molecular function. Pathways in which DEP of GD versus IM, GD versus SX, and IM versus SX were mostly protein processing in endoplasmic reticulum for the first 2 groups and metabolic pathways for the last. Protein-protein interaction network analysis demonstrated that the most prominent DEP was heat shock protein 90 ß family member 1 for both the GD versus IM and the GD versus SX groups, and haptoglobin for the IM versus SX group. Data from this study may offer useful information for further investigation of the protein composition of Saanen goat milk and its application in the dairy industry.

Exposure to short-chain chlorinated paraffins induces astrocyte activation via JAK2/STAT3 signaling pathway.

In the last few decades, short-chain chlorinated paraffins (SCCPs) have become the most heavily produced monomeric organohalogen compounds, and have been reported to induce multiple organ toxicity. However, the effects of SCCPs on the central nervous system are unknown. In the present study, we show that SCCP exposure induced astrocyte proliferation and increased the expression of two critical markers of astrocyte activation, glial fibrillary acidic protein and inducible nitric oxide synthase, in vivo and in vitro. SCCP exposure also increased inflammatory factory gene expression. Moreover, SCCP treatment triggered Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signalling, as shown by increased phosphorylation and STAT3 translocation to the nucleus. Both JAK2 and STAT3 inhibition effectively attenuated SCCP-induced astrocyte activation. Finally, JAK2 inhibition significantly rescued STAT3 phosphorylation and nuclear translocation. Taken together, JAK2/STAT3 pathway activation contributed to SCCP-induced astrocyte activation. These data will help elucidate the molecular mechanism underlying SCCP-induced neurotoxicity.

GPX4 degradation via chaperone-mediated autophagy contributes to antimony-triggered neuronal ferroptosis.

Exposure to antimony (Sb), recently identified as a nerve pollutant, can result in neuron damage; but, associated-neurotoxicological mechanisms were still not clear. Herein, we assessed the role of ferroptosis in Sb-mediated neurotoxicity and clarified the underlying mechanism. Following Sb exposure, ferroptosis was significantly promoted in vivo and in vitro. Moreover, following use of ferrostatin-1 (fer-1) to inhibit ferroptosis, Sb-induced ferroptosis in PC12 cells was effectively attenuated. Sb accelerated lysosomal transport and subsequent degradation of glutathione peroxidase 4 (GPX4), resulting in ferroptosis. Furthermore, chaperone-mediated autophagy (CMA) was activated following treatment with Sb, while inhibition of CMA by lysosomal associated protein 2 A (LAMP2A) knockdown attenuated Sb-induced GPX4 degradation. Sb treatment also increased expression of the chaperones heat shock cognate protein 70 (HSC70) and heat shock protein 90 (HSP90) and the lysosome receptor LAMP2A, and increased binding of HSP90, HSC70, and LAMP2A with GPX4 was observed, indicating increased formation of the chaperone-GPX4 complex. Finally, GPX4 overexpression significantly protected PC12 cells from activation of Sb-stimulated ferroptosis and subsequent cytotoxicity. Collectively, our results provide a original mechanism by which Sb triggers neurotoxicity, to concluded that Sb stimulates neuronal ferroptosis through CMA-mediated GPX4 degradation.

Characterizing Key Volatile Pollutants Emitted from Adhesives by Chemical Compositions, Odor Contributions and Health Risks.

As one of the major sources of volatile pollutants in indoor air, gaseous emissions from adhesives during interior decoration have attracted increasing concern. Identifying major volatile pollutants and the risk in adhesive gaseous emissions is of great significance, but remains rarely reported. In the present research, we assessed the major volatile pollutants emitted from white emulsion adhesive and silicone adhesive samples (n = 30) from three aspects: chemical composition, odor and health risk contributions. The results showed that a total of 21 volatile pollutants were detected. Significantly, xylene was the most concentrated compound from white emulsion adhesives, accounting for 45.51% of the total concentrations. Butanone oxime was the most concentrated compound in silicone adhesives, accounting for 69.86% of the total concentrations. The trends in odor concentration (evaluated by the odor activity value method) over time were well correlated with the total chemical concentrations. Xylene (58.00%) and butanone oxime (76.75%) showed the highest odor contribution, respectively. Moreover, from an integrated perspective of chemical emissions, odor and health risk contributions, xylene, ethylbenzene, ethyl acetate and benzene were identified as the key volatile pollutants emitted from the white emulsion adhesives, while butanone oxime, butanone, and ethanol were the key volatile pollutants emitted from the silicone adhesives. This study not only identified the key volatile pollutants but also provided characteristics of odor and health risks of gas emitted from adhesives.

Cost-utility analysis of imrecoxib compared with diclofenac for patients with osteoarthritis.

BACKGROUND: To estimate the cost -utility of imrecoxib compared with diclofenac, as well as the addition of a proton pump inhibitor to both two treatment strategies, for patients with osteoarthritis, from a Chinese healthcare perspective. METHODS: A Markov model was built. Costs of managing osteoarthritis and initial adverse events were collected from a Medical Database which collected information from 170 hospitals. Other parameters were obtained from the literature. Subgroup analyses were conducted for people at high risk of gastrointestinal or cardiovascular adverse events. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Imrecoxib was highly cost-effective than diclofenac (the ICER was $401.58 and $492.77 in patients at low and high gastrointestinal and cardiovascular risk, respectively). The addition of a proton pump inhibitor was more cost -effective compared with single drug for both treatment strategies. Findings remained robust to sensitivity analyses. 59.04% and 57.16% probability for the co-prescription of imrecoxib and a proton pump inhibitor to be the most cost-effective strategy in all patients considered using the cost-effectiveness threshold of $30,000. CONCLUSIONS: The addition of a proton pump inhibitor to both imrecoxib and diclofenac was advised. Imrecoxib provides a valuable option for patients with osteoarthritis. Uncertainties existed in the model, and the suggestions can be adopted with caution.