Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

Prmt5 promotes ciliated cell specification of airway epithelial progenitors via transcriptional inhibition of Tp63.

The epithelium of the pulmonary airway is composed of several distinct cell types that differentiate from common progenitor cells to provide defense against environmental insults. Epigenetic mechanisms regulating lineage differentiation of airway epithelial progenitors remain poorly understood. Protein arginine methyltransferase 5 (Prmt5) is a predominant type II arginine methyltransferase that methylates >85% of symmetric arginine residues. Here, we provide evidence for the function of Prmt5 in promoting ciliated cell fate specification of airway epithelial progenitors. We show that lung epithelial-specific deletion of Prmt5 resulted in a complete loss of ciliated cells, an increased number of basal cells, and ecotopic-expressed Tp63-Krt5+ putative cells in the proximal airway. We further identified that transcription factor Tp63 is a direct target of Prmt5, and Prmt5 inhibited Tp63 transcription expression through H4R3 symmetric dimethylation (H4R3sme2). Moreover, inhibition of Tp63 expression in Prmt5-deficient tracheal progenitors could partially restore the ciliated cell deficient phenotype. Together, our data support a model where Prmt5-mediated H4R3sme2 represses Tp63 expression to promote ciliated cell fate specification of airway progenitors.

Artificial intelligence in the risk prediction models of cardiovascular disease and development of an independent validation screening tool: a systematic review.

BACKGROUND: A comprehensive overview of artificial intelligence (AI) for cardiovascular disease (CVD) prediction and a screening tool of AI models (AI-Ms) for independent external validation are lacking. This systematic review aims to identify, describe, and appraise AI-Ms of CVD prediction in the general and special populations and develop a new independent validation score (IVS) for AI-Ms replicability evaluation. METHODS: PubMed, Web of Science, Embase, and IEEE library were searched up to July 2021. Data extraction and analysis were performed for the populations, distribution, predictors, algorithms, etc. The risk of bias was evaluated with the prediction risk of bias assessment tool (PROBAST). Subsequently, we designed IVS for model replicability evaluation with five steps in five items, including transparency of algorithms, performance of models, feasibility of reproduction, risk of reproduction, and clinical implication, respectively. The review is registered in PROSPERO (No. CRD42021271789). RESULTS: In 20,887 screened references, 79 articles (82.5% in 2017-2021) were included, which contained 114 datasets (67 in Europe and North America, but 0 in Africa). We identified 486 AI-Ms, of which the majority were in development (n = 380), but none of them had undergone independent external validation. A total of 66 idiographic algorithms were found; however, 36.4% were used only once and only 39.4% over three times. A large number of different predictors (range 5-52,000, median 21) and large-span sample size (range 80-3,660,000, median 4466) were observed. All models were at high risk of bias according to PROBAST, primarily due to the incorrect use of statistical methods. IVS analysis confirmed only 10 models as "recommended"; however, 281 and 187 were "not recommended" and "warning," respectively. CONCLUSION: AI has led the digital revolution in the field of CVD prediction, but is still in the early stage of development as the defects of research design, report, and evaluation systems. The IVS we developed may contribute to independent external validation and the development of this field.

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 µM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

Natural Product Baohuoside I Impairs the Stability and Membrane Location of MRP2 Reciprocally Regulated by SUMOylation and Ubiquitination in Hepatocytes.

Epimedii Folium (EF) is a botanical dietary supplement to benefit immunity. Baohuoside I (BI), a prenylated flavonoid derived from EF, has exhibited the cholestatic risk before. Here, the mechanism of BI on the stability and membrane localization of liver MRP2, a bile acid exporter in the canalicular membrane of hepatocytes, was investigated. The fluorescent substrate of MRP2, CMFDA was accumulated in sandwich-cultured primary mouse hepatocytes (SCH) under BI stimulation, followed by reduced membrane MRP2 expression. BI triggered MRP2 endocytosis associated with oxidative stress via inhibition of the NRF2 signaling pathway. Meanwhile, BI promoted the degradation of MRP2 by reducing its SUMOylation and enhancing its ubiquitination level. Co-IP and fluorescence colocalization experiments all proved that MRP2 was a substrate protein for SUMOylation for SUMO proteins. CHX assays showed that SUMO1 prolonged the half-life of MRP2 and further increased its membrane expression, which could be reversed by UBC9 knockdown. Correspondingly, MRP2 accumulated in the cytoplasm by GP78 knockdown or under MG132 treatment. Additionally, the SUMOylation sites of MRP2 were predicted by the algorithm, and a conversion of lysines to arginines at positions 940 and 953 of human MRP2 caused its decreased stability and membrane location. K940 was further identified as the essential ubiquitination site for MRP2 by an in vitro ubiquitination assay. Moreover, the decreased ubiquitination of MRP2 enhanced the SUMOylation MRP2 and vice versa, and the crosstalk of these two modifiers could be disrupted by BI. Collectively, our findings indicated the process of MRP2 turnover from the membrane to cytoplasm at the post-translational level and further elucidated the novel toxicological mechanism of BI.

TRAF6-mediated ubiquitination of AKT in the nucleus is a critical event underlying the desensitization of G protein-coupled receptors.

BACKGROUND: Desensitization of G protein-coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of ß-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D2-like receptors (D2R, D3R, D4R), have suggested the existence of other desensitization mechanisms. The present study employed D2R/D3R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. RESULTS: AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin ß1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of ß-Arr2. The deubiquitinated ß-Arr2 then forms a complex with Gßγ, which serves as a biomarker for GPCRs desensitization. Like in D3R, ubiquitination of AKT is also involved in the desensitization of ß2 adrenoceptors. CONCLUSION: Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.

Short-term exposure to air pollution on peripheral white blood cells and inflammation biomarkers: a cross-sectional study on rural residents.

Effects of short-term exposure to ambient air pollution on systemic immunological and inflammatory biomarkers in rural population have not been adequately characterized. From May to July 2021, 5816 participants in rural villages of northern Henan Province, China, participated in this cross-sectional study. Blood biomarkers of systemic inflammation were determined including peripheral white blood cells (WBC), eosinophils (EOS), basophils (BAS), monocytes (MON), lymphocytes (LYM), neutrophils (NEU), neutrophil-lymphocyte ratio (NLR), and serum high-sensitivity C-reactive protein (hs-CRP). The concentrations of ambient fine particulate matter (PM2.5), PM10, nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) were assessed up to 7 days prior to the blood draw. A generalized linear model was used to analyze the associations between air pollution exposure and the above-mentioned blood biomarkers. Significantly positive associations were revealed between PM2.5, CO and WBC; CO, O3 and LYM; PM2.5, PM10, SO2, CO and NEU; PM2.5, PM10, SO2, CO and NLR; PM2.5, PM10, SO2, NO2, CO, O3 and hs-CRP. Meanwhile, negative associations were found between SO2 and WBC; PM2.5, PM10, NO2, CO, or O3 and EOS; PM2.5, SO2, or CO and BAS; SO2, NO2 or O3 and MON; PM2.5, PM10, SO2, or NO2 and LYM. Moreover, men, individuals with normal body mass index (BMI), current smokers, and those older than 60 years were found vulnerable to air pollution effects. Taken together, short-term exposure to air pollution was associated with systemic inflammatory responses, providing insight into the potential mechanisms for air pollution-induced detrimental systemic effects in rural residents.

Response surface methodology optimization of extraction and enrichment conditions of total triterpenoid saponins from Celosiae Semen and evaluation of its lipid-lowering activity.

The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug.

Pitfalls in Developing Machine Learning Models for Predicting Cardiovascular Diseases: Challenge and Solutions.

UNSTRUCTURED: In recent years, there has been an explosive development of artificial intelligence (AI), which has been widely applied in the healthcare field. As a typical AI technology, machine learning (ML) models have emerged as great potential in predicting cardiovascular diseases (CVDs) by leveraging large amounts of medical data for training and optimization, which are expected to play a crucial role in reducing the incidence and mortality rates of CVDs. Although the field has become a research hotspot, there are still many pitfalls that researchers need to pay close attention to. These pitfalls may affect the predictive performance, credibility, reliability, reproducibility of the studied models, ultimately reducing the value of the research and affecting the prospects for clinical application. Therefore, identifying and avoiding these pitfalls is a crucial task before implementing the research. However, there is currently a lack of comprehensive summary on this topic. This viewpoint aims to analyze the existing problems in terms of data quality, dataset characteristics, model design and statistical methods as well as clinic implication, and provide possible solutions to these problems, like gathering objective data, improving training, repeating measurements, increasing sample size, preventing overfitting using statistical methods, utilizing specific AI algorithms to address targeted issues, standardizing outcomes and evaluation criteria, as well as enhancing fairness and replicability, with the goal of offering reference and assistance to researchers, algorithm developers, policy makers, and clinical practitioners.

Clinical effects of combined use of carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot.

OBJECTIVE: This study aims to analyze the clinical effects of combining carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot. METHODS: A total of 120 diabetic neuropathy patients treated at our hospital from June 2022 to November 2023 were included in the study. Patients meeting the inclusion criteria were registered, and their basic data were collected. The patients were randomly divided into two groups: the control group treated with amitriptyline and the study group treated with a combination of carbamazepine and amitriptyline. RESULTS: The study group demonstrated significantly better clinical efficacy compared to the control group (p < 0.05). There were no significant differences in psychological status and pain perception before treatment between the two groups (p > 0.05). However, post-treatment, the study group showed improved psychological status, reduced pain perception, and overall better quality of life in both physiological and psychological dimensions compared to the control group (p < 0.05). CONCLUSION: The combined use of carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot yields positive clinical outcomes. It effectively alleviates symptoms, improves psychological well-being, reduces pain sensation, and enhances overall quality of life. These findings can guide physicians in adopting a more evidence-based treatment approach and provide patients with more effective individualized treatment strategies.

A prospective study on maternal periodontal diseases and neonatal adverse outcomes.

OBJECTIVE: It is evident that periodontitis is linked to various adverse pregnancy outcomes. This prospective study explored the potential link of maternal periodontal diseases to neonatal adverse outcomes. MATERIALS AND METHODS: A total of 193 generally healthy females in their third trimester (34-36 weeks) of pregnancy were enrolled. All subjects received full-mouth periodontal assessment, and the periodontal inflamed surface area (PISA) was calculated. Demographic data, lifestyles and anthropometric measurements of the neonates (e.g., body length and head circumference) were recorded. Herein, small-for-gestational age (SGA) referred to gender- and age-adjusted birth weight below the 10th percentile in line with the standard reference. Multivariable logistic regression analysis and restricted cubic spline were performed for examining the association of periodontal parameters with SGA.  Results: There were 8.3% (16/193) of neonates with SGA. Significantly positive correlation existed between the percentage of tooth sites with increased probing depth and an elevated risk of SGA (OR: 1.052; P < 0.05). Yet, the PISA was positively associated with the risk of SGA (OR: 1.002; P < 0.05) as well. No significant link occurred between maternal periodontal status and other neonatal outcome measures. CONCLUSION: Within the limitations of this study, the findings suggest that there could be a link between maternal periodontal diseases and neonatal adverse outcomes like SGA. Further investigation is required to clarify the current findings and potential implications for promoting maternal oral/periodontal health and newborn health.

Response of the C-fixing bacteria community to precipitation changes and its impact on bacterial necromass accumulation in semiarid grassland.

Climate change-induced warming has the potential to intensify drought conditions in certain regions, resulting in uneven precipitation patterns. However, the impact of precipitation-induced changes on soil C-fixing bacterial community composition to changes and their subsequent effect on the accumulation of microbial necromass in the soil remains unclear. To address this knowledge gap, we conducted an in-situ simulated precipitation control experiment in semi-arid grasslands, encompassing five primary precipitation gradients: ambient precipitation as a control (contr), decreased precipitation by 80% and 40% (DP80, DP40), and increased precipitation by 40% and 80% (IP80, IP40). Our findings indicate that while an increase in precipitation promotes greater total bacterial diversity, it reduces the diversity of cbbM-harboring bacteria. The dominance of drought-tolerant Proteobacteria within the cbbM-harboring bacterial community was responsible for the observed increase in their relative abundance, ranging from 8.9% to 15.6%, under conditions of decreased precipitation. In arid environments characterized by limited soil moisture and nutrient availability, certain dominant genera such as Thiobacillus, Sulfuritalea, and Halothiobacillus, which possess cbbM genes, exhibit strong synergistic effects with other bacteria, thereby leading to a high nutrient use efficiency. Linear regression analysis shows that bacterial necromass C was significantly negatively correlated with cbbM-harboring bacterial diversity but positively correlated with cbbM-harboring bacterial community composition. Consequently, in the extreme drought environment of DP80, the contribution of bacterial necromass C to SOC was dramatically reduced by 75% relative to the control. Although bacterial necromass C was preferentially consumed as nutrients and energy for microorganisms, C-fixing microorganisms supplemented the soil C pool by assimilating atmospheric CO2. Bacterial necromass was primarily controlled by accessible C and N rather than by the total bacterial community composition and relative abundance. Our results provide compelling evidence for the critical role of the composition of the bacterial community and its necromass in the accumulation of SOC in semiarid grassland ecosystems.

Development of the pediatric family-based dignity therapy protocol for terminally ill children (ages 7-18) and their families: A mixed-methods study.

OBJECTIVES: Dignity therapy (DT) is well-established in adults, and it might potentially benefit the younger population. This study aims to develop a pediatric family-based dignity therapy (P-FBDT) protocol for terminally ill children and their families. METHODS: A parallel mixed-methods design was used. The P-FBDT protocol was developed based on the adult DT, and meanwhile by taking children-specific dignity characteristics and Chinese family-oriented culture into consideration. The protocol was then evaluated and modified based on the quantitative and qualitative feedback from 2-round surveys of 14 pediatric oncology or pediatric palliative care experts. RESULTS: The P-FBDT involves terminally ill children and their families in meaningful interactions including a series of conversations and creative activities, which will be recorded and then edited into a document-based generativity entity. The P-FBDT protocol was recognized as highly reasonable and the P-FBDT interview guide was endorsed as important, acceptable, clear, comprehensive, and suitable to be used in pediatric palliative care practice in Chinese culture (>90%). Potential benefits, possible challenges, and practical considerations of the P-FBDT were also proposed. SIGNIFICANCE OF RESULTS: The P-FBDT was perceived to be potentially beneficial to terminally ill children and their families by engaging in a series of meaningful family interactions and creating a lasting memento to be preserved. The protocol needs to be pilot tested among terminally ill children and families for feasibility and potential efficacy in practice.

[Variant analysis and prenatal diagnosis for two Chinese pedigrees affected with Spinal muscular atrophy with respiratory distress type 1].

OBJECTIVE: To explore the genetic etiology of two children with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), and prevent the recurrence of birth defects. METHODS: Two unrelated families who had visited the Obstetrics and Gynecology Medical Center of Drum Tower Hospital from August to November 2021 were selected as the study subjects. Copy number of SMN1 gene exon 7 for the probands and their parents was detected by multiple ligation-dependent probe amplification (MLPA). and whole exome sequencing (WES) was carried out to screen the variants in the probands. Sanger sequencing was used to validate the variants within the families. Pathogenicity of the variants were predicted by bioinformatic analysis. Based on the results, prenatal diagnosis was performed for the fetuses. RESULTS: Both probands were found to harbor compound heterozygous variants of the IGHMBP2 gene, which were inherited from their parents. Among these, c.1144C>T, c.866delG and c.1666C>G were previously unreported and respectively classified as pathogenic variant (PVS1+PM2_Supporting+PP3+PP4), likely pathogenic variant (PM1+PM2_Supporting+PM4+PP3+PP4) and likely pathogenic variant (PM1+PM2_Supporting+PP2+PP3+PP4) based on the ACMG guidelines. Through preimplantation genetic testing for monogenic (PGT-M) and interventional prenatal diagnosis, transmission of the variants within the families was successfully blocked. CONCLUSION: The SMARD1 in both children may be attributed to the compound heterozygous variants of the IGHMBP2 gene, which has facilitated the genetic diagnosis and counselling, and provided reference for delineating the molecular pathogenesis of this disease.

Prevalence of Depression and Anxiety Disorders in Patients with Glaucoma: A Systematic Review and Meta-Analysis Based on Cross-Sectional Surveys.

OBJECTIVE: Glaucoma is a chronic disease with an insidious onset that often brings severe psychological burden to patients. Therefore, based on a systematic review and meta-analysis, we explore the prevalence and severity of depression and anxiety in glaucoma patients, and provide clinically valuable information for medical staff. METHODS: Computer searches were conducted for relevant studies in PubMed, Embase, ProQuest PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, The Cochrane Library, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure, Wanfang Database, and China VIP Database. The search date range was from the establishment of the database to December 2023. Literature was screened and data were extracted. The Cochrane risk of bias assessment tool was used to evaluate the quality of the literature, and RevMan5.4 was used for meta-analysis. RESULTS: The total sample size of the 15 included studies was 24,334 cases. All included studies were of high quality. The results of the meta-analysis revealed that, compared with control patients without glaucoma, patients with glaucoma were more likely to experience depression and to have more severe depressive symptoms [RR (Relative Risk) = 5.92, 95% CI (Confidence Interva) (3.29, 10.66), p < 0.01]; they were also more likely to experience anxiety and to have more severe anxiety symptoms [RR = 2.99, 95% CI (1.93, 4.64), p < 0.01]. The results of the sensitivity analysis showed that the two studies by Cumurcu E. 2005 and Yochim 2012 were the sources of heterogeneity in the meta-analysis of depression; and the three studies by Mabuchi 2012, Otori 2017, and Yochim 2012 were the sources of heterogeneity in the meta-analysis of anxiety disorders. CONCLUSION: People with glaucoma are more likely to experience depression and anxiety than people without glaucoma. Medical staff should pay greater attention to patients' emotional problems and help patients improve their quality of life.

Assessment of 13 essential and toxic trace elements in tumor and peritumoral brain tissues from human glioblastoma.

Trace elements within the brain are important for proper neurological function, but their imbalance has been rarely investigated in glioblastoma. This study enrolled a total of 14 patients with glioblastoma, and the tumor and peritumoral brain tissues were collected while undergoing surgery. The concentrations of Mg, Ca, Cr, Mn, Fe, Co, Cu, Zn, Se, As, Cd, Tl and Pb were determined using a well-evaluated ICP-MS method. The Cu- and Cd-binding proteomes were further analyzed using the anatomic transcriptional atlas from Ivy GAP. Histological evaluation was based on rubeanic acid staining and immunohistochemistry, respectively. The 13 trace element concentrations were obtained, and the highest were Ca, Mn, Fe, Zn and Cu, ranging from a few to dozens of ug/g. Correlation analysis suggested the existence of two intra-correlated clusters: essential metals (Cu-Ca-Zn-Mg) and heavy metals (Pb-As-Cd-Tl-Co-Cr-Mn). Compared to the tumor samples, significantly higher levels of Cu and Cd were observed in the peritumoral region. Further analysis of the Cu- and Cd-binding proteins from the anatomic view suggested that DBH and NOS1 were obviously increased in the leading edge than the central tumor region. Consistent with the above findings, histological evaluation of Cu and DBH further confirmed more copper and DBH expressions in the peritumoral area compared to the tumor core. Trace elements differ in tumor and peritumoral brain zone in glioblastoma, which may associate with tumor angiogenesis.

Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER α degradation.

Epimedii folium (EF) is an effective herbal medicine in osteoporosis treatment, but the clinical utilization of EF has been limited due to potential hepatotoxicity. The previous studies identified that baohuoside I (BI), the main active component of EF, was relevant to EF-induced liver injury. However, the mechanisms of BI causing direct injury to hepatocytes remain unclear. Here, we reveal that BI inhibits FXR-mediated signaling pathway via targeting estrogen receptor α (ER α), leading to the accumulation of bile acids (BAs). Targeted bile acid analyses show BI alters the BA composition and distribution, resulting in impaired BA homeostasis. Mechanistically, BI induces FXR-dependent hepatotoxicity at transcriptional level. Additionally, ER α is predicted to bind to the FXR promoter region based on transcription factor binding sites databases and we further demonstrate that ER α positively regulates FXR promoter activity and affects the expression of target genes involved in BA metabolism. Importantly, we discover that ER α and its mediated FXR transcription regulation might be involved in BI-induced liver injury via ligand-dependent ER α degradation. Collectively, our findings indicate that FXR is a newly discovered target gene of ER α mediated BI-induced liver injury, and suggest BI may be responsible for EF-induced liver injury.

Air pollution associated acute respiratory inflammation and modification by GSTM1 and GSTT1 gene polymorphisms: a panel study of healthy undergraduates.

Epidemiological evidence has linked air pollution with adverse respiratory outcomes, but the mechanisms underlying susceptibility to air pollution remain unclear. This study aimed to investigate the role of glutathione S-transferase (GST) polymorphism in the association between air pollution and lung function levels. A total of 75 healthy young volunteers aged 18-20 years old were recruited for six follow-up visits and examinations. Spirometry was conducted to obtain lung function parameters such as forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1). Nasal fluid concentrations of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and 8-epi-prostaglandin F2α (8-epi-PGF2a) were measured using ELISA kits. Linear mixed-effect models were used to evaluate the association of air pollutants with respiratory outcomes. Additionally, polymorphisms of glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) were estimated to explore its role in the association between air pollutants and lung function. We found that short-term exposure to atmospheric particulates such as PM2.5 and PM10 can cause an increase in nasal biomarkers of inflammation, oxidative stress, and lung function, while air gaseous pollutant exposure is linked with decreased lung function, except for CO. Stratification analyses showed that an increase in nasal inflammatory cytokines caused by exposure to atmospheric particulates is more obvious in subjects with GSTM1-sufficient (GSTM1+) than GSTM1-null (GSTM1-), while elevated lung function levels due to air particles are more significant in subjects with the genotype of GSTM1- when compared to GSTM1+. As for air gaseous pollutants, decreased lung function levels caused by O3, SO2, and NO2 exposure is more manifest in subjects with the genotype of GSTM1- compared to GSTM1+. Taken together, short-term exposure to air pollutants is associated with alterations in nasal biomarkers and lung function levels in young healthy adults, and susceptible genotypes play an important mediation role in the association between exposure to air pollutants and inflammation, oxidative stress, and lung function levels.

Minority stress, social support and mental health among lesbian, gay, and bisexual college students in China: a moderated mediation analysis.

BACKGROUND: The existing body of research exploring minority stressors and their impact on the mental health of Lesbian, Gay, and Bisexual (LGB) students in China remains limited in scope and often restricted to specific geographic regions.. METHODS: A combination of snowball and targeted sampling strategies was used to recruit lesbian, gay and bisexual students (N = 1,393) for a cross-sectional, online survey in China. Participants (Mage = 20.00 years; 60.23% assigned male at birth) were tasked with completing a comprehensive questionnaire designed to capture various dimensions, including gender expression, minority stressors (e.g., school bullying, internalized homophobia), social psychological resources (e.g., perceived social support), and mental health-related outcomes (e.g., depression, anxious and stress). Our analytical approach involved hierarchical multiple regression analyses, mediation and moderated mediation modeling to elucidate the intricate interplay among these factors. RESULTS: Our findings shed light on the pronounced mental health disparities afflicting LGB college students in China, with notable prevalence rates of depression (48.1%), anxiety (57.1%), and stress (37.5%). A significant positive correlation was observed between experiences of school-based victimization and internalized homophobia, which, in turn, exhibited a direct association with affective symptoms.School bullying was positive with internalized homophobia, which was positively associated with affective symptoms.In addition to unveiling the indirect effects of school bullying on affective symptoms, our study identified direct links in this complex relationship. Notably, the availability of social support emerged as a pivotal factor, serving as a moderator within the mediation model by mitigating the path from school-based victimization bullying to internalized homophobia (ß = -0.077, P = 0.040). CONCLUSIONS: This study underscores the pervasive and concerning mental health disparities experienced by LGB college students in China. In response, institutions of higher learning should intensify anti-bullying initiatives tailored to LGB students and implement comprehensive gender education programs. Moreover, concerted efforts should be directed at enhancing the accessibility of social support resources for LGB college students, with the aim of cultivating and sustaining favorable psychological well-being.

Analytical Evaluation and Reference Interval Investigation for Chinese Han Population in Wuhan of CA72-4 Performed on an Architect i2000sr System.

BACKGROUND: Carbohydrate antigen 72-4 (CA72-4) is a mucin-like, tumor-associated glycoprotein. Its elevation in serum has been found to be associated with various carcinomas. The purpose of this study was to evaluate the analytical performance of the Architect chemiluminescent immunoassay CA72-4 on the Architect i2000sr platform and to determine the reference interval (RI) of CA72-4 for the Chinese Han population in the city of Wuhan. METHODS: We evaluated the precision, analytical sensitivity, linearity and interference according to the guidelines of the Clinical Laboratory Standardization Institute. Additionally, the Abbott Architect i2000sr CA72-4 assay was compared to the Roche Cobas E602 CA72-4 assay. A total of 448 healthy individuals were selected to determine the RIs of CA72-4. RESULTS: The assay had an imprecision of 1.38% - 2.63% within runs, 1.41% - 2.73% between runs and a total imprecision of 2.54% - 4.10%. The limit of blank, limit of detection and limit of quantitation concentrations were 0.19 U/mL, 0.21 U/mL, and 0.21 U/mL. Linearity was confirmed across the entire measurable range. Additionally, the carryover was less than 0.065%. Interferences with hemoglobin, conjugated bilirubin and lipemia were acceptable with changes of less than 10%. A correlation coefficient of 0.9450 was determined through the method comparison experiment (95% CI 0.9318 - 0.9557). The RI for serum CA72-4 in the Han population was established as an upper limit, 11.13 U/mL (90% CI 9.39 - 12.99) by using the Abbott Architect i2000sr system. CONCLUSIONS: This study establishes a RI for the Chinese Han population in Wuhan using the Abbott Architect i2000sr CA72-4 assay and demonstrates an analytical performance for clinical use.