ABSTRACT
Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous ß-phenylethylamine (ß-PEA)1 as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and ß-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.
Subject(s)
Methamphetamine , Phenethylamines , Receptors, G-Protein-Coupled , Humans , Ligands , Methamphetamine/metabolism , Nervous System Diseases/metabolism , Phenethylamines/metabolism , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Substance-Related Disorders/metabolism , Heterotrimeric GTP-Binding Proteins/metabolism , Polypharmacology , Hydrogen BondingABSTRACT
Our previous study confirmed that umbilical cord mesenchymal stem cells-exosomes (ucMSC-Ex) inhibit apoptosis of pancreatic acinar cells to exert protective effects. However, the relationship between apoptosis and autophagy in traumatic pancreatitis (TP) has rarely been reported. We dissected the transcriptomics after pancreatic trauma and ucMSC-Ex therapy by high-throughput sequencing. Additionally, we used rapamycin and MHY1485 to regulate mTOR. HE, inflammatory factors and pancreatic enzymatic assays were used to comprehensively determine the local versus systemic injury level, fluorescence staining and electron microscopy were used to detect the effect of autophagy, and observe the expression levels of autophagy-related markers at the gene and protein levels. High-throughput sequencing identified that autophagy played a crucial role in the pathophysiological process of TP and ucMSC-Ex therapy. The results of electron microscopy, immunofluorescence staining, polymerase chain reaction and western blot suggested that therapeutic effect of ucMSC-Ex was mediated by activation of autophagy in pancreatic acinar cells through inhibition of mTOR. ucMSC-Ex can attenuate pancreas injury by inhibiting mTOR to regulate acinar cell autophagy after TP. Future studies will build on the comprehensive sequencing of RNA carried by ucMSC-Ex to predict and verify specific non-coding RNA.
Subject(s)
Exosomes , Mesenchymal Stem Cells , Pancreatitis , Humans , Exosomes/metabolism , Mesenchymal Stem Cells/metabolism , Umbilical Cord , TOR Serine-Threonine Kinases/metabolism , Pancreatitis/metabolism , Autophagy/genetics , ApoptosisABSTRACT
BACKGROUND: Artificial intelligence shows promise in assessing knee osteoarthritis (OA) progression on MR images, but faces challenges in accuracy and interpretability. PURPOSE: To introduce a temporal-regional graph convolutional network (TRGCN) on MR images to study the association between knee OA progression status and network outcome. STUDY TYPE: Retrospective. POPULATION: 194 OA progressors (mean age, 62 ± 9 years) and 406 controls (mean age, 61 ± 9 years) from the OA Initiative were randomly divided into training (80%) and testing (20%) cohorts. FIELD STRENGTH/SEQUENCE: Sagittal 2D IW-TSE-FS (IW) and 3D-DESS-WE (DESS) at 3T. ASSESSMENT: Anatomical subregions of cartilage, subchondral bone, meniscus, and the infrapatellar fat pad at baseline, 12-month, and 24-month were automatically segmented and served as inputs to form compartment-based graphs for a TRGCN model, which containing both regional and temporal information. The performance of models based on (i) clinical variables alone, (ii) radiologist score alone, (iii) combined features (containing i and ii), (iv) composite TRGCN (combining TRGCN, i and ii), (v) radiomics features, (vi) convolutional neural network based on Densenet-169 were compared. STATISTICAL TESTS: DeLong test was performed to compare the areas under the ROC curve (AUC) of all models. Additionally, interpretability analysis was done to evaluate the contributions of individual regions. A P value <0.05 was considered significant. RESULTS: The composite TRGCN outperformed all other models with AUCs of 0.841 (DESS) and 0.856 (IW) in the testing cohort (all P < 0.05). Interpretability analysis highlighted cartilage's importance over other structures (42%-45%), tibiofemoral joint's (TFJ) dominance over patellofemoral joint (PFJ) (58%-67% vs. 12%-37%), and importance scores changes in compartments over time (TFJ vs. PFJ: baseline: 44% vs. 43%, 12-month: 52% vs. 39%, 24-month: 31% vs. 48%). DATA CONCLUSION: The composite TRGCN, capturing temporal and regional information, demonstrated superior discriminative ability compared with other methods, providing interpretable insights for identifying knee OA progression. TECHNICAL EFFICACY: Stage 2.
ABSTRACT
OBJECTIVE: Examining the relationship between the plant-based dietary index and vision impairment (VI), hearing impairment (HI), and dual sensory impairment (DSI) among Chinese aged 65 and older. METHODS: Based on the 2018 data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a cross-sectional study was conducted on 14,859 samples. The assessment of dietary quality utilized the Plant-Based Diet Index (PDI), Healthy Plant-Based Diet Index (hPDI), and Unhealthy Plant-Based Diet Index (uPDI). Logistic regression analysis was used to examine the associations between PDIs and sensory impairments. Additionally, restricted cubic spline analysis was utilized to investigate the non-linear association between PDIs and sensory impairments. RESULTS: Participants in the highest quintile of PDI exhibited reduced prevalence of VI (OR 0.78, 95% CI:0.67-0.90, Ptrend <0.001), HI (OR 0.83, 95% CI:0.70-0.99, Ptrend <0.001) and DSI (OR 0.62, 95%CI:0.51-0.77, Ptrend <0.001) relative to those in the lowest quintile. Moreover, individuals who ranked in the highest quintile for hPDI exhibited a 25% reduced risk of VI disease. Conversely, those in the highest quintile of uPDI were associated with increased prevalence of VI (OR 1.37, 95% CI: 1.17-1.61, Ptrend <0.001), HI (OR 1.36, 95% CI: 1.12-1.65, Ptrend <0.001) and DSI (OR 1.56, 95% CI: 1.25-1.95, Ptrend <0.001). The relationship between PDIs increasing by every 10 units and sensory impairments showed similar patterns. Notably, hPDI demonstrated a non-linear relationship with HI (Pfor nonlinearity = 0.001), while the others exhibited linear associations. CONCLUSION: The increase in PDI and hPDI correlates with a reduced prevalence of one or more sensory impairments. Conversely, an increase in uPDI is associated with an elevated prevalence of multiple sensory impairments. Our study findings emphasize the significance of plant-based food quality, advocating for adherence to a plant-based dietary pattern while reducing the intake of less healthy plant foods and animal-based products.
ABSTRACT
BACKGROUND: Acute pancreatitis (AP) has become a significant global health concern, and a high body mass index (BMI) has been identified as a key risk factor exacerbating this condition. Within this context, lipid metabolism assumes a critical role. The complex relationship between elevated BMI and AP, mediated by lipid metabolism, markedly increases the risk of complications and mortality. This study aimed to accurately define the correlation between BMI and AP, incorporating a comprehensive analysis of the interactions between individuals with high BMI and AP. METHODS: Mendelian randomization (MR) analysis was first applied to determine the causal relationship between BMI and the risk of AP. Subsequently, three microarray datasets were obtained from the GEO database. This was followed by an analysis of differentially expressed genes and the application of weighted gene coexpression network analysis (WGCNA) to identify key modular genes associated with AP and elevated BMI. Functional enrichment analysis was then performed to shed light on disease pathogenesis. To identify the most informative genes, machine learning algorithms, including Random Forest (RF), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), were employed. Subsequent analysis focused on the colocalization of the Quantitative Trait Loci (eQTL) data associated with the selected genes and Genome-Wide Association Studies (GWAS) data related to the disease. Preliminary verification of gene expression trends was conducted using external GEO datasets. Ultimately, the diagnostic potential of these genes was further confirmed through the development of an AP model in mice with a high BMI. RESULTS: A total of 21 intersecting genes related to BMI>30, AP, and lipid metabolism were identified from the datasets. These genes were primarily enriched in pathways related to cytosolic DNA sensing, cytokineâcytokine receptor interactions, and various immune and inflammatory responses. Next, three machine learning techniques were utilized to identify HADH as the most prevalent diagnostic gene. Colocalization analysis revealed that HADH significantly influenced the risk factors associated with BMI and AP. Furthermore, the trend in HADH expression within the external validation dataset aligned with the trend in the experimental data, thus providing a preliminary validation of the experimental findings.The changes in its expression were further validated using external datasets and quantitative real-time polymerase chain reaction (qPCR). CONCLUSION: This study systematically identified HADH as a potential lipid metabolism-grounded biomarker for AP in patients with a BMI>30.
Subject(s)
Body Mass Index , Genome-Wide Association Study , Mendelian Randomization Analysis , Pancreatitis , Quantitative Trait Loci , Humans , Pancreatitis/genetics , Mice , Animals , Biomarkers/blood , Biomarkers/metabolism , Gene Expression Profiling , Transcriptome/genetics , Machine Learning , Lipid Metabolism/genetics , Gene Regulatory Networks , Risk FactorsABSTRACT
Understanding consumers' sensory preferences for dairy products is essential. This study employed sensory analysis and instrumental techniques to analyze the flavor of pasteurized milk and ultra-high temperature (UHT) milk. There were 6 milk samples with similar fat content (4.0-4.6 g/100mL) and protein content (3.2-3.8 g/100mL). Sensory data from consumer tests was collected using CATA (n = 100) and 9-point hedonic preferences. Research showed that Chinese consumers could distinguish the flavor of the 2 types of milk, and UHT milk showed a higher preference score, which may be due to the more pronounced milky flavor and sweet taste of UHT milk. A total of 48 aroma-active compounds were sniffed through GC × GC-O-TOF-MS, among which 11 were determined as key aroma-active compounds. Correlation analysis showed that milky odor, sweetness, and aftertaste-milky were positively correlated with γ-dodecalactone and γ-nonanolactone. Cooked and oxidized taste were positively correlated with 1-octen-3-ol and E-2-octenal. This study is important for developing Chinese dairy products and exporting dairy products to China by multinational companies.
ABSTRACT
The traditional production mode of the sericulture industry is no longer suitable for the development requirements of modern agriculture; to facilitate the sustainable development of the sericulture industry, factory all-age artificial diet feeding came into being. Understanding the structural characteristics and properties of silk fibers obtained from factory all-age artificial diet feeding is an important prerequisite for application in the fields of textiles, clothing, biomedicine, and others. However, there have been no reports so far. In this paper, by feeding silkworms with factory all-age artificial diets (AD group) and mulberry leaves (ML group), silk fibers were obtained via two different feeding methods. The structure, mechanical properties, hygroscopic properties, and degradation properties were studied by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Structurally, no new functional groups appeared in the AD group. Compared with the ML group, the structure of the two groups was similar, and there was no significant difference in mechanical properties and moisture absorption. The structure of degummed silk fibers is dominated by crystalline regions, but α-chymotrypsin hydrolyzes the amorphous regions of silk proteins, so that after 28 d of degradation, the weight loss of both is very small. This provides further justification for the feasibility of factory all-age artificial diets for silkworms.
Subject(s)
Bombyx , Silk , Animals , Silk/chemistry , Bombyx/chemistry , X-Ray Diffraction , Spectroscopy, Fourier Transform Infrared , Thermogravimetry , Morus/chemistryABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and approximately 5% of patients with chronic pancreatitis (CP) inevitably develop PDAC. This study aims explore the key gene regulation involved in the progression of CP to PDAC, with a particular emphasis on the function of lncRNAs. RESULTS: A total of 103 pancreatic tissue samples collected from 11 to 92 patients with CP and PDAC, respectively, were included in this study. After normalizing and logarithmically converting the original data, differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEGs) in each dataset were selected. To determine the main functional pathways of differential mRNAs, we further annotated DEGs using gene ontology (GO) and analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. In addition, the interaction between lncRNA-miRNA-mRNA was clarified and the protein-protein interaction (PPI) network was constructed to screen for key modules and determine hub genes. Finally, quantitative real-time polymerase chain reaction (qPCR) was used to detect the changes in non-coding RNAs and key mRNAs in the pancreatic tissues of patients with CP and PDAC. In this study, 230 lncRNAs and 17,668 mRNAs were included. There were nine upregulated lncRNAs and 188 downregulated lncRNAs. Furthermore, 2334 upregulated differential mRNAs and 10,341 downregulated differential mRNAs were included in the enrichment analysis. From the KEGG enrichment analysis, cytokine-cytokine receptor interaction, calcium signaling pathway, cAMP signaling pathway, and nicotine addiction exhibited significant differences. Additionally, a total of 52 lncRNAs, 104 miRNAs, and 312 mRNAs were included in the construction of a potential lncRNA-miRNA-mRNA regulatory network. PPI network was established and two of the five central DEGs were created in this module, suggesting that lysophosphatidic acid receptor 1 (LPAR1) and regulator of calcineurin 2 (RCAN2) may play significant roles in the progression from CP to PDAC. Finally, the PCR results suggested that LINC01547/hsa-miR-4694-3p/LPAR1 and LINC00482/hsa-miR-6756-3p/RCAN2 play important roles in the carcinogenesis process of CP. CONCLUSION: Two signaling axes critical in the progression of CP to PDAC were screened out. Our findings will be useful for novel insights into the molecular mechanism and potential diagnostic or therapeutic biomarkers for CP and PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , MicroRNAs , Pancreatic Neoplasms , Pancreatitis, Chronic , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Pancreatitis, Chronic/genetics , MicroRNAs/genetics , Pancreatic NeoplasmsABSTRACT
INTRODUCTION AND HYPOTHESIS: International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS) is a simple and effective questionnaire for evaluating vaginal symptoms, sexual problems and the quality of life (QOL) in patients. This study was aimed at validating the simplified Chinese version of the ICIQ-VS. METHODS: A total of 120 women with pelvic organ prolapse (POP) stage <2, 124 with stage ≥ 2, and 51 patients who underwent POP surgery (POP stage ≥2) were included. Cronbach's alpha coefficient and intraclass correlation coefficient (ICC) were used for reliability analysis. We used the content validity index, Kruskal-Wallis H test, and Mann-Whitney U test to study validity. Paired sample t test, Wilcoxon signed-rank test, effect size and standardized response mean were used to assess sensitivity. RESULTS: The Cronbach's alpha coefficients of the vaginal symptoms score (VSS) and sexual matters score (SMS) were 0.787 and 0.861 respectively. The test-retest reliabilities of the VSS, SMS, and QOL score were 0.830, 0.894, and 0.948 respectively. The test-retest reliability was from good to excellent (ICC 0.669-0.948). The item-level content validity index was 0.60 to 1.00. The scale-level content validity index/universal agreement was 0.95, and the scale-level content validity index/average was 0.96. Significant score differences existed between the symptomatic and asymptomatic groups (p < 0.001). Criterion validity was significant (p < 0.001). VSS and QOL score had high sensitivity (p < 0.001, effect size and standardized response mean >0.8). CONCLUSIONS: The simplified Chinese version of the ICIQ-VS can objectively and reliably access vaginal symptoms, sexual matters, and QOL in Chinese women.
Subject(s)
Quality of Life , Urinary Incontinence , Humans , Female , Reproducibility of Results , Urinary Incontinence/diagnosis , Surveys and Questionnaires , Referral and ConsultationABSTRACT
Guishan goats, a unique goat breed in Yunnan Province, have a long history and representation, but their whey protein and function remain unclear. In this study, we carried out a quantitative analysis of the Guishan and Saanen goat whey proteome using a label-free proteomic approach. A total of 500 proteins were quantified from the 2 kinds of goat whey proteins, including 463 common proteins, 37 uniquely expressed whey proteins (UEWP), and 12 differentially expressed whey proteins (DEWP). Bioinformatics analysis indicated that UEWP and DEWP were mainly involved in cellular and immune system processes, membrane, and binding. In addition, UEWP and DEWP in Guishan goats participated primarily in metabolism and immune-related pathways, whereas Saanen goat whey proteins were associated mostly with environmental information processing-related pathways. Guishan goat whey promoted the growth of RAW264.7 macrophages more than Saanen goat whey, and significantly reduced the production of nitric oxide in lipopolysaccharide-stimulated RAW264.7 cells. This study provides a reference for further understanding these 2 goat whey proteins and finding functional active substances from them.
Subject(s)
Milk , Proteomics , Animals , Milk/chemistry , Whey Proteins/chemistry , China , Proteome/metabolism , Goats/metabolism , Metabolic Networks and Pathways , Milk Proteins/analysisABSTRACT
Estrogen-related receptor α (ERRα), a member of nuclear receptors (NRs), plays a role in the regulation of cellular energy metabolism and is reported to be a novel potential target for type 2 diabetes therapy. To date, only a few agonists of ERRα have been identified to improve insulin sensitivity and decrease blood glucose levels. Herein, the discovery of novel potent agonists of ERRα determined using a combined virtual screening approach is described. Molecular dynamics (MD) simulations were used to obtain structural ensembles that can consider receptor flexibility. Then, an efficient virtual screening strategy with a combination of similarity search and ensemble docking was performed against the Enamine, SPECS, and Drugbank databases to identify potent ERRα agonists. Finally, a total of 66 compounds were purchased for experimental testing. Biological investigation of promising candidates identified seven compounds that have activity against ERRα with EC50 values ranging from 1.11 to 21.70 µM, with novel scaffolds different from known ERRα agonists until now. Additionally, the molecule GX66 showed micromolar inverse activity against ERRα with an IC50 of 0.82 µM. The predicted binding modes showed that these compounds were anchored in ERRα-LBP via interactions with several residues of ERRα. Overall, this study not only identified the novel potent ERRα agonists or an inverse agonist that would be the promising starting point for further exploration but also demonstrated a successful molecular dynamics-guided approach applicable in virtual screening for ERRα agonists.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Molecular Dynamics Simulation , Receptors, Estrogen/metabolism , ERRalpha Estrogen-Related ReceptorABSTRACT
Adolescents may have educational aspirations that are different from their parents' educational aspirations for them, and such discrepancy may affect adolescents' psychological adjustment. This longitudinal study examined how parent-child discrepancy in educational aspirations relate to depressive symptoms in early adolescents, both concurrently and prospectively, when controlling for parents' depressive symptoms. Moreover, parent and child gender differences in the effects were explored. Data were collected from 3799 students (52.0% boys; Mage = 10.78) and their fathers and mothers when the students were in fifth and seventh grade over 2 years. Polynomial regression with response surface analysis was used to analyze the effects of parent-child aspiration discrepancy on depressive symptoms separately in four parent-child gender dyads. Cross-sectional results demonstrated that for all parent-child gender dyads, congruently higher aspirations were related to lower depressive symptoms, and greater incongruence in aspirations was related to higher depressive symptoms. Moreover, for parent-son dyads, adolescents whose aspirations were lower than those of their parents reported higher depressive symptoms than adolescents whose aspirations were higher than those of their parents. However, longitudinal results further showed that, for father-son dyads only, congruently higher aspirations were related to increased depressive symptoms over time, while for parent-daughter dyads only, greater incongruence in aspirations was related to increased depressive symptoms over time. The findings support the importance of considering parent-child discrepancy when exploring the role of educational aspirations in adolescents' psychological adjustment and call for a more detailed and rigorous analysis and interpretation of this relationship.
Subject(s)
Depression , Parent-Child Relations , Adolescent , Child , Cross-Sectional Studies , Depression/psychology , Educational Status , Female , Humans , Longitudinal Studies , Male , Parents/psychologyABSTRACT
OBJECTIVE: This study examined the relationship between sociodemographic characteristics and maternal health use from a policy perspective. It aimed to provide an overview of maternal health in Heilongjiang's rural provinces and its implications on rural areas in countries with low and middle income gross domestic products. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Fifth Health Service Survey of Heilongjiang Province. Participants included 481 mothers who delivered a baby after August 15, 2008. Trained investigators collected data on their family and sociodemographic characteristics, antenatal care, delivery at specialised obstetric institutions (e.g. hospitals, clinics, other medical institutions), and postnatal care services. RESULTS: The number of women with more than five antenatal care visits and the delivery rate at specialised obstetric institutions were high. Approximately 50% of the participants had three or more postnatal care visits. Maternal healthcare use among women less than 20 years old and those with natural deliveries were higher. There were fewer antenatal care visits among women who had been pregnant once or twice before. CONCLUSIONS: Delivery rates at specialised obstetric institutions and the number of antenatal care visits were higher than the World Health Organization requirements, while the frequency of postnatal care visits were better than most countries. This study identified several demographic characteristics that influenced maternal health service use. Policymakers should consider these findings when developing maternal health policies that protect women's interests and expand free services. Additional resources should be given to increase the postnatal care capacity and quality of maternal healthcare.
Subject(s)
Maternal Health Services/statistics & numerical data , Rural Population/statistics & numerical data , Social Determinants of Health , Adult , China , Cross-Sectional Studies , Female , Health Surveys , Humans , Mothers/statistics & numerical data , Pregnancy , Quality of Life , Young AdultABSTRACT
PURPOSE: Physicians and Standardised Residency Training physicians (SRTPs) have relatively high exposure to psychological violence. Its adverse effects are far greater than those of physical violence. However, no previous research has paid attention to the problem of psychological violence among them. This study aims to evaluate the extent, characteristics, and risk factors of psychological violence among SRTPs in comparison to physicians, and also to highlight the psychological violence experienced by SRTPs and suggest preventive measures. METHODS: A cross-sectional survey was conducted in northern China. 884 physicians and 537 SRTPs completed a questionnaire which compiled by the ILO, ICN, WHO and PSI in 2003 to measure violence in the workplace. Descriptive statistics and logistic regression analysis were used to analyse results. RESULTS: The effective response rates of physicians and SRTPs were 63.1%(884/1400) and 86.3%(537/622) respectively. 73.0%(645/884) of physicians and 24.8%(133/537) of SRTPs suffered psychological violence in the past year. Compared to physicians (29/645, 4.5%), SRTPs (42/133, 31.6%) experience more internal violence. Further, after experiencing psychological violence, physicians are willing to talk to family and friends, but SRTPs generally take no action. Shift work was a risk factor for both physicians (OR 1.440, 95% CI 1.014-2.203) and SRTPs (OR 1.851, 95% CI 1.217-2.815) suffering from psychological violence. In contrast, no anxiety symptoms protected physicians (OR 0.406, 95% CI 0.209-0.789) and SRTPs (OR 0.404, 95% CI 0.170-0.959) against psychological violence. CONCLUSIONS: SRTPs and physicians in northern China have a high risk of experiencing psychological violence, and physicians experience more. Meanwhile, there are obvious differences in responses to psychological violence and risk factors between them. Therefore, medical institutions should pay more attention to psychological violence, especially among SRTPs, such as supporting the reporting of psychological violence, strengthening team relationships, and providing psychological comfort and counselling. Trial registration number (Project Identification Code: HMUIRB20160014), Registered May 10, 2016.
Subject(s)
Bullying/psychology , Internship and Residency , Physicians/psychology , Workplace Violence/psychology , Adult , Bullying/statistics & numerical data , China , Cross-Sectional Studies , Female , Humans , Male , Occupational Stress/psychology , Quality of Life , Risk Factors , Surveys and Questionnaires , Workplace Violence/statistics & numerical dataSubject(s)
Autoimmune Diseases , Hypertension , Interleukin-17 , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Blood Pressure/drug effects , Hypertension/drug therapy , Hypertension/physiopathology , Hypertension/immunology , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
Interleukin-17 (IL-17), a pivotal cytokine in immune regulation, has attracted significant attention in recent years due to its roles in various physiological and pathological processes. This review explores IL-17 in immunological context, emphasizing its structure, production, and signaling pathways. Specifically, we explore its involvement in inflammatory diseases and autoimmune diseases, with a notable focus on its emerging implications in cardiovascular system. Through an array of research insights, IL-17 displays multifaceted functions yet awaiting comprehensive discovery. Highlighting therapeutic avenues, we scrutinize the efficacy and clinical application of four marketed IL-17 mAbs along other targeted therapies, emphasizing their potential in immune-mediated disease management. Additionally, we discussed the novel IL-17D-CD93 axis, elucidating recent breakthroughs in their biological function and clinical implications, inviting prospects for transformative advancements in immunology and beyond.
Subject(s)
Autoimmune Diseases , Cardiovascular Diseases , Interleukin-17 , Humans , Interleukin-17/immunology , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Cardiovascular Diseases/immunology , Cardiovascular Diseases/therapy , Signal Transduction , Inflammation/immunology , Cardiovascular System/immunology , Antibodies, Monoclonal/therapeutic useABSTRACT
Foods rich in carbohydrates or fats undergo the Maillard reaction during frying, which promotes the color, flavor and sensory characteristics formation. In the meanwhile, Maillard reaction intermediates and advanced glycation end products (AGEs) have a negative impact on food sensory quality and gut homeostasis. This negative effect can be influenced by food composition and other processing factors. Whole grain products are rich in polyphenols, which can capture carbonyl compounds in Maillard reaction, and reduce the production of AGEs during frying. This review summarizes the Maillard reaction production intermediates and AGEs formation mechanism in fried food and analyzes the factors affecting the sensory formation of food. In the meanwhile, the effects of Maillard reaction intermediates and AGEs on gut homeostasis were summarized. Overall, the innovative processing methods about the Maillard reaction are summarized to optimize the sensory properties of fried foods while minimizing the formation of AGEs.
Subject(s)
Glycation End Products, Advanced , Maillard Reaction , Food , Polyphenols , HomeostasisABSTRACT
The evidence regarding the effects of blood pressure changes on older individuals remains inconclusive, and the impact of frailty throughout the life course is not known. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality. Participants included 7335 persons from 2008 to 2014 of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Change in blood pressure was calculated as the difference between follow-up and baseline. Frailty was evaluated using a 40-item frailty index. Mortality status was ascertained up to December 31, 2014. The mean age of participants was 82.6 ± 10.7 years. The optimal blood pressure level (SBP, 130-150 mmHg; DBP, 70-90 mmHg) was associated with the lowest risk of frailty while decreasing follow-up SBP and DBP were significantly correlated with frailty. Lower baseline blood pressure levels (SBP < 130 mmHg; DBP < 70 mmHg) were associated with decreased mortality risk when participants increased their blood pressure to optimal levels during follow-up SBP and DBP (0.78, 0.63-0.98), compared to maintaining a steady low SBP (< 130 mmHg) and DBP (< 70 mmHg). For those with DBP around 70-90 mmHg, decreasing follow-up DBP (< 70 mmHg) was associated with higher mortality (1.23, 1.07-1.42) compared to maintaining stable follow-up DBP (70-90 mmHg). These results remain significant after adjusting for frailty. Optimal blood pressure levels were associated with the lowest risk of frailty. The association between lower blood pressure and increased mortality risk persisted even after accounting for frailty. We used a nationally representative longitudinal cohort study by using 2008-2014 of the Chinese Longitudinal Healthy Longevity in China. Change in blood pressure was calculated as the difference between follow-up and baseline. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality.
Subject(s)
Blood Pressure , Frailty , Humans , Male , Female , Blood Pressure/physiology , Aged , China/epidemiology , Frailty/mortality , Aged, 80 and over , Longitudinal Studies , Cohort Studies , Hypertension/mortality , Hypertension/physiopathology , Risk Factors , Longevity , Frail Elderly/statistics & numerical data , MortalityABSTRACT
OBJECTIVES: Diabetic cardiomyopathy (DCM) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients, with its underlying mechanisms still elusive. This study aims to investigate the role of cholesterol-25-monooxygenase (CH25H) in T2DM induced cardiomyopathy. METHODS: High fat diet combined with streptozotocin (HFD/STZ) were used to establish a T2DM model. CH25H and its product 25-hydroxycholesterol (25HC) were detected in the hearts of T2DM model. Gain- or loss-of-function of CH25H were performed by receiving AAV9-cTNT-CH25H or CH25H knockout (CH25H-/-) mice with HFD/STZ treatment. Cardiac function was evaluated using echocardiography, and cardiac tissues were collected for immunoblot analysis, histological assessment and quantitative polymerase chain reaction (qPCR). Mitochondrial morphology and function were evaluated using transmission electron microscopy (TEM) and Seahorse XF Cell Mito Stress Test Kit. RNA-sequence analysis was performed to determine the molecular changes associated with CH25H deletion. RESULTS: CH25H and 25HC were significantly decreased in the hearts of T2DM mice. CH25H-/- mice treated with HFD/STZ exhibited impaired mitochondrial function and structure, increased lipid accumulation, and aggregated cardiac dysfunction. Conversely, T2DM mice receiving AAV9-CH25H displayed cardioprotective effects. Mechanistically, RNA sequencing and qPCR analysis revealed that CH25H deficiency decreased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target gene expression. Additionally, administration of ZLN005, a potent PGC-1α activator, partially protected against high glucose and palmitic acid induced mitochondria dysfunction and lipid accumulation in vitro. CONCLUSION: Our study provides compelling evidence supporting the protective role of CH25H in T2DM-induced cardiomyopathy. Furthermore, the regulation of PGC-1α may be intricately involved in this cardioprotective process.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Diabetic Cardiomyopathies , Mice, Knockout , Animals , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/prevention & control , Diabetic Cardiomyopathies/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Mice , Male , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Steroid Hydroxylases/metabolism , Steroid Hydroxylases/genetics , Diet, High-Fat/adverse effects , Mice, Inbred C57BL , Hydroxycholesterols/metabolism , Myocardium/metabolism , Myocardium/pathology , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/geneticsABSTRACT
Background: Anterior cruciate ligament (ACL) injuries are closely associated with knee osteoarthritis (OA). However, diagnosing ACL injuries based on knee magnetic resonance imaging (MRI) has been subjective and time-consuming for clinical doctors. Therefore, we aimed to devise a deep learning (DL) model leveraging MRI to enable a comprehensive and automated approach for the detection of ACL injuries. Methods: A retrospective study was performed extracting data from the Osteoarthritis Initiative (OAI). A total of 1,589 knees (comprising 1,443 intact, 90 with partial tears, and 56 with full tears) were enrolled to construct the classification model. This one-stop detection pipeline was developed using a tailored YOLOv5m architecture and a ResNet-18 convolutional neural network (CNN) to facilitate tasks based on sagittal 2-dimensional (2D) intermediate-weighted fast spin-echo sequence at 3.0T. To ensure the reliability and robustness of the classification system, it was subjected to external validation across 3 distinct datasets. The accuracy, sensitivity, specificity, and the mean average precision (mAP) were utilized as the evaluation metric for the model performance by employing a 5-fold cross-validation approach. The radiologist's interpretations were employed as the reference for conducting the evaluation. Results: The localization model demonstrated an accuracy of 0.89 and a sensitivity of 0.93, achieving a mAP score of 0.96. The classification model demonstrated strong performance in detecting intact, partial tears, and full tears at the optimal threshold on the internal dataset, with sensitivities of 0.941, 0.833, and 0.929, specificities of 0.925, 0.947, and 0.991, and accuracies of 0.940, 0.941, and 0.989, respectively. In comparison, on a subset consisting of 171 randomly selected knees from the OAI, the radiologists demonstrated a sensitivity ranging between 0.660 and 1.000, specificity ranging between 0.691 and 1.000, and accuracy ranging between 0.689 and 1.000. On a subset consisting of 170 randomly selected knees from the Chinese dataset, the radiologists exhibited a sensitivity ranging between 0.711 and 0.948, specificity ranging between 0.768 and 0.977, and accuracy ranging between 0.683 and 0.917. After retraining, the model achieved sensitivities ranging between 0.630 and 0.961, specificities ranging between 0.860 and 0.961, and accuracies ranging between 0.832 and 0.951, respectively, on the external validation dataset. Conclusions: The proposed model utilizing knee MRI showcases robust performance in the domains of ACL localization and classification.