In recent years, the incidence of autism spectrum disorder (ASD) has increased, but the etiology and pathogenesis remain unclear. In this narrative review, we review and systematically summarize the methods used to construct animal models to study ASD and the related behavioral studies based on recent literature. Utilization of various ASD animal models can complement research on the etiology, pathogenesis, and core behaviors of ASD, providing information and a foundation for further basic research and clinical treatment of ASD.
Autism Spectrum Disorder , Animals , Autism Spectrum Disorder/genetics , Models, Animal
Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.
With the increasing number of diabetic patients in the world, there is an urgent requirement to reduce the incidence of diabetes. It is considered that a viable prophylactic treatment for type 2 diabetes mellitus is to reduce starch digestibility and oxidative stress. In this study, a novel type of slowly digested starch [pea starch (PS)-gingerol complex] was fabricated to evaluate its in vitro enzymatic digestibility and antioxidant activities. Theoretical and experimental analyses showed that PS can encapsulate gingerols with long alkyl chains to form starch-gingerol complexes, which are further stacked into a mixture of V6- and V7-crystallites. These complexes, in particular the PS-10-gingerol complex, showed high resistance to amylolysis and good antioxidant activities. This study demonstrates that these novel starch-gingerol complexes have the potential to deliver antioxidants encapsulated in starch with slow-digesting properties and reduce oxidative stress. Moreover, this new type of slowly digested starch with antioxidant properties showed great potential in the prevention of type 2 diabetes.
Nutrient reduction is an essential environmental policy for water quality remediation, but climate change can offset the ecological benefits of nutrient reduction and lead to the difficulty of environmental evaluation. Here, based on the records of three lipid microalgal biomarkers and stable isotopes of carbon and nitrogen in two sediment cores from the embayment of Perth, Australia, we reconstructed the microalgal biomasses (diatoms, dinoflagellates and coccolithophores) over the past century and evaluated the ecological effects of nutrient reduction on them, using Change Point Modeling (CPM) and redundancy analysis (RDA). The CPM result showed that total microalgal biomarkers increased by 25% and 51% in deep and shallow areas, respectively, due to nutrient enrichment caused by industrial wastewater in the 1950s and the causeway construction in the 1970s, and dinoflagellates were beneficiaries of eutrophication. The nutrient reduction policy since the 1980s had not decreased total microalgal biomass, and diatoms were beneficiaries of this period. RDA based on time series of sediment cores and water monitoring data revealed that the increase of sea-surface temperature and the decrease of rainfall since the 1980s may be important factors sustaining the high total microalgal biomass and increasing the degree of diatom dominance. The result also indicated that the variations of microalgal assemblages may better explain the effect of nutrient reduction rather than total microalgal biomass.
Bipolar affective disorder refers to a category of mood disorders characterized clinically by the presence of both manic or hypomanic episodes and depressive episodes. Lithium stands out as the primary pharmacological intervention for managing bipolar affective disorder. However, its therapeutic dosage closely approaches toxic levels. Toxic symptoms appear when the blood lithium concentration surpasses 1.4 mmol/L, typically giving rise to gastrointestinal and central nervous system reactions. Cardiac toxicity is rare but serious in cases of lithium poisoning. The study reports a case of a patient with bipolar affective disorder who reached a blood lithium concentration of 6.08 mmol/L after the patient took lithium carbonate sustained-release tablets beyond the prescribed dosage daily and concurrently using other mood stabilizers. This resulted in symptoms such as arrhythmia, shock, impaired consciousness, and coarse tremors. Following symptomatic supportive treatment, including blood dialysis, the patient's physical symptoms gradually improved. It is necessary for clinicians to strengthen the prevention and recognition of lithium poisoning.
Hemodynamics , Lithium , Humans , Anticonvulsants , Arrhythmias, Cardiac/chemically induced , Central Nervous System
Objective:By analyzing and summarizing the relationship between anaerobic capacity, technical changes of 100m breaststroke en route and speed changes of short distance breaststroke athletes, the interrelationship and internal pathways between the three are revealed to provide reference for improving athletic performance of short distance breaststroke athletes and provide theoretical basis for anaerobic capacity training.Method:Fifteen male short-distance breaststroke athletes (age 19.67±2.61 years, height 178.4±7.04 cm, weight 71.6±7.79 kg) were selected to perform anaerobic power cycling and 100 m breaststroke tests on the upper and lower extremities. The correlations and intrinsic linkage pathways between the three were explored by calculating Pearson correlation coefficients and using a mediating effects model.Result:Significant differences existed in speed, stroke rate, cycle time per stroke, and swim efficiency index in the 100 m breaststroke all-out test. There were significant correlations between the rate of anaerobic power decrease in the upper limb and the changes in stroke amplitude, cycle time per stroke, and speed. There were significant correlations between the change in mean stroke rate, the change in cycle time per stroke, the change in swim efficiency index and the change in speed. Anaerobic power indirectly influenced the speed variation during the en-route swim, which was mediated by the technical variation in cycle time per stroke.Conclusion:The upper limb anaerobic fatigue resistance of short distance breaststroke athletes is a key factor affecting the technique and speed stability of the 100m breaststroke en route, and the rate of decline in upper limb anaerobic power leads to a decrease in speed by affecting the change in time per stroke cycle. (AU)
Humans , Exercise , Athletes , Walking Speed , Respiratory Rate , Swimming
Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
OBJECTIVE: To investigate the therapeutic efficacy of scalp acupuncture combined with repetitive transcranial magnetic stimulation (rTMS) for post-stroke cognitive impairment at different time intervals. METHOD: This retrospective cohort study divided patients into two groups according to the timing of the scalp acupuncture combined with rTMS intervention. Group A received scalp acupuncture combined with rTMS at 1 month post-stroke and routine basic treatment and cognitive function training at two months post-stroke. Group B received routine basic treatment and cognitive function training at 1 month post-stroke and scalp acupuncture combined with rTMS at 2 months post-stroke. Both groups underwent cognitive assessment using the Montreal Cognitive Assessment (MoCA) before treatment and at the ends of the first and second months post-stroke. RESULTS: The study population included 92 total stroke patients divided evenly into Groups A and B. Group A's total scores were higher at the end of the first month of treatment compared with baseline and remained stable at the end of the second month of treatment. By contrast, Group B's total score remained stable at the end of the first month of treatment compared with baseline and increased by the end of the second month. There were no significant differences in the scores at baseline or the end of the second month between the two groups. CONCLUSION: Scalp acupuncture combined with rTMS can effectively treat cognitive function in patients with post-stroke cognitive impairment, regardless of the timing of the intervention.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion, and progression of nonmelanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic CpG methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamine metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate, and thiamine metabolism during the promotion phase; and beta-alanine and pathothenate CoA biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic, and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibited PIEZO2, but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analogue carbocyclic phosphatidic acid (ccPA) also inhibited PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibited PIEZO2, but not PIEZO1. Conversely, inhibiting PLD led to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity.
Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.
Carcinoma, Hepatocellular , Daphne , Diterpenes , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Proliferation , Daphne/chemistry , Diterpenes/pharmacology , Diterpenes/chemistry , Liver Neoplasms/drug therapy , Molecular Docking Simulation , Oxadiazoles/chemistry , Oxadiazoles/pharmacology
Background: CD36 deficiency is closely associated with fetal/neonatal alloimmune thrombocytopenia, platelet transfusion refractoriness, and other hemorrhage disorders, particularly in Asian and African populations. There is a clinical need for rapid and high-throughput methods of platelet CD36 (pCD36) phenotyping to improve the availability of CD36 typing of donors and assist clinical blood transfusions for patients with anti-CD36 antibodies. Such methods can also support the establishment of databases of pCD36-negative phenotypes. Study Design and Methods: A sandwich enzyme-linked immunosorbent assay (ELISA) for CD36 phenotyping of human platelets was developed using anti-CD36 monoclonal antibodies. The reliability of the assay was evaluated by calculating the intra-assay and inter-assay coefficients of variation (CV). A total of 1,691 anticoagulant whole blood samples from healthy blood donors were randomly selected. PCD36 expression was measured using a sandwich ELISA. PCD36 deficiency was confirmed by flow cytometry (FC). Mutations underlying pCD36 deficiency were identified using polymerase chain reaction sequence-based typing (PCR-SBT). Results: The sandwich ELISA for pCD36 phenotyping had high reliability (intra-assay CV, 2.1-4.8%; inter-assay CV, 2.3-5.2%). The sandwich ELISA was used to screen for CD36 expression on platelets isolated from 1,691 healthy blood donors. Of these, 36 samples were pCD36-negative. FC demonstrated absence of CD36 expression on monocytes in three of the 36 cases. In the present study population, the frequency of CD36 deficiency was 2.13% (36/1,691), of which 0.18% (3/1,691) was type I deficiency and 1.95% (33/1,691) was type II deficiency. In addition, we used PCR-SBT to characterize the gene mutations in exons 3-14 of the CD36 gene in 27 cases of CD36 deficiency and discovered 10 types of mutations in 13 pCD36-negative samples. Conclusion: The present study describes the development and characterization of a highly reliable sandwich ELISA for high-throughput screening for pCD36 expression. This novel method is feasible for clinical applications and provides a useful tool for the establishment of databases of pCD36-negative phenotype donors.
Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.
Objective: With the arrival of the experience economy era, changes in the marketing environment, and the evolution of consumer psychological needs, a good user experience will bring them freshness. Based on user experience, this paper analyzes the relationship among product brand image, brand trust, and brand loyalty, aiming to promote product values and improve brand loyalty and trust. Methods: Through case analysis, consumers' favorite brands were selected and conducted positioning analysis on brand color, image, package form, and so on. The study proposed a hypothetical model of user experience on brand loyalty and performed a questionnaire survey on 357 consumers. The relational model of the impact of user experience on consumers was verified using the SEM (Structural Equation Model) method. Results: It is shown that sensory experience, emotional experience, behavioral experience, and thinking experience have significant impacts on brand image; brand image apparently affects brand trust; and brand trust and image remarkably influence brand loyalty. Conclusions: Extending the concept of user experience to the fast-moving consumer goods industry will contribute to the package design of products and the theory and practice of brand loyalty. The research findings can provide effective strategies and approaches for marketers to improve product market competitiveness and enhance consumer brand stickiness.
BACKGROUND: The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer. RESEARCH DESIGN AND METHODS: Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation. RESULTS: In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice. CONCLUSIONS: We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.
Extracellular Vesicles , MicroRNAs , Uterine Cervical Neoplasms , Animals , Mice , Female , Humans , Uterine Cervical Neoplasms/genetics , Mice, Nude , Angiogenesis , Endothelial Cells , MicroRNAs/genetics , Cell Proliferation/genetics , Cell Line, Tumor
Light-absorbing organic aerosols, referred to as brown carbon (BrC), play a vital role in the global climate and air quality. Due to the complexity of BrC chromophores, the identified absorbing substances in the ambient atmosphere are very limited. However, without comprehensive knowledge of the complex absorbing compounds in BrC, our understanding of its sources, formation, and evolution mechanisms remains superficial, leading to great uncertainty in climatic and atmospheric models. To address this gap, we developed a constrained non-negative matrix factorization (NMF) model to resolve the individual ultraviolet-visible spectrum for each substance in dissolved organic aerosols, with the power of ultrahigh-performance liquid chromatography-diode array detector-ultrahigh-resolution mass spectrometry (UHPLC-DAD-UHRMS). The resolved spectra were validated by selected standard substances and validation samples. Approximately 40,000 light-absorbing substances were recognized at the MS1 level. It turns out that BrC is composed of a vast number of substances rather than a few prominent chromophores in the urban atmosphere. Previous understanding of the absorbing feature of BrC based on a few identified compounds could be biased. Weak-absorbing substances missed previously play an important role in BrC absorption when they are integrated due to their overwhelming number. This model brings the property exploration of complex dissolved organic mixtures to a molecular level, laying a foundation for identifying potentially significant compositions and obtaining a comprehensive chemical picture.
The humpback grouper (Cromileptes altivelis), a medium-sized coral reef teleost, is a naturally rare species distributed in the tropical waters of the Indian and Pacific Oceans. It has high market value, but artificial reproduction and breeding remain limited and need to be improved. Here, we assembled the genome with 1.08 Gb, with a contig N50 of 43.78 Mb. A total of 96.59% of the assembly anchored to 24 pseudochromosomes using Hi-C technology. It contained 24,442 protein-coding sequences, of which 99.3% were functionally annotated. The completeness of the assembly was estimated to be 97.3% using BUSCO. The phylogenomic analysis suggested that humpback grouper should be classified into the genus Epinephelus rather than Cromileptes. The comparative genomic analysis revealed that the gene families related to circadian entrainment were significantly expanded. The high-quality reference genome provides useful genomic tools for exploiting the genomic resource of humpback grouper and supports the functional genomic study of this species in the future.
Bass , Genome , Animals , Chromosomes , Open Reading Frames
Coastal seas receive and store large amounts of organic carbon (OC) from land and ocean, thereby playing a crucial role in the global carbon cycle. Understanding factors that influencing OC sources and burial efficiencies in coastal areas have been challenging. We selected the Jiaozhou Bay (JZB) and its surrounding rivers heavily affected by human activities as a case study small bay. We presented bulk parameters of grain size, sediment surface area (SSA), TOC content and carbon isotopes (δ13Corg and Δ14Corg), terrestrial biomarkers (∑C27 + C29 + C31n-alkanes) and marine biomarkers (brassicasterol and dinosterol) in surface sediments and suspended particulates. Our results showed low TOC and biomarker contents in the Dagu River Estuary from the west of the JZB associated with coarse sediments and lower SSA. To estimate the OC proportions, we applied a three-end member mixing model based on TOC δ13Corg and biomarker ratios and obtained the OC contribution from phytoplankton (average 52 %), soil (average 34 %) and wetlands (average 14 %). A transect from east to west of the JZB was selected to further assess the OC age composition based on radiocarbon isotopic (14C) measurements for a new perspective. The lower Δ14Corg values in the east revealed fossil OC contributions from human activities, such as petroleum pollutant inputs from sewage outlets. Based on a dualcarbon isotope (δ13Corg and Δ14Corg) mass balance mixing model, the OC contributions were 40 %, 34 %, 14 %, 12 % from fossil carbon, phytoplankton, wetlands and soil, respectively. The very high burial efficiency of fossil OC in JZB (111 ± 19 %) indicated that small bays such as the JZB could be an important sedimentary carbon sink.
Naturally aged microplastics (NAMPs) and arsenic (As) have been reported to coexist in and threaten potentially to soil-plant ecosystem. The research explored the combined toxic effects of NAMPs and As to lettuce (Lactuca sativa L.) growth, and the distribution, accumulation and bioavailability of As in soil aggregates. The As contaminated soil with low, medium and high concentrations (L-As, M-As, H-As) were treated with or without NAMPs, and a total of six treatments. The results displayed that, in comparison to separate treatments of L-As and M-As, the presence of NAMPs increased the total biomass of lettuce grown at these two As concentrations by 68.9 % and 55.4 %, respectively. Simultaneous exposure of NAMPs and L-As or M-As led to a decrease in As content in shoot (0.45-2.17 mg kg-1) and root (5.68-14.66 mg kg-1) of lettuce, indicating an antagonistic effect between them. In contrast, co-exposure to H-As and NAMPs showed synergistic toxicity, and the leaf chlorophyll and nutritional quality of lettuce were also reduced. NAMPs altered the ratio of different soil aggregate fractions and the distribution of bioavailable As within them, which influenced the absorption of As by lettuce. In conclusion, these direct observations assist us in enhancing the comprehend of the As migration and enrichment characteristics in soil-plant system under the influence of NAMPs.
Arsenic , Soil Pollutants , Arsenic/analysis , Lactuca , Microplastics , Plastics , Soil , Biological Availability , Ecosystem , Soil Pollutants/analysis
