ABSTRACT
The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.
Subject(s)
Amyotrophic Lateral Sclerosis , Ubiquitin-Protein Ligases , Animals , Mice , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/immunology , Endosomal Sorting Complexes Required for Transport/metabolism , Immunity, Innate/genetics , Nucleotidyltransferases/metabolism , Proteolysis , Signal Transduction/physiology , Disease Models, Animal , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/immunology , Ubiquitin-Protein Ligases/metabolismABSTRACT
Natural killer (NK) cells are triggered by the innate immune response in the tumor microenvironment. The extensive set of stimulating and inhibiting receptors mediates the target recognition of NK cells, and controls the strength of the effector reaction countering specific targeted cells. Yet, lacking major MHC (histocompatibility complex) MICA/B class I chain-related proteins on the membrane of tumor cells results in the failure of NK cell recognition and ability to resist NK cell destruction. Searching databases and molecular docking suggested that in cervical cancer, pterostilbene (3,5-dimethoxy-40-hydroxystilbene; PTS) in Vaccinium corymbosum extract could constrain PI3K/AKT signaling and improving the MICA/B expression. In flow cytometry, MTT assay, viability/cytotoxicity assay, and colony development assays, PTS reduced the development of cervical cancer cells and increased apoptosis. The quantitative real-time PCR (qRT-PCR) and a Western blot indicate that PTS controlled the cytolytic action of NK cells in tumor cells via increasing the MICA/B expression, thus modifying the anti-tumor immune response in cervical cancer.
Subject(s)
Proto-Oncogene Proteins c-akt , Uterine Cervical Neoplasms , Female , Humans , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/metabolism , Molecular Docking Simulation , Cell Line, Tumor , Histocompatibility Antigens Class I/genetics , Killer Cells, Natural , Signal Transduction , Cytotoxicity, Immunologic , Tumor MicroenvironmentABSTRACT
A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERß/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression.
Subject(s)
Estrogens , Menopause , Humans , Female , Menopause/immunology , Menopause/metabolism , Estrogens/metabolism , Animals , Depression/immunology , Depression/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Signal Transduction/physiology , Cytokines/metabolismABSTRACT
BACKGROUND: Recently, the hemoglobin to albumin ratio (HAR) has been shown to be closely associated with the survival of certain malignancies. However, its prognostic value in nasopharyngeal carcinoma (NPC) remained to be elucidated. Herein, we aimed to explore the correlation between HAR and overall survival (OS) in NPC patients treated with concurrent chemoradiotherapy (CCRT). METHODS: This retrospective study included a total of 858 patients with NPC receiving CCRT between January 2010 and December 2014 in Sun Yat-sen University Cancer Center. We randomly divided them into the training cohort (N = 602) and the validation cohort (N = 206). We performed univariate and multivariate Cox regression analyses to identify variables associated with OS, based on which, a predictive nomogram was constructed and assessed. RESULTS: In both the training and validation cohorts, patients were classified into low- and high-HAR groups according to the cutoff value determined by the maximally selected rank statistics. This HAR cutoff value effectively divided patients into two distinct prognostic groups with significant differences. Multivariable Cox analysis revealed that higher T-stage, N-stage, and HAR values were significantly related to poorer prognosis in NPC patients and served as independent prognostic factors for NPC. Based on these, a predictive model was constructed and graphically presented as a nomogram, whose predictive performance is satisfactory with a C-index of 0.744 [95%CI: 0.679-0.809] and superior to traditional TNM staging system [C-index = 0.609, 95%CI: 0.448-0.770]. CONCLUSION: The HAR value was an independent predictor for NPC patients treated with CCRT, the predictive model based on HAR with superior predictive performance than traditional TNM staging system might improve individualized survival predictions.
Subject(s)
Chemoradiotherapy , Hemoglobins , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Nomograms , Humans , Male , Female , Middle Aged , Chemoradiotherapy/methods , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/blood , Hemoglobins/analysis , Prognosis , Retrospective Studies , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/blood , Adult , Neoplasm Staging , Aged , Serum Albumin/analysisABSTRACT
BACKGROUND: Although there is a strong correlation between the novel cholesterol-to-lymphocyte ratio (CLR) and tumor survival, its prognostic significance in breast cancer (BC) is unknown. After analyzing the relationship between CLR and the overall survival (OS) of patients with BC, we created a predictive model. METHODS: Following retrospective enrollment, 1316 patients with BC were randomized into two cohorts: validation (n = 392) and training (n = 924). Distinct factors within the training dataset were identified for OS by univariate and multivariate Cox analyses; two-tailed P-value < 0.05 were considered to indicate statistical significance. On this premise, we developed novel signals for survival prediction and utilized the calibration curve, receiver operating characteristic curves, and concordance index (C-index) to validate their efficacy across both datasets. RESULTS: Patients with BC were categorized into two categories with differing prognoses based on the CLR score [hazard ratio = 0.492; 95% confidence interval (CI): 0.286-0.846, P = 0.009]. A prediction nomogram was created based on multivariate analysis, which showed that N stage, postoperative pathological categorization, and CLR score were all independently correlated with OS. In the training [C-index = 0.831 (95% CI: 0.788-0.874)] and validation [C-index = 0.775 (95% CI: 0.694-0.856)] cohorts, the nomogram demonstrated favorable performance in predicting OS. In both the training and validation cohorts, it outperformed the traditional staging system [C-index = 0.702 (95% CI: 0.623-0.782)] and [C-index = 0.709 (95% CI: 0.570-0.847)]. The accurate prediction by the signature was further demonstrated by the time-dependent receiver operating characteristic curves. CONCLUSIONS: The novel immunonutritional marker CLR could function as a simplified, cost-effective, easily accessible, non-invasive, and readily promotive prognostic indicator for patients with early-stage BC and demonstrates superior predictive power than the traditional staging system.
Subject(s)
Breast Neoplasms , Cholesterol , Lymphocytes , Nomograms , Humans , Female , Breast Neoplasms/pathology , Breast Neoplasms/blood , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Prognosis , Middle Aged , Cholesterol/blood , Retrospective Studies , Adult , Aged , ROC Curve , Biomarkers, Tumor/blood , Lymphocyte Count , Neoplasm StagingABSTRACT
Neuroinflammation is a significant pathological event involving the neurodegenerative process associated with many neurological disorders. Diagnosis and treatment of neuroinflammation in its early stage are essential for the prevention and management of neurological diseases. Herein, we designed macrophage membrane-coated photoacoustic (PA) probes (MSINPs), with targeting specificities based on naturally existing target-ligand interactions for the early diagnosis of neuroinflammation. The second near-infrared dye, IR1061, was doped into silica as the core and was encapsulated with a macrophage membrane. In vitro as well as in vivo, the MSINPs could target inflammatory cells via the inflammation chemotactic effect. PA imaging was used to trace the MSINPs in a neuroinflammation mouse model and showed a great targeted effect of MSINPs in the prefrontal cortex. Therefore, the biomimetic nanoprobe prepared in this study offers a new strategy for PA molecular imaging of neuroinflammation, which can enhance our understanding of the evolution of neuroinflammation in specific brain regions.
Subject(s)
Nanoparticles , Photoacoustic Techniques , Animals , Mice , Neuroinflammatory Diseases , Photoacoustic Techniques/methods , Biomimetics , Optical ImagingABSTRACT
The synergistic effect between multicomponent electrode materials often makes them have better lithium storage performance than single-component electrode materials. Therefore, to enhance surface reaction kinetics and encourage electron transfer, using multicomponent anode materials is a useful tactic for achieving high lithium-ion battery performance. In this article, ZnS/ZnO composites were synthesized by solvothermal sulfidation and calcination, with the utilization of metal-organic frameworks acting as sacrificial templates. From the point of material design, both ZnS and ZnO have high theoretical specific capacities, and the synergistic effect of ZnS and ZnO can promote charge transport. From the perspective of electrode engineering, the loose porous carbon skeleton that results from the calcination of metal-organic frameworks can enhance composite material conductivity as well as full electrolyte penetration and the area of contact between the electrolyte and active material, all of which are beneficial to enhancing lithium storage performance. As expected, ZnS/ZnO anode materials displayed remarkably high specific capacities and outstanding performance at different rates. Combining material design and electrode engineering, this paper provides another idea for preparing anode materials with excellent lithium storage properties.
ABSTRACT
Poorly identified tumor boundaries and nontargeted therapies lead to the high recurrence rates and poor quality of life of prostate cancer patients. Near-infrared-II (NIR-II) fluorescence imaging provides certain advantages, including high resolution and the sensitive detection of tumor boundaries. Herein, a cyanine agent (CY7-4) with significantly greater tumor affinity and blood circulation time than indocyanine green was screened. By binding albumin, the absorbance of CY7-4 in an aqueous solution showed no effects from aggregation, with a peak absorbance at 830 nm and a strong fluorescence emission tail beyond 1000 nm. Due to its extended circulation time (half-life of 2.5 h) and high affinity for tumor cells, this fluorophore was used for primary and metastatic tumor diagnosis and continuous monitoring. Moreover, a high tumor signal-to-noise ratio (up to ~ 10) and excellent preferential mitochondrial accumulation ensured the efficacy of this molecule for photothermal therapy. Therefore, we integrated NIR-II fluorescence-guided surgery and intraoperative photothermal therapy to overcome the shortcomings of a single treatment modality. A significant reduction in recurrence and an improved survival rate were observed, indicating that the concept of intraoperative combination therapy has potential for the precise clinical treatment of prostate cancer.
Subject(s)
Carbocyanines , Mitochondria , Neoplasm Recurrence, Local , Photothermal Therapy , Prostatic Neoplasms , Male , Prostatic Neoplasms/diagnostic imaging , Photothermal Therapy/methods , Humans , Animals , Mitochondria/metabolism , Mitochondria/drug effects , Cell Line, Tumor , Carbocyanines/chemistry , Optical Imaging/methods , Mice , Surgery, Computer-Assisted/methods , Fluorescent Dyes/chemistry , Mice, Nude , Mice, Inbred BALB C , Infrared Rays , Indocyanine Green/chemistry , Indocyanine Green/therapeutic use , Indocyanine Green/pharmacologyABSTRACT
Malus toringoides (Rehd.) Hughes, called "Eseye (Ese)," is a traditional medicinal plant from the Tibet province of China that has proven effective in treating cardiac conditions due to its anti-inflammatory, antioxidative, and antiapoptotic properties. In this study, we explored the underlying protective mechanisms of Ese decoction in isoproterenol (ISO)-induced cardiac fibrosis (CF) and established the fact that treatment with an Ese decoction attenuated tissue injury, decreased the release of IL-1ß, IL-18, TNF-α, and caspase-3, and elevated the Bax/Bcl-2 ratio in CF mice. We also found that with Ese treatment damage to the mitochondrial ultrastructure of myocardium was alleviated, and the level of reactive oxygen species was markedly diminished. Ese inhibited the expression of proteins associated with pyroptosis by the HK1/NLRP3 signaling pathway and also improved CF. Due to the anti-inflammatory, antioxidative, and antiapoptotic characteristics of Ese decoction, we found that Ese protected against ISO-induced CF, by inhibiting inflammation and pyroptosis as mediated by the HK1/NLRP3 signaling pathway.
Subject(s)
Inflammation , Isoproterenol , Myocytes, Cardiac , Pyroptosis , Signal Transduction , Animals , Male , Mice , Fibrosis , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/chemically induced , Mice, Inbred C57BL , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , Pyroptosis/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
OBJECTIVES: Although cold stress-induced damage to the heart and thyroid has been reported, specific organ associations between the heart and thyroid with delayed injury mechanisms have not been investigated. In this study, we determined the damage time and transcript levels of a large number of genes in the heart and thyroid after cold exposure. Meanwhile, we analysed the relationship between heart and thyroid injury in human medical records to determine the association of delayed injury from cold exposure. METHODS: Mice were exposed to cold stress and hysteresis injury. Gene changes at the transcriptional level were detected using high throughput sequencing technology. The most variable genes were verified at the protein level using Western Blotting and medical records were collected and analysed. RESULTS: The damage was the most severe when the animals were allowed to recover to room temperature for 4 h after exposure to cold stress. During this process, STAT1 and ATF3 genes were acutely up-regulated. Analysis of human medical records showed the highest correlation between AST and T4 under cold stress (p = 0.0011). CONCLUSIONS: Exposure to cold increases blood level of free thyroid hormone and biomarkers of myocardial injury, as well as related mRNA levels. These changes were more pronounced after return to room temperature.
Subject(s)
Thyroid Gland , Thyroid Hormones , Mice , Animals , Humans , Cold Temperature , Cold-Shock ResponseABSTRACT
The association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) is controversial. HDL-C is one content type of high-density lipoprotein (HDL). HDL consists of diverse proteins and lipids and can be classified into different subclasses based on size, shape, charge, and density, and can change dynamically in disease states. Therefore, HDL-C levels alone cannot represent HDLs' cardioprotective role. In this review, we summarized the methods for separating HDL subclasses, the studies on the association between HDL subclasses and cardiovascular risk (CVR), and the impact of lipid-modifying medications and nonpharmacological approaches (exercise training, dietary omega fatty acids, and low-density lipoprotein apheresis) on HDL subclasses. As HDL is a natural nanoplatform, recombinant HDLs (rHDLs) have been used as a delivery system in vivo by loading small interfering RNA, drugs, contrast agents, etc. Therefore, we further reviewed the HDL subclasses used in rHDLs and their advantages and disadvantages. This review would provide recommendations and guidance for future studies on HDL subclasses' cardioprotective roles.
Subject(s)
Cardiovascular Diseases , Lipoproteins, HDL , Humans , Cardiovascular Diseases/prevention & control , Lipoproteins, HDL/metabolism , Lipoproteins, HDL/therapeutic use , Lipoproteins, HDL/classification , Animals , Cholesterol, HDL/metabolism , Cholesterol, HDL/bloodABSTRACT
Cellulose-based adsorbents have been extensively developed in heavy metal capture and wastewater treatment. However, most of the reported powder adsorbents suffer from the difficulties in recycling due to their small sizes and limitations in detecting the targets for the lack of sensitive sensor moieties in the structure. Accordingly, carbon dots (CDs) were proposed to be encapsulated in cellulosic hydrogel beads to realize the simultaneous detection and adsorption of Hg (II) in water due to their excellent fluorescence sensing performance. Besides, the molding of cellulose was beneficial to its recycling and further reduced the potential environmental risk generated by secondary pollution caused by adsorbent decomposition. In addition, the detection limit of the hydrogel beads towards Hg (II) reached as low as 8.8 × 10-8 M, which was below the mercury effluent standard declared by WHO, exhibiting excellent practicability in Hg (II) detection and water treatment. The maximum adsorption capacity of CB-50 % for Hg (II) was 290.70 mg/g. Moreover, the adsorbent materials also had preeminent stability that the hydrogel beads could maintain sensitive and selective sensing performance towards Hg (II) after 2 months of storage. Additionally, only 3.3% of the CDs leaked out after 2 weeks of immersion in water, ensuring the accuracy of Hg (II) evaluation. Notably, the adsorbent retained over 80% of its original adsorption capacity after five consecutive regeneration cycles, underscoring its robustness and potential for sustainable environmental applications.
Subject(s)
Carbon , Cellulose , Hydrogels , Mercury , Water Pollutants, Chemical , Mercury/analysis , Cellulose/chemistry , Adsorption , Hydrogels/chemistry , Carbon/chemistry , Water Pollutants, Chemical/analysis , Water Purification/methods , Quantum Dots/chemistryABSTRACT
We conducted this study aimed to evaluate the analgesic effect of dexmedetomidine in thoracoscopic surgery on postoperative wound pain, and to provide a reference for clinical use of the drug. We searched PubMed, Embase, Cochrane Library, Web of Science, Wanfang, Chinese Biomedical Literature Database and China National Knowledge Infrastructure databases, and supplemented with manual searching. We searched from database inception to October 2023, to collect the randomised controlled trials (RCTs) on dexmedetomidine application in thoracoscopic surgery. Two researchers screened all the literature according to the inclusion and exclusion criteria and the literature included in the study was evaluated for quality, extracted information and required data. Stata 17.0 software was employed for data analysis and the outcomes were 2 6, 12, 24 and 48 h postoperative wound visual analog scores (VAS). Twenty-four RCTs totalling 2246 patients undergoing thoracoscopic surgery were finally included. The analysis revealed dexmedetomidine applied to thoracoscopic surgery significantly reduced the postoperative wound VAS scores at 2 h (SMD: -0.96, 95% CI: -1.57 to -0.36, p = 0.002), 6 h (SMD: -0.98, 95% CI: -1.27 to -0.69, p < 0.001), 12 h (SMD: -1.19, 95% CI: -1.44 to -0.94, p < 0.001), 24 h (SMD: -0.91, 95% CI: -1.16 to -0.66, p < 0.001) and 48 h (SMD: -0.75, 95% CI: -1.02 to -0.48, p < 0.001). Our results suggest dexmedetomidine applied to thoracoscopic surgery can significantly reduce postoperative wound pain, which is worthy of clinical application.
Subject(s)
Analgesics, Non-Narcotic , Dexmedetomidine , Pain, Postoperative , Thoracoscopy , Dexmedetomidine/therapeutic use , Humans , Pain, Postoperative/drug therapy , Analgesics, Non-Narcotic/therapeutic use , Thoracoscopy/methods , Male , Adult , Female , Middle Aged , Randomized Controlled Trials as Topic , Aged , Surgical Wound/drug therapy , Pain MeasurementSubject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/virology , COVID-19/immunology , COVID-19/complications , Male , Female , Middle Aged , Adult , Aged , Skin Diseases, Viral/virology , Skin Diseases, Viral/pathologyABSTRACT
Microglia are crucial immune cells found in the central nervous system. Multiple investigations have substantiated the correlation between the development of depression and neuroinflammation resulting from impaired microglial activity. Through extensive research on the phenotype, function, imaging technology, multi-omics analysis, and in vitro culture of microglia in depressive disorder, the understanding of the relationship between microglia and depression has become more intricate. Various therapeutic approaches have been suggested, but a thorough analysis of the obstacles to clinical application has not been conducted. This paper explores the innovative advancement of microglia detection technology, recent research findings on microglia identification and epigenetic modification, the variability of microglia in different conditions, the relationship between microglia dysfunction and the onset of depression, the progress and challenges of microglia-targeted therapy for depression, and the current obstacles and future prospects in studying dysregulated microglial function in depressive disorders.
ABSTRACT
Currently, CAR-T cell therapy relies on an individualized manufacturing process in which patient's own T cells are infused back into patients after being engineered and expanded ex vivo. Despite the astonishing outcomes of autologous CAR-T cell therapy, this approach is endowed with several limitations and drawbacks, such as high cost and time-consuming manufacturing process. Switching the armature of CAR-T cell therapy from autologous settings to allogeneic can overcome several bottlenecks of the current approach. Nevertheless, the use of allogeneic CAR-T cells is limited by the risk of life-threatening GvHD. Thus, in recent years, developing a method to move CAR-T cell therapy to allogeneic settings without the risk of GvHD has become a hot research topic in this field. Since the alloreactivity of αß T-cell receptor (TCR) accounts for developing GvHD, several efforts have been made to disrupt endogenous TCR of allogeneic CAR-T cells using gene editing tools to prevent GvHD. Nonetheless, the off-target activity of gene editing tools and their associated genotoxicities, as well as the negative consequences of endogenous TCR disruption, are the main concerns of using this approach. As an alternative, CAR αß-T cells can be replaced with other types of CAR-engineered cells that are capable of recognizing and killing malignant cells through CAR while avoiding the induction of GvHD. These alternatives include T cell subsets with restricted TCR repertoire (γδ-T, iNKT, virus-specific T, double negative T cells, and MAIT cells), killer cells (NK and CIK cells), non-lymphocytic cells (neutrophils and macrophages), stem/progenitor cells, and cell-free extracellular vesicles. In this review, we discuss how these alternatives can move CAR-based immunotherapy to allogeneic settings to overcome the bottlenecks of autologous manner without the risk of GvHD. We comprehensively discuss the pros and cons of these alternatives over the traditional CAR αß-T cells in light of their preclinical studies and clinical trials.
ABSTRACT
As part of the epigenetic machinery, microRNAs (miRNAs) are extensively utilized by eukaryotes. By modulating gene expression in a variety of ways, these short RNAs mediate crucial physiological processes. This suggests that abnormalities in miRNA biogenesis and expression can be traced back to a variety of diseases. In addition, miRNAs are promising clinical candidates, especially for preclinical diagnosis. The Let family of miRNAs was one of the first to be discovered. As a prominent member of this category, extensive research has been conducted on Let-7e. The vast majority of evidence indicates an association between let-7e dysregulation and the onset and progression of disease, including malignancies. Because their effect depends on the genetic profile of disease and the affected tissue, different miRNAs play diverse roles in various diseases. However, what counts in miRNA studies is that just one miRNA may target numerous mRNAs in a cell at the exact time, therefore summarizing the effect of a single miRNA in human diseases can provide better insights into disease detection and treatment. The goal of this study is to gain a deeper understanding of how let-7e functions in human cells so that it can be utilized more effectively in clinical settings for diagnosis, prognosis, and treatment. We have reviewed the research on let-7e, focusing on the molecular underpinnings of biological processes controlled by this miRNA that contribute to the development and etiology of numerous disorders.
Subject(s)
MicroRNAs , Neoplasms , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms/genetics , Neoplasms/pathologyABSTRACT
There is evidence that physical activity (PA) has a long-term positive impact on disease. Whether PA is a risk factor for knee osteoarthritis (OA) is still controversial. The purpose of this study was to explore whether there is a causal relationship between PA and knee OA. We extracted PA and knee OA data from genome-wide association study (GWAS) databases. We used single-nucleotide polymorphisms (SNPs) as instrumental variables. We performed MR analysis by random-effects inverse-variance weighting (IVW), MRâEgger, weighted median, simple mode, and weighted mode methods. We evaluated the stability and reliability of the results through sensitivity analysis. There was no significant association between PA and knee OA (p > 0.05). We did not detect any pleiotropy (MRâEgger intercept test et al.: p > 0.05). The sensitivity analysis confirmed our results (p > 0.05). There is no causal relationship between PA and knee OA.
Subject(s)
Genome-Wide Association Study , Osteoarthritis, Knee , Humans , Mendelian Randomization Analysis , Osteoarthritis, Knee/etiology , Osteoarthritis, Knee/genetics , Reproducibility of Results , Exercise , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: The key to the prevention and treatment of Alzheimer's disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved. METHODS: We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aß, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aß plaques by Bielschowsky's silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence. RESULTS: We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased ß-amyloid (Aß) 42 and Aß40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aß plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death. CONCLUSIONS: Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aß and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.
Subject(s)
Alzheimer Disease , Diabetes Mellitus, Type 2 , Animals , Alzheimer Disease/pathology , Macaca fascicularis/metabolism , Amyloid beta-Peptides/metabolism , Inflammation/pathology , Brain/metabolism , Biomarkers , Diabetes Mellitus, Type 2/complications , Cytokines/metabolism , tau Proteins/metabolismABSTRACT
Missing modality sentiment analysis is a prevalent and challenging issue in real life. Furthermore, the heterogeneity of multimodality often leads to an imbalance in optimization when attempting to optimize the same objective across all modalities in multimodal networks. Previous works have consistently overlooked the optimization imbalance of the network in cases when modalities are absent. This paper presents a Prototype-Based Sample-Weighted Distillation Unified Framework Adapted to Missing Modality Sentiment Analysis (PSWD). Specifically, it fuses features with a more efficient transformer-based cross-modal hierarchical cyclic fusion module. Subsequently, we propose two strategies, namely sample-weighted distillation and prototype regularization network, to address the issues of missing modality and optimization imbalance. The sample-weighted distillation strategy assigns higher weights to samples that are located closer to class boundaries. This facilitates the obtaining of complete knowledge by the student network from the teacher's network. The prototype regularization network calculates a balanced metric for each modality, which adaptively adjusts the gradient based on the prototype cross-entropy loss. Unlike conventional approaches, PSWD not only connects the sentiment analysis study in the missing modality to the full modality, but the proposed prototype regularization network is not reliant on the network structure and can be expanded to more multimodal studies. Massive experiments conducted on IEMOCAP and MSP-IMPROV show that our method achieves the best results compared to the latest baseline methods, which demonstrates its value for application in sentiment analysis.