A prospective cohort-based artificial intelligence evaluation system for the protective efficacy and immune response of SARS-CoV-2 inactivated vaccines.

BACKGROUND: Novel coronaviruses constitute a significant health threat, prompting the adoption of vaccination as the primary preventive measure. However, current evaluations of immune response and vaccine efficacy are deemed inadequate. OBJECTIVES: The study sought to explore the evolving dynamics of immune response at various vaccination time points and during breakthrough infections. It aimed to elucidate the synergistic effects of epidemiological factors, humoral immunity, and cellular immunity. Additionally, regression curves were used to determine the correlation between the protective efficacy of the vaccine and the stimulated immune response. METHODS: Employing LASSO for high-dimensional data analysis, the study utilised four machine learning algorithms-logistical regression, random forest, LGBM classifier, and AdaBoost classifier-to comprehensively assess the immune response following booster vaccination. RESULTS: Neutralising antibody levels exhibited a rapid surge post-booster, escalating to 102.38 AU/mL at one week and peaking at 298.02 AU/mL at two weeks. Influential factors such as sex, age, disease history, and smoking status significantly impacted post-booster antibody levels. The study further constructed regression curves for neutralising antibodies, non-switched memory B cells, CD4+T cells, and CD8+T cells using LASSO combined with the random forest algorithm. CONCLUSION: The establishment of an artificial intelligence evaluation system emerges as pivotal for predicting breakthrough infection prognosis after the COVID-19 booster vaccination. This research underscores the intricate interplay between various components of immunity and external factors, elucidating key insights to enhance vaccine effectiveness. 3D modelling discerned distinctive interactions between humoral and cellular immunity within prognostic groups (Class 0-2). This underscores the critical role of the synergistic effect of humoral immunity, cellular immunity, and epidemiological factors in determining the protective efficacy of COVID-19 vaccines post-booster administration.

A prognostic model for SARS-CoV-2 breakthrough infection: Analyzing a prospective cellular immunity cohort.

BACKGROUND: Following the COVID-19 pandemic, studies have identified several prevalent characteristics, especially related to lymphocyte subsets. However, limited research is available on the focus of this study, namely, the specific memory cell subsets among individuals who received COVID-19 vaccine boosters and subsequently experienced a SARS-CoV-2 breakthrough infection. METHODS: Flow cytometry (FCM) was employed to investigate the early and longitudinal pattern changes of cellular immunity in patients with SARS-CoV-2 breakthrough infections following COVID-19 vaccine boosters. XGBoost (a machine learning algorithm) was employed to analyze cellular immunity prior to SARS-CoV-2 breakthrough, aiming to establish a prognostic model for SARS-CoV-2 breakthrough infections. RESULTS: Following SARS-CoV-2 breakthrough infection, naïve T cells and TEMRA subsets increased while the percentage of TCM and TEM cells decreased. Naïve and non-switched memory B cells increased while switched and double-negative memory B cells decreased. The XGBoost model achieved an area under the curve (AUC) of 0.78, with an accuracy rate of 81.8 %, a sensitivity of 75 %, and specificity of 85.7 %. TNF-α, CD27-CD19+cells, and TEMRA subsets were identified as high predictors. An increase in TNF-α, cTfh, double-negative memory B cells, IL-6, IL-10, and IFN-γ prior to SARS-CoV-2 infection was associated with enduring clinical symptoms; conversely, an increase in CD3+ T cells, CD4+ T cells, and IL-2 was associated with clinical with non-enduring clinical symptoms. CONCLUSION: SARS-CoV-2 breakthrough infection leads to disturbances in cellular immunity. Assessing cellular immunity prior to breakthrough infection serves as a valuable prognostic tool for SARS-CoV-2 infection, which facilitates clinical decision-making.

Proteome microarray identifies autoantibody biomarkers for diagnosis of hepatitis B-related hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) has the highest mortality rate among malignant tumors worldwide. This study aimed to analyze the biological characteristics of serum proteins in hepatitis B (HBV)-related liver diseases, identify diagnostic biomarkers for HBV-infected HCC, and provide a scientific basis for its prevention and treatment. MATERIALS AND METHODS: We used HuProt arrays to identify candidate biomarkers for HBV-related liver diseases and verified the differential biomarkers by using an HCC-focused array. The biological characteristics of serum proteins were analyzed via bioinformatics. Serum biomarkers levels were validated by ELISA. RESULTS: We identified 547 differentially expressed proteins from HBV-infected HCC in a screening cohort. After analyzing the biological characteristics of serum proteins, we identified 10 potential differential autoantibodies against tumor-associated antigens (TAAbs) and a candidate biomarker panel (APEX2, RCSD1, and TP53) for the diagnosis of HBV-associated HCC with 61.9% sensitivity and 81.7% specificity in an HCC-focused array validation cohort. Finally, the protein levels and diagnostic capability of the biomarker panel were confirmed in a large-sample validation cohort, and this panel was found to be superior to alpha-fetoprotein, the standard hallmark for the diagnosis of HCC. CONCLUSION: The APEX2, RCSD1, and TP53 biomarker panels could be used for the diagnosis of HBV-associated HCC, providing a scientific basis for clinical practice.

Aluminum exposure induces central nervous system impairment via activating NLRP3-medicated pyroptosis pathway.

PURPOSE: Aluminum is an environmental toxicant whose long-term exposure is closely associated with nervous system impairment. This study mainly investigated neurological impairment induced by subchronic aluminum exposure via activating NLRP3-medicated pyroptosis pathway. METHODS: In vivo, Kunming mice were exposed to AlCl3 (30.3 mg/kg, 101 mg/kg and 303 mg/kg) via drinking water for 3 months, and administered with Rsv (100 mg/kg) by gavage for 1 month. Cognitive impairment was assessed by Morris water maze test, and pathological injury was detected via H&E staining. BBB integrity, pyroptosis and neuroinflammation were evaluated through western blotting and immunofluorescence methods. In vitro, BV2 microglia was treated with AlCl3 (0.5 mM, 1 mM and 2 mM) to sensitize pyroptosis pathway. The protein interaction was verified by co-immunoprecipitation, and neuronal damage was estimated via a conditioned medium co-culture system with BV2 and TH22 cells. RESULTS: Our results showed that AlCl3 induced mice memory disorder, BBB destruction, and pathological injury. Besides, aluminum caused glial activation, sensitized DDX3X-NLRP3 pyroptosis pathway, released cytokines IL-1ß and IL-18, initiating neuroinflammation. BV2 microglia treated with AlCl3 emerged hyperactivation and pyroptotic death, and Ddx3x knockdown inhibited pyroptosis signaling pathway. DDX3X acted as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome and G3BP1 stress granules. Furthermore, aluminum-activated microglia had an adverse effect on co-cultured neurons and destroyed nervous system homeostasis. CONCLUSION: Aluminum exposure could induce pyroptosis and neurotoxicity. DDX3X determined live or die via selectively regulating pro-survival stress granules or pro-death NLRP3 inflammasome. Excessive activation of microglia might damage neurons and aggravate nerve injury.

Aluminum induces neuroinflammation via P2X7 receptor activating NLRP3 inflammasome pathway.

INTRODUCTION: Aluminum is everywhere in nature and is a recognized neurotoxicant closely associated with various neurodegenerative diseases. Neuroinflammation occurs in the early stage of neurodegenerative diseases, but the underlying mechanism by which aluminum induces neuroinflammation remains unclear. MATERIAL AND METHODS: A 3-month subchronic aluminum exposure mouse model was established by drinking water containing aluminum chloride (AlCl3). Microglia BV2 cells and hippocampal neuron HT22 cells were treated with AlCl3 in vitro. BBG and YC-1 were used as intervention agents. RESULTS: Aluminum could activate microglia and increase the level of extracellular ATP, stimulate P2X7 receptor, HIF-1α, activate NLRP3 inflammasome and CASP-1, release more cytokine IL-1ß, and induce an inflammatory response in nerve cells. There was a mutual regulatory relationship between P2X7 and HIF-1α at mRNA and protein levels. The co-culture system of BV2-HT22 cells observed that conditioned medium from microglia treated with aluminum could aggravate neuronal morphological damage, inflammatory response and death. While BBG and YC-1 intervention could rescue these injuries to some extent. CONCLUSION: The P2X7-NLRP3 pathway was involved in aluminum-induced neuroinflammation and injury. P2X7 and HIF-1α might mutually regulate and promote the progression of neuroinflammation, both BBG and YC-1 could relieve it.

Metformin alleviates the cognitive impairment caused by aluminum by improving energy metabolism disorders in mice.

Long-term exposure to environmental aluminum was found to be related to the occurrence and development of neurodegenerative diseases. Energy metabolism disorders, one of the pathological features of neurodegenerative diseases, may occur in the early stage of the disease and are of potential intervention significance. Here, sub-chronic aluminum exposure mouse model was established, and metformin was used to intervene. We found that sub-chronic aluminum exposure decreased the protein levels of phosphorylation AMPK (p-AMPK), glucose transporter 1 (GLUT1) and GLUT3, taking charge of glucose uptake in the brain, reduced the levels of lactate shuttle-related proteins monocarboxylate transporter 4 (MCT4) and MCT2, as well as lactate content in the cerebral cortex, while increased hypoxia-inducible factor-1α (HIF-1α) level to drive downstream pyruvate dehydrogenase kinase 1 (PDK1) expression, thereby inhibiting pyruvate dehydrogenase (PDH) activity, and ultimately led to ATP depletion, neuronal death, and cognitive dysfunction. However, metformin could rescue these injuries. Thus, it came to a conclusion that aluminum could damage glucose uptake, interfere with astrocyte-neuron lactate shuttle (ANLS), interrupt the balance in energy metabolism, and resulting in cognitive function, while metformin has a neuroprotective effect against the disorder of energy metabolism caused by aluminum in mice.

Resveratrol alleviates aluminum-induced intestinal barrier dysfunction in mice.

BACKGROUND: Aluminum is mainly exposed to the general population through food and water, and is absorbed into the systemic circulation through intestine, which in turn damages the intestinal barrier. METHODS: The mice model of subchronic exposure to aluminum chloride (AlCl3 ) was established via oral. Tail suspension test was used to detect depressive behavior. H&E staining was performed to assess pathological intestinal injury. Intestinal permeability was estimated by exogenous Evans blue content. The level of inflammatory cytokines and tight junction protein were assessed via ELISA and western blotting. Simultaneously, resveratrol (Rsv, an agonist of Sirt1) was evaluated the protective role against intestinal barrier injuries caused by aluminum exposure. RESULTS: Our results showed that AlCl3 induced depressive-like behavior, intestinal pathological damage and intestinal barrier permeability, resulting in intestinal barrier dysfunction. Besides, aluminum induced the expression of inflammatory cytokines, which further triggered IRF8-MMP9-mediated downregulation of tight junction proteins including CLD1, OCLD and ZO-1. After Rsv treatment, SIRT1 expression was increased, depressive symptom was improved, pathological injury was reduced, inflammatory reaction was alleviated, and intestinal barrier function restored. CONCLUSION: Our findings revealed that aluminum exposure induced intestinal barrier dysfunction by IRF8-MMP9 signaling pathway. Rsv alleviated these injuries via activating SIRT1.

Aluminum induced intestinal dysfunction via mechanical, immune, chemical and biological barriers.

Aluminum is the most abundant metal element in the Earth's crust, which exists naturally in the form of aluminum compounds. Aluminum is mainly absorbed through the gastrointestinal tract, which varies with different aluminum compounds. During this process, aluminum could induce the disruption of intestinal mucosa barrier. However, its underlying mechanism has not been elucidated yet. Previous studies have reported that aluminum can firstly promote the apoptosis of intestinal epithelial cells, destroy the structure of tight-junction proteins, and increase the intestinal permeability, injuring the mechanical barrier of gut. Also, it can induce the activation of immune cells to secrete inflammatory factors, and trigger immune responses, interfering with immune barrier. Moreover, aluminum treatment can regulate intestinal composition and bio-enzyme activity, impairing the function of chemical barrier. In addition, aluminum accumulation can induce an imbalance of the intestinal flora, inhibit the growth of beneficial bacteria, and promote the proliferation of harmful bacteria, which ultimately disrupting biological barrier. Collectively, aluminum may do extensive damage to intestinal barrier function covering mechanical barrier, immune barrier, chemical barrier and biological barrier.

Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway.

INTRODUCTION: Aluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet. MATERIAL AND METHODS: The mice model of subacute exposure to aluminum chloride (AlCl3) was established. BV2 microglia cells was treated with AlCl3 in vitro. Resveratrol (Rsv) was adopted as intervention agent. RESULTS: Our results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1ß and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent. CONCLUSION: Aluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1).