Implementation of the healthy school construction plan to promote students' health and well-being

With the development of society, the health and well-being of children and adolescents are receiving increasing attention from the government and scholars. The implementation of the health (promoting) school construction plan has a significant effect on promoting students' health and well-being, which is especially important in the normalized stage of COVID-19 epidemic prevention and control. The study summarizes the importance of health (promoting) schools for students' health and well-being, reviews the development of health (promoting) school construction in China, and proposes countermeasures and recommendations to further promote health (promoting) school construction in China in the light of the new era.

Genetic comparison of transmissible gastroenteritis coronaviruses.

Transmissible gastroenteritis virus (TGEV) is a porcine coronavirus that threatens animal health and remains elusive despite years of research efforts. The systematical analysis of all available full-length genomes of TGEVs (a total of 43) and porcine respiratory coronaviruses PRCVs (a total of 7) showed that TGEVs fell into two independent evolutionary phylogenetic clades, GI and GII. Viruses circulating in China (until 2021) clustered with the traditional or attenuated vaccine strains within the same evolutionary clades (GI). In contrast, viruses latterly isolated in the USA fell into GII clade. The viruses circulating in China have a lower similarity with that isolated latterly in the USA all through the viral genome. In addition, at least four potential genomic recombination events were identified, three of which occurred in GI clade and one in GII clade. TGEVs circulating in China are distinct from the viruses latterly isolated in the USA at either genomic nucleotide or antigenic levels. Genomic recombination serves as a factor driving the expansion of TGEV genomic diversity.

Sustained Response to Eculizumab in a Patient With COVID-19–Associated Acute Thrombotic Microangiopathy of the Allograft Kidney: A Case Report

Acute thrombotic microangiopathy (TMA) developing in association with SARS-CoV-2 infection is a rare but recognized phenomenon in native kidneys. In the allograft kidney, a diagnosis of TMA has a broad etiologic differential, including antibody-mediated rejection and recurrent and de novo causes of TMA that affect the native kidney. Prior case reports have described plasma exchange or eculizumab use in patients with COVID-19–associated TMA. Herein, we describe the course of a kidney transplant patient with COVID-19–associated TMA with response to eculizumab that was sustained after medication withdrawal and review the literature on COVID-19–associated TMA of the allograft kidney.

In situ electrospun aloe-nanofiber membrane for chronic wound healing.

Alleviating excessive inflammation while accelerating chronic wound healing to prevent wound infection has remained challenging, especially during the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 when patients experienced difficulties with receive appropriate healthcare. We addressed this issue by developing handheld electrospun aloe-nanofiber membranes (ANFMs) with convenient, environmentally friendly properties and a therapeutic capacity for wound closure. Our results showed that ANFMs fabricated with high molecular weight polyvinyl alcohol (PVA) to form fibers during electrospinning had uniform fibrous architecture and a porous structure. Given the value of aloe gel in accelerating wound healing, liquid extracts from ANFMs significantly downregulated the expression of the pro-inflammatory genes, interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), and markedly suppress the generation of reactive oxygen species (ROS) induced by lipopolysaccharide in RAW264.7 macrophages. These results indicated the excellent antioxidant and anti-inflammatory effects of ANFMs. After implantation into a mouse diabetic wound model for 12 days in situ, ANFMs notably expedited chronic wound healing via promoting angiogenesis and enhancing cell viability. Our ANFMs generated by handheld electrospinning in situ healed chronic wounds offer a convenient and promising alternative for patients to heal their own wounds under variable conditions.

Sustained Response to Eculizumab in a Patient With COVID-19-Associated Acute Thrombotic Microangiopathy of the Allograft Kidney: A Case Report.

Acute thrombotic microangiopathy (TMA) developing in association with SARS-CoV-2 infection is a rare but recognized phenomenon in native kidneys. In the allograft kidney, a diagnosis of TMA has a broad etiologic differential, including antibody-mediated rejection and recurrent and de novo causes of TMA that affect the native kidney. Prior case reports have described plasma exchange or eculizumab use in patients with COVID-19-associated TMA. Herein, we describe the course of a kidney transplant patient with COVID-19-associated TMA with response to eculizumab that was sustained after medication withdrawal and review the literature on COVID-19-associated TMA of the allograft kidney.

Ectopic expression of SARS-CoV-2 S and ORF-9B proteins alters metabolic profiles and impairs contractile function in cardiomyocytes

Coronavirus disease 2019 (COVID-19) is associated with adverse impacts in the cardiovascular system, but the mechanisms driving this response remain unclear. In this study, we conducted "pseudoviral infection” of SARS-CoV-2 subunits to evaluate their toxic effects in cardiomyocytes (CMs), that were derived from human induced pluripotent stem cells (hiPSCs). We found that the ectopic expression of S and ORF-9B subunits significantly impaired the contractile function and altered the metabolic profiles in human cardiomyocytes. Further mechanistic study has shown that the mitochondrial oxidative phosphorylation (OXPHOS), membrane potential, and ATP production were significantly decreased two days after the overexpression of S and ORF-9B subunits, while S subunits induced higher level of reactive oxygen species (ROS). Two weeks after overexpression, glycolysis was elevated in the ORF-9B group. Based on the transcriptomic analysis, both S and ORF-9B subunits dysregulated signaling pathways associated with metabolism and cardiomyopathy, including upregulated genes involved in HIF-signaling and downregulated genes involved in cholesterol biosynthetic processes. The ORF-9B subunit also enhanced glycolysis in the CMs. Our results collectively provide an insight into the molecular mechanisms underlying SARS-CoV-2 subunits-induced metabolic alterations and cardiac dysfunctions in the hearts of COVID-19 patients.

Ectopic expression of SARS-CoV-2 S and ORF-9B proteins alters metabolic profiles and impairs contractile function in cardiomyocytes.

Coronavirus disease 2019 (COVID-19) is associated with adverse impacts in the cardiovascular system, but the mechanisms driving this response remain unclear. In this study, we conducted "pseudoviral infection" of SARS-CoV-2 subunits to evaluate their toxic effects in cardiomyocytes (CMs), that were derived from human induced pluripotent stem cells (hiPSCs). We found that the ectopic expression of S and ORF-9B subunits significantly impaired the contractile function and altered the metabolic profiles in human cardiomyocytes. Further mechanistic study has shown that the mitochondrial oxidative phosphorylation (OXPHOS), membrane potential, and ATP production were significantly decreased two days after the overexpression of S and ORF-9B subunits, while S subunits induced higher level of reactive oxygen species (ROS). Two weeks after overexpression, glycolysis was elevated in the ORF-9B group. Based on the transcriptomic analysis, both S and ORF-9B subunits dysregulated signaling pathways associated with metabolism and cardiomyopathy, including upregulated genes involved in HIF-signaling and downregulated genes involved in cholesterol biosynthetic processes. The ORF-9B subunit also enhanced glycolysis in the CMs. Our results collectively provide an insight into the molecular mechanisms underlying SARS-CoV-2 subunits-induced metabolic alterations and cardiac dysfunctions in the hearts of COVID-19 patients.

Prevalence, risk factors, and clinical correlates of anxiety, depression, and sleep disorders in chaperones for children in the emergency department in China during COVID-19.

The outbreak of novel coronavirus pneumonia in Wuhan, Hubei Province, in 2019 and its rapid spread across the country caused severe public panic in China. The purpose of this study was to investigate the mental health problems of children's chaperones at the emergency clinic during the coronavirus disease 2019 (COVID-19) outbreak and to analyze the related influencing factors. A total of 260 chaperones for children in the emergency department participated in this cross-sectional study through the questionnaire constellation platform. The survey period was from February to June 2021. Information collected included demographic data and mental health scales. The Self-Assessment Scale for Anxiety, the Self-Rating Scale for Depression, and the Pittsburgh Sleep Quality Index assessed anxiety, depression, and sleep quality, respectively. Logistic regression was used to analyze influential factors associated with mental health problems. The prevalence of depression, anxiety, and sleep disorders among family members accompanying children attending the emergency room was 41.54%, 20.00%, and 93.08%, respectively, with 21.54% of family members suffering from moderate sleep disorders. Univariate analysis showed that being in Wuhan or not during the city closure (X2 = 8.61, P < .01) was strongly associated with the occurrence of depression; female (X2 = 4.87, P = .03), working or not (X2 = 6.39, P = .01) and fear of going to the hospital (X2 = 7.80, P = .01) were key factors for the occurrence of anxiety symptoms; Knowledge of transmission routes and prevention of COVID-19 (X2 = 12.56, P = .03) was a key factor for sleep disorders; logistic stepwise regression analysis showed that fear of going to the hospital was a risk factor for anxiety symptoms (odds ratio = 2.51, P < .01, 95% confidence interval = 1.30-4.85). Our findings suggest that mental health problems were prevalent among family members accompanying children attending the emergency department during the COVID-19 outbreak, with a high prevalence of sleep disturbances in particular. Relevant factors included presence or absence in Wuhan during the outbreak closure, gender, work or absence, and fear of hospital visits. There is a need to focus on the mental health distress of the chaperones for children in the emergency department, and to provide timely intervention and diversion.

SARS-CoV-2 NSP8 suppresses type I and III IFN responses by modulating the RIG-I/MDA5, TRIF, and STING signaling pathways.

SARS-CoV-2 has developed a variety of approaches to counteract host innate antiviral immunity to facilitate its infection, replication and pathogenesis, but the molecular mechanisms that it employs are still not been fully understood. Here, we found that SARS-CoV-2 NSP8 inhibited the production of type I and III interferons (IFNs) by acting on RIG-I/MDA5 and the signaling molecules TRIF and STING. Overexpression of NSP8 downregulated the expression of type I and III IFNs stimulated by poly (I:C) transfection and infection with SeV and SARS-CoV-2. In addition, NSP8 impaired IFN expression triggered by overexpression of the signaling molecules RIG-I, MDA5, and MAVS, instead of TBK1 and IRF3-5D, an active form of IRF3. From a mechanistic view, NSP8 interacts with RIG-I and MDA5, and thereby prevents the assembly of the RIG-I/MDA5-MAVS signalosome, resulting in the impaired phosphorylation and nuclear translocation of IRF3. NSP8 also suppressed the TRIF- and STING- induced IFN expression by directly interacting with them. Moreover, ectopic expression of NSP8 promoted virus replications. Taken together, SARS-CoV-2 NSP8 suppresses type I and III IFN responses by disturbing the RIG-I/MDA5-MAVS complex formation and targeting TRIF and STING signaling transduction. These results provide new insights into the pathogenesis of COVID-19.

iProMix: A mixture model for studying the function of ACE2 based on bulk proteogenomic data.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over six million deaths in the ongoing COVID-19 pandemic. SARS-CoV-2 uses ACE2 protein to enter human cells, raising a pressing need to characterize proteins/pathways interacted with ACE2. Large-scale proteomic profiling technology is not mature at single-cell resolution to examine the protein activities in disease-relevant cell types. We propose iProMix, a novel statistical framework to identify epithelial-cell specific associations between ACE2 and other proteins/pathways with bulk proteomic data. iProMix decomposes the data and models cell-type-specific conditional joint distribution of proteins through a mixture model. It improves cell-type composition estimation from prior input, and utilizes a non-parametric inference framework to account for uncertainty of cell-type proportion estimates in hypothesis test. Simulations demonstrate iProMix has well-controlled false discovery rates and favorable powers in non-asymptotic settings. We apply iProMix to the proteomic data of 110 (tumor adjacent) normal lung tissue samples from the Clinical Proteomic Tumor Analysis Consortium lung adenocarcinoma study, and identify interferon α/γ response pathways as the most significant pathways associated with ACE2 protein abundances in epithelial cells. Strikingly, the association direction is sex-specific. This result casts light on the sex difference of COVID-19 incidences and outcomes, and motivates sex-specific evaluation for interferon therapies.

Role of Necroptosis in Central Nervous System Diseases.

Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.

Doctors' and Patients' Perceptions of Impacts of Doctors' Communication and Empathy Skills on Doctor-Patient Relationships During COVID-19.

BACKGROUND: During the COVID-19 pandemic, the performance of Chinese doctors may have led to improved doctor-patient relationships (DPRs). However, it is unclear how doctors and patients perceived the impact of doctors' communication and empathy skills on DPRs during the COVID-19 pandemic. OBJECTIVE: To examine the perceptions of doctors and patients on how doctors' communication skills and empathy skills influence DPRs during COVID-19. MAIN MEASURES: Doctors' and patients' perceptions of doctors' communication skills were measured using the Chinese version of the SEGUE Framework. To measure empathy skills and DPRs, the Jefferson Scale of Empathy and Difficult Doctor-Patient Relationship Questionnaire were administered to doctors, and the Consultation and Relational Empathy Measure and Patient-Doctor Relationship Questionnaire were administered to patients. RESULTS: A total of 902 doctors and 1432 patients in China were recruited during the pandemic via online or offline surveys (overall response rate of 69.8%). Both doctors and patients rated doctors' empathy skills as more impactful on DPRs than communication skills. Doctors believed that only their empathy skills influenced DPRs. But patients believed that there was a significant bi-directional relationship between doctors' communication and empathy skills and these two skills interacted to directly and indirectly influence DPRs, and doctors' empathy had a greater mediating effect than their communication. CONCLUSIONS: During COVID-19, there were both similarities and differences between Chinese doctors' and patients' views on how doctors' communication and empathy skills influenced DPRs. The greater effect of doctors' empathy skills suggests that both doctors and patients attach more importance to doctors' empathy in doctor-patient interactions. The bi-directional effect on patient outcomes suggests that both doctors' communication and empathy skills are important to patients' perceptions of DPRs.

SARS-CoV-2 NSP7 inhibits type I and III IFN production by targeting the RIG-I/MDA5, TRIF, and STING signaling pathways.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III interferons (IFNs) by targeting the RIG-I/MDA5, Toll-like receptor (TLR3)-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3-5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF- and STING-induced IFN responses. Mechanistically, NSP7 associated with RIG-I and MDA5 prevented the formation of the RIG-I/MDA5-MAVS signalosome and interacted with TRIF and STING to inhibit TRIF-TBK1 and STING-TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nuclear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS-CoV-2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG-I/MDA5-MAVS, TLR3-TRIF, and cGAS-STING signaling pathways, thus providing novel insights into the interactions between SARS-CoV-2 and innate antiviral immunity.

Manipulation of innate immune signaling pathways by SARS-CoV-2 non-structural proteins.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic, induces an unbalanced immune response in the host. For instance, the production of type I interferon (IFN) and the response to it, which act as a front-line defense against virus invasion, are inhibited during SARS-CoV-2 infection. In addition, tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine, is upregulated in COVID-19 patients with severe symptoms. Studies on the closely related betacoronavirus, SARS-CoV, showed that viral proteins such as Nsp1, Orf6 and nucleocapsid protein inhibit IFN-ß production and responses at multiple steps. Given the conservation of these proteins between SARS-CoV and SARS-CoV-2, it is not surprising that SARS-CoV-2 deploys similar immune evasion strategies. Here, we carried out a screen to examine the role of individual SARS-CoV-2 proteins in regulating innate immune signaling, such as the activation of transcription factors IRF3 and NF-κB and the response to type I and type II IFN. In addition to established roles of SARS-CoV-2 proteins, we report that SARS-CoV-2 proteins Nsp6 and Orf8 inhibit the type I IFN response but at different stages. Orf6 blocks the translocation of STAT1 and STAT2 into the nucleus, whereas ORF8 inhibits the pathway in the nucleus after STAT1/2 translocation. SARS-CoV-2 Orf6 also suppresses IRF3 activation and TNF-α-induced NF-κB activation.

Willingness to pay for and willingness to vaccinate with the COVID-19 vaccine booster dose in China.

Objective: The present study aims to assess the willingness to pay (WTP) for and willingness to vaccinate (WTV) with the Coronavirus (COVID-19) vaccine booster dose in China when the pandemic is under adequate control and the majority of the population is vaccinated. This study is also to identify significant factors associated with the WTP. Methods: This was a cross-sectional study on adults with no past or present COVID-19 infection. An online questionnaire was distributed to collect data on vaccination status, quarantine experience, and factors related to health beliefs on vaccination. The WTV was assessed through the vaccination preference. The WTP was examined by payment scale (PS) and iterative bidding game (IBG) administered in random order. Three IBG algorithms with different starting-price were presented randomly. The average WTP of PS and IBG were analyzed as primary outcomes using univariate and multivariate analyses. Multivariate ordered logistic regression was performed to identify significant factors for the WTP. Results: The survey recruited 543 participants with a mean age of 32 years and 57.80% being female. The WTV rate was 86.74%, while 94.66% of participants completed full-schedule or enhanced vaccination. The mean WTP was CNY 149 (±CNY 197) and the median WTP was CNY 80. Regarding significant factors for the WTP, urban residents were 57% more likely (95% CI: 1.11-2.22) to pay for a high-priced vaccine than rural residents. Respondents who completed full-schedule vaccination were 46% more likely (95% CI: 1.03-2.07) to pay for a high-priced vaccine than those who completed enhanced vaccination. Respondents with a low household income of CNY 40k or lower were 62% less likely (95% CI: 0.21-0.66) to pay for a high-priced vaccine than those with a middle household income of CNY 110k-210k. Other significant factors associated with the WTP included the perceived benefit of vaccination and peer environmental pressure in the health belief model. Conclusion: The WTV with the COVID-19 vaccine booster dose was high in China. The WTP was influenced by the place of residence, vaccination status, household income, perceived benefit of vaccination, and environmental peer pressure. Study findings can inform policymakers to better design vaccination programs and financial schemes involving out-of-pocket payments.

The Impact of Preventive Strategies Adopted during Large Events on the COVID-19 Pandemic: A Case Study of the Tokyo Olympics to Provide Guidance for Future Large Events.

This study aimed to analyze the impact of hosting large events on the spread of pandemics, taking Tokyo Olympics 2020 as a case study. A risk assessment method for the whole organization process was established, which could be used to evaluate the effectiveness of various risk mitigation measures. Different scenarios for Games participants and Japanese residents during the Tokyo Olympics were designed based on the infection control protocols proposed by the Olympic Committee and local governments. A modified Wells-Riley model considering the influence of social distance, masking and vaccination, and an SIQRV model that introduced the effect of quarantine and vaccination strategies on the pandemic spread were developed in this study. Based on the two models, our predicted results of daily confirmed cases and cumulative cases were obtained and compared with reported data, where good agreement was achieved. The results show that the two core infection control strategies of the bubble scheme and frequent testing scheme curbed the spread of the COVID-19 pandemic during the Tokyo Olympics. Among Games participants, Japanese local staff accounted for more than 60% of the total in positive cases due to their large population and most relaxed travel restrictions. The surge in positive cases was mainly attributed to the high transmission rate of the Delta variant and the low level of immunization in Japan. Based on our simulation results, the risk management flaws for the Tokyo Olympics were identified and improvement measures were investigated. Moreover, a further analysis was carried out on the impact of different preventive measures with respect to minimizing the transmission of new variants with higher transmissibility. Overall, the findings in this study can help policymakers to design scientifically based and practical countermeasures to cope with pandemics during the hosting of large events.

Evolutionary plasticity of zoonotic porcine Deltacoronavirus (PDCoV): genetic characteristics and geographic distribution.

The emergence and rapid spread of the acute respiratory syndrome coronavirus-2 have confirmed that animal coronaviruses represent a potential zoonotic source. Porcine deltacoronavirus is a worldwide evolving enteropathogen of swine, detected first in Hong Kong, China, before its global identification. Following the recent detection of PDCoV in humans, we attempted in this report to re-examine the status of PDCoV phylogenetic classification and evolutionary characteristics. A dataset of 166 complete PDCoV genomes was analyzed using the Maximum Likelihood method in IQ-TREE with the best-fitting model GTR + F + I + G4, revealing two major genogroups (GI and GII), with further seven and two sub-genogroups, (GI a-g) and (GII a-b), respectively. PDCoV strains collected in China exhibited the broadest genetic diversity, distributed in all subgenotypes. Thirty-one potential natural recombination events were identified, 19 of which occurred between China strains, and seven involved at least one China strain as a parental sequence. Importantly, we identified a human Haiti PDCoV strain as recombinant, alarming a possible future spillover that could become a critical threat to human health. The similarity and recombination analysis showed that PDCoV spike ORF is highly variable compared to ORFs encoding other structural proteins. Prediction of linear B cell epitopes of the spike glycoprotein and the 3D structural mapping of amino acid variations of two representative strains of GI and GII showed that the receptor-binding domain (RBD) of spike glycoprotein underwent a significant antigenic drift, suggesting its contribution in the genetic diversity and the wider spread of PDCoV.

Manipulation of innate immune signaling pathways by SARS-CoV-2 non-structural proteins

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic, induces an unbalanced immune response in the host. For instance, the production of type I interferon (IFN) and the response to it, which act as a front-line defense against virus invasion, are inhibited during SARS-CoV-2 infection. In addition, tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine, is upregulated in COVID-19 patients with severe symptoms. Studies on the closely related betacoronavirus, SARS-CoV, showed that viral proteins such as Nsp1, Orf6 and nucleocapsid protein inhibit IFN-β production and responses at multiple steps. Given the conservation of these proteins between SARS-CoV and SARS-CoV-2, it is not surprising that SARS-CoV-2 deploys similar immune evasion strategies. Here, we carried out a screen to examine the role of individual SARS-CoV-2 proteins in regulating innate immune signaling, such as the activation of transcription factors IRF3 and NF-κB and the response to type I and type II IFN. In addition to established roles of SARS-CoV-2 proteins, we report that SARS-CoV-2 proteins Nsp6 and Orf8 inhibit the type I IFN response but at different stages. Orf6 blocks the translocation of STAT1 and STAT2 into the nucleus, whereas ORF8 inhibits the pathway in the nucleus after STAT1/2 translocation. SARS-CoV-2 Orf6 also suppresses IRF3 activation and TNF-α-induced NF-κB activation.