Thyroid function and associated mood changes after COVID-19 vaccines in patients with Hashimoto thyroiditis.

Context: Severe acute respiratory syndrome-coronavirus 2 (COVID-19) vaccines may incur changes in thyroid functions followed by mood changes, and patients with Hashimoto thyroiditis (HT) were suggested to bear a higher risk. Objectives: We primarily aim to find whether COVID-19 vaccination could induce potential subsequent thyroid function and mood changes. The secondary aim was to find inflammatory biomarkers associated with risk. Methods: The retrospective, multi-center study recruited patients with HT receiving COVID-19-inactivated vaccines. C-reactive proteins (CRPs), thyroid-stimulating hormones (TSHs), and mood changes were studied before and after vaccination during a follow-up of a 6-month period. Independent association was investigated between incidence of mood state, thyroid functions, and inflammatory markers. Propensity score-matched comparisons between the vaccine and control groups were carried out to investigate the difference. Results: Final analysis included 2,765 patients with HT in the vaccine group and 1,288 patients in the control group. In the matched analysis, TSH increase and mood change incidence were both significantly higher in the vaccine group (11.9% versus 6.1% for TSH increase and 12.7% versus 8.4% for mood change incidence). An increase in CRP was associated with mood change (p< 0.01 by the Kaplan-Meier method) and severity (r = 0.75) after vaccination. Baseline CRP, TSH, and antibodies of thyroid peroxidase (anti-TPO) were found to predict incidence of mood changes. Conclusion: COVID-19 vaccination seemed to induce increased levels and incidence of TSH surge followed by mood changes in patients with HT. Higher levels of pre-vaccine serum TSH, CRP, and anti-TPO values were associated with higher incidence in the early post-vaccine phase.

Interplay between swine enteric coronaviruses and host innate immune.

Swine enteric coronavirus (SeCoV) causes acute diarrhea, vomiting, dehydration, and high mortality in neonatal piglets, causing severe losses worldwide. SeCoV includes the following four members: transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine delta coronavirus (PDCoV), and swine acute diarrhea syndrome coronavirus (SADS-CoV). Clinically, mixed infections with several SeCoVs, which are more common in global farms, cause widespread infections. It is worth noting that PDCoV has a broader host range, suggesting the risk of PDCoV transmission across species, posing a serious threat to public health and global security. Studies have begun to focus on investigating the interaction between SeCoV and its host. Here, we summarize the effects of viral proteins on apoptosis, autophagy, and innate immunity induced by SeCoV, providing a theoretical basis for an in-depth understanding of the pathogenic mechanism of coronavirus.

Innate Immune Evasion of Porcine Epidemic Diarrhea Virus through Degradation of the FBXW7 Protein via the Ubiquitin-Proteasome Pathway.

Porcine epidemic diarrhea virus (PEDV) causes a porcine disease associated with swine epidemic diarrhea. Different antagonistic strategies have been identified, and the mechanism by which PEDV infection impairs the production of interferon (IFN) and delays the activation of the IFN response to escape host innate immunity has been determined, but the pathogenic mechanisms of PEDV infection remain enigmatic. Our preliminary results revealed that endogenous F-box and WD repeat domain-containing 7 (FBXW7) protein, the substrate recognition component of the SCF-type E3 ubiquitin ligase, is downregulated in PEDV-infected Vero E6 cells, according to the results from an isobaric tags for relative and absolute quantification (iTRAQ) analysis. Overexpression of FBXW7 in target cells makes them more resistant to PEDV infection, whereas ablation of FBXW7 expression by small interfering RNA (siRNA) significantly promotes PEDV infection. In addition, FBXW7 was verified as an innate antiviral factor capable of enhancing the expression of RIG-I and TBK1, and it was found to induce interferon-stimulated genes (ISGs), which led to an elevated antiviral state of the host cells. Moreover, we revealed that PEDV nonstructural protein 2 (nsp2) interacts with FBXW7 and targets FBXW7 for degradation through the K48-linked ubiquitin-proteasome pathway. Consistent with the results proven in vitro, FBXW7 reduction was also confirmed in different intestinal tissues from PEDV-infected specific-pathogen-free (SPF) pigs. Taken together, the data indicated that PEDV has evolved with a distinct antagonistic strategy to circumvent the host antiviral response by targeting the ubiquitin-proteasome-mediated degradation of FBXW7. Our findings provide novel insights into PEDV infection and pathogenesis. IMPORTANCE To counteract the host antiviral defenses, most viruses, including coronaviruses, have evolved with diverse strategies to dampen host IFN-mediated antiviral response, by interfering with or evading specific host regulators at multiple steps of this response. In this study, a novel antagonistic strategy was revealed showing that PEDV infection could circumvent the host innate response by targeted degradation of endogenous FBXW7 in target cells, a process that was verified to be a positive modulator for the host innate immune system. Degradation of FBXW7 hampers host innate antiviral activation and facilitates PEDV replication. Our findings reveal a new mechanism exploited by PEDV to suppress the host antiviral response.

Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen.

Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.

Porcine deltacoronavirus E protein induces interleukin-8 production via NF-κB and AP-1 activation.

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and interleukin-6 (IL-6). Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present study, we found that interleukin-8 (IL-8) was upregulated by PDCoV infection. We then demonstrated that PDCoV E protein induced IL-8 production and that the TM domain and the C-terminal domain of the E protein were important for IL-8 production. Subsequently, we showed here that deleting the AP-1 and NF-κB binding motif in porcine IL-8 promoter abrogated its activation, suggesting that IL-8 expression was dependent on AP-1 and NF-κB. Furthermore, PDCoV E induced IL-8 production, which was also dependent on the NF-κB pathway through activating nuclear factor p65 phosphorylation and NF-κB inhibitor alpha (IκBα) protein phosphorylation, as well as inducing the nuclear translocation of p65, eventually resulting in the promotion of IL-8 production. PDCoV E also activated c-fos and c-jun, both of which are members of the AP-1 family. These findings provide new insights into the molecular mechanisms of PDCoV-induced IL-8 production and help us further understand the pathogenesis of PDCoV infection.

Stromal Antigen 2 Deficiency Induces Interferon Responses and Restricts Porcine Deltacoronavirus Infection.

Porcine deltacoronavirus (PDCoV) is a recently discovered enteropathogenic coronavirus and has caused significant economic impacts on the pork industry. Although studies have partly uncovered the molecular mechanism of PDCoV-host interaction, it requires further research. In this study, we explored the roles of Stromal Antigen 2 (STAG2) in PDCoV infection. We found that STAG2-deficient cells inhibited infection with vesicular stomatitis virus (VSV) and PDCoV, whereas restoration of STAG2 expression in STAG2-depleted (STAG2-/-) IPEC-J2 cells line restored PDCoV infection, suggesting that STAG2 is involved in the PDCoV replication. Furthermore, we found that STAG2 deficiency results in robust interferon (IFN) expression. Subsequently, we found that STAG2 deficiency results in the activation of JAK-STAT signaling and the expression of IFN stimulated gene (ISG), which establish an antiviral state. Taken together, the depletion of STAG2 activates the JAK-STAT signaling and induces the expression of ISG, thereby inhibiting PDCoV replication. Our study provides new insights and potential therapeutic targets for unraveling the mechanism of PDCoV replication.

Impact of High-Speed Rail on the Development Efficiency of Low-Carbon Tourism: A Case Study of an Agglomeration in China

As an important indicator for measuring the development level of low-carbon tourism, reducing the carbon emissions of tourism transportation has become an essential strategic goal and task for the sustainable development of tourism. Among many tourism vehicles, high-speed rails have a significant role in reducing the carbon emissions of tourism transportation. To clarify the impact of high-speed rails on the development efficiency of low-carbon tourism, using the relevant data of Zhengzhou urban agglomeration from 2010 to 2020, the DEA-BCC model and the Malmquist index method were used to measure these data. The results show the following: (1) the average comprehensive development efficiency of the Zhengzhou metropolitan high-speed rail for low-carbon tourism is low, and the comprehensive development efficiency of each city varies greatly;(2) the impact of high-speed rails on the development efficiency of low-carbon tourism in some underdeveloped areas is increasing. The impact on the development efficiency of low-carbon tourism in more developed areas is declining;(3) affected by COVID-19, tourism carbon emissions have shown a downward trend, reflecting the importance of low-carbon travel to low-carbon tourism to a certain extent. The research results not only verify the existing research conclusions but also verify the role of high-speed rails in the development of low-carbon tourism, and have practical value with respect to targeted guidance for the development of low-carbon tourism.

Understanding Consumer Online Impulse Buying in Live Streaming E-Commerce: A Stimulus-Organism-Response Framework.

With the proliferation of live streaming, there is evidence that online impulse buying is becoming an emerging phenomenon. Although many studies have investigated impulse buying in the context of offline shopping and business-to-consumer e-commerce, online impulse buying in live streaming has attracted little attention. In this study, we aim to explore the effect of social presence in live streaming on customer impulse buying based on the stimulus-organism-response framework. The research model presented here identifies pleasure and arousal as the mediation of impulse buying in live streaming. We use the AMOST and IBM SPSS PROCESS software to estimate our model based on data at the minute level from 189 customers, who watched live streaming in the past three months. The results suggest that the social presence of the broadcaster and the social presence of the live streamer positively affect impulse buying directly and indirectly via pleasure and arousal, promoting consumer online impulse buying in live streaming, but the social presence of the viewers has no significant effect on pleasure and arousal. For practice, our results can help policymakers and operators of the live streaming platform alleviate impulse buying in the digital world.

Transportation connectivity strategies and regional tourism economy - empirical analysis of 153 cities in China

PurposeA transportation connectivity strategy is a crucial part of an adaptive, congruent and sustainable tourism transportation system and is of concern to countries focusing on growing their tourism economy. This study aims to gain a better understanding of the relationship between transportation connectivity and the tourism economy through a configuration analysis.Design/methodology/approachThis study uses fuzzy-set qualitative comparative analysis on a sample of 153 cities in China to provide an understanding of the impacts of transportation connectivity strategies, with the co-effecting factors of socio-economic status, tourism resource endowment and hospitality capacity, on the development of regional tourism economies.FindingsThere are multiple paths that lead to regional tourism economic development (a high level of tourist arrivals or a high level of tourism revenue). High-speed rail can play a supportive role, while air travel or traditional rail remains central to the tourism economy. Socio-economic status (i.e. city size and city gross domestic product) and hospitality capacity are identified as crucial influencers for the development of the tourism economy.Research limitations/implicationsThis study confirms the validity of deploying configuration analysis (based on the equifinality theory) to establish the relationship between transportation and the tourism economy. The finding of more than one configuration led to a new consensus on how multiple factors influence the tourism economy.Practical implicationsSuggestions on transportation connectivity strategies for different regions are provided.Originality/valueThis study demonstrates the need to place greater emphasis on configurations that lead to tourism economy development instead of the effect of a single transportation mode.

Porcine epidemic diarrhea virus antagonizes host antiviralresponse by downregulating the expression of FBXW7

To investigate the interaction between FBXW7 and PEDV infection, the endogenous expression level of FBXW7was assessed after PEDV infection. The results showed that PEDV infection inhibited the expression of FBXW7 in Vero E6 cells. Then the effects of FBXW7 on PEDV replication was evaluated by western blot after transfection of pCAGGS-HA-FBXW7 to VeroE6 cells. The results showed that PEDV N proteins were significantly suppressed by FBXW7 overexpression, indicating theinhibitory effect of FBXW7 on PEDV replication. Further using fluorescent quantitative kit to detect the influence of overexpressingFBXW7 on interferon and interferon-stimulated genes under PEDV infection conditions, the results showed that compared with thepCAGGS-HA control group, The transcription level of IFN-beta, ISG15, ISG54 and ISG56 were significantly enhanced in host cellstransfected with pGAGGS-HA-FBXW7 (p0.05). Collectively, PEDV replication was facilitated by down regulating the expressionof FBXW7, which provides a novel strategy utilizing by PEDV to antagonize the host innate immune response.

Porcine Epidemic Diarrhea Virus nsp15 Antagonizes Interferon Signaling by RNA Degradation of TBK1 and IRF3.

Porcine epidemic diarrhea virus (PEDV) causes a porcine disease associated with swine epidemic diarrhea. The type I interferon (IFN-I or IFN α/ß) is a key mediator of innate antiviral response during virus infection. Different antagonistic strategies have been identified and determined as to how PEDV infection inhibits the host's IFN responses to escape the host innate immune pathway, but the pathogenic mechanisms of PEDV infection are not fully elucidated. Our preliminary results revealed that endogenous TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), the key components in the IFN signaling pathway were downregulated in PEDV infected IPEC-J2 cells by iTRAQ analysis. In this study, we screened nsp15 as the most important viral encoded protein involved in TBK1 and IRF3 reduction. Endoribonuclease (EndoU) activity has been well determined for coronavirus nsp15. Three residues (H226, H241, and K282) of PEDV nsp15 were identified as critical amino acids for PEDV EndoU but not D265, which was not well correlated with published results of other coronaviruses, such as severe acute respiratory syndrome virus (SARS-CoV). Moreover, PEDV nsp15 can directly degrade the RNA levels of TBK1 and IRF3 dependent on its EndoU activity to suppress IFN production and constrain the induction of IFN stimulated genes (ISGs), by which PEDV antagonizes the host innate response to facilitate its replication. Collectively, these results have confirmed that PEDV nsp15 was capable of subverting the IFN response by the RNA degradation of TBK1 and IRF3.