In Situ Polymerization-Mediated Antigen Presentation.

Activating antigen-presenting cells is essential to generate adaptive immunity, while the efficacy of conventional activation strategies remains unsatisfactory due to suboptimal antigen-specific priming. Here, in situ polymerization-mediated antigen presentation (IPAP) is described, in which antigen-loaded nanovaccines are spontaneously formed and efficiently anchored onto the surface of dendritic cells in vivo through co-deposition with dopamine. The resulting chemically bound nanovaccines can promote antigen presentation by elevating macropinocytosis-based cell uptake and reducing lysosome-related antigen degradation. IPAP is able to prolong the duration of antigen reservation in the injection site and enhance subsequent accumulation in the draining lymph nodes, thereby eliciting robust antigen-specific cellular and humoral immune responses. IPAP is also applicable for different antigens and capable of circumventing the disadvantages of complicated preparation and purification. By implementation with ovalbumin, IPAP induces a significant protective immunity against ovalbumin-overexpressing tumor cell challenge in a prophylactic murine model. The use of the SARS-CoV-2 Spike protein S1 subunit also remarkably increases the production of S1-specific immunoglobulin G in mice. IPAP offers a unique strategy for stimulating antigen-presenting cells to boost antigen-specific adaptive responses and proposes a facile yet versatile method for immunization against various diseases.

Research on price transmission in Chinese mining stock market: Based on industry

The strong impact of COVID-19 on the global mining market has caused severe fluctuations in the prices of mineral products and mining stocks. Meanwhile, geopolitical conflicts have exacerbated risks in minerals trade and mining stock transactions. In the face of uncertainties in the international economic landscape and volatility of stock prices, China, as the world's major mineral trading country, has become increasingly linked between its stock market and the mining economy. To clarify the characteristics of mining stock price fluctuations and the evolution of the transmission relationships, and identify the key nodes and main paths of price transmission, we select 100 Chinese mining stocks from January 2019 to October 2022, distinguish them according to the industry category, and use Granger causality test, minimum spanning tree model and complex network analysis method to study. The results show that: (1) Chinese mining stock prices have risen significantly since 2020, and there has been a "decoupling” phenomenon within the stock market, that is, the linkage between some mining stocks has weakened. (2) The stock price fluctuation characteristics and transmission effects of different mining industries are obviously different. Precious metal minerals (PM) have the most dramatic changes in price fluctuations, the most prominent hedging characteristics, and the rapid price response ability, which is the first to accept price transmission. rare earth and rare metal minerals (RE) are sensitive to price fluctuations and are usually the "leader” of the transmission path. Bulk non-ferrous minerals (BNFM) have the most stable price fluctuations and are closely related to other stocks, which is a "transit warehouse” in the transmission path. (3) The price transmission mechanism of Chinese mining stock market has gradually stabilized, and the main transmission paths of "Coal→Agricultural minerals (Agri)→BNFM→Steel” and "PM, Core minerals for new energy (NEM), and RE→BNFM” have been formed in 2022.

PIMT is a novel and potent suppressor of endothelial activation.

Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.

Relation between young children's anger and fathers' mental health during the covid-19 epidemic: Moderating role of gender and child number

The father-child interaction deserves attention during the COVID-19 epidemic. This study administrated the Child Anger Questionnaire and the SCL-90 Symptom Checklist to collect primary data from 1862 fathers of Chinese young children during the COVID-19 outbreak, examined the relation between young children's anger and their fathers' mental health, and verified whether the relation was moderated by the gender or the child number. The results demonstrated that the detection rate of anger among Chinese young children was 60.08%, the scores of SCL-90 factors of their fathers were significantly lower than the Chinese normal adult male norms and those of infant parents, and the anger of young children had a significant effect on their fathers' mental health. Gender and child number moderated this relation. It is of great significance to strengthen the attention to the anger of young children and the mental health of fathers during the period of public health emergencies, and to promote the harmonious interpersonal relationship between young children and their fathers. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

Global prevalence of self-harm during the COVID-19 pandemic: a systematic review and meta-analysis.

BACKGROUND: COVID-19 and its transmission mitigation measures have caused widespread mental health problems. Previous studies have suggested that psychological, economic, behavioral, and psychosocial problems associated with the COVID-19 pandemic may lead to a rise in self-harm. However, little is known about the prevalence of self-harm worldwide during COVID-19. Therefore, a quantitative synthesis is needed to reach an overall conclusion regarding the prevalence of self-harm during the pandemic. METHODS: By using permutations of COVID-19, self-harm or relevant search terms, we searched the following electronic databases from November 2019 to January 2022: Web of Science, PubMed, MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, China National Knowledge Infrastructure (CNKI), Wanfang Database and systematically reviewed the evidence according to MOOSE guidelines. We employed Cochran's chi-squared test (Cochran's Q), I2test and subgroup analysis to assess and address the heterogeneity. Sensitivity analysis was conducted by eliminating each included study individually and then combining the effects. RESULTS: Sixteen studies that met the inclusion and exclusion criteria were identified, with sample sizes ranging from 228 to 49,227. The methodological quality of the included studies was mostly at the medium level. By using a random effect model, the pooled prevalence of self-harm was 15.8% (95% CI 13.3-18.3). Based on subgroup analysis, the following characteristics of the included studies were more likely to have a higher prevalence of self-harm: studies conducted in Asia or prior to July 2020, cross-sectional studies, samples recruited in hospitals or schools, adolescents, females, the purpose of self-harm (NSSI), mental symptoms and restriction experiences. CONCLUSIONS: We provided the first meta-analytic estimated prevalence of self-harm based on a large sample from different countries and populations. The prevalence of self-harm during COVID-19 was not encouraging and requires attention and intervention. Further high-quality and prospective research are needed in order to determine the prevalence of self-harm with greater accuracy because to the clear heterogeneity across the included studies. In addition, this study also provides new directions for future research, including the identification of high-risk groups for self-harm, the formulation and implementation of prevention and intervention programs, and the long-term impact of COVID-19 on self-harm.

A Newly Identified Spike Protein Targeted Linear B-Cell Epitope Based Dissolvable Microneedle Array Successfully Eliciting Neutralizing Activities against SARS-CoV-2 Wild-Type Strain in Mice.

Vaccination is a cost-effective medical intervention. Inactivated whole virusor large protein fragments-based severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccines have high unnecessary antigenic load to induce allergenicity and/orreactogenicity, which can be avoided by peptide vaccines of short peptide fragments that may induce highly targeted immune response. However, epitope identification and peptide delivery remain the major obstacles in developing peptide vaccines. Here, a multi-source data integrated linear B-cell epitope screening strategy is presented and a linear B-cell epitope enriched hotspot region is identified in Spike protein, from which a monomeric peptide vaccine (Epitope25) is developed and applied to subcutaneously immunize wildtype BALB/c mice. Indirect ELISA assay reveals specific and dose-dependent binding between Epitope25 and serum IgG antibodies from immunized mice. The neutralizing activity of sera from vaccinated mice is validated by pseudo and live SARS-CoV-2 wild-type strain neutralization assays. Then a dissolvable microneedle array (DMNA) is developed to pain-freely deliver Epitope25. Compared with intramuscular injection, DMNA and subcutaneous injection elicit neutralizing activities against SARS-CoV-2 wild-type strain as demonstrated by live SARS-CoV-2 virus neutralization assay. No obvious damages are found in major organs of immunized mice. This study may lay the foundation for developing linear B-cell epitope-based vaccines against SARS-CoV-2.

Examining the impacts of a syphilis awareness campaign among gay, bisexual, and other men who have sex with men (gbMSM) in British Columbia, Canada.

OBJECTIVES: Syphilis rates have increased in BC and disproportionately affect gay, bisexual, and other men who have sex with men (gbMSM). A social marketing campaign (Syphistory) ran from January to September 2017 with the primary goal of increasing syphilis knowledge and a secondary goal of increasing syphilis screening among gbMSM in BC. METHODS: We used pre- and post-campaign surveys to assess changes in syphilis knowledge from a convenience sample of clients attending STI clinics using one-sided t-tests. We used online Piwik metrics to examine the campaign reach, and provincial testing data to examine trends in syphilis screening. We used data from the Engage Study to examine factors associated with campaign awareness and associations with syphilis testing. RESULTS: Of the 2155 visitors to the Syphistory website with known geography, 79.4% were from BC. Moreover, STI clinic participants who saw the campaign demonstrated a greater knowledge of syphilis (9.7/12, 80.8%) than those who did not see the campaign (mean 8.9/12, 74%) (p < 0.001). Provincial syphilis testing rates were 8764 and 9749 in the 12 months before and after the campaign; however, we did not find an overall trend in testing before versus after the campaign (p = 0.147). Among Engage participants, 12.7% reported seeing the campaign and we found an association between campaign exposure and recent syphilis testing (aOR = 2.73; 95% CI = 1.51, 4.93). CONCLUSION: gbMSM who saw the campaign were more likely to report being tested for syphilis in the previous 6 months. STI clinic attendees who reported seeing the campaign also had higher syphilis knowledge compared to those who did not.

RéSUMé: OBJECTIFS: Les taux de syphilis ont augmenté en Colombie-Britannique et affectent de manière disproportionnée les hommes gais, bisexuels et autres hommes ayant des relations sexuelles avec des hommes (gbHARSAH). Une campagne de marketing social (Syphistory) a été mené de janvier à septembre 2017 avec pour objectif principal d'informer sur la syphilis et pour objectif secondaire d'augmenter le dépistage de la syphilis chez les gbHARSAH en Colombie-Britannique. MéTHODES: Nous avons réalisé deux sondages, l'un avant et l'autre après la campagne, sur un échantillon de convenance constitué de patients fréquentant des cliniques ITS, pour évaluer les changements dans les connaissances sur la syphilis à l'aide de tests t unilatéraux. Nous avons utilisé les mesures Piwik en ligne pour examiner la portée de la campagne et les données provinciales sur les tests pour examiner les tendances quant au dépistage de la syphilis. Nous avons utilisé les données de l'étude Engage à Vancouver, pour identifier les facteurs associés à la sensibilisation lors de la campagne et les associations avec le dépistage de la syphilis. RéSULTATS: Sur les 2 155 visiteurs du site Web Syphistory dont la position géographique était connue, 79,4 % provenaient de la Colombie-Britannique. De plus, les participants aux cliniques ITS ayant vu la campagne ont démontré une meilleure connaissance de la syphilis (9,7/12, 80,8 %) par rapport à ceux n'ayant pas vu la campagne (moyenne 8,9/12, 74 %) (p<0,001). Les taux provinciaux de dépistage de la syphilis étaient de 8 764 et 9 749 au cours des 12 mois précédant et suivant la campagne; cependant, nous n'avons pas trouvé de tendance globale à la hausse des dépistages suite à la campagne (p=0,147). Parmi les participants Engage, 12,7 % ont déclaré avoir vu la campagne en ligne et nous avons trouvé une association entre l'exposition à la campagne et le dépistage récent de la syphilis (RCa=2,73; IC à 95 %=1,51, 4,93). CONCLUSION: Les gbHARSAH qui ont vu la campagne étaient plus susceptibles de déclarer avoir été testés pour la syphilis au cours des six derniers mois. Les participants aux cliniques ITS qui ont déclaré avoir vu la campagne avaient également une meilleure connaissance de la syphilis que ceux qui ne l'ont pas vue.

REFRAMING HATE

The concept and naming of "hate crime," and the adoption of special laws to address it, provoked controversy and raised fundamental questions when they were introduced in the 1980s. In the decades since, neither hate crime itself nor those hotly debated questions have abated. To the contrary, hate crime has increased in recent years-although the prominent target groups have shifted over time-and the debate over hate crime laws has reignited as well. The still-open questions range from the philosophical to the doctrinal to the pragmatic: What justifies the enhanced punishment that hate crime laws impose based on the perpetrator's motivation? Does that enhanced punishment infringe on the perpetrator's rights to freedom of belief and expression? How can we know or prove a perpetrator's motivation? And, most practical of all: Do hate crime laws work? This Essay proposes that we reframe our understanding of what we label as hate crimes. It argues that those crimes are not necessarily the acts of hate-filled extremists motivated by deeply held, fringe beliefs, but instead often reflect the broader, even mainstream, social environment that has marked some social groups as the expected or even acceptable targets for crime and violence. In turn, hate crimes themselves influence the social environment by reinforcing recognizable patterns of discrimination. The Essay maintains that we should broaden our understanding of the motivations for and effects of hate crimes and draws connections between hate crimes and seemingly disparate phenomena that have recently captured the nation's attention.

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.

BACKGROUND: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS. METHODS: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332. FINDINGS: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection. INTERPRETATION: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Evaluation of [18F]Favipiravir in Rodents and Nonhuman Primates (NHP) with Positron Emission Tomography.

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [18F]Favipiravir in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [18F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [18F]Favipiravir in vivo. The [18F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET.

Preparation and characterization of nanobodies targeting SARS-CoV-2 papain-like protease.

Coronavirus Papain-like protease (PLpro) mediates the cleavage of viral polyproteins and assists the virus escaping from innate immune response. Thus, PLpro is an attractive target for the development of broad-spectrum drugs as it has a conserved structure across different coronaviruses. In this study, we purified SARS-CoV-2 PLpro as an immune antigen, constructed a nanobody phage display library, and identified a set of nanobodies with high affinity for SARS-CoV-2. In addition, enzyme activity experiments demonstrated that two nanobodies had a significant inhibitory effect on the PLpro. These nanobodies should therefore be investigated as candidates for the treatment of coronaviruses.

Evaluation of pharmacist impact on diabetes outcomes for telehealth and hybrid care delivery versus in-office visits.

BACKGROUND: Few studies have examined the effect of pharmacist-led telemanagement on diabetes outcomes during the COVID-19 pandemic. OBJECTIVES: Assess for noninferiority for the absolute change in mean A1C between telehealth and hybrid groups versus the in-office group during the COVID-19 pandemic. Secondary objectives were to compare the percentage of patients achieving population health A1C goals and patient no-show rates between study groups. METHODS: A retrospective, noninferiority analysis was conducted for patients seen by a primary care pharmacist from November 1, 2020 to May 31, 2021 across 17 primary care clinics in the Northeast Ohio region of Cleveland Clinic. The noninferiority margin was prespecified at > 0.3% A1C reduction. Patients with a baseline A1C of 8% or greater were included. Patients were separated into 3 study groups (telehealth, in-office, and hybrid) based on the visit types that were conducted by the pharmacist during the study period. RESULTS: Hybrid care delivery (N = 366) was noninferior to in-office care delivery (N = 180), with regards to absolute change in mean A1C reduction (0.24% [95% CI: -0.13, 0.61], P = 0.002). Similar results were shown when comparing the telehealth group (N = 691) to the in-office group (0.04 [95% CI: -0.28, 0.36], P = 0.02). The mean A1C reduction in the in-office (1.36 ± 1.9), hybrid (1.60 ± 2.2), and telehealth (1.40 ± 2.0) groups were not significantly different (P = 0.23). Subgroup analyses showed that newly consulted patients had a larger reduction in A1C compared to the overall population, in all groups. No-show rates and percentage of patients achieving population health A1C goals were not significantly different based on visit type. CONCLUSION: Telehealth and hybrid visit types were noninferior to in-office visits with regards to mean change in A1C reduction. Results demonstrate the importance of primary care pharmacists continuing to offer diverse visit types based on patient preference.

COVID-19 risk perception and tourist satisfaction: A mixed-method study of the roles of destination image and self-protection behavior.

This study aimed to examine the effects of COVID-19 risk perception on negative destination image and self-protection behavior, and the resultant effects on tourist satisfaction. Hence, this study applied a continuous interpretive mixed-method design combining quantitative and qualitative analyses. A quantitative survey (n = 486) in the cities of Ningbo, Huangshan, and Chengdu, China, and 19 qualitative interviews were conducted online. The results of the quantitative study show that: (1) Risk perception and negative destination image are antecedent variables influencing tourist satisfaction, and (2) there are significant positive correlations between risk perception and negative destination image, risk perception and tourist self-protection behavior, and negative destination image and tourist self-protection behavior. Moreover, (3) negative destination image had a partial mediating effect between risk perception and satisfaction. Furthermore, to supplement the research data and expand the quantitative findings, this study further examined whether the above variables are related to tourist satisfaction, through in-depth interviews with tourists. The findings showed that COVID-19 risk perception, negative destination image, and self-protection behavior all affect tourist satisfaction. The findings provide valuable crisis management suggestions for the government and should contribute to the efforts of tourist destinations to build a healthy and safe image, thereby contributing to the sustainable development of tourism industries in the post-epidemic era.

Effect of Chinese young children's epidemic cognition on their coping behavior: mediating role of emotion.

INTRODUCTION: Young children's epidemic awareness and risk prevention about public health emergencies such as the COVID-19 are issues of great importance deserving research. OBJECTIVE: To explore the effect of young children's epidemic cognition on their coping behavior, and the mediating role of emotion. METHOD: An online anonymous survey was administrated on 2221 Chinese parents of young children aged three to six during the COVID-19 overwhelming period. RESULTS: (1) The epidemic cognition (M = 4.17, SD = 0.73), the coping behavior (M = 4.16, SD = 0.65), and the emotion (M = 3.99, SD = 0.81) were at a relatively high level. (2) Young children's epidemic cognition significantly predicted their coping behavior (ß = 0.71, t = 45.29, P < 0.001). The positive prediction effect of epidemic cognition on young children's emotion was significant (ß = 0.19, t = 8.56, P < 0.001), and emotion had a significant positive predictive effect on young children's coping behavior (ß = 0.20, t = 4.89, P < 0.001). CONCLUSION: Young children's epidemic cognition can significantly predict their coping behavior, and emotion plays a significant mediating role in their relation. It is necessary for practitioners to optimize the contents and methods of epidemic education on young children.

Impaired Humoral Immunity Identified in Inactivated SARS-CoV-2 Vaccine Recipients without Anti-Spike RBD Antibodies.

Inactivated SARS-CoV-2 vaccines have been deployed in a significant portion of the world population, who have widely varied responses to vaccination. Understanding this differential response would help the development of new vaccines for non-responders. Here, we conducted surveillance of anti-Spike receptor-binding domain (RBD) antibody levels in a large cohort of 534 healthy Chinese subjects vaccinated with two doses of inactivated SARS-CoV-2 vaccines. We show that the positive rate of antibodies among vaccinated subjects rapidly wanes as the interval between antibody testing and vaccination increases (14 to 119 days: 81.03%, 363 of 448 subjects; 120 to 149 days: 46.43%, 13 of 28 subjects; more than 150 days: 20%, 1 of 5 subjects). However, the antibodies were maintained at high levels in 16 convalescent COVID-19 patients at more than 150 days after recovery. We also found that increased age and body mass index are associated with decreased antibody levels. Vaccinated subjects who fail to produce antibodies display impaired B-cell activating humoral immunity, which was confirmed in COVID-19 patients without antibodies detected at 4 to 18 days after diagnosis. IMPORTANCE Our study illustrates the immune responses engaged by encountering antigen, highlighting the critical roles of B-cell activating humoral immunity in the body's antibody production.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the road for future clinical trials.

Dressing Bacteria With a Hybrid Immunoactive Nanosurface to Elicit Dual Anticancer and Antiviral Immunity.

Approaches capable of simultaneously treating cancer and protecting susceptible patients from lethal infections such as coronavirus disease 2019, are highly desirable but prove to be difficult. Here, dressing bacteria with a hybrid immunoactive nanosurface is reported to elicit dual anticancer and antiviral immunity. A combination of a checkpoint blocking antibody and a virus-specific antigen is covalently conjugated to polydopamine nanoparticles, which can be anchored onto bacterial surface, by a one-step in situ polymerization of dopamine under a cell-friendly condition. By virtue of the ability to colonize and penetrate deep tumor tissue, dressed bacteria enable sustained release and expanded exposure of carried immunoactivators to stimulate immune cells. In addition to a carrier role, bacteria are able to further provoke innate immunity due to the native immunogenicity of the pathogen-associated molecular patterns. Immunization with dressed bacteria promotes the maturation, and activation of antigen-presenting cells, which induces robust humoral and cellular immune responses in tumor-bearing mice. As evidenced by efficient production of viral-antigen-specific immunoglobulin G antibody in serum and significantly suppressed tumor growth in different models, dressing bacteria with a hybrid immunoactive nanosurface paves an avenue to prepare next-generation therapeutics for synergistic treatment and prevention.

Chiral-Selective Antigen-Presentation by Supramolecular Chiral Polymer Micelles.

Chirality is ubiquitous in biological systems, which is closely related to biological functions, life process, and even pathogenesis of diseases. However, the interface between the chirality of synthetic materials and organisms, particularly the immune system, remains poorly understood. Here, supramolecular chiral polymer micelles (SCPMs) are prepared by complexing antigenic proteins with chiral amino acid modified polyethyleneimine. The introduction of chirality not only reduces the toxicity of cationic polymer, but also benefits cell uptake and antigen presentation. Especially, D-chirality presents the lowest cytotoxicity, while promotes the highest expression level of costimulatory molecules on dendritic cells compared to L-chirality and achirality. The superiority of D-chirality to stimulate dendritic cell maturation is supported by immunization with D-SCPMs, which achieves significant antigen-specific proliferation of T cells in the spleen, lymph nodes and tumor of mice. Chirality-mediated antigen processing and presentation is demonstrated by D-SCPMs self-assembled from chiral alkaline histidine or neutral phenylalanine modified polyethyleneimine and tumor associated ovalbumin or severe acute respiratory syndrome coronavirus 2 spike 1 antigenic protein. Immunoactivation enabled by D-chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment. This article is protected by copyright. All rights reserved.

Increasing Couriers' Job Satisfaction through Social-Sustainability Practices: Perceived Fairness and Psychological-Safety Perspectives.

Due to the spike in online-retail demand during the pandemic, couriers confront increased workload and safety concerns, posing significant social-sustainability challenges for courier companies. This study explores the impact of social-sustainability practices on couriers' job satisfaction in the context of the COVID-19 pandemic. We designed the research model from the theoretical lens of Maslow's hierarchy of needs, equity, and psychological-safety theories. We collected the views of 428 couriers from the Chinese market, where there is a developed e-commerce industry. The structural-equation-model analysis results found that social-sustainability practices such as working environment, working conditions, health and safety, education, and training positively affected the job satisfaction of couriers during the pandemic through the mediators (psychological safety and perceived fairness). These findings provide empirical recommendations for improving employees' job satisfaction in courier companies during COVID-19 and addressing the social-sustainability issues of courier companies.