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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the respiratory mucosa. We developed a vaccine strategy that we call “prime and spike,” which leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike). We show that prime and spike induces robust resident memory B and T cell responses, induces immunoglobulin A at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, prime and spike enables the induction of cross-reactive immunity against sarbecoviruses.

This study aims to investigate whether globalisation promotes economic output in Sub-Saharan African countries in both the short run and the long run. Based on the latest version of the KOF globalisation index, we employ a newly developed bootstrap autoregressive distributed lag model to analyse this question. Compared to the traditional autoregressive distributed lag model, which ignores the degenerate cases, the new approach could avoid spurious cointegration. Results show that globalisation and economic output are positively correlated for most Sub-Saharan African countries, while the causal effect cannot be concluded except for a couple of exceptions. This finding implies that globalisation cannot guarantee an increase in economic output in the long run for most Sub-Saharan African countries. The Granger causality test shows that globalisation leads to economic output for Burundi, Gabon, Rwanda, Senegal and Zambia in the short run. Conversely, economic output leads to globalisation for Burkina Faso, Cameroon, Ghana, Kenya and Senegal. For Senegal, globalisation and economic output mutually determine each other and therefore form a positive spiral development path. Policymakers should be aware of the specific features of different economies in making sound globalisation policies to avoid the underlying adverse effects of global integration.

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain1-3. Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.One-sentence summaryBroad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.

The Sichuan-Chongqing region is the leader and growth pole of economic development in western China. With the rapid development of economy and unique geographical environment, high concentration of sulfur dioxide air pollution has existed for a long time in Sichuan-Chongqing area. Based on 10 years of remote sensing data, this paper studies the temporal and spatial distribution characteristics, stability, and influencing factors of sulfur dioxide in this area. Based on potential sources, the impact of surrounding areas on sulfur dioxide in Sichuan and Chongqing is analyzed. The results shows that the spatial distribution of sulfur dioxide in the Sichuan-Chongqing region is higher in the southeast and lower in the west. The Midwest region has low fluctuation and good stability. The time distribution shows obvious seasonal regularity. The concentration of sulfur dioxide is affected by socio-economic factors and natural factors. In this study, it is found that the distribution of sulfur dioxide is closely related to PM2.5, which provides an important reference for the comprehensive management of air pollution. The OMI data effectively reflects the distribution and change of atmospheric sulfur dioxide in the Sichuan-Chongqing region, and provides certain ideas for air pollution control in the Sichuan-Chongqing region and other regions in China.

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)–dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.

A stem-loop RNA (SLR) RIG-I agonist is effective in preventing and treating acute SARS-CoV-2 infection in mice. A single injection of SLR can clear chronic SARS-CoV-2 in immunocompromised mice. SLR is effective against the ancestral virus as well as variants of concern., As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)–dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients., Graphical Abstract

The Sichuan-Chongqing region is the leader and growth pole of economic development in western China. With the rapid development of economy and unique geographical environment, high concentration of sulfur dioxide air pollution has existed for a long time in Sichuan-Chongqing area. Based on 10 years of remote sensing data, this paper studies the temporal and spatial distribution characteristics, stability, and influencing factors of sulfur dioxide in this area. Based on potential sources, the impact of surrounding areas on sulfur dioxide in Sichuan and Chongqing is analyzed. The results shows that the spatial distribution of sulfur dioxide in the Sichuan-Chongqing region is higher in the southeast and lower in the west. The Midwest region has low fluctuation and good stability. The time distribution shows obvious seasonal regularity. The concentration of sulfur dioxide is affected by socio-economic factors and natural factors. In this study, it is found that the distribution of sulfur dioxide is closely related to PM

The goal of this study was to understand the current status of ozone pollution in Northeast China and to distinguish the main influencing factors of ozone, in order to provide a scientific basis for the future prevention and control of ozone in this region. In this study, the Ozone Monitoring Instrument data product was used as the source data, and the pixel space analysis method and grey correlation analysis method were utilized to examine the tropospheric ozone column concentration in Northeast China from 2010 to 2018. The results revealed that the ozone column concentration in Northeast China was relatively high compared to other parts of the country. The high-value areas were primarily distributed in Tahe County, Heihe City, Hegang City, and Qiqihar City. The temporal variation of the ozone column concentration in Northeast China exhibited an obvious periodicity of 9 years, and its interannual change displayed a downward trend. The maximum value occurred in 2010, and the minimum value was found in 2016. The seasonal changes manifested a relative trend of spring > winter > summer > autumn, which was contrary to the research results for other parts of China, which showed a summer maximum. Among the influencing factors, atmospheric pressure, relative humidity, sunshine hours, GDP, and primary and secondary industries exhibited the closest relationships with ozone. The high concentration of ozone in Northeast China was determined to result from the superimposed effects of long-distance atmospheric transport and anthropogenic emissions.

Israelow et al. show that AAV-mediated expression of human ACE2 allows for SARS-CoV-2 infection and disease investigation in mice. This pathology is in part driven by type I interferon signaling, which recruits inflammatory immune cells without aborting viral replication., Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus’s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)–mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds., Graphical Abstract

Endogenous retroviruses (ERV) are found throughout vertebrate genomes and failure to silence their activation can have deleterious consequences on the host. Introduction of mutations that subsequently prevent transcription of ERV loci is therefore an indispensable cell-intrinsic defense mechanism that maintains the integrity of the host genome. Abundant in vitro and in silico evidence have revealed that APOBEC3 cytidine-deaminases, including human APOBEC3G (hA3G) can potently restrict retrotransposition; yet in vivo data demonstrating such activity is lacking, particularly since no replication competent human ERV has been identified. In mice deficient for Toll-like receptor 7 (TLR7), transcribed ERV loci can recombine and generate infectious ERV. In this study, we show that mice deficient in the only copy of Apobec3 in the genome did not have spontaneous reactivation of ERVs, nor elevated ERV reactivation when crossed to Tlr7-/- mice. In contrast, expression of a human APOBEC3G transgene abrogated emergence of infectious ERV in the Tlr7-/- background. No ERV RNA was detected in the plasma of hA3G+Apobec3-/-Tlr7-/- mice, and infectious ERV virions could not be amplified through co-culture with permissive cells. These data reveal that hA3G can potently restrict active ERV in vivo, and suggest that the expansion of the APOBEC3 locus in primates has helped restrict ERV reactivation in the human genome.ImportanceAlthough APOBEC3 proteins are known to be important antiviral restriction factors in both mice and humans, their roles in the restriction of endogenous retroviruses (ERV) have been limited to in vitro studies. Here, we report that human APOBEC3G expressed as a transgene in mice prevents the emergence of infectious ERV from endogenous loci. This study reveals that APOBEC3G can powerfully restrict active retrotransposons in vivo and demonstrates how ectopic expression of human factors in transgenic mouse models can be used to investigate host mechanisms that inhibit retrotransposons and reinforce genomic integrity.

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not known. Here we used herpes simplex virus type 2 (HSV-2) infection and found that mice deficient in Toll-like receptor 7 (Tlr7−/−) that have high systemic levels of infectious ERVs are resistant to intravaginal HSV-2 infection compared with wildtype C57BL/6 (B6) mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7−/− background (Emv2−/−Tlr7−/−) and found that Emv2−/−Tlr7−/− mice are no longer protected against HSV-2. Intravaginal application of purified ERVs prior to HSV-2 infection in both B6 and highly susceptible interferon-alpha receptor-deficient (Ifnar1−/−) mice delayed disease course. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7−/− mice or B6 mice treated with purified ERVs. Instead, we observed enhanced expression of epithelial tight junction protein, E-cadherin, in the vaginal epithelium of ERV-treated B6 mice. Similar increase in tight junction proteins was observed in Tlr7−/− but not in the Emv2−/−Tlr7−/− mice. Together, our results showed that IFN-independent modulation of the vaginal epithelium by ERVs protects mice against vaginal HSV-2 infection and lowers disease burden.

Flu immunity shows its age As we age, our immune systems change; in many ways not for the better. For instance, the elderly account for 90% of influenza deaths annually. Pillai et al. now report that influenza-infected human monocytes, a type of immune cell, exhibit reduced antiviral activity. In influenza-infected mice, two innate immune sensing pathways work together to promote antiviral immunity to influenza. Mice lacking antiviral immunity (similar to the situation in elderly people) had elevated bacterial burdens in their lungs and increased inflammatory responses, which both contributed to their increased susceptibility to influenza. Science , this issue p. 463

Recent studies have revealed that cytosolic nucleic acid-sensing pathways such as cGAS-STING and RIG-I-MAVS are involved in cancer biology. How to employ agents or agonists of these pathways to develop new approaches for cancer treatment is a promising direction. In this study, we synthesized a unique, binding-specific RIG-I agonist called Stem Loop RNA (SLR) 14 and evaluated its in vivo anti-tumor efficacy. When tumor volume reached 40–80 mm3, SLR14 was delivered intratumorally, every 2–3 days, for a total of 5–6 doses. Our results show that, after SLR14 treatment, B16 melanoma growth was dramatically blocked and the mice displayed long-term survival. We also observed a significant increase of tumor-infiltrating lymphocytes, and demonstrated that anti-tumor efficacy of SLR14 was T cell-dependent using RAG−/− mice and T cell depletion. Next, we tested anti-tumor efficacy of SLR14 in the mice with immunogenic tumor --YUMMER1.7 (melanoma) or MC38 (colon cancer). Similarly, we also observed a significant delay of tumor growth and extended mouse survival. Moreover, combination treatment with SLR14 and anti-PD1 in these mice led to more remarkable antitumor effects than single treatment. Lastly, we found that SLR14 was mainly taken up by CD45+CD11b+ leukocytes including neutrophils and myeloid cells, suggesting that anti-tumor efficacy of SLR14 is initiated through activation of the RIG-I pathway in innate cells within the tumor microenvironment. Taken together, our data demonstrate that synthetic RIG-I agonist SLR14 is a promising therapeutic agent for a broad spectrum of tumor subtypes. A better understanding of nucleic-acid sensing mechanisms within the tumor microenvironment may yield novel approaches for cancer immunotherapy.

This article investigates the influence of tourism on foreign direct investment. Firms' foreign direct investment (FDI) decisions require detailed information about the host country's competitors, regulatory environment, work ethic, and culture. Incorporating tourism improves on existing research into FDI, which does not include measures for this complex information. Empirical analysis using a TOBIT methodology shows a positive and significant relationship between tourism and subsequent new foreign direct investment in the USA. Surprisingly, the analysis does not support expected industry-specific effects, which suggests that tourism associates with increased investment in capital-intensive as well as service industries.

Background The large conductance calcium-activated potassium channel alpha-subunit (Slo) is widely distributed throughout the body and plays an important role in a number of diseases. Prior work has shown that Slo, through its S10 region, interacts with β-catenin, a key component of the cytoskeleton framework and the Wnt signaling pathway. However, the physiological significance of this interaction was not clear. Methodology/Principal Findings Using a combination of proteomic and cell biology tools we show the existence of additional multiple binding sites in Slo, and explore in detail β-catenin interactions with the S10 region. We demonstrate that deletion of this region reduces Slo surface expression in HEK cells, which indicates that interaction with beta-catenin is important for Slo surface expression. This is confirmed by reduced expression of Slo in HEK cells and chicken (Gallus gallus domesticus leghorn white) hair cells treated with siRNA to β-catenin. HSlo reciprocally co-immunoprecipitates with β-catenin, indicating a stable binding between these two proteins, with the S10 deletion mutant having reduced binding with β-catenin. We also observed that mutations of the two putative GSK phosphorylation sites within the S10 region affect both the surface expression of Slo and the channel's voltage and calcium sensitivities. Interestingly, expression of exogenous Slo in HEK cells inhibits β-catenin-dependent canonical Wnt signaling. Conclusions and Significance These studies identify for the first time a central role for β-catenin in mediating Slo surface expression. Additionally we show that Slo overexpression can lead to downregulation of Wnt signaling.