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Dendritic cell (DC) modification to enhance antigen presentation is a valuable strategy in cancer immune therapy. Other than focusing on regulating interactions between DC and antigens, we intend to promote cell interactions between DC and T cell by cell surface engineering. T cell activation is greatly improved and generates higher tumor toxicity with the aid of the synthetic glycopolymer modified on the DC surface, although the glycopolymer alone shows no effect. The great promotion of DC–T cell attraction is revealed by cell image tracking in terms of both frequency and duration of contacts. Our findings provide a new method of T cell activation by these engineered "sweet DCs." This strategy is beneficial for developing more efficient DC-based vaccines.…

To affect the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies, or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop may decrease shedding duration and immune response intensity but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed before viral peak during presymptomatic infection could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration, not AUC, is most predictive of clinical severity.…

The adaptor proteins, STING and MAVS, are components of critical pathogen-sensing pathways that induce innate immunity. Phosphorylation of either adaptor results in activation of the type I interferon pathway. How this phosphorylation is regulated and how it is manipulated by pathogens remain largely unknown. Here, we identified host protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G) as a negative regulator of innate immune pathways and showed that this host system is hijacked by Kaposi’s sarcoma-associated herpesvirus (KSHV). Mechanistically, KSHV tegument protein ORF33 interacts with STING/MAVS and enhances recruitment of PPM1G to dephosphorylate p-STING/p-MAVS for immunosuppression. Inhibition of PPM1G expression improves the antiviral response against both DNA and RNA viruses. Collectively, our study shows that PPM1G restricts both cytosolic DNA– and RNA–sensing pathways to naturally balance the intensity of the antiviral response. Manipulation of PPM1G by KSHV provides an important strategy for immune evasion.…

We study the role of social connections in compliance of U.S. households with mobility restrictions imposed in response to the coronavirus disease 2019 (COVID-19) pandemic, using aggregated and anonymized Facebook data on social connections and mobile phone data for measuring social distancing at the county level. Relative to the average restriction efficacy, a county with one-SD more social connections with China and Italy—the first countries with major COVID-19 outbreaks—has a nearly 50% higher compliance with mobility restrictions. By contrast, social connections of counties with less-educated populations, a higher Trump vote share, and a higher fraction of climate change deniers show decreased compliance with mobility restrictions. Our analysis suggests that social connections are conduits of information about the pandemic and an economically important factor affecting compliance with, and impact of, mobility restrictions.…

Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8–dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved. Here, we report that caspase-8–dependent GSDMD cleavage confers susceptibility to tumor necrosis factor (TNF)–induced lethality independently of caspase-1 and that GSDMD activation provides host defense against Yersinia infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti-Yersinia defense. Last, we show that caspase-8 dimerization and autoprocessing are required for GSDMD cleavage, and provide evidence that the caspase-8 autoprocessing and activity on various complexes correlate with its ability to directly cleave GSDMD. These findings reveal GSDMD as a potential therapeutic target to reduce inflammation associated with mutations in the death receptor signaling machinery.…

Microglia are the tissue-resident macrophages in the central nervous system and are critically involved in immune defense, neural development and function, and neuroinflammation. The versatility of microglia has long been attributed to heterogeneity. Recent studies have revealed possible heterogeneity in human but not in murine microglia, yet a firm demonstration linking microglial heterogeneity to functional phenotypes remains scarce. Here, we identified two distinct microglial populations in adult zebrafish that differ in morphology, distribution, development, and function. The predominant population, phagocytotic microglia, which expresses ccl34b.1, is broadly distributed, amoeboid in shape, highly mobile, and phagocytotic. The other white matter–enriched ccl34b.1– population, regulatory microglia, has ramified protrusions but has limited mobility and phagocytosis capability. These functional differences are further supported by distinct transcriptomes and responses to bacterial infection, where ccl34b.1+ microglia function in tissue clearance and ccl34b.1– microglia release immune regulators. Our study sheds light on the heterogeneity and functional diversification of microglia.…

Introduction Rapid technology development due to the introduction of Industrial Revolution 4.0 and Internet of Things has created a demand and gradual transition from traditional teaching and learning to technology-based learning in higher education, including healthcare education. The COVID-19 pandemic has accelerated this process, with educators now required to quickly adapt to and adopt such changes. The abundance of available systematic reviews has made the effectiveness of such approaches ambiguous especially in healthcare education. Therefore, a protocol of the overview of systematic reviews (OoSR) is planned to extrapolate the effectiveness of technology-based learning in undergraduate healthcare education. Methods and analysis Scopus, CINAHL, Academic Search Complete, Cochrane Library, MEDLINE and Psychology and Behavioral Sciences Collection databases were selected. Screening was conducted independently by at least two authors and the decision for inclusion was done through discussion or involvement of an arbiter against a predetermined criteria. Included articles will be evaluated for quality using A MeaSurement Tool to Assess systematic Reviews and Risk of Bias in Systematic Review tools, while primary systematic review articles will be cross-checked and reported for any overlapping using the ‘corrected covered area’ method. Only narrative synthesis will be employed according to the predefined themes into two major dimensions—theory and knowledge generation (focusing on cognitive taxonomy due to its ability to be generalised across disciplines), and clinical-based competence (focusing on psychomotor and affective taxonomies due to discipline-specific influence). The type of technology used will be identified and extracted. Ethics and dissemination The OoSR involves analysis of secondary data from published literature, thus ethical approval is not required. The findings will provide a valuable insight for policymakers, stakeholders, and researchers in terms of technology-based learning implementation and gaps identification. The findings will be published in several reports due to the extensiveness of the topic and will be disseminated through peer-reviewed publications and conferences. PROSPERO registration number CRD4202017974.…