Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, ...and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.
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•CH25H and its enzymatic product, 25HC, inhibit ZIKV entry in vitro•25HC attenuates ZIKV-associated viremia and disease in mice and non-human primates•25HC prevents ZIKV infection in human cortical organoids•25HC protects fetal mice from microcephaly caused by ZIKV infection
Zika virus (ZIKV) presents a major challenge to the global health system. Li et al. find that 25-hydroxycholesterol (25HC) inhibits ZIKV infection in monkeys and human cortical organoids and protects mice from microcephaly. 25HC has potential as a first-line antiviral agent to combat a broad array of pathogenic species, including ZIKV.
Hypoxia and the Tumor Microenvironment Li, Yue; Zhao, Long; Li, Xiao-Feng
Technology in Cancer Research & Treatment,
2021, Letnik:
20
Book Review, Journal Article
Recenzirano
Odprti dostop
Hypoxia is an important feature of the tumor microenvironment, and is closely associated with cell proliferation, angiogenesis, metabolism and the tumor immune response. All these factors can further ...promote tumor progression, increase tumor aggressiveness, enhance tumor metastatic potential and lead to poor prognosis. In this review, these effects of hypoxia on tumor biology will be discussed, along with their significance for tumor detection and treatment.
Thermal barrier coatings (TBCs) can effectively protect the alloy substrate of hot components in aeroengines or land-based gas turbines by the thermal insulation and corrosion/erosion resistance of ...the ceramic top coat. However, the continuous pursuit of a higher operating temperature leads to degradation, delamination, and premature failure of the top coat. Both new ceramic materials and new coating structures must be developed to meet the demand for future advanced TBC systems. In this paper, the latest progress of some new ceramic materials is first reviewed. Then, a comprehensive spalling mechanism of the ceramic top coat is summarized to understand the dependence of lifetime on various factors such as oxidation scale growth, ceramic sintering, erosion, and calcium-magnesium-aluminium-silicate (CMAS) molten salt corrosion. Finally, new structural design methods for high-performance TBCs are discussed from the perspectives of lamellar, columnar, and nanostructure inclusions. The latest developments of ceramic top coat will be presented in terms of material selection, structural design, and failure mechanism, and the comprehensive guidance will be provided for the development of next-generation advanced TBCs with higher temperature resistance, better thermal insulation, and longer lifetime.
Organoboron compounds are among the most versatile and useful building blocks in modern synthetic chemistry. The past decades have seen impressive developments in the direct C−H bond borylation of ...(hetero)arenes in which the applied catalysts are shifting from noble metals to metal‐free systems. This Highlight gives a brief summary on this evolution and focuses on recent elegant work in this field.
Impressive developments in the direct C−H bond borylation of (hetero)arenes have been achieved in the past decades. The applied catalysts are shifting from noble metals to metal‐free systems. This Highlight gives a brief summary of this evolution and focuses on recent elegant work in this field.
Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Abstract
Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is ...the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8
+
T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.
There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as ...a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.
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•Development of LNP-encapsulated mRNA vaccine (ARCoV) targeting the RBD of SARS-CoV-2•ARCoV induces neutralizing antibodies and T cell immunity in mice and NHPs•ARCoV vaccination confers full protection against SARS-CoV-2 challenge in mice•ARCoV is a thermostable vaccine candidate for phase I studies
ARCoV is an LNP-encapsulated mRNA vaccine platform that is highly immunogenic and safe in mice and non-human primates, conferring protection against challenge with a SARS-CoV-2 mouse-adapted strain.
Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated ...protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has prioritized the development of small-animal models for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We adapted a clinical ...isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. The resulting mouse-adapted strain at passage 6 (called MASCp6) showed increased infectivity in mouse lung and led to interstitial pneumonia and inflammatory responses in both young and aged mice after intranasal inoculation. Deep sequencing revealed a panel of adaptive mutations potentially associated with the increased virulence. In particular, the N501Y mutation is located at the receptor binding domain (RBD) of the spike protein. The protective efficacy of a recombinant RBD vaccine candidate was validated by using this model. Thus, this mouse-adapted strain and associated challenge model should be of value in evaluating vaccines and antivirals against SARS-CoV-2.
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