In comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 appears to be more contagious 1, and coronavirus disease 2019 (COVID-19) patients demonstrate varied clinical ...manifestations distinct from those seen in patients with SARS-CoV and Middle East respiratory syndrome coronavirus infections 2. Collective results from the clinical and epidemiological observations suggest a distinct viral–host interaction in COVID-19 patients. Profiling of the antibody response during SARS-CoV-2 infection may help improve our understanding of the viral–host interaction and the immunopathological mechanisms of the disease.
Humoral immune response to SARS-CoV-2 showed an early response of IgA, instead of IgM, in COVID-19 patients. As highlighted by this study, enhanced IgA responses observed in severe COVID-19 might confer damaging effects in severe COVID-19.
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Background and Purpose
The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, ...inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. Therefore, we aimed to demonstrate that nitazoxanide would protect against atherosclerosis.
Experimental Approach
The mitochondrial oxygen consumption of cells was measured by using the high‐resolution respirometry system, Oxygraph‐2K. The proliferation and migration of A10 cells were measured by using Edu immunofluorescence staining, wound‐induced migration and the Boyden chamber assay. Protein levels were measured by using the western blot technique. ApoE (−/−) mice were fed with a Western diet to establish an atherosclerotic model in vivo.
Key Results
The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum‐ and PDGF‐induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF‐κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL‐1β and IL‐6 levels and suppressed atherosclerosis in Western diet‐fed ApoE (−/−) mice.
Conclusion and Implications
Nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (−/−) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti‐atherosclerotic drug with clinical translational potential.
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.
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.
We report a 2-family cluster of persons infected with severe acute respiratory syndrome coronavirus 2 in the city of Zhoushan, Zhejiang Province, China, during January 2020. The infections resulted ...from contact with an infected but potentially presymptomatic traveler from the city of Wuhan in Hubei Province.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Carbon-based materials, as one of the most important electrode materials for supercapacitors, have attracted tremendous attention. At present, it is highly desirable but remains challenging to ...prepare one-dimensional carbon complex hollow nanomaterials for further improving the performance of supercapacitors. Herein, we report an effective strategy for the synthesis of hollow particle-based nitrogen-doped carbon nanofibers (HPCNFs-N). By embedding ultrafine zeolitic imidazolate framework (ZIF-8) nanoparticles into electrospun polyacrylonitrile (PAN), the as-prepared composite nanofibers are carbonized into hierarchical porous nanofibers composed of interconnected nitrogen-doped carbon hollow nanoparticles. Owing to its unique structural feature and the desirable chemical composition, the derived HPCNFs-N material exhibits much enhanced electrochemical properties as an electrode material for supercapacitors with remarkable specific capacitance at various current densities, high energy/power density and long cycling stability over 10 000 cycles.
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.
Restricted by the poor ability of polymers to dissociate lithium salts and transport ions, solid‐state polymer electrolytes (SPEs) show extremely low ionic conductivities (≈10−7–10−5 S cm−1) and ...transference number of lithium ions (tLi+ ≈0.2–0.4) at 25 °C. Here, a novel polymer matrix of SPEs that simultaneously promotes lithium salt dissociation and ion transportation based on a high dielectric poly(vinylidene fluoride‐trifluoroethylene‐chlorotrifluoroethylene) (TerP) and an all‐trans conformational poly(vinylidene fluoride‐trifluoroethylene) (CoP), is developed. The high dielectric constant increases the polarity of CH2CF2 polar groups; then, brings a strong electronegative end that dissociates Li+ from lithium salts. The all‐trans conformation assures all fluorine atoms locate on one side of the chain, constructing ion hopping highways. As a result, the TerP/CoP (TC) SPE exhibits a high ionic conductivity (2.37 × 10−4 S cm−1) and a quite large tLi+ of 0.61 at 25 °C. The Li/TC SPE/Li symmetric cells cycle stably for more than half a year (>4500 h) and the LiNi0.8Co0.1Mn0.1O2/TC SPE/Li cell cycles steadily for 1000 and 600 cycles at 1 C and 2 C at 25 °C, respectively. This work paves a new way to prepare high‐performance SPEs by simultaneously modulating dielectric constants and conformation of polymers.
Through conformational regulation of the high dielectric P(VDF‐TrFE‐CTFE), an all‐trans conformation with all F atoms located on one side of the chain is achieved, which constructs ion hopping highways and results in a high lithium‐ion transference number of 0.61. Both the Li//Li symmetric cells and the high‐voltage NCM811//Li cells show long‐term cycling stability at 25 °C.
Modern engineered systems generally work under complex operational conditions. However, most of the existing artificial intelligence (AI)-based prognostic methods still lack an effective model that ...can utilize operational conditions data for remaining useful life (RUL) prediction. This paper develops a novel prognostic method based on bidirectional long short-term memory (BLSTM) networks. The method can integrate multiple sensors data with operational conditions data for RUL prediction of engineered systems. The proposed architecture based on BLSTM networks includes three main parts: first, one BLSTM network is used to directly extract features hidden in the multiple raw sensors signals; second, another BLSTM network is employed to learn higher features from operational conditions signals and the learned features from the sensors signals; and, third, fully connected layers and a linear regression layer are stacked to generate the target output of the RUL prediction. Unlike other AI-based prognostic methods, the developed method can simultaneously model both sensors data and operational conditions data in a consolidated framework. The proposed approach is demonstrated through a case study on aircraft turbofan engines, and comparisons with other popular state-of-the-art methods are also presented.
Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought ...an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
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•Human ACE2 knockin mice were generated by using CRISPR/Cas9 technology•SARS-CoV-2 leads to robust replication in lung, trachea, and brain•SARS-CoV-2 causes interstitial pneumonia and elevated cytokine in aged hACE2 mice•High dose of SARS-CoV-2 can establish infection via intragastric route in hACE2 mice
The COVID-19 pandemic has brought an urgent need for small animal models. Here, Sun et al. established an ACE2 humanized mouse by CRISPR/Cas9 knockin technology. These hACE2 mice are susceptible to SARS-CoV-2 infection upon intranasal inoculation, and the resulting pulmonary infection and pathological changes resemble those observed in COVID-19 patients.
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