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.
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.
Background and purpose
Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the ...PD‐related genes and determine the mutational spectrum of early‐onset PD in ethnic Chinese.
Methods
In this study, whole‐exome sequencing and/or gene dosage analysis were performed in 704 early‐onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty‐six PD‐related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed.
Results
Eighty‐two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD‐related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi‐allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein‐truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late‐onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction.
Conclusions
Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.
Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1 and PLA2G6 contributed the collective risk for early‐onset Parkinson’s disease (PD). The protein‐truncating variants in CHCHD2 were significantly enriched in early‐onset PD, especially for p.P53Afs*38, which was confirmed in an independent cohort of patients with late‐onset PD and functional experiments.
The present study was conducted to evaluate the effects of marine polysaccharides from seaweed Enteromorpha on growth performance, immune responses, intestinal morphology and microbial community in ...the banana shrimp Fenneropenaeus merguiensis. Two thousand and four hundred juvenile shrimps with an average body weight of 2.18 ± 0.06 g were fed for 42 d with diets containing different levels of Enteromorpha polysaccharides (EPS): 0 (control), 1, 2 and 3 g/kg as treatment groups, each of group was replicated three times with two hundred shrimps per replicate. Dietary supplementation of 1 g/kg EPS showed a consistent improvement in the final weight, weight gain, average daily gain rate (ADGR) and specific growth rate (SGR) (P < 0.05), while showed a decrease in the feed conversion ratio (FCR) of shrimp (P < 0.05). Besides, the total anti-oxidative capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), lysozyme (Lyz), alkaline phosphatase (ALP), and phenoloxidase (PO) activities in hemolymph were enhanced by dietary supplementation of 1 g/kg EPS (P < 0.05), while it reduced the hemolymph MDA content (P < 0.05). Shrimp fed 1 g/kg EPS supplemented diets up-regulated FmLyz, FmSOD5 and FmCLAP gene expression level of hepatopancreas and gill (P < 0.05), and also improved the intestinal FmLC2, FmLyz, FmSOD5 and FmCLAP gene expression levels (P < 0.05). In addition, shrimp fed diets containing 1 g/kg EPS increased the villus width (P < 0.05) and resulted in a higher villus surface area (P < 0.05). According to 16S rRNA sequencing results, dietary supplementation of 1 g/kg EPS tended to increase the relative abundance of Firmicutes at phylum level (P = 0.07) and decrease the relative abundance of Vibrio at genus level (P = 0.08). There was a significant positive correlation between the relative abundance of Firmicutes and mRNA expression of intestinal immune-related genes (P < 0.05). These findings revealed that dietary 1 g/kg EPS could improve growth performance, enhance nonspecific immunity and modulate intestinal function of banana shrimp F. merguiensis.
•Enteromorpha polysaccharides (EPS) as dietary immunostimulants in banana shrimp Fenneropenaeus merguiensis was investigated.•EPS supplementation promoted the growth performance of F. merguiensis.•EPS supplemented diets could enhance the nonspecific immunity of F. merguiensis.•Dietary EPS supplementation improved the intestinal morphology of F. merguiensis.•EPS supplementation improved the intestinal microbial community of F. merguiensis.
Cyano‐bridged 4d–4f molecular nanomagnets have re‐called increasing research interests in molecular magnetism since they offer more possibilities in achieving novel nanomagnets with versatile ...structures and magnetic interactions. In this work, four β‐diketone ligands bearing different substitution N‐sites were designed and synthesized, namely 1‐(2‐pyridyl)‐3‐(3‐pyridyl)‐1,3‐propanedione (HL1), 1,3‐Bis (3‐pyridyl)‐1,3‐propanedione (HL2), 1‐(4‐pyridyl)‐3‐(3‐pyridyl)‐1,3‐propanedione (HL3), and 1,3‐Bis (4‐pyridyl)‐1,3‐propanedione (HL4), to tune the magnetic relaxation behaviors of cyano‐bridged {DyIIIMoV} systems. By reacting with DyCl3 ⋅ 6H2O and K4Mo(CN)8 ⋅ 2H2O, four cyano‐bridged complexes, namely {DyMoV(CN)8(HL1)2(H2O)3} ⋅ 6H2O (1), {DyMoV(CN)8(HL2)(H2O)3(CH3OH)}2 ⋅ 2CH3OH ⋅ 3H2O (2), {DyMoV(CN)8(HL3)(H2O)2(CH3OH) ⋅ H2O}n (3), and {DyMoV(CN)8(HL4)2(H2O)3} ⋅ 2H2O⋅CH3OH (4) were obtained. Structural analyses revealed that 1 and 4 are binuclear complexes, 2 has a tetragonal structure, and 3 exhibits a stair‐like polymer chain structure. The DyIII ions in all complexes have eight‐coordinated configurations with the coordination spheres DyO7N1 for 1 and 4, DyO6N2 for 2, and DyO5N3 for 3. Magnetic measurements indicate that 1 is a zero‐field single‐molecule magnet (SMM) and complexes 2–4 are field‐induced SMMs, with complex 4 featuring a two‐step relaxation process. The magnetic characterizations and ab initio calculations revealed that changing the N‐sites in the β‐diketone ligands can effectively alter the structures and magnetic properties of cyano‐bridged 4d–4f nanomagnets by adjusting the coordination environments of the DyIII centers.
Four cyano‐bridged {DyIIIMoV} complexes 1–4, consisting of DyIII ions, β‐diketone (HLn: n=1, 2, 3, 4) ligands, and Mo(CN)83−, are obtained by adjusting the N‐sites of β‐diketone ligands. Their magnetic properties are highly dependent on the magnetic axis and magnetic anisotropy of the DyIII centers, which can be regulated by different coordination environments (DyOnN(8‐n): n=5, 6, 7) of the DyIII centers.
The blood-brain barrier breakdown, as a prominent feature after traumatic brain injury, always triggers a cascade of biochemical events like inflammatory response and free radical-mediated oxidative ...damage, leading to neurological dysfunction. The dynamic monitoring the status of blood-brain barrier will provide potent guidance for adopting appropriate clinical intervention. Here, we engineer a near-infrared-IIb Ag
Te quantum dot-based Mn single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown of mice after traumatic brain injury. The dynamic change of blood-brain barrier, including the transient cerebral hypoperfusion and cerebrovascular damage, could be resolved with high spatiotemporal resolution (150 ms and ~ 9.6 µm). Notably, the isolated single Mn atoms on the surface of Ag
Te exhibited excellent catalytic activity for scavenging reactive oxygen species to alleviate neuroinflammation in brains. The timely injection of Mn single-atom catalyst guided by imaging significantly promoted the reconstruction of blood-brain barrier and recovery of neurological function after traumatic brain injury.
To establish cost-efficient operating conditions for potential application of Fenton oxidation process to treat wastewater containing an azo dye Orange G (OG), some important operating parameters ...such as pH value of solutions, dosages of H
2O
2 and Fe
2+, temperature, presence/absence of chloride ion and concentration of the dye, which effect on the decolorization of OG in aqueous solution by Fenton oxidation have been investigated systematically. In addition, the decolorization kinetics of OG was also elucidated based on the experimental data. The results showed that a suitable decolorization condition was selected as initial pH 4.0, H
2O
2 dosage 1.0
×
10
−2
M and molar ratio of H
2O
2/Fe
2+ 286:1. The decolorization of OG enhanced with the increasing of reaction temperature but decreased as a presence of chloride ion. On the given conditions, for 2.21
×
10
−5 to 1.11
×
10
−4
M of OG, the decolorization efficiencies within 60
min were more than 94.6%. The decolorization kinetics of OG by Fenton oxidation process followed the second-order reaction kinetics, and the apparent activation energy
E, was detected to be 34.84
kJ
mol
−1. The results can provide fundamental knowledge for the treatment of wastewater containing OG and/or other azo dyes by Fenton oxidation process.
A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding ...the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers.
A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in
. Forty-one ALS-associated genes were analysed.
155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified.
was the most common mutated gene, followed by
,
,
,
and
. By burden analysis, rare variants in
,
and
contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level
p.Gly294Val and
p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in
and
were associated with poor prognosis, in
linked with younger age of onset, and
repeats tended to affect cognition.
Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.
Since the switchable spontaneous polarization of ferroelectric materials endows it with many useful properties such as a large pyroelectric coefficient, switchable spontaneous polarization, and ...semiconductor, it has a wide range of application prospects, and the research of high-performance molecular ferroelectric materials has become a hot spot. We obtained a 0D organic–inorganic hybrid ferroelectric (CH3)3NCH2CH2CH32FeCl4 (1) with well-defined ferroelectric domains and excellent domain inversion and exhibited a relatively large spontaneous polarization (Ps = 9 μC/m–2) and a Curie temperature (Tc ) of 394 K. Furthermore, compound 1 belongs to the non-centrosymmetrical space group Cmc21 and has a strong second-harmonic generation signal. Interestingly, we also performed magnetic tests on 1, which confirmed that it is a magnetic material. This work provides clues for exploring the application of high-performance molecular ferroelectric materials in future multifunctional smart devices.
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