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.
Display omitted
•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.
Particle swarm optimization (PSO) relies on its learning strategy to guide its search direction. Traditionally, each particle utilizes its historical best experience and its neighborhood's best ...experience through linear summation. Such a learning strategy is easy to use, but is inefficient when searching in complex problem spaces. Hence, designing learning strategies that can utilize previous search information (experience) more efficiently has become one of the most salient and active PSO research topics. In this paper, we proposes an orthogonal learning (OL) strategy for PSO to discover more useful information that lies in the above two experiences via orthogonal experimental design. We name this PSO as orthogonal learning particle swarm optimization (OLPSO). The OL strategy can guide particles to fly in better directions by constructing a much promising and efficient exemplar. The OL strategy can be applied to PSO with any topological structure. In this paper, it is applied to both global and local versions of PSO, yielding the OLPSO-G and OLPSO-L algorithms, respectively. This new learning strategy and the new algorithms are tested on a set of 16 benchmark functions, and are compared with other PSO algorithms and some state of the art evolutionary algorithms. The experimental results illustrate the effectiveness and efficiency of the proposed learning strategy and algorithms. The comparisons show that OLPSO significantly improves the performance of PSO, offering faster global convergence, higher solution quality, and stronger robustness.
Reduced haemodynamic response in the frontotemporal cortices of patients with major depressive disorder (MDD) has been demonstrated using functional near-infrared spectroscopy (fNIRS). Most notably, ...changes in cortical oxy-haemoglobin during a Japanese phonetic fluency task can differentiate psychiatric patients from healthy controls (HC). However, this paradigm has not been validated in the English language. Therefore, the present work aimed to distinguish patients with MDD from HCs, using haemodynamic response measured during an English letter fluency task. One hundred and five HCs and 105 patients with MDD took part in this study. NIRS signals during the verbal fluency task (VFT) was acquired using a 52-channel system, and changes in oxy-haemoglobin in the frontal and temporal regions were quantified. Depression severity, psychosocial functioning, pharmacotherapy and psychiatric history were noted. Patients with MDD had smaller changes in oxy-haemoglobin in the frontal and temporal cortices than HCs. In both regions of interest, oxy-haemoglobin was not associated with any of the clinical variables studied. 75.2% and 76.5% of patients with MDD were correctly classified using frontal and temporal region oxy-haemoglobin, respectively. Haemodynamic response measured by fNIRS during an English letter fluency task is a promising biomarker for MDD.
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.
Social learning in particle swarm optimization (PSO) helps collective efficiency, whereas individual reproduction in genetic algorithm (GA) facilitates global effectiveness. This observation recently ...leads to hybridizing PSO with GA for performance enhancement. However, existing work uses a mechanistic parallel superposition and research has shown that construction of superior exemplars in PSO is more effective. Hence, this paper first develops a new framework so as to organically hybridize PSO with another optimization technique for "learning." This leads to a generalized "learning PSO" paradigm, the *L-PSO. The paradigm is composed of two cascading layers, the first for exemplar generation and the second for particle updates as per a normal PSO algorithm. Using genetic evolution to breed promising exemplars for PSO, a specific novel *L-PSO algorithm is proposed in the paper, termed genetic learning PSO (GL-PSO). In particular, genetic operators are used to generate exemplars from which particles learn and, in turn, historical search information of particles provides guidance to the evolution of the exemplars. By performing crossover, mutation, and selection on the historical information of particles, the constructed exemplars are not only well diversified, but also high qualified. Under such guidance, the global search ability and search efficiency of PSO are both enhanced. The proposed GL-PSO is tested on 42 benchmark functions widely adopted in the literature. Experimental results verify the effectiveness, efficiency, robustness, and scalability of the GL-PSO.
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.
Display omitted
•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.
BackgroundA 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.MethodsA 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 C9orf72. Forty-one ALS-associated genes were analysed.Findings155 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. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition.ConclusionsOur 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.
In nature, almost every organism ages and has a limited lifespan. Aging has been explored by biologists to be an important mechanism for maintaining diversity. In a social animal colony, aging makes ...the old leader of the colony become weak, providing opportunities for the other individuals to challenge the leadership position. Inspired by this natural phenomenon, this paper transplants the aging mechanism to particle swarm optimization (PSO) and proposes a PSO with an aging leader and challengers (ALC-PSO). ALC-PSO is designed to overcome the problem of premature convergence without significantly impairing the fast-converging feature of PSO. It is characterized by assigning the leader of the swarm with a growing age and a lifespan, and allowing the other individuals to challenge the leadership when the leader becomes aged. The lifespan of the leader is adaptively tuned according to the leader's leading power. If a leader shows strong leading power, it lives longer to attract the swarm toward better positions. Otherwise, if a leader fails to improve the swarm and gets old, new particles emerge to challenge and claim the leadership, which brings in diversity. In this way, the concept "aging" in ALC-PSO actually serves as a challenging mechanism for promoting a suitable leader to lead the swarm. The algorithm is experimentally validated on 17 benchmark functions. Its high performance is confirmed by comparing with eight popular PSO variants.
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
Copper-ceria is one of the very active catalysts for the preferential oxidation of carbon monoxide (CO-PROX) reaction, which is also a typical system in which the complexity of copper chemistry is ...clearly exhibited. In the present manuscript, copper–ceria catalysts with different Cu contents up to 20 wt % supported on CeO2 nanorods were synthesized by a deposition–precipitation (DP) method. The as-prepared samples were characterized by various structural and textural detections including X-ray diffraction (XRD), Vis-Raman, transmission electron microscopy (TEM), ex situ/in situ X-ray absorption fine structure (XAFS), and temperature-programmed reduction by hydrogen (H2-TPR). It has been confirmed that the highly dispersed copper oxide (CuO x ) clusters, as well as the strong interaction of Cu-O x -Ce structure, were the main copper species deposited onto the ceria surface. No separated copper phase was detected for both preoxidized and prereduced samples with the Cu contents up to 10 wt %. The fresh copper–ceria catalysts were pretreated in either O2- or H2-atmosphere and then tested for the CO-PROX reaction at a space velocity (SV) of 60 000 mL·h–1·gcat –1. The prereduced 5 and 10 wt % Cu samples exhibited excellent catalytic performance with high CO conversions (>50%, up to 100%) and O2 selectivities (>60%, up to 100%) within a wide temperature window of 80–140 °C. The in situ XAFS technique was carried out to monitor the structural evolution on the copper–ceria catalysts during the PROX experiments. The X-ray absorption near edge spectra (XANES) profiles, by the aid of linear combination analysis, identified the oxidized Cu(II) were the dominant copper species in both O2- and H2-pretreated samples after CO-PROX at 80 °C. Furthermore, the extended X-ray absorption fine structure (EXAFS) fitting results, together with the corresponding H2-TPR data distinctly determined that the highly dispersed CuO x (x = 0.2−0.5) cluster, other than the Cu–O x –Ce (x = 0.7−3.2) structure, were the crucial active species for the studied CO-PROX reaction.
PDF
