The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale 1, 2. Although bats are regarded as the ...most likely natural hosts for SARS-CoV-2 3, the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomic analysis of samples from 227 bats collected from Yunnan Province in China between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor-binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.
•Metagenomic analysis identified a novel coronavirus, RmYN02, from R. malayanus•RmYN02 was the closest relative of SARS-CoV-2 in most of the virus genome•Two loop deletions in RBD may reduce the binding of RmYN02 with ACE2•RmYN02 contains an insertion at the S1/S2 cleavage site in the spike protein
Zhou et al. report a bat-derived coronavirus, RmYN02, which is the closest relative of SARS-CoV-2 in most of the virus genome reported to date. RmYN02 contains an insertion at the S1/S2 cleavage site in the spike protein in a similar manner to SARS-CoV-2. This suggests that such insertion events can occur naturally in animal betacoronaviruses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim
Coastal wetlands provide crucial ecosystem functions and services, such as coastal protection, nutrient retention and C sequestration. Despite the important roles in global C, N and P cycling, ...the global variation in leaf stoichiometry across coastal wetlands remains unclear.
Location
Global.
Time period
1980–2018.
Major taxa studied
Vascular plants.
Methods
By compiling a global dataset of 698 data records in 205 sites, we carried out systematic analyses of the world‐wide trends and their determinants of leaf element contents and ratios of plants across coastal wetlands.
Results
Leaf N and P contents increased significantly, but C:N, C:P and N:P ratios decreased with increasing latitude in coastal wetlands. The mean annual temperature was the predominant driver of leaf N, P and C:N, whereas soil N:P was a good predictor of leaf C:P and N:P ratios. Furthermore, N increased faster with P in plant leaves of coastal wetlands compared with terrestrial ecosystems. Within coastal wetlands, herb‐dominated salt marshes had a significantly higher leaf P content, lower leaf N:P ratio and lower scaling exponent of leaf N to P than tree‐dominated mangroves.
Main conclusions
The similar latitudinal patterns of leaf stoichiometry in coastal wetlands compared with terrestrial ecosystems reflected the similar influences of temperature. However, different slopes of leaf P and N:P ratios and N and P scaling relationships between these two ecosystems suggested that different salinity and tidal inundation levels result in different strategies of N and P use in coastal wetland plants. These differences in leaf stoichiometry between ecosystems and between different types of coastal wetlands might need to be emphasized in future biogeochemical modelling owing to their different roles in global nutrient and carbon cycling.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland ...(Up221, flooding‐intolerant) and lowland (Low88, flooding‐tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding‐tolerant type (T‐type) or a flooding‐intolerant type (I‐type). The OsCBL10 T‐type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I‐type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding‐tolerant rice cultivars containing the OsCBL10 T‐type promoter have shown lower Ca2+ flow and higher α‐amylase activities in comparison to those in flooding‐intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild‐type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade.
Significance Statement
This study identifies that OsCBL10 is able to communicate with upstream calcium signaling and downstream flooding responses by affecting OsCIPK15 protein accumulation or stability. The variation in OsCBL10 promoter regions could be a general mechanism in Sub1A‐deficient lowland japonica cultivars in response to flooding germination.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Adoptive NK cell infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients. The aim of this study was to test the activity of clinical‐grade membrane‐bound ...IL‐21/4‐1BBL‐expanded NK cell products against AML in vivo.
Methods
Fresh peripheral blood mononuclear cells (PBMCs) were incubated with equal numbers of irradiated membrane‐bound IL‐21/4‐1BBL‐expressing K562 cells for 2–3 weeks to induce clinical‐grade NK cell expansion.
Results
Expansion for 2 and 3 weeks produced ∼4 and 8 × 109 NK cells from 2 × 107 PBMCs. The production of CD107a and TNF‐α in NK cell products in response to AML cell lines and primary blasts was higher than that observed in resting NK cells. The 2‐week expanded NK cell products were xenografted into immunodeficient mice with leukemia and were persistently found in the BM, spleen, liver, lung, and peripheral blood for at least 13 days; furthermore, these expanded products reduced the AML burden in vivo. Compared with matched AML patients with persistent or relapsed minimal residual disease (MRD+) who underwent regular consolidation therapy, MRD+ patients who underwent NK treatment had better overall survival and showed no major adverse events.
Conclusions
Clinical‐grade mbIL‐21/4‐1BBL‐expanded NK cells exhibited antileukemic activity against AML in vitro and in vivo.
Clinical‐grade NK cell products were produced with irradiated membrane‐bound IL‐21/4‐1BBL‐expressing K562 cells. NK cell products showed enhanced expression of activating receptors and chemokine receptors, therefore exhibit cytotoxicity against acute myeloid leukemia cells in vitro, in leukemia mice model as well as in persistent minimal residual disease positive leukemia patients
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The standard chemotherapy for squamous NSCLC (sqNSCLC) includes platinum plus gemcitabine. Sintilimab, an anti–programmed cell death protein 1 antibody, plus platinum and gemcitabine (GP) has ...revealed encouraging efficacy as first-line therapy for sqNSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to further compare the efficacy and safety of sintilimab with placebo, both in combination with GP.
ORIENT-12, a randomized, double-blind, phase 3 study, was conducted at 42 centers in the People’s Republic of China (ClinicalTrials.gov, number NCT03629925). Patients with locally advanced or metastatic sqNSCLC and without EGFR-sensitive mutations or ALK rearrangements were enrolled in the study. The stratification factors included clinical stage, choice of platinum, and programmed death-ligand 1 tumor proportion score. The patients, investigators, research staff, and sponsor team were masked to treatment assignment. Eligible patients were randomized 1:1, using an integrated web-response system, to receive sintilimab 200 mg or placebo plus GP every 3 weeks for four or six cycles, followed by sintilimab or placebo as maintenance therapy until disease progression or 2 years. The primary end point was progression-free survival (PFS), assessed by an independent radiographic review committee.
Between September 25, 2018 and July 26, 2019, a total of 543 patients were screened, of whom 357 patients were randomized to the sintilimab-GP group (n = 179) and the placebo-GP group (n = 178). After a median follow-up period of 12.9 months, sintilimab-GP continued to reveal a meaningful improvement in PFS than placebo-GP (hazard ratio = 0.536 95% confidence interval: 0.422–0.681, p < 0.00001). Treatment-emergent adverse events of grade 3 or worse occurred in 86.6% patients in the sintilimab-GP group and in 83.1% in the placebo-GP group. The incidence of treatment-emergent adverse event leading to death was 4.5% and 6.7% in the two treatment groups, respectively.
Regarding PFS, sintilimab plus GP reveals clinical benefit than GP alone as first-line therapy in patients with locally advanced or metastatic sqNSCLC. The toxicity was acceptable, and no new unexpected safety signals were observed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Purpose
Anxiety disorder is a common mental health disorder. However, there are few safe and fast‐acting anxiolytic drugs available that can treat anxiety disorder. We previously ...demonstrated that the interaction of neuronal NOS (nNOS) with its carboxy‐terminal PDZ ligand (CAPON) is involved in regulating anxiety‐related behaviours. Here, we further investigated the anxiolytic effects of nNOS–CAPON disruptors in chronic stress‐induced anxiety in animals.
Experimental Approach
Mice were intravenously treated with nNOS–CAPON disruptors, ZLc‐002 or Tat‐CAPON12C, at the last week of chronic mild stress (CMS) exposure. We also infused corticosterone (CORT) into the hippocampus of mice to model anxiety behaviours and also delivered ZLc‐002 or Tat‐CAPON12C on the last week of chronic CORT treatment via pre‐implanted cannula. Anxiety‐related behaviours were examined using elevated plus maze, open field, novelty‐suppressed feeding and light–dark (LD) tests. The level of nNOS–CAPON interaction was determined by co‐immunoprecipitation (CO‐IP) and proximity ligation assay (PLA). The neural mechanisms underlying the behavioural effects of nNOS–CAPON uncoupling in anxiety animal models were assessed by western blot, immunofluorescence and Golgi‐Cox staining.
Key Results
ZLc‐002 and Tat‐CAPON12C reversed CMS‐ or CORT‐induced anxiety‐related behaviours. ZLc‐002 and Tat‐CAPON12C increased synaptogenesis along with improved dendritic remodelling in CMS mice or CORT‐treated cultured neurons. Meanwhile, blocking nNOS–CAPON interaction significantly activated the cAMP response element‐binding protein (CREB)–brain‐derived neurotrophic factor (BDNF) pathway, which is associated with synaptic plasticity.
Conclusion and Implications
Collectively, these results provide evidence for the anxiolytic effects of nNOS–CAPON uncouplers and their underlying mechanisms in anxiety disorders.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Warburg effect is known as a hallmark of cancer and targeting this process is a promising therapeutic method. • 2-Deoxy-D-glucose is an effective glycolytic inhibitor and also exhibits ...other metabolic functions. • 2-Deoxy-D-glucose mono-therapy is inefficient in inducing death to some cell types leading to the come-up of combined therapies. • 2-Deoxy-D-glucose is generally considered to be a safe agent for clinical use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Safety related incidents and accidents involving lithium-ion batteries (LIBs) are often in the news. Even though catastrophic failure is rare, the high socioeconomic risks associated with battery ...thermal runaway reactions cannot be overlooked, as demonstrated by recent high-profile events. Among all the known types of battery failure modes, the internal short circuit (ISC) tops the list of the major safety concerns for the lithium-ion battery. However, a clear picture of the LIB's electrochemical safety behavior in the context of the ISC remains to be fully established. Herein we show that mechanical indentation techniques are capable of producing highly repeatable and controllable ISC modes in a manner that allows the electrochemical safety behavior of LIBs to be categorized based on the state of charge (SOC), ISC resistance, and electrode area. Our results identify the fundamental mechanism(s) of various electrochemical responses to the ISC through a combination of experiment, numerical simulation, and analysis. With the understanding that complicated electrochemical phenomena occur after the triggering of an ISC, we examine the safety boundaries and create an electrochemical behavior map for LIBs after ISCs. We anticipate that this discovery will lead to new opportunities for battery safety design, manufacturing, monitoring, and utilization with beneficial consequences to a battery-intensive, mobile, and green society in terms of much reduced battery safety concerns.
In this study, 18 mitochondrial genomes (mitogenomes) of Syrphidae were sequenced. These mitogenomes ranged from 15,648 to 16,405 bp and contained 37 genes that were similar to those from other ...Syrphidae species. Most protein-coding genes (PCGs) started with a standard ATN codon and ended with TAA/G. All transfer RNAs (tRNAs) could be folded into the cloverleaf secondary structure except tRNA-Ser (AGN), which lacks a dihydrouridine arm. The secondary structures of ribosomal RNAs (rRNAs) were predicted. Six domains (III is absent in arthropods) and 44 helices were included in the 16S rRNA, and three domains and 24 helices were included in the 12S rRNA. We found three conserved fragments in all syrphid mitogenomes. Phylogenetic analyses were performed based on the nucleotide data of 13 PCGs and two rRNAs from 76 Muscomorpha and three outgroup species. In results the paraphyly of Aschiza and Schizophora were supported, the Acalyptratae was also paraphyletic but the relationships of its superfamilies were difficult to determine, the monophyly of Calyptratea was supported with the relationships of Oestroidea and Muscoidea need to be further reconsidered. Within Syrphidae the monophyly of family level was supported, the Syrphinae were clustered into one branch, while the paraphyly of Eristalinae was still well supported.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Light-flavour Baijiu is a type of Chinese liquor with a pure and mild flavour produced by traditional spontaneous solid-state fermentation. The flavour of this liquor has been found to vary in the ...different periods of annual production. To explore the factors affecting flavour, the microbiota of the surrounding environment, starter and fermentation process in different periods were investigated. Results showed that the ester content and acidity of light-flavour Baijiu were significantly lower when annual production was resumed after a summer break. HCA plot of volatile flavour profile and bacterial PCoA results indicated that the differences occurred at later stages, mainly due to different structures of Lactobacillus. Correlation analysis by O2PLS indicated that Lactobacillus positively correlated with esters. Species-level analysis showed that the lack of L. acetotolerans on the surface of the jar might cause a lag in fermentation and lower ester content. Thereafter, L. acetotolerans was revived during fermentation and enriched on the surface of the jar, which promoted ester formation. As important sources of L. acetotolerans, the air and fermentation jars played a critical role during fermentation. Therefore, this systematic study on environmental microbial ecology is valuable for quality control and to explore environmental microbiota functions during spontaneous fermentation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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