The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune ...system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
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•S100A8 is dramatically upregulated in SARS-CoV-2-infected animal models and patients•A group of aberrant immature neutrophils is induced during SARS-CoV-2 infection•Immune disorder is mediated by the S100A8/A9-TLR4 pathway•S100A8/A9 inhibitor, Paquinimod, could prevent COVID-19-associated immune disorder
Guo et al. demonstrate that over-activation of S100A8/A9-TLR4 signaling results in immune imbalance and expansion of aberrant immature neutrophils during SARS-CoV-2 infection. Relevant therapeutic targets were validated in animal infection models.
The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still ...controversial whether Cas13 exhibits collateral activity in mammalian cells.
Here, we find that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which may result from the collateral activity of RfxCas13d rather than the loss of target gene function or off-target effects. Mechanistically, we show that RfxCas13d exhibits collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNK/p38-immediate early gene pathway.
These findings provide new mechanistic insights into the collateral activity of RfxCas13d in mammalian cells and warn that the biosafety of the CRISPR-Cas13 system needs further evaluation before application to clinical treatments.
Nucleocytoplasmic transport receptors play key roles in the nuclear translocation of disease resistance proteins, but the associated mechanisms remain unclear. The
gene
encodes an importin β-like ...protein. A transgenic Arabidopsis line overexpressing
(OESAD2/Col-0) showed obvious resistance to
pv. tomato DC3000 (
DC3000) compared to the wild type (Col-0), but the knockout mutant
was susceptible. Transcriptomic analysis was then performed on Col-0, OESAD2/Col-0, and
leaves at 0, 1, 2, and 3 days post-inoculation with
DC3000. A total of 1825 differentially expressed genes (DEGs) were identified as putative biotic stress defense genes regulated by SAD2, 45 of which overlapped between the
knockout and overexpression datasets. Gene Ontology (GO) analysis indicated that the DEGs were broadly involved in single-organism cellular metabolic processes and in response to stimulatory stress. Kyoto Encyclopedia of Genes and Genomes (KEGG) biochemical pathway analysis revealed that many of the DEGs were associated with the biosynthesis of flavonoids and other specialized metabolites. Transcription factor analysis showed that a large number of ERF/AP2, MYB, and bHLH transcription factors were involved in SAD2-mediated plant disease resistance. These results provide a basis for future exploration of the molecular mechanisms associated with SAD2-mediated disease resistance and establish a set of key candidate disease resistance genes.
Natural enzymes possess remarkable catalytic activity and high substrate specificity. Many efforts have been dedicated to construct artificial enzymes with high catalytic activity. However, how to ...mimic the exquisite substrate specificity of a natural enzyme remains challenging because of the complexity of the enzyme structure. Here, we report artificial carboxylesterases that are specific for short chain fatty acids and were constructed via peptide self-assembly. These artificial systems have esterase-like activity rather than lipase-like activity towards p-nitrophenyl esters. The designer peptides self-assembled into nanofibers with strong β-sheet character. The extending histidine units and the hydrophobic edge of the fibrillar structure collectively form the active center of the artificial esterase. These artificial esterases show substrate specificity for short-chain acids esters. Moreover, 1-isopropoxy-4-nitrobenzene could function as a competitive inhibitor of hydrolysis of p-nitrophenyl acetate for an artificial esterase.
The innate immune system is the first line of host defense, which responds rapidly to viral infection. Innate recognition of viruses is mediated by a set of pattern recognition receptors (PRRs) that ...sense viral genomic nucleic acids and/or replication intermediates. PRRs are mainly localized either to the endosomes, the plasma membrane or the cytoplasm. Recent evidence suggested that several proteins located in the nucleus could also act as viral sensors. In turn, these important elements are becoming the target for most viruses to evade host immune surveillance. In this review, we focus on the recent progress in the study of viral recognition and evasion.
Mitochondria not only serve as a platform for innate immune signaling transduction but also enhance immune responses by releasing mitochondrial DNA and RNA into the cytoplasm. However, whether ...mitochondrial matrix proteins could be liberated and involved in immune responses remains enigmatic. Here, we identify the mitochondrial protein ERA G-protein-like 1 (ERAL1) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein by using proximity-based labeling technology. ERAL1 deficiency markedly reduces the downstream antiviral signaling triggered by RNA viruses. Moreover, ERAL1-deficient mice are more susceptible to lethality following RNA virus infection than wild-type mice. After virus infection, ERAL1 is released from mitochondria through the BAX/BAK pore. The cytosolic ERAL1 facilitates lysine 63 (K63)-linked ubiquitination of retinoicacid inducible gene-1 (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) and promotes downstream MAVS polymerization, thus positively regulating antiviral responses.
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•Mitochondrial protein ERAL1 positively regulates RNA virus-triggered innate immunity•ERAL1 can translocate from mitochondria to cytoplasm after viral infection•ERAL1 is released through the BAX/BAK pore in a RIG-I- and MDA5-dependent manner•ERAL1 mediates polyubiquitination and activation of RIG-I and MDA5
Li et al. demonstrate that during RNA virus infection, ERAL1 is released from mitochondria to cytoplasm. The cytosolic ERAL1 facilitates the activation of RIG-I/MDA5 and promotes downstream MAVS polymerization, thereby acting as an important modulator of innate antiviral response.
In this paper, we study the assortment optimization problem faced by many online retailers such as Amazon. We develop a cascade multinomial logit model, based on the classic multinomial logit model, ...to capture the consumers' purchasing behavior across multiple stages. Unlike most of existing studies, our model allows for repeated exposures of a product. In addition, each consumer has a patience budget that is sampled from a known distribution and each product is associated with a patience cost, which is the required amount of the cognitive efforts on browsing that product. We propose an approximation solution to the assortment optimization problem under cascade multinomial logit model.
Textbooks shape teaching and learning in introductory biology and highlight scientists as potential role models who are responsible for significant discoveries. We explore a potential demographic ...mismatch between the scientists featured in textbooks and the students who use textbooks to learn core concepts in biology. We conducted a demographic analysis by extracting hundreds of human names from common biology textbooks and assessing the binary gender and race of featured scientists. We found that the most common scientists featured in textbooks are white men. However, women and scientists of colour are increasingly represented in contemporary scientific discoveries. In fact, the proportion of women highlighted in textbooks has increased in lockstep with the proportion of women in the field, indicating that textbooks are matching a changing demographic landscape. Despite these gains, the scientists portrayed in textbooks are not representative of their target audience—the student population. Overall, very few scientists of colour were highlighted, and projections suggest it could take multiple centuries at current rates before we reach inclusive representation. We call upon textbook publishers to expand upon the scientists they highlight to reflect the diverse population of learners in biology.
Accurate nucleocytoplasmic transport of signal molecules is essential for plant growth and development. Multiple studies have confirmed that nucleocytoplasmic transport and receptors are involved in ...regulating plant disease resistance responses, however, little is known about the regulatory mechanism in plants. In this study, we showed that the mutant of the importin beta-like protein SAD2 exhibited a more susceptible phenotype than wild-type Col-0 after treatment with Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) experiments demonstrated that SAD2 interacts with the hypersensitive response (HR)-positive transcriptional regulator MYB30. Subcellular localization showed that MYB30 was not fully localized in the nucleus in sad2–5 mutants, and western-blot experiments further indicated that SAD2 was required for MYB30 nuclear trafficking during the pathogen infection process. A phenotypic test of pathogen inoculation demonstrated that MYB30 partially rescued the disease symptoms of sad2–5 caused by Pst DC3000, and that MYB30 worked downstream of SAD2 in plant pathogen defense. These results suggested that SAD2 might be involved in plant pathogen defense by mediating MYB30 nuclear trafficking. Taken together, our results revealed the important function of SAD2 in plant pathogen defense and enriched understanding of the mechanism of nucleocytoplasmic transport-mediated plant pathogen defense.
•SAD2 positively regulates disease resistance to Pst DC3000.•SAD2 functions in plant pathogen defense by mediating MYB30 nuclear trafficking.•MYB30 works downstream of SAD2 in plant pathogen defense.
As rice is a staple food for nearly half of the world’s population, rice varieties with excellent agronomic traits as well as high flavor and nutritional quality such as fragrant rice and purple rice ...are naturally favored by the market. In the current study, we adopt a fast breeding strategy to improve the aroma and anthocyanin content in the excellent rice inbred line, F25. The strategy skillfully used the advantages of obtaining editing pure lines in T0 generation of CRISPR/Cas9 editing system and easy observation of purple character and grain shape, integrated the subsequent screening of non-transgenic lines, and the elimination of undesirable edited variants from gene-editing and cross-breeding at the same time as the separation of the progeny from the purple cross, thus expediting the breeding process. Compared with conventional breeding strategies, this strategy saves about 6–8 generations and reduces breeding costs. Firstly, we edited the
OsBADH2
gene associated with rice flavor using an
Agrobacterium
-mediated CRISPR/Cas9 system to improve the aroma of F25. In the T0 generation, a homozygous
OsBADH2
-edited F25 line (F25B) containing more of the scented substance 2-AP was obtained. Then, we crossed F25B (♀) with a purple rice inbred line, P351 (♂), with high anthocyanin enrichment to improve the anthocyanin content of F25. After nearly 2.5 years of screening and identification over five generations, the undesirable variation characteristics caused by gene-editing and hybridization and the transgenic components were screened out. Finally, the improved F25 line with highly stable aroma component, 2-AP, increased anthocyanin content and no exogenous transgenic components were obtained. This study not only provides high-quality aromatic anthocyanin rice lines that meet the market demand, but also offers a reference for the comprehensive use of CRISPR/Cas9 editing technology, hybridization, and marker-assisted selection to accelerate multi-trait improvement and breeding process.
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