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Introduction: Artificial enzyme mimics have lately sparked a lot of attention since they offer a lot of benefits over natural enzymes. Methods: Because of their proteic origin and tailorable structures, self-assembling peptides are ideal building blocks for the creation of artificial enzymes. Results: Recently, a series of histidine-bearing self-assembling peptides with β-sheet structures, which are selective for short-chain fatty acids, were described. In this work, the catalytic behaviors of these peptides were further investigated using 2,4-dinitrophenyl acetate (DNPA) as a model substrate. Conclusion: Furthermore, the peptide was capable of forming a solid hydrogel that was also catalytically active at higher concentrations.

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.

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.

SummaryThe 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 found that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which was not resulted from the loss of target gene function or off-target effects. Mechanistically, we showed that RfxCas13d exhibited 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 (IEG) pathway. These results provide new mechanistic insights into the collateral activity of RfxCas13d and warn that the biosafety of CRISPR-Cas13 system needs further evaluation before applying it to clinical treatments.

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., Graphical abstract, Highlights • 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.

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.

Histogram of effect sizes () of yearly deviations between observed and expected textbook citations by binary men and women scientists. Orange lines indicate a ‘ small’ = 0.1, ‘medium’ = 0.3, ‘large’ = 0.5 effect sizes following Cohen's (1988) conventions. Mean effect size across 35 years of data is plotted in purple (0.2338) indicate that most of our effect sizes were overall small indicating high overlap between observed and expected values with fewer years with a large effect size. ; Power analysis to explore variation in the effect of effect size () need to detect a significant difference in observed and expected textbook citations as a function of the number of citations per year (replicates) (black). Vertical dotted grey lines indicate the lower- and upper bounds of the number of citations within all textbooks in a given year, with the dashed vertical grey line indicating the mean number of citations. Dotted horizontal grey lines indicate the lower- and upper bounds of within each year and the dashed horizontal grey line indicates the mean across all years (0.2338). Years in orange indicate p < 0.05, purple indicates p < 0.10.

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Accumulating evidences suggest that SARS-CoV-2 infection causes dysregulation of 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 by SARS-CoV-2 in animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could reduce inflammatory response and rescue the pneumonia with substantial reduction of viral titers in SASR-CoV-2 infected animals. Remarkably, Paquinimod treatment resulted in 100% survival of mice in a lethal model of mouse coronavirus (MHV) infection. A novel group of neutrophils that contributed to the uncontrolled inflammation and onset of COVID-19 were dramatically induced by coronavirus infections. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and noncanonical neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention. Funding: This work was supported by the National Natural Science Foundation of China (31570891; 31872736), the National Key Research and Development Program of China (2016YFA0500302; 2020YFA0707800), the National Key Research and Development Program (2020YFA0707500) and the Strategic Priority Research Program (XDB29010000). Xiangxi Wang was supported by Ten Thousand Talent Program and the NSFS Innovative Research Group (81921005). We thank National Mega projects of China for Major Infectious Diseases (2017ZX10304402), CAMS initiative for Innovative Medicine of China (2016-12M-2-006) and The National Natural Science Foundation of China (82041008) for the support on the animal model study. Conflict of Interest: The authors have no conflicts of interest to declare. Ethical Approval: All experiments with live SARS-CoV-2 viruses were carried out in the enhanced biosafety level 3 (P3+) facilities in the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) approved by the National Health Commission of the People’s Republic of China. All animals care and use were in accordance with the Guide for the Care and Use of Laboratory Animals of the Chinese Association for Laboratory Animal Science. All procedures of animal handling were approved by the Animal Care Committee of Peking University Health Science Center.

Mitochondrion not only serves as a platform for innate immune signaling transduction, but also acts as an accelerator to boost antiviral responses. The DNA and RNA released by mitochondrion can amplify type I IFNs induction. However, whether mitochondrial matrix proteins could be liberated out and involved in immune responses remains enigmatic. Here we use proximity-based labeling technology and identify the mitochondrial protein, ERAL1, as a MAVS interacting protein. ERAL1 deficiency can markedly reduce the downstream antiviral signaling triggered by RNA viruses. And ERAL1-deficient mice were more likely to die from RNA virus infection than wild-type mice. After virus infection, ERAL1 was released from mitochondria through BAX/BAK pore. The cytosolic ERAL1 positively regulated the RIG-I signaling by recruiting the E3 ubiquitin ligase TRIM25 to RIG-I, further facilitated RIG-I K63-linked polyubiquitination and downstream MAVS polymerization.

mRNA m6A modification is involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification remains unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex to enhance proteins translation, including IRF3, thus facilitating antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which was required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3fl/fl-lyz2-Cre mice were more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1—/— mice showed higher mortality than wild type mice due to decreased IRF3 expression and subsequently attenuated IFNs production. Together, we demonstrated that innate signals activated METTL3 via TBK1, then METTL3 mediated m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.