The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

24The summer rainfall climate of East Asia underwent large and abrupt changes during past 25 climates, in response to precessional forcing, glacial-interglacial cycles as well as abrupt changes 26 to the North Atlantic during the last glacial. However, current interpretations of said changes are 27 typically formulated in terms of modulation of summer monsoon intensity, and do not account 28 for the known complexity in the seasonal evolution of East Asian rainfall, which exhibits sharp 29 transition from the Spring regime to the Meiyu, and then again from the Meiyu to the Summer 30 regime. 31We explore the interpretation that East Asian rainfall climate undergoes a modulation of its 32 seasonality during said paleoclimate changes. Following previous suggestions we focus on role 33 of the westerly jet over Asia, namely that its latitude relative to Tibet is critical in determining 34 the stepwise transitions in East Asian rainfall seasons. In support of this linkage, we show from 35 observational data that the interannual co-variation of June (July-August) rainfall and upper 36 tropospheric zonal winds show properties consistent with an altered timing of the transition to 37 the Meiyu (Summer), and with more northward-shifted westerlies for earlier transitions. 38We similarly suggest that East Asian paleoclimate changes resulted from an altered timing in 39 the northward evolution of the jet and hence the seasonal transitions, in particular the transition 40 of the jet from south of the Plateau to the north that determines the seasonal transition from 41Spring rains to the Meiyu. In an extreme scenario -which we speculate the climate system 42 tended towards during stadial (cold) phases of D/O stadials and periods of low Northern 43Hemisphere summer insolation -the jet does not jump north of the Plateau, essentially keeping 44East Asia in prolonged Spring conditions. 45We argue that this hypothesis provides a viable explanation for a key paleoproxy signature of 46 3 D/O stadials over East Asia, namely the heavier mean δ 18 O of precipitation as recorded in 47 speleothem records. The southward jet position prevents the low-level monsoonal flow -which 48 is isotopically light -from penetrating into the interior of East Asia; as such, precipitation there 49 will be heavier, consistent with speleothem records. This hypothesis can also explain other key 50 evidences of East Asian paleoclimate changes, in particular the occurrence of dusty conditions 51 during North Atlantic stadials, and the southward migration of the Holocene optimal rainfall. 52Earth's orbit. Other records corroborate the sense of large and abrupt change in East Asia; for 60 example, paleoproxy dust records show East Asia to be dustier during cold stadials (and in 61 particular Heinrich stadials) Nagashima et al., 2011], and more generally during 62 glacial periods [An, 2000]. 63The dominant interpretation of variability in the speleothem records is as a record of 64 changes in East Asian summer monsoon intensity, with δ 18 O relatively light when m...

We developed a clinical model and laboratory model for predicting the in-hospital mortality of COVID-19 patients, the AUCs (95% CI) were 0.88 (0.80, 0.95) and 0.98 (0.92, 0.99) in training cohort, and 0.83 (0.68, 0.93) and 0.88 (0.77, 0.95) in validation cohort, respectively. ABSTRACT BackgroundThis study aimed to develop mortality-prediction models for patients with Coronavirus disease 2019 .baseline clinical and laboratory data through the stepwise Akaike information criterion and ensemble XGBoost model to build mortality-prediction models. We then validated these models by randomly collecting COVID-19 patients in the Infection department of Union Results296 patients with COVID-19 were enrolled in the training cohort, 19 of whom died during hospitalization and 277 were discharged from the hospital. The clinical model developed with age, history of hypertension and coronary heart disease showed AUC of 0.88 (95% CI, 0.80-0.95); threshold, -2.6551; sensitivity, 92.31%; specificity, 77.44% and negative predictive value (NPV), 99.34%. The laboratory model developed with age, high-sensitivity C-reactive protein (hsCRP), peripheral capillary oxygen saturation (SpO2), neutrophil and lymphocyte count, D-dimer, aspartate aminotransferase (AST) and glomerular filtration rate (GFR) had a significantly stronger discriminatory power than the clinical model (p=0.0157), with AUC of 0.98 (95% CI, 0.92-0.99); threshold, -2.998; sensitivity, 100.00%; specificity, 92.82% and NPV, 100.00%. In the subsequent validation cohort (N=44), the AUCs (95% CI) were 0.83 (0.68, 0.93) and 0.88 (0.75, 0.96) for clinical model and laboratory model, respectively. ConclusionsWe developed two predictive models for the in-hospital mortality of patients with COVID-19 in Wuhan and validated in patients from another center.

Interest in relationship between diet and ageing is growing. Research has shown that dietary calorie restriction and some antioxidants extend lifespan in various ageing models. On the one hand, oxygen is essential to aerobic organisms because it is a final electron acceptor in mitochondria. On the other hand, oxygen is harmful because it can continuously generate reactive oxygen species (ROS), which are believed to be the factors causing ageing of an organism. To remove these ROS in cells, aerobic organisms possess an antioxidant defense system which consists of a series of enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). In addition, dietary antioxidants including ascorbic acid, vitamin A, vitamin C, α-tocopherol, and plant flavonoids are also able to scavenge ROS in cells and therefore theoretically can extend the lifespan of organisms. In this connection, various antioxidants including tea catechins, theaflavins, apple polyphenols, black rice anthocyanins, and blueberry polyphenols have been shown to be capable of extending the lifespan of fruit flies. The purpose of this review is to brief the literature on modern biological theories of ageing and role of dietary antioxidants in ageing as well as underlying mechanisms by which antioxidants can prolong the lifespan with focus on fruit flies as an model.

The immobilization of enzymes on solid supports is widely used in many applications, including biosensors, antifouling coatings, food packaging materials, and biofuel cells. Enzymes tend to lose their activity when in contact with a support surface, a phenomenon that has been attributed to unfavorable orientation and (partial) unfolding. In this work, specific immobilization of 6-phospho-β-galactosidase (β-Gal) on a self-assembled monolayer (SAM) containing maleimide end groups and oligo(ethylene glycol) spacer segments was achieved through a unique cysteinyl residue. A systematic means to characterize the interfacial orientation of immobilized enzymes has been developed using a combination of sum frequency generation vibrational spectroscopy and attenuated total reflectance FTIR-spectroscopy. The possible orientations of the immobilized β-Gal were determined and found to be well-correlated with the tested activity of β-Gal. This study will impact the development of an increasingly wide range of devices that use surface-immobilized enzymes as integral components with improved functions, better sensitivity, enhanced stability, and longer shelf life.

Epithelial-to-mesenchymal transition (EMT) is a complex multistep process in which phenotype switches are mediated by a network of transcription factors (TFs). Systematic characterization of all dynamic TFs controlling EMT state transitions, especially for the intermediate partial-EMT state, represents a highly relevant yet largely unexplored task. Here, we performed a computational analysis that integrated time-course EMT transcriptomic data with public cistromic data and identified three synergistic master TFs (ETS2, HNF4A and JUNB) that regulate the transition through the partial-EMT state. Overexpression of these regulators predicted a poor clinical outcome, and their elimination readily abolished TGF-β-induced EMT. Importantly, these factors utilized a clique motif, physically interact and their cumulative binding generally characterized EMT-associated genes. Furthermore, analyses of H3K27ac ChIP-seq data revealed that ETS2, HNF4A and JUNB are associated with super-enhancers and the administration of BRD4 inhibitor readily abolished TGF-β-induced EMT. These findings have implications for systematic discovery of master EMT regulators and super-enhancers as novel targets for controlling metastasis.

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Molecular structures such as conformation and orientation are crucial in determining the activity of peptides immobilized to solid supports. In this study, sum frequency generation (SFG) vibrational spectroscopy was applied to investigate such structures of peptides immobilized on self-assembled monolayers (SAMs). Here cysteine-modified antimicrobial peptide cecropin P1 (CP1) was chemically immobilized onto SAM with a maleimide terminal group. Two important characteristics, length of the poly(ethylene glycol) (PEG) segment in the SAM and location of the cysteine residue in the peptide, were examined using SFG spectroscopy to determine the effect of each on surface immobilization as well as peptide secondary structure and its orientation in the immobilized state. Results have shown that while each length of PEG chain studied promotes chemical immobilization of the target peptide and prevents nonspecific adsorption, CP1 immobilized on long-chain (PEG2k) maleimide SAMs shows random coil structure in water, whereas CP1 demonstrates α-helical structure when immobilized on short-chain (with four ethylene glycol units - (EG4)) maleimide SAMs. Placement of the cysteine residue at the C-terminus promotes the formation of α-helical structure of CP1 with a single orientation when tethered to EG4 maleimide SAM surfaces. In contrast, immobilization via the N-terminal cysteine of CP1 results in a random coil or lying-down helical structure. The bacteria capturing/killing capability was tested, showing that the surface-immobilized CP1 molecules via C- and N- terminal cysteine exhibit only slight difference, even though they have different secondary structures and orientations.