Longitudinal neutralization activities on authentic Omicron variant provided by three doses of BBIBP-CorV vaccination during one year.

The majority of people in China have been immunized with the inactivated viral vaccine BBIBP-CorV. The emergence of the Omicron variant raised the concerns about protection efficacy of the inactivated viral vaccine in China. However, longitudinal neutralization data describing protection efficacy against Omicron variant is still lacking. Here we present one-year longitudinal neutralization data of BBIBP-CorV on authentic Omicron, Delta, and wild-type strains using 224 sera collected from 14 volunteers who have finished three doses BBIBP-CorV. The sera were also subjected for monitoring the SARS-CoV-2 specific IgG, IgA, and IgM responses on protein and peptide microarrays. The neutralization titers showed different protection efficacies against the three strains. By incorporating IgG and IgA signals of proteins and Spike protein derived peptide on microarray, panels as potential surrogate biomarkers for rapid estimation of neutralization titers were established. These data support the necessity of the 3rd dose of BBIBP-CorV vaccination. After further validation and assay development, the panels could be used for reliable, convenient and fast evaluation of the efficacy of vaccination.

Spatio-temporal evolution of resources and environmental carrying capacity and its influencing factors: A case study of Shandong Peninsula urban agglomeration.

Promoting ecological conservation and high-quality development in the Yellow River basin is an important objective in China's 14th Five-Year Plan. Understanding the spatio-temporal evolution of and factors affecting the resources and environmental carrying capacity (RECC) of the urban agglomerations is critical for boosting high-quality green-oriented development. We first combined the Driver-Pressure-State-Impact-Response (DPSIR) framework and the improved Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) model to evaluate the RECC of Shandong Peninsula urban agglomeration in 2000, 2010 and 2020; we then used trend analysis and spatial autocorrelation analysis to understand the spatio-temporal evolution and distribution pattern of RECC. Furthermore, we employed Geodetector to detect the influencing factors and classified the urban agglomeration into six zones based on the weighted Voronoi diagram of RECC as well as specific conditions of the study area. The results show that the RECC of Shandong Peninsula urban agglomeration increased consistently over time, from 0.3887 in 2000 to 0.4952 in 2010 and 0.6097 in 2020, respectively. Geographically, RECC decreased gradually from the northeast coast to the southwest inland. Globally, only in 2010 the RECC presented a significant spatial positive correlation, and that in the other years were not significant. The high-high cluster was mainly located in Weifang, while the low-low cluster in Jining. Furthermore, our study reveals three key factors-advancement of industrial structure, resident consumption level, and water consumption per ten thousand yuan of industrial added value-that affected the distribution of RECC. Other factors, including the interactions between residents' consumption level and environmental regulation, residents' consumption level and advancement of industrial structure, as well as between the proportion of R&D expenditure in GDP and resident consumption level also played important roles resulting in the variation of RECC among different cities within the urban agglomeration. Accordingly, we proposed suggestions for achieving high-quality development for different zones.

Antibody Binding Epitope Mapping (AbMap) of Hundred Antibodies in a Single Run.

Antibodies play essential roles in both diagnostics and therapeutics. Epitope mapping is essential to understand how an antibody works and to protect intellectual property. Given the millions of antibodies for which epitope information is lacking, there is a need for high-throughput epitope mapping. To address this, we developed a strategy, Antibody binding epitope Mapping (AbMap), by combining a phage displayed peptide library with next-generation sequencing. Using AbMap, profiles of the peptides bound by 202 antibodies were determined in a single test, and linear epitopes were identified for >50% of the antibodies. Using spike protein (S1 and S2)-enriched antibodies from the convalescent serum of one COVID-19 patient as the input, both linear and potentially conformational epitopes of spike protein specific antibodies were identified. We defined peptide-binding profile of an antibody as the binding capacity (BiC). Conceptually, the BiC could serve as a systematic and functional descriptor of any antibody. Requiring at least one order of magnitude less time and money to map linear epitopes than traditional technologies, AbMap allows for high-throughput epitope mapping and creates many possibilities.

Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology.

The adhesion GPCR ADGRG2, also known as GPR64, is a critical regulator of male fertility that maintains ion/pH homeostasis and CFTR coupling. The molecular basis of ADGRG2 function is poorly understood, in part because no endogenous ligands for ADGRG2 have been reported, thus limiting the tools available to interrogate ADGRG2 activity. It has been shown that ADGRG2 can be activated by a peptide, termed p15, derived from its own N-terminal region known as the Stachel sequence. However, the low affinity of p15 limits its utility for ADGRG2 characterization. In the current study, we used alanine scanning mutagenesis to examine the critical residues responsible for p15-induced ADGRG2 activity. We next designed systematic strategies to optimize the peptide agonist of ADGRG2, using natural and unnatural amino acid substitutions. We obtained an optimized ADGRG2 Stachel peptide T1V/F3Phe(4-Me) (VPM-p15) that activated ADGRG2 with significantly improved (>2 orders of magnitude) affinity. We then characterized the residues in ADGRG2 that were important for ADGRG2 activation in response to VPM-p15 engagement, finding that the toggle switch W6.53 and residues of the ECL2 region of ADGRG2 are key determinants for VPM-p15 interactions and VPM-p15-induced Gs or arrestin signaling. Our study not only provides a useful tool to investigate the function of ADGRG2 but also offers new insights to guide further optimization of Stachel peptides to activate adhesion GPCR members.

Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase.

PI3K kinase plays an important role in regulating key processes in cells, such as cell growth, metabolism, proliferation, and apoptosis. The overexpression of PI3K kinase exists in many cancers. The proteolytic target chimera (PROTAC) technology is a new technology that uses the ubiquitin-proteasome system to degrade a given target protein. It has been described that CRBN-based PROTAC targets the degradation of PI3K kinase. However, PROTAC based on VHL has not been reported yet. Here, we connected the previously obtained highly active PI3K inhibitor to the VHL ligand through different small molecules, and obtained a series of PROTAC molecules targeting PI3K kinase. Obtain the most active compound through screening. It provides evidence for the feasibility of PROTAC technology to recruit VHL E3 ligase in PI3K kinase.

SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

Identification of Serum Biomarkers for Systemic Lupus Erythematosus Using a Library of Phage Displayed Random Peptides and Deep Sequencing.

Systemic lupus erythematosus (SLE) is one of the most serious autoimmune diseases, characterized by highly diverse clinical manifestations. A biomarker is still needed for accurate diagnostics. SLE serum autoantibodies were discovered and validated using serum samples from independent sample cohorts encompassing 306 participants divided into three groups, i.e. healthy, SLE patients, and other autoimmune-related diseases. To discover biomarkers for SLE, a phage displayed random peptide library (Ph.D. 12) and deep sequencing were applied to screen specific autoantibodies in a total of 100 serum samples from 50 SLE patients and 50 healthy controls. A statistical analysis protocol was set up for the identification of peptides as potential biomarkers. For validation, 10 peptides were analyzed using enzyme-linked immunosorbent assays (ELISA). As a result, four peptides (SLE2018Val001, SLE2018Val002, SLE2018Val006, and SLE2018Val008) were discovered with high diagnostic power to differentiate SLE patients from healthy controls. Among them, two peptides, i.e. SLE2018Val001 and SLE2018Val002, were confirmed between SLE with other autoimmune patients. The procedure we established could be easily adopted for the identification of autoantibodies as biomarkers for many other diseases.

Phage display: an ideal platform for coupling protein to nucleic acid.

Display technology, especially phage display technology, has been widely applied in many fields. The theoretical core of display technology is the physical linkage between the protein/peptide on the surface of a phage and the coding DNA sequence inside the same phage. Starting from phage-displayed peptide/protein/antibody libraries and taking advantage of the ever-growing power of next-generation sequencing (NGS) for DNA sequencing/decoding, rich protein-related information can easily be obtained in a high-throughput way. Based on this information, many scientific and clinical questions can be readily addressed. In the past few years, aided by the development of NGS, droplet technology, and massive oligonucleotide synthesis, we have witnessed and continue to witness large advances of phage display technology, in both technology development and application. The aim of this review is to summarize and discuss these recent advances.

The binding epitope of sintilimab on PD-1 revealed by AbMap.

PD-1 plays an important role as an immune checkpoint. Sintilimab is a newly approved PD-1 antibody for cancer immunotherapy with an unknown binding epitope on PD-1. In this study, to elucidate the molecular mechanism by which sintilimab blocks PD-1 activation, we applied Antibody binding epitope Mapping (AbMap) to identify the binding epitope of sintilimab. An epitope was successfully identified, i.e. SLAPKA, aa 127-132. By constructing a series of point mutations, the dominant residues S127, L128, A129, P130, and A132 of PD-1 were further validated by western blot analysis, biolayer interferometry, and flow cytometry. Structural analysis showed that the epitope is partially within the binding interface of PD-1 and PD-L1, and this epitope also partially overlaps with that of nivolumab and pembrolizumab. These results demonstrate that sintilimab can attenuate PD-1 activation by directly competing with the interaction between PD-1 and PD-L1 through binding with the key residues of the FG loop on PD-1. This study also demonstrates the high efficiency and accuracy of AbMap for determining the binding epitope of therapeutic antibodies.

Distinct spatiotemporal variation patterns of surface ozone in China due to diverse influential factors.

A better knowledge of surface ozone variations and the relevant influential factors is of great significance for controlling frequent ozone pollution events. In this study, we first examined the primary variation patterns of surface ozone in space and time across China via a clustering analysis on the basis of daily maximum 8h average surface ozone (MDA8) between 2015 and 2018. Statistical models were then established between MDA8 and a set of influential factors to pinpoint dominant factors contributing to regional MDA8 variations. The clustering results revealed four typical variation patterns of MDA8 in China given distinct pollution levels, seasonality, and long-term trends. Statistical modeling results indicated that the seasonal variability of MDA8 was closely associated with UV radiation and meteorological factors like boundary layer height, temperature and relative humidity. In contrast, the long-term trends of MDA8 were largely linked to ozone precursors and meteorological variables including temperature, relative humidity, and total cloud cover. Moreover, the phenomenal increasing trends of MDA8 in North China were found to be statistically associated with the depletion of nitrogen dioxide (NO2) and carbon monoxide (CO). Specifically, substantial increases in volatile organic compounds (VOCs) along with depletions in NO2 and CO significantly boosted the photochemical ozone formation chain process in a VOC-limited regime like the North China plain. Overall, the inferred linkage in this study provides evidence and clues to help control increasing ozone pollution events in North China.

Design, Synthesis, and Evaluation of Near-Infrared Fluorescent Molecules Based on 4H-1-Benzopyran Core.

A series of novel fluorescent 4H-1-benzopyrans was designed and developed as near-infrared fluorescent molecules with a compact donor-acceptor-donor architecture. Spectral intensity of the fluorescent molecules M-1, M-2, M-3 varied significantly with the increasing polarities of solvents, where M-3 showed high viscosity sensitivity in glycerol-ethanol system with a 3-fold increase in emission intensity. Increasing concentrations of compound M-3 to 5% BSA in PBS elicited a 4-fold increase in fluorescence intensity, exhibiting a superior environmental sensitivity. Furthermore, the in vitro cellular uptake behavior and CLSM assay of cancer cell lines demonstrated that M-3 could easily enter the cell nucleus and bind to proteins with low toxicity. Therefore, the synthesized near-infrared fluorescent molecules could provide a new direction for the development of optical imaging probes and potential further drugs.

Pharmacological activation of the p53 pathway by a new compound CYZ2017 exerts anti-tumor effects.

Blockage of p53-MDM2 protein-protein interaction has long been a promising strategy of drug development for cancers with wild type p53. In this study, we report a new p53-MDM2 interaction inhibitor, CYZ2017, which could induce p53 nuclear translocation and possess p53-dependent anti-proliferation activity in a range of cancer cells. CYZ2017 treatment led to increase of p53 levels and induced the transactivation of its target genes p21. In addition, CYZ2017 induced G0/G1 cell cycle arrest and apoptosis in HCT116 cells. Besides, CYZ2017 suppressed tumor growth in a HCT116 xenograft model without visible toxicity. These results support that CYZ2017 might be a promising p53-MDM2 interaction inhibitor with good anti-tumor activity. Our finding provides some cues for further investigation of developing anti-tumor drugs based on the blockage of p53-MDM2 interaction.

Design, synthesis, and structure activity relationship (SAR) studies of novel imidazo[1,2-a] pyridine derivatives as Nek2 inhibitors.

Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.

Spatiotemporal trend analysis for fine particulate matter concentrations in China using high-resolution satellite-derived and ground-measured PM2.5 data.

Atmospheric fine particulate matters (PM2.5) have raised global concerns because of their markedly adverse effects on public health and environmental quality. In parallel with technological variations and social changes in the evolving industrialization pathways in China, there is an acute need to evaluate the long-term spatiotemporal trend of PM2.5 concentrations across China after years of elevation. Toward this end, an integrated high-resolution satellite-derived (1998-2016) and ground-measured (2015-2017) PM2.5 data base was applied. Satellite-derived annual mean PM2.5 grids were firstly validated via comparison with collocated surface in situ PM2.5 measurements and were then used for trend analyses. The estimated linear trends from gridded PM2.5 data indicated that PM2.5 concentrations in China increased mainly before 2008 and have decreased since then, with prominent decreases observed primarily in south China. To corroborate the satellite-based PM2.5 trend estimations, surface in situ PM2.5 measurements from the period from 2015 to 2017 were applied to further evaluate the decreasing rate after 2014, at which time the Chinese "Air Pollution Prevention and Control Action Plan" was enforced. The results revealed that the national mean PM2.5 concentrations decreased by about 6.5 µg/m3 from 2015 to 2017, with prominent decreases (by a rate of 5-10 µg/m3 per year) observed primarily associated with large PM2.5 concentrations in Central China, North China, Northeast China, and East China during the period from October to December. Our systematic trend assessment provides a deepened understanding of PM2.5 variations across China in the past few years in association with the newly promoted action plan and offers a brief guideline for relevant policy making in the future.

Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein.

The very large G protein-coupled receptor 1 (VLGR1) is a core component in inner ear hair cell development. Mutations in the vlgr1 gene cause Usher syndrome, the symptoms of which include congenital hearing loss and progressive retinitis pigmentosa. However, the mechanism of VLGR1-regulated intracellular signaling and its role in Usher syndrome remain elusive. Here, we show that VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. The cleaved VLGR1 ß-subunit constitutively inhibited adenylate cyclase (AC) activity through Gαi coupling. Co-expression of the Gαiq chimera with the VLGR1 ß-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Gαi protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Gαi coupling, but the pathogenic VLGR1 Y6236fsx1 mutant showed increased AC inhibition. Furthermore, overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 ß-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Gαi signaling pathway of the VLGR1 ß-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome.

Understanding cadherin EGF LAG seven-pass G-type receptors.

The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development.

Design, synthesis and biological activity of flavonoid derivatives as selective agonists for neuromedin U 2 receptor.

Central neuromedin U 2 receptor (NMU2R) plays important roles in the regulation of food intake and body weight. Identification of NMU2R agonists may lead to the development of pharmaceutical agents to treat obesity. Based on the structure of rutin, a typical flavonoid and one of the NMU2R agonists we previously identified from an in-house made natural product library, 30 flavonoid derivatives have been synthesized and screened on a cell-based reporter gene assay. A number of compounds were found to be selective and highly potent to NMU2R. For example, the EC50 value of compound NRA 4 is very close to that of NMU, the endogenous peptide ligand of NMU2R. Structure-activity relationship analysis revealed that a 3-hydroxyl group in ring C and a 2'-fluoride group in ring B were essential for this class of compounds to be active against NMU2R.

Fabrication of hollow core-shell NiCo2O4@polypyrrole nanofibers/reduced graphene oxide ternary composites with excellent microwave absorption performances.

In contemporary times, electromagnetic radiation poses a significant threat to both human health and the normal functioning of electronic devices. Developing composites as adsorption materials possess exceptional electromagnetic wave absorption performances can efficient address this critical issue. Herein, hollow core-shell NiCo2O4@polypyrrole nanofibers/reduced graphene oxide (NiCo-HFPR) composites are fabricated by the combination of electrostatic spinning, air calcination, in-situ polymerization, freeze-drying and hydrazine vapor reduction. As anticipated, NiCo-HFPR-0.2 exhibits noteworthy properties, with the minimum reflection loss (RLmin) of -61.20 dB at 14.26 GHz and 1.56 mm, as well as the effective absorption bandwidth (EAB) of 4.90 GHz at 1.57 mm. Additionally, the simulation procedure is employed to determine the radar cross-section (RCS) attenuation. In comparison to a singular perfect electrically conductive (PEC) layer, the PEC layer coated with NiCo-HFPR-0.2 consistently yields an RCS value below -10 dB m2 within the range of -60° < θ < 60°. The RCS attenuation value of the NiCo-HFPR-0.2 coating achieves an outstanding 31.0 dB m2 at θ = 0°, strongly affirming the ability to effectively attenuate electromagnetic wave in real-world applications. The employed experimental methodology, the meticulously crafted composite, and the simulation outcomes presented in this study bear great promise for the progressive advancement of both theoretical investigations and practical applications within the domain of electromagnetic wave absorption.

Recent Developments in Polyurea Research for Enhanced Impact Penetration Resistance and Blast Mitigation.

Polyurea has gained significant attention in recent years as a functional polymer material, specifically regarding blast and impact protection. The molecular structure of polyurea is characterized by the rapid reaction between isocyanate and the terminal amine component, and forms an elastomeric copolymer that enhances substrate protection against blast impact and fragmentation penetration. At the nanoscale, a phase-separated microstructure emerges, with dispersed hard segment microregions within a continuous matrix of soft segments. This unique microstructure contributes to the remarkable mechanical properties of polyurea. To maximize these properties, it is crucial to analyze the molecular structure and explore methods like formulation optimization and the incorporation of reinforcing materials or fibers. Current research efforts in polyurea applications for protective purposes primarily concentrate on construction, infrastructure, military, transportation and industrial products and facilities. Future research directions should encompass deliberate formulation design and modification, systematic exploration of factors influencing protective performance across various applications and the integration of numerical simulations and experiments to reveal the protective mechanisms of polyurea. This paper provides an extensive literature review that specifically examines the utilization of polyurea for blast and impact protection. It encompasses discussions on material optimization, protective mechanisms and its applications in blast and impact protection.