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1.
Artigo em Inglês | MEDLINE | ID: mdl-34389437

RESUMO

Among all psychiatric disorders, anorexia nervosa (AN) has the highest mortality rate. However, there is still no pharmacological therapy for AN. The human plasma proteome may be a great cornerstone for the development of new drugs against AN. Here we performed a Mendelian randomization (MR) analysis to identify causal risk proteins for AN. Exposure data were extracted from a large genome-wide association study (GWAS) of 2994 plasma proteins in 3301 subjects of European descent, while outcome data were obtained from another GWAS of AN (16,992 cases and 55,525 controls of European descent). MR analyses were performed using the inverse-variance weighted (IVW) method and other sensitivity analysis methods. Using single nucleotide polymorphisms as instruments, this study suggested that high TXNDC12 levels were associated with a higher risk of AN (IVW Odd's ratio [OR]: 1.12; 95% confidence interval [CI]: 1.08-1.16; P = 2.35 × 10-10), while another protein ADH1B showed the opposite effect (IVW OR: 0.89; 95% CI: 0.85-0.93; P = 2.99 × 10-7). The causal associations were robust in multivariable models, genome-wide significant models, and with additional MR methods. No pleiotropy was observed. Our findings suggest that TXNDC12 was associated with a high risk of AN, while AHD1B was associated with a low risk of AN. They might both have implications in AN by regulating the brain dopamine reward system. In combination with existing knowledge on AN, these proteins may be novel drug targets for AN treatment.

2.
J Hazard Mater ; 421: 126745, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34364206

RESUMO

Sulfide precipitation is an efficient method to remove Cu(II) and As(III) from strongly acidic wastewater, but the instantaneous release of H2S from traditional sulfuration reagents causes serious H2S pollution. Moreover, the obtained precipitates are mixtures of CuS and As2S3, leading to difficulties in resource recovery. In this study, a calcium sulfide-organosilicon complex (CaS-OSCS), in which CaS was coated into a matrix of {[O1.5Si(CH2)3NH]CS}n (OSCS) via the coordination bonding, was developed. OSCS, as a matrix of CaS-OSCS, can ensure the sustained and stable release of H2S under strongly acidic conditions owing to its low swelling (1.75% swelling ratio) and excellent acid resistance. The release longevity of H2S from CaS-OSCS extended from 5 min up to 50 min compared with that from CaS because the hydrophobic OSCS prevented solution diffusing to the pores of CaS-OSCS and thus slowed down the hydrolysis of CaS in pores. 99% of Cu(II)/As(III) was precipitated without H2S escape, and the dosage of sulfuration reagents was reduced by 30%. In addition, CaS-OSCS improved the selective separation of copper from wastewater, and a separation factor between Cu(II) and As(III) reached 2376. This study provides a potential approach for the elimination of H2S pollution and selective recovery of copper.


Assuntos
Sulfeto de Hidrogênio , Águas Residuárias , Compostos de Cálcio , Preparações de Ação Retardada , Sulfetos
3.
Chemosphere ; 287(Pt 1): 132120, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34523462

RESUMO

Water environmental pollution caused by spent batteries is a nonignorable environmental issue. In this study, the early life stage of zebrafish was employed to assess the environmental risk of spent batteries after exposure to 0, 1%, 2%, 5% and 10% spent battery extract for 120 h. Our results clearly indicated that spent battery extract can significantly decrease the survival rate, hatching rate and body length and increase heart rate. Moreover, spent battery extract exposure-induced zebrafish larvae generate oxidative stress and inhibit the mRNA transcriptional levels of heat shock protein (HSP70) and metallothionein (MT) genes. These results showed that the spent batteries not only affected the survival and development performance of zebrafish at an early life stage but also caused oxidative stress and interfered with the detoxification of zebrafish. This study provided novel insight into spent battery induced toxicity in the early life stage of fish.

4.
Environ Pollut ; 292(Pt A): 118326, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34653591

RESUMO

Bauxite residue, an industrial alkaline solid waste, has a low organic carbon content which hinders plant growth. Dissolved organic matter (DOM) drives many biogeochemical processes including carbon storage and soil formation in soils. Input of exogenous organic materials may provide organic carbon and accelerate soil formation processes in bauxite residue. However, the potential effects of ameliorants on the quantity and quality of DOM in bauxite residue are still poorly understood. Here, the integration of ultraviolet-visible (UV-Vis) spectra, fluorescence spectra, and parallel factor (PARAFAC) analysis were used to investigate the vertical characteristics of DOM in bauxite residue treated by PV (the combined addition of 2% phosphogypsum and 4% vermicompost, w/w) and BS (6% w/w including 4% bagasse and 2% bran) with 2-year column experiments. The content of DOM in untreated residues ranged from 0.064 to 0.096 g/kg, whilst higher contents of DOM were observed in PV (0.13 g/kg) and BS (0.26 g/kg) treatment. Meanwhile, with the increase of residue depth, the aromaticity and hydrophobic components of DOM in residue decreased, which indicated that the degree of humification of the treated residues in the upper layer was higher than that in the lower layer. Compared with BR, BS and PV treatment accumulated the related content of fulvic acid-like substance from 36.14% to 71.33% and 74.86%, respectively. The incorporation of vermicompost and biosolids increased the content of humic-like substances, whilst decreasing the content of protein-like substances in the surface layer, which may be due to the enrichment of the microbial community. During soil formation processes, the application of organic amendments reduced both salinity and alkalinity, enhanced microbial community diversity, and changed the quantity and quality of DOM in bauxite residue. These findings improve our understanding of the dynamics of DOM and response of DOM to soil formation processes in bauxite residue.

5.
Chemosphere ; 286(Pt 3): 131864, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34399270

RESUMO

In this article, the degradation of 4, 4'-(hexafluoroisopropylidene) diphenol (bisphenol AF, BPAF) by ozone was studied and toxicity of the degradation products was evaluated. Kinetic studies showed that acidic conditions were more conducive to the ozone degradation of BPAF than alkaline conditions. In the presence of common anions, Br- and SO42- promoted the degradation of BPAF, whereas NO2-, NO3-, HSO3- inhibited the degradation, and the other anions and cations had no significant effect. The degradation products were analyzed by mass spectrometry, and were mainly manifested in hydroxylation, carboxylation and cleavage of benzene ring. The addition of NO2-, HSO3- and Br-produced the corresponding free radicals, resulting in the parent compound being attacked and affecting the degradation efficiency and pathways. The theoretical calculated results showed that the ortho-site of the BPAF phenolic hydroxyl group was more active than the meta-position, and it's more likely for free radicals to attack ortho-sites and initiate substitution reactions. Toxicity assessment of the products in the process of ozone degradation showed that toxicity of the products was reduced by benzene ring cleavage and a reduction in the F atomic number. However, the toxicity of nitro and brominated products of BPAF was increased. These findings provide some new insights into the role of common ions in ozonation process and product formation, and supplement the existing conclusions. The results of this study remind future researchers to concern that inorganic ions in real water may be converted into corresponding free radicals that affect the formation of ozone oxidation products.


Assuntos
Ozônio , Poluentes Químicos da Água , Ânions , Compostos Benzidrílicos , Cinética , Oxirredução , Fenóis , Poluentes Químicos da Água/toxicidade
6.
Mol Psychiatry ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728799

RESUMO

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine-receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

7.
Front Immunol ; 12: 755549, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777367

RESUMO

Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709-1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34785054

RESUMO

Silver nanoparticles (Ag NPs) have attracted extensive research interest in bioimaging and biosensing due to their unique surface plasmon resonance. However, the potential aggregation and security anxiety of Ag NPs hinder their further application in biomedical field due to their high surface energy and the possible ionization. Here, binary heterogeneous nanocomplexes constructed from silver nanoparticles and carbon nanomaterials (termed as C-Ag NPs) were reported. The C-Ag NPs with multiple yolk structure were synthesized via a one-step solvothermal route using toluene as carbon precursor and dispersant. The hydrophilic functional groups on the carbon layer endowed the C-Ag NPs excellent chemical stability and water-dispersity. Results showed that C-Ag NPs demonstrated excellent safety profile and excellent biocompatibility, which could be used as an intracellular imaging agent. Moreover, the C-Ag NPs responded specifically to hydroxyl radicals and were expected to serve as a flexible sensor to efficiently detect diseases related to the expression of hydroxyl radicals in the future.

9.
Front Cell Dev Biol ; 9: 758339, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805166

RESUMO

The tumor microenvironment heterogeneity of papillary thyroid cancer (PTC) is poorly characterized. The relationship between PTC and Hashimoto thyroiditis (HT) is also in doubt. Here, we used single-cell RNA sequencing to map the transcriptome landscape of PTC from eight PTC patients, of which three were concurrent with HT. Predicted copy number variation in epithelial cells and mesenchymal cells revealed the distinct molecular signatures of carcinoma cells. Carcinoma cells demonstrated intertumoral heterogeneity based on BRAF V600E mutation or lymph node metastasis, and some altered genes were identified to be correlated with disease-free survival in The Cancer Genome Atlas datasets. In addition, transcription factor regulons of follicular epithelial cells unveil the different transcription activation state in PTC patients with or without concurrent HT. The immune cells in tumors exhibited distinct transcriptional states, and the presence of tumor-infiltrating B lymphocytes was predominantly linked to concurrent HT origin. Trajectory analysis of B cells and plasma cells suggested their migration potential from HT adjacent tissues to tumor tissues. Furthermore, we revealed diverse ligand-receptor pairs between non-immune cells, infiltrating myeloid cells, and lymphocytes. Our results provided a single-cell landscape of human PTC. These data would deepen the understanding of PTC, as well as the immunological link between PTC and HT.

10.
J Healthc Eng ; 2021: 7036863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733456

RESUMO

The aim of this research was to explore the relationship between depression and brain nerve function in patients with end-stage renal disease (ESRD) and long-term maintenance hemodialysis (MHD) based on watershed segmentation algorithm using diffusion tensor imaging (DTI) technology. A total of 29 ESRD patients with depression who received MHD treatment in the hemodialysis center of hospital were included as the research subjects (case group). A total of 29 healthy volunteers were recruited as the control group, and a total of 29 ESRD patients with depression and brain lesions were recruited as the control group (HC group). Within 24 h after hemodialysis, the blood biochemical indexes were collected before this DTI examination. All participants completed the neuropsychological scale (MoCA, TMT A, DST, SAS, and SDS) test. The original DTI data of all subjects were collected and processed based on watershed segmentation algorithm, and the results of automatic segmentation according to the image were evaluated as DSC = 0.9446, MPA = 0.9352, and IOU = 0.8911. Finally, the average value of imaging brain neuropathy in patients with depression in the department of nephrology was obtained. The differences in neuropsychological scale scores (PSQI, MoCA, TMTA, DST, SAS, and SDS) between the two groups were statistically significant (P < 0.05). The differences of FA values in all the white matter partitions of Fu organs, except the cingulum of hippocampus (CgH) between the two groups, were statistically significant (P < 0.05). ESRD and DTI quantitative detection under the guidance of watershed segmentation algorithm in MHD patients showed that ESRD patients can be early identified, so as to carry out psychological nursing as soon as possible to reduce the occurrence of depression, and then protect the brain nerve to reduce brain neuropathy.

11.
Nucleic Acids Res ; 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34747471

RESUMO

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on.

13.
Front Oncol ; 11: 765216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760707

RESUMO

Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial-mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.

14.
Adv Sci (Weinh) ; : e2103714, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791832

RESUMO

In flexible electronics, appropriate inlaid structures for stress dispersion to avoid excessive deformation that can break chemical bonds are lacking, which greatly hinders the fabrication of super-foldable composite materials capable of sustaining numerous times of true-folding. Here, mimicking the microstructures of both cuit cocoon possessing super-flexible property and Mimosa leaf featuring reversible scatheless folding, super-foldable C-web/FeOOH-nanocone (SFCFe) conductive nanocomposites are prepared, which display cone-arrays on fiber structures similar to Mimosa leaf, as well as non-crosslinked junctions, slidable nanofibers, separable layers, and compressible network like cuit cocoon. Remarkably, the SFCFe can undergo over 100 000 times of repeated true-folding without structural damage or electrical conductivity degradation. The mechanism underlying this super-foldable performance is further investigated by real-time scanning electron microscopy folding characterization and finite-element simulations. The results indicate its self-adaptive stress-dispersion mechanism originating from multilevel biomimetic structures. Notably, the SFCFe demonstrates its prospect as a super-foldable anode electrode for aqueous batteries, which shows not only high capacities and satisfactory cycling stability, but also completely coincident cyclic voltammetry and galvanostatic charge-discharge curves throughout the 100 000 times of true-folding. This work reports a mechanical design considering the self-adaptive stress dispersion mechanism, which can realize a scatheless super-foldable electrode for soft-matter electronics.

15.
Autophagy ; : 1-2, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34781818

RESUMO

Macroautophagy/autophagy is a conserved mechanism responsible for the degradation of unnecessary or dysfunctional components and recycling of the nutrients they contain in order to promote cellular or organismal longevity. In plants photosynthesis is massively impaired under extended darkness stress and the transition to heterotrophic metabolism results in carbon and nitrogen starvation which induces metabolic and autophagic shifts to recycle nutrients for plant survival. The majority of research concerning dark-induced senescence focuses on single genes or pathways, and the global characterization of primary and lipid metabolites and autophagy remains limited. To address these aspects we recently developed a time-resolved genome-wide association-based approach to analyze these shifts following 0 d, 3 d and 6 d of darkness. Six patterns of metabolic shifts and 215 associations with enzymes, transcriptional regulators and autophagy genes (such as AT2G31260/ATG9, AT4G16520/ATG8F, AT5G45900/ATG7 and AT2G05630/ATG8D) were identified. Furthermore detailed characterization of candidate genes further demonstrated that the metabolic and autophagic shifts in response to dark-induced senescence is under tightly coordinated genetic regulation.

16.
Chem Catal ; 1(4): 870-884, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34738092

RESUMO

Selective modifications of peptides and proteins have emerged as a promising strategy to develop novel mechanistic probes and prepare compounds with translational potentials. Here, we report alanine carbastannatranes AlaSn as a universal synthon in various C-C and C-heteroatom bond-forming reactions. These reagents are compatible with peptide manipulation techniques and can undergo chemoselective conjugation in minutes when promoted by Pd(0). Despite their increased nucleophilicity and propensity to transfer the alkyl group, C(sp3)-C(sp2) coupling with AlaSn can be accomplished at room temperature under buffered conditions (pH 6.5-8.5). We also show that AlaSn can be easily transformed into several canonical L- and D-amino acids in arylation, acylation, and etherification reactions. Furthermore, AlaSn can partake in macrocyclizations exemplified by the synthesis of medium size cyclic peptides with various topologies. Taken together, metalated alanine AlaSn demonstrates unparalleled scope and represents a new type of umpolung reagents suitable for structure-activity relationship studies and peptide diversification.

18.
Plant Dis ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597154

RESUMO

Peach shoot blight (PSB) caused by Phomopsis amygdali is a serious threat to the healthy development of the peach industry and leads to 30-50 % damage to peach production in southern China. In this study, loop-mediated isothermal amplification (LAMP) technology was used to detect the P. amygdali target of a gene of GME6801 that was unique in the whole genome of the pathogen compared with that of Diaporthe (Phomopsis) longicolla TWH P74, Fusurium graminearum PH-1, Colletotrichum gloeosporioides SMCG1 and Magnaporthe oryzae 70-15. Blast comparison of this gene sequence in NCBI database showed that no homologous sequences were found. Therefore, the gene sequence of GME6801 was used to design two pairs of LAMP primers and one pair of PCR primers. The results showed that both of primer sets were specific to the 15 strains of P. amygdali, and the other 15 fungal strains presented negative reactions, similar to the control. In addition, 50 pg of genomic DNA of P. amygdali in a 25 µl reaction system could be detected by LAMP assay which was 100 times more sensitive than PCR. Furthermore, the GME6801 LAMP assay was used to detect artificially inoculated twigs of the pathogen, disease twigs within significantly symptomatic PSB in the field and healthy twigs in the same orchard, with the detection rates of 100%, 75% and 20.8%, respectively. However, the detection rates of conventional PCR were separately 100%, 62.5% and 16.7%. The results indicated that GME6801-based LAMP could be used for P. amygdali detection as its specificity, sensitivity and simplicity. This study provides a rapid experimental basis for the identification and prediction of P. amygdali that causes PSB and is beneficial for precise prevention and control of the disease.

19.
J Exp Bot ; 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34599807

RESUMO

A citrus R2R3 MYB transcription factor (CsMYB96) was found to alleviate water loss by simultaneously regulating plasma membrane intrinsic proteins (CsPIPs) and wax-related genes. Expression profiling indicated that CsPIP1;1 and CsPIP2;4 are representative aquaporins with high expression, and are down-regulated in the peel of postharvest citrus fruit. CsPIP2;4 was further characterized as the predominant CsPIP with high expression and high-water channel activity. Besides, transient overexpression of CsPIP2;4 accelerated the water loss of citrus fruit. The in silico analysis further revealed that the expression of CsMYB96 had a significant negative correlation with that of CsPIPs. In vivo and in vitro experiments confirmed that CsMYB96 can directly repress the expression of CsPIPs. Furthermore, CsMYB96 can activate the wax-related genes and promote wax biosynthesis for defense against water loss. The transient and stable overexpression of CsMYB96 reduced the water loss of citrus fruit and Arabidopsis.

20.
Natl Sci Rev ; 8(8): nwab053, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34676098

RESUMO

Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting the N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, a combination of RBD-targeting NAbs and NTD-binding NAbs, FC05, enhanced the neutralization potency in cell-based assays and an animal model. Results of competitive surface plasmon resonance assays and cryo-electron microscopy (cryo-EM) structures of antigen-binding fragments bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in the NTD and RBD of S, when immunized in rabbits and macaques, elicited potent protective immune responses against SARS-CoV-2. More importantly, two immunizations of this combination of NTD and RBD immunogens provided complete protection in macaques against a SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection. These results provide a proof of concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD.

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