Abstract
Background
Coronavirus disease 2019 (COVID-19) is a pandemic with no specific antiviral treatments or vaccines. There is an urgent need for exploring the neutralizing antibodies from ...patients with different clinical characteristics.
Methods
A total of 117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients. Antibodies were determined with a modified cytopathogenic neutralization assay (NA) based on live severe acute respiratory syndrome coronavirus 2 and enzyme-linked immunosorbent assay (ELISA). The dynamics of neutralizing antibody levels at different time points with different clinical characteristics were analyzed.
Results
The seropositivity rate reached up to 100.0% within 20 days since onset, and remained 100.0% till days 41–53. The total geometric mean titer was 1:163.7 (95% confidence interval CI, 128.5–208.6) by NA and 1:12 441.7 (95% CI, 9754.5–15 869.2) by ELISA. The antibody level by NA and ELISA peaked on days 31–40 since onset, and then decreased slightly. In multivariate generalized estimating equation analysis, patients aged 31–45, 46–60, and 61–84 years had a higher neutralizing antibody level than those aged 16–30 years (β = 1.0470, P = .0125; β = 1.0613, P = .0307; β = 1.3713, P = .0020). Patients with a worse clinical classification had a higher neutralizing antibody titer (β = 0.4639, P = .0227).
Conclusions
The neutralizing antibodies were detected even at the early stage of disease, and a significant response was shown in convalescent patients.
The neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in patients with COVID-19 depends on time since onset and severity of disease.
SARS-CoV-2 variants could induce immune escape by mutations on the receptor-binding domain (RBD) and N-terminal domain (NTD). Here we report the humoral immune response to circulating SARS-CoV-2 ...variants, such as 501Y.V2 (B.1.351), of the plasma and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine), ZF2001 (RBD-subunit vaccine) and natural infection. Among 86 potent NAbs identified by high-throughput single-cell VDJ sequencing of peripheral blood mononuclear cells from vaccinees and convalescents, near half anti-RBD NAbs showed major neutralization reductions against the K417N/E484K/N501Y mutation combination, with E484K being the dominant cause. VH3-53/VH3-66 recurrent antibodies respond differently to RBD variants, and K417N compromises the majority of neutralizing activity through reduced polar contacts with complementarity determining regions. In contrast, the 242-244 deletion (242-244Δ) would abolish most neutralization activity of anti-NTD NAbs by interrupting the conformation of NTD antigenic supersite, indicating a much less diversity of anti-NTD NAbs than anti-RBD NAbs. Plasma of convalescents and CoronaVac vaccinees displayed comparable neutralization reductions against pseudo- and authentic 501Y.V2 variants, mainly caused by E484K/N501Y and 242-244Δ, with the effects being additive. Importantly, RBD-subunit vaccinees exhibit markedly higher tolerance to 501Y.V2 than convalescents, since the elicited anti-RBD NAbs display a high diversity and are unaffected by NTD mutations. Moreover, an extended gap between the third and second doses of ZF2001 leads to better neutralizing activity and tolerance to 501Y.V2 than the standard three-dose administration. Together, these results suggest that the deployment of RBD-vaccines, through a third-dose boost, may be ideal for combating SARS-CoV-2 variants when necessary, especially for those carrying mutations that disrupt the NTD supersite.
Although most patients with COVID-19 pneumonia have a good prognosis, some patients develop to severe or critical illness, and the mortality of critical cases is up to 61.5%. However, specific ...molecular information about immune response in critical patients with COVID-19 is poorly understood. A total of 54 patients were enrolled and divided into three groups, among which 34 were common, 14 were severe, and 6 were critical. The constitution of peripheral blood mononuclear cells (PBMC) in patients was analyzed by CyTOF. The profile of cytokines was examined in plasma of patients using luminex. The IL-2 signaling pathway was investigated in the PBMC of patients by qRT-PCR. The count and percentage of lymphocytes were significantly decreased in critical patients compared to common and severe patients with COVID-19 pneumonia. The count of T cells, B cells, and NK cells was remarkably decreased in critical patients compared to normal controls. The percentage of CD8
T cells was significantly lower in critical patients than that in common and severe patients with COVID-19 pneumonia. The expression of IL-2R, JAK1, and STAT5 decreased in PBMC of common, severe, and critical patients, but IL-2 level was elevated in severe patients and decreased in critical patients with COVID-19 pneumonia. The decrease of CD8
T cells in critical patients with COVID-19 pneumonia may be related to the IL-2 signaling pathway. The inhibition of IL-2/IL-2R gives rise to CD8
T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia.
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•Dynamic compression characteristics and reaction behavior of W-Zr reactive material are investigated.•Hypervelocity impact experiments of long rods on multi-spaced plates are ...performed.•The debris clouds during the impact process are recorded with a high-speed camera.•Damage properties of the multi-spaced plates with long rods are obtained and compared.•W-Zr reactive material has the damage effects of kinetic and chemical energy.
The damage or penetration research of the long rods has attracted more and more attention from scholars worldwide. In this article, the dynamic compression tests of W-Zr reactive material are performed. Six experiments of the long rods impacting the multi-spaced plates at hypervelocity are carried out on a two-stage light gas gun. Two kinds of long rods, inert 40CrNi2MoA steel and W-Zr reactive material, are used. The initial impact speed ranges from 2040 m/s to 3200 m/s. According to results, W-Zr reactive material reacts at the strain rate of 2200 s−1 and higher, whose strength limit is related to the strain rate. The long rods can produce debris clouds when hitting the multi-spaced plates at the speed of 2040 m/s and higher, causing large perforation and great damaged area in the subsequent plates. The perforations and damaged areas of the multi-spaced plates depend on the specific kinetic energy of the long rods. The violent reaction behavior of the W-Zr reactive material helps to cause large perforation and damaged area of the subsequent plates than inert materials. It proves that the damage ability of the W-Zr reactive material is stronger than that of the inert material with a similar density.
A novel, molecularly imprinted, upconversion fluorescence probe (UCNP@MIFP) for sulfonamide sensing was fabricated by Pickering emulsion polymerization using UCNP@SiO
particles as the stabilizer and ...sulfamethazine/sulfamerazine as the co-templates. The synthesis conditions of the UCNP@MIFP were optimized, and the synthesized probe was characterized by scanning electron microscopy, Fourier transform infrared spectrometer, thermogravimetric analyzer, and fluorescence spectrometer. The UCNP@MIFPs showed a good adsorption capacity and a fast kinetic feature for the template. The selectivity experiment revealed that the UCNP@MIFP has a broad-spectrum molecular recognition capability. Good linear relationships were obtained over the concentration range of 1-10 ng/mL for sulfamerazine, sulfamethazine, sulfathiazole, and sulfafurazole, with low limits of detection in the range of 1.37-2.35 ng/mL. The prepared UCNP@MIFP has the potential to detect four sulfonamide residues in food and environmental water.
T cell receptor (TCR) of all enrolled patients was also sequenced, in which the transcriptome of one sample was excluded from downstream analysis because of the “low fraction reads in cells” alert ...displayedinthe Cell Ranger websummary.A flowchart is presented in Figure 1A. Based on the expression level of canonical cell markers and highly expressed differential expressed genes (DEGs) of each cluster, eight major cell types were identified: T cells (CD3D, CD3E), B cells (CD79A), natural killer (NK) cells (NKG7, GNLY, FCGR3A), monocytes (CD14, FCGR3A), monocyte-derived dendritic cells (MO-DCs; CD1C), plasmacytoid dendritic cells (pDCs; IL3RA, GZMB), hemopoietic stem cells (CYTL1), and platelets (PPBP, PF4, GP9). ...plasma levels of anti-S1S2, anti-RBD, and anti-N proteins were lower in the recurrent patient in comparison with the others Figure 1F. To further elucidate the potential mechanisms associated with impaired B cell development and function in the recurrent patient, gene set enrichment analysis (GSEA) was subsequently performed based on significant DEGs (adjusted P < 0.05).
This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease ...remission.
We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks.
Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse.
Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.
There is growing concern about mitochondrial DNA (mtDNA) mutations with long-term NRTI exposure in HIV-1 infected children.
Twenty-four HIV-1 infected children who started ART more than 2 years ...earlier who had an excellent virological response and had not changed their regimen were enrolled retrospectively. Their corresponding PBMCs in 2009 (T1), 2010 (T2) and 2013 (T3) were included. Sequencing of the entire mtDNA using next-generation sequencing revealed the spectrum of mtDNA variants.
The trend showed that the number of mtDNA mutations during ART occurred as T1 < T2 < T3 (P = 0.086). Interestingly, the numbers of whole mtDNA mutations at T3 (median 41, range 24-62) were significantly greater than at T1 (34, 25-46, P = 0.029). A positive correlation was found between total mtDNA mutations and treatment time (r = 0.352, P = 0.002). During the observation period, mtDNA mutations more frequently occurred in the D-loop, cytochrome b (CYTB) and 12S rRNA regions. The heteroplasmic ratio of T3 was higher than that of T1 in CYTB and 12S rRNA (P = 0.034 and P = 0.042, respectively). High heteroplasmic population levels were found at nt 263 (A263G, D-loop) and nt 8860 (A8860G, ATPase6). A significant difference in heteroplasmy between T1, T2 and T3 occurred at nt 14783 (T14783C, CYTB, P = 0.048, T3 > T2 > T1).
Our findings reveal the spectrum of mtDNA variants in HIV-1-infected children who had an excellent virological response. mtDNA mutations accumulated during ART may play an important role in facilitating the occurrence of mitochondrial dysfunction.
Hepatocellular carcinoma (HCC) originates from fully differentiated hepatocytes, but the decisive events for converting hepatocytes to the cells of origin for HCC are still unclear. Liver cancer stem ...cells (LCSCs) cause HCC but are not bona fide cells of origin. Here, the expressions of POU2F2 and IL‐31 are identified in macroscopically normal livers of diethylnitrosamine‐challenged mice. An autoregulatory circuit formed by mutual induction between POU2F2 and IL‐31 drives hepatocytes to progress to LCSCs by acquiring stemness, as well as stimulates them to in vivo grow and malignantly progress. The development of the autoregulatory circuit is a decisive event for converting hepatocytes into the cells of origin, since hepatocytes expressing the circuit have acquired tumorigenic potential before progressing to LCSCs. Nonetheless, acquiring stemness is still required for the cells of origin to initiate hepatocarcinogenesis. The circuit also occurs in human cirrhotic tissues, partially elucidating how premalignant lesions progress to HCC.
POU2F2 and IL‐31 form an autoregulatory circuit that functionally promotes fully differentiated hepatocytes to be converted into liver cancer stem cells by inducing pluripotent transcription factors such as NANOG, OCT4, and SOX2, as well as suppressing p53.
Highlights • IEL potential is present in CD103− cells in the thymic IEL precursor population. • IL-15 alone can support maturation of thymic IEL precursors in vitro. • Three distinct fractions are ...observed in the TCRαβ+ CD8αα+ IEL population.
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