After two doses of mRNA vaccine, health care workers had less viral neutralizing-antibody activity against the BA.4/5 and BA.2.12.1 omicron subvariants than against the BA.1 and BA.2 subvariants, but ...titers increased significantly with a booster dose.
Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the ...sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta-infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants and provide insight into the immunity from natural infection against Omicron sub-lineages.
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•BA.1.1, BA.1, and BA.2 escape neutralization by two-dose mRNA vaccinee sera•Booster vaccination recovers Omicron immunity to levels comparable to Delta•Sera from Omicron, but not D614G or Delta, COVID-19 patients neutralize Omicron•The Omicron “EPE214” insertion does not dictate neutralization resistance
The emerging SARS-CoV-2 Omicron variants may threaten existing COVID-19 immunity. Evans and colleagues examine immunity against the BA.1.1 and BA.2 variants, as well as prior SARS-CoV-2 variants, in two- and three-dose vaccinated individuals and recovered COVID-19 patients. Booster vaccination, but not two-dose vaccinee or non-Omicron-infected patient sera, neutralizes Omicron.
The continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Here, we examine the neutralization resistance ...of these subvariants against sera from 3-dose vaccinated healthcare workers, hospitalized BA.1-wave patients, and BA.4/5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially in the BQ.1 and BQ.1.1 subvariants driven by N460K and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation. All Omicron subvariants maintained their weakened infectivity in Calu-3 cells, with the F486S mutation driving further diminished titer for the BA.2.75.2 subvariant. Molecular modeling revealed the mechanisms of antibody-mediated immune evasion by R346T, K444T, F486S, and D1199N mutations. Altogether, these findings shed light on the evolution of newly emerging SARS-CoV-2 Omicron subvariants.
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•Enhanced neutralization resistance of BQ.1 and BQ.1.1 is driven by N460K and K444T•Enhanced neutralization resistance of BA.2.75.2 is driven by F486S•R346T and K444T contribute to evasion of class III antibody recognition•Modeling reveals that F486S reduces binding for both ACE2 and class I and II antibodies
Numerous Omicron subvariants have emerged following BA.4/5 and BA.2.75 subvariants. Qu and colleagues investigate the neutralizing antibody resistance of these subvariants and their ancestral variants. BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2 exhibit enhanced neutralizing antibody escape, with BQ.1/BQ.1.1 and BA.2.75.2 driven by N460K/K444T and F486S mutations, respectively.
The evolution of SARS‐CoV‐2 paired with immune imprinting by prototype messenger RNA (mRNA) vaccine has challenged the current vaccination efficacy against newly emerged Omicron subvariants. In our ...study, we investigated a cohort of macaques infected by SIV and vaccinated with two doses of bivalent Pfizer mRNA vaccine containing wildtype and BA.5 spikes. Using a pseudotyped lentivirus neutralization assay, we determined neutralizing antibody (nAb) titers against new XBB variants, i.e., XBB.1.5, XBB.1.16, and XBB.2.3, alongside D614G and BA.4/5. We found that compared to humans vaccinated with three doses of monovalent mRNA vaccine plus a bivalent booster, the monkeys vaccinated with two doses of bivalent mRNA vaccines exhibited relatively increased titers against XBB subvariants. Of note, SIV‐positive dam macaques had reduced nAb titers relative to SIV‐negative dams. Additionally, SIV positive dams that received antiretroviral therapy had lower nAb titers than untreated dams. Our study underscores the importance of reformulating the COVID‐19 vaccine to better protect against newly emerged XBB subvariants as well as the need for further investigation of vaccine efficacy in individuals living with HIV‐1.
After a third (booster) dose of SARS-CoV-2 vaccine, immunity waned more slowly than after two doses and even more slowly in persons with breakthrough Covid-19. Neutralization of subvariant BA.4–BA.5 ...was particularly resistant to vaccine-induced immunity.
Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies ...stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants.
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•Bivalent booster induces 2- to 8-fold higher nAb titer than monovalent against XBB and XBB.1.5•CH.1.1 and CA.3.1 exhibit nearly complete escape of neutralization from bivalent booster•XBB.1.5, CH.1.1, and CA.3.1 show increased fusogenicity compared with BA.2•Homology modeling shows impacts of F486P mutation present in XBB.1.5 on ACE2 binding
Qu et al. show that bivalent booster recipients, compared with monovalent recipients, exhibit higher nAb titers against Omicron subvariants XBB, XBB.1, and XBB.1.5. The CH.1.1 and CA.3.1 variants show more substantial neutralization escape than the XBB variants. Further, structural modeling reveals that the F486P mutation in XBB.1.5 enhances ACE2 binding.
Background. Adipokines are reported to participate in many common pathologic processes of glucose dysregulation, such as insulin resistance, β-cell dysfunction, and chronic inflammation. Objective. ...To detect the concentrations of plasma asprosin in subjects with impaired glucose regulation (IGR) and newly diagnosed type 2 diabetes (nT2DM) and its relationship to parameters of glucose and lipid metabolism, insulin resistance, and pancreatic β-cell function. Methods. 143 eligible participants were included and were divided into three groups including normal glucose regulation (NGR, n=52), IGR (n=40), and nT2DM group (n=51). The intravenous glucose tolerance test (IVGTT) and clinical and biochemical parameters were measured in all participants. Results. Plasma asprosin levels were higher in IGR (82.40 ± 91.06 ng/mL, P<0.001) and nT2DM (73.25 ± 91.69 ng/mL, P<0.001) groups compared with those in the NGR (16.22 ± 9.27 ng/mL) group, especially in IGR subjects. Correlation analysis showed that plasma asprosin levels were positively correlated with waist circumference (Wc), fasting plasma glucose (FPG), postchallenge plasma glucose (2hPG), HbA1c, triglyceride (TG), and homeostasis model assessment for insulin resistance (HOMA-IR) and negatively correlated with homeostasis model assessment for β-cell function (HOMA-β), area under the curve of the first-phase (0–10 min) insulin secretion (AUC), acute insulin response (AIR), and glucose disposition index (GDI) (all P<0.05). Multiple logistical regression analyses revealed that plasma asprosin concentrations were significantly correlated with IGR and nT2DM after controlling for age, sex, BMI, and WHR. Conclusions. Circulating asprosin might be a predictor of early diagnosis in DM and might be a potential therapeutic target for prediabetes and T2DM.
UV radiation is the primary cause of skin photoaging, which results in an increase in matrix metalloproteinases and degradation of collagen. Developing new natural antioxidant as photoprotective ...agents has become a popular area of research. Orobanche cernua Loefling is a parasitic plant that is rich in phenylethanoid glycosides (PhGs). This study investigated the photoprotective effects of the ethanolic extract of Orobanche cernua Loefling (OC) and its principal component acteoside on UVB‐induced photoaging as well as their underlying molecular mechanisms in normal human dermal fibroblasts (NHDFs). Biological testing demonstrated that OC and acteoside possessed significant photoprotective activities, reducing MMP and IL‐6 levels while improving type‐I procollagen synthesis in UVB‐irradiated NHDFs. Further study showed that the protective mechanisms were the improvement of transcription factor Nrf2‐mediated antioxidant defensive system, suppression of MAPK/AP‐1 and activation of the TGF‐β/Smad pathway. Together, our results suggested that OC might be a promising antiphotoaging agent against UV radiation‐induced skin damage.
Chronic exposure to UV radiation results in skin premature aging (photoaging), clinically accompanied with loss of elasticity and tension. In this study, we demonstrated that OC could reverse this damage via increasing procollagen synthesis and blocking MMPs expression. The studies of molecular mechanism indicated OC could inhibit MMPs expression via inactivating MAPK/AP‐1 pathway and accelerate type‐I procollagen synthesis through activating the TGF‐β/Smad pathway. Furthermore, OC reduced UVB‐enhanced ROS via promoting Nrf2 nuclear location and enhancing the expression of cytoprotective antioxidants.
Abstract
Plant NRT2 nitrate transporters commonly require a partner protein, NAR2, for transporting nitrate at low concentrations, but their role in plants is not well understood. In this study, we ...characterized the gene for one of these transporters in the rice genome, OsNRT2.4, in terms of its activity and roles in rice grown in environments with different N supply. In Xenopus oocytes, OsNRT2.4 alone without OsNAR2 co-expression facilitated nitrate uptake showing biphasic kinetics at a wide concentration range, with high- and low-affinity KM values of 0.15 and 4 mM, respectively. OsNRT2.4 did not have nitrate efflux or IAA influx activity. In rice roots, OsNRT2.4 was expressed mainly in the base of lateral root primordia. Knockout of OsNRT2.4 decreased lateral root number and length, and the total N uptake per plant at both 0.25 and 2.5 mM NO3− levels. In the shoots, OsNRT2.4 was expressed mainly in vascular tissues, and its knockout decreased the growth and NO3−-N distribution. Knockout of OsNRT2.4, however, did not affect rice growth and N uptake under conditions without N or with only NH4+ supply. We conclude that OsNRT2.4 functions as a dual-affinity nitrate transporter and is required for nitrate-regulated root and shoot growth of rice.
The newly emerged BA.2.75 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant contains 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here, ...we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in S. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2 but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, reduces BA.2.75 neutralization resistance. The impact of these mutations is consistent with their locations in common neutralizing antibody epitopes. Further, BA.2.75 shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling reveals enhanced receptor contacts introduced by N460K, suggesting a mechanism of potentiated receptor utilization and syncytia formation.
•BA.2.75 shows enhanced neutralization resistance and fusion over BA.2 but not BA.4/5•G446S, and to a lesser extent N460K, determines enhanced neutralization resistance•N460K drives enhanced spike processing and cell-cell fusion of BA.2.75•N460K potentiates ACE2 interactions likely by forming a salt bridge and hydrogen bond
Newly emerged Omicron subvariants reignite concerns over escape from existing immunity. Qu and colleagues compare the immunity resistance and fusogenicity of BA.2.75 with prior variants. BA.2.75 exhibits stronger neutralization resistance than BA.2 but weaker than BA.4/5, as well as enhanced fusogenicity, which are largely driven by G446S and N460K, respectively.
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