To fully decipher the immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein, it is essential to assess which part is highly immunogenic in a systematic way. ...We generate a linear epitope landscape of the Spike protein by analyzing the serum immunoglobulin G (IgG) response of 1,051 coronavirus disease 2019 (COVID-19) patients with a peptide microarray. We reveal two regions rich in linear epitopes, i.e., C-terminal domain (CTD) and a region close to the S2′ cleavage site and fusion peptide. Unexpectedly, we find that the receptor binding domain (RBD) lacks linear epitope. We reveal that the number of responsive peptides is highly variable among patients and correlates with disease severity. Some peptides are moderately associated with severity and clinical outcome. By immunizing mice, we obtain linear-epitope-specific antibodies; however, no significant neutralizing activity against the authentic virus is observed for these antibodies. This landscape will facilitate our understanding of SARS-CoV-2-specific humoral responses and might be useful for vaccine refinement.
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•A linear epitope landscape of the SARS-CoV-2 Spike from 1,051 COVID-19 patients•Responsive epitopes are highly variable among patients and correlate with severity•The RBD lacks linear epitopes, but two other regions are rich in linear epitopes•Little neutralization activity is observed for the linear-epitope-elicited antibodies
Li et al. construct a B cell linear epitope landscape of SARS-CoV-2 Spike protein, based on a large cohort of COVID-19 patients. The epitope responses were related to disease severity and outcome but mainly elicit non-neutralizing antibodies.
Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral ...organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
Exploring high‐rate electrode materials with excellent kinetic properties is imperative for advanced sodium‐storage systems. Herein, novel cubic‐like XFe (X = Co, Ni, Mn) Prussian blue analogs ...(PBAs), as cathodes materials, are obtained through as‐tuned ionic bonding, delivering improved crystallinity and homogeneous particles size. As expected, Ni‐Fe PBAs show a capacity of 81 mAh g−1 at 1.0 A g−1, mainly resulting from their physical–chemical stability, fast kinetics, and “zero‐strain” insertion characteristics. Considering that the combination of elements incorporated with carbon may increase the rate of ion transfer and improve the lifetime of cycling stability, they are expected to derive binary metal‐selenide/nitrogen‐doped carbon as anodes. Among them, binary Ni0.67Fe0.33Se2 coming from Ni‐Fe PBAs shows obvious core–shell structure in a dual‐carbon matrix, leading to enhanced electron interactions, electrochemical activity, and “metal‐like” conductivity, which could retain an ultralong‐term stability of 375 mAh g−1 after 10 000 loops even at 10.0 A g−1. The corresponding full‐cell Ni‐Fe PBAs versus Ni0.67Fe0.33Se2 deliver a remarkable Na‐storage capacity of 302.2 mAh g−1 at 1.0 A g−1. The rational strategy is anticipated to offer more possibilities for designing advanced electrode materials used in high‐performance sodium‐ion batteries.
Cubic‐like XFe (X = Co, Ni, Mn) Prussian blue analogs (PBAs) are designed through as‐tuned ionic bonding of XFe. Ni‐Fe PBAs as cathode show “zero‐strain” insertion traits with physical–chemical stability, and their derived binary metal‐selenide as anode displays strong metal‐like conductivity. Their matched sodium full‐cell systems deliver reasonably high and fast specific capacity.
Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung ...epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme A20, causing progressive accumulation of the transcription factor C/EBPβ in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3β (GSK-3β) interacted with and phosphorylated A20 to suppress C/EBPβ degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3β interaction accelerated C/EBPβ degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3β-A20-C/EBPβ axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.
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•A20 activity in alveolar macrophages negatively correlates with lung fibrosis•A20 exerts its anti-fibrotic activities by destabilizing C/EBPβ in AMs•GSK-3β interacts with and phosphorylates A20 to impede its activity•Targeting GSK-3β/A20 interaction reduces lung fibrosis by degrading C/EBPβ
Dysregulation of the ubiquitin-editing enzyme A20 contributes to the development of several human inflammatory diseases. Liu et al. demonstrate that suppression of A20 enzymatic activity in alveolar macrophages promotes lung fibrosis by reducing transcriptional factor C/EBPβ degradation and enhancing targeted gene expression, which directs the profibrotic phenotype of macrophages.
Background
The missing asymptomatic COVID‐19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in ...asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic.
Measure
Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty‐three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS‐CoV‐2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset.
Results
A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS‐CoV‐2. Different from strong and persistent N‐specific antibodies, S1‐specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months.
Conclusion
Our findings might have important implications for the definition of asymptomatic COVID‐19 infections, diagnosis, serological survey, public health, and immunization strategies.
The combination of NAT and serological testing for IgM antibody significantly improves the detection sensitivity of asymptomatic COVID‐19 infections, compared with NAT alone. S1‐specific IgM antibody response with rapid emergence and disappearance might be helpful to assist NAT for early identification of infectious individuals. A majority of asymptomatics induce very low levels of neutralizing antibody that disappear in two months. Abbreviations: NAT, nucleic acid testing; FI, fluorescence intensity; NT50, half‐maximal neutralizing titer.
Astragaloside IV (AsIV) is an active saponin extracted from Astragalus membranaceus, which has shown cardioprotective effects in a number of experimental animals. In this study we investigated the ...molecular mechanisms by which AsIV attenuated the myocardial ischemia reperfusion (MI/R)-induced injury in vitro and in vivo by focusing on calcium-sensing receptor (CaSR) and extracellular signal-regulated kinase 1/2 (ERK1/2). Rat neonatal cardiac myocytes were subjected to a hypoxia/reoxygenation (H/R) procedure in vitro, which significantly decreased the cell viability, increased lactate dehydrogenase (LDH) release, induced cardiomyocyte apoptosis, and increased Ca
. H/R also increased the expression of CaSR and decreased ERK1/2 phosphorylation levels in H/R-exposed myocytes. Pretreatment with AsIV (60 μmol/L) significantly improved the cell viability and decreased LDH release, attenuated myocyte apoptosis, decreased Ca
and CaSR expression, and increased the ERK1/2 phosphorylation levels. The protective effects of AsIV against H/R injury were partially inhibited by co-treatment with a CaSR agonist, gadolinium chloride (GdCl
) or with a specific ERK1/2 inhibitor U0126. For in vivo studies, a rat MI/R model was established. Pre-administration of AsIV (80 mg/kg every day, ig) significantly decreased the myocardium infarct size, creatine kinase-MB (CK-MB) production, serum cardiac troponin (cTnI) levels, and cardiomyocyte apoptosis in the rats with MI/R injury. The therapeutic effects of AsIV were associated with the downregulation of CaSR expression and upregulation of ERK1/2 phosphorylation in myocardial tissues. In summary, astragaloside IV attenuates myocardial I/R injury via inhibition of CaSR/ERK1/2 and the related apoptotic signaling pathways.
Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering (TE) and regenerative medicine. In contrast to conventional biomaterials or synthetic materials, ...biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix (ECM). Additionally, such materials have mechanical adaptability, microstructure interconnectivity, and inherent bioactivity, making them ideal for the design of living implants for specific applications in TE and regenerative medicine. This paper provides an overview for recent progress of biomimetic natural biomaterials (BNBMs), including advances in their preparation, functionality, potential applications and future challenges. We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM. Moreover, we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications. Finally, we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.
Expanded azahelicenes, as heteroanalogues of helically chiral helicenes, hold significant potential for chiroptical materials. Nevertheless, their investigation and research have remained largely ...unexplored. Herein, we present the facile synthesis of a series of expanded azahelicenes NHn (n=1–5) consisting of 11, 19, 27, 35, and 43 fused rings, mainly by Suzuki coupling followed by Bi(OTf)3‐mediated cyclization of vinyl ethers. The structures of NH2, NH3 and NH4 were confirmed through X‐ray crystallography analysis, and their (P)‐ and (M)‐ enantiomers were also isolated with chiral high performance liquid chromatography. The enantiomers exhibit large absorption (abs) and luminescence (lum) dissymmetry factors, with |gabs|max=0.044; |glum|max=0.003 for NH2, |gabs|max=0.048; |glum|=0.014 for NH3, and |gabs|max=0.043; |glum|max=0.021 for NH4, which are superior to their respective all‐carbon analogues.
Expanded azahelicenes consisting of up to 43 rings are accessible by a facile synthesis. The enantiomers of the acquired azahelicenes exhibited large dissymmetry factors with up to 0.048 (gabs) and 0.021 (glum), respectively.
We sought to investigate the capacity of cerebral autoregulation and cerebrovascular reactivity (CVR) in patients with middle cerebral artery (MCA) stenosis.
Twenty-one patients with MCA stenosis ...diagnosed by magnetic resonance angiography and 15 healthy controls were enrolled. Cerebral autoregulation was assessed by autoregulatory parameters (rate of recovery/phase/gain) derived from transfer function from spontaneous oscillations of cerebral blood flow velocity and blood pressure. CVR was tested by a rebreathing maneuver.
Rate of recovery, phase and CVR estimated from moderate MCA stenosis (rate of recovery = 17.76 ± 8.21%/s, phase = 26.93 ± 15.67°, and CVR = 1.53 ± 0.84%/mmHg, respectively) were significantly different (p<0.05) from controls (rate of recovery = 39.62 ± 27.99%/s, phase = 55.66 ± 22.10°, and CVR = 2.18 ± 0.80%/mmHg, respectively). Rate of recovery (r = -0.698, p<0.001), phase (r = -0.738, p<0.001)) and CVR (r = -0.690, p<0.001) were all significantly correlated with the degree of stenosis.
Cerebral autoregulation and CVR were impaired in patients with ≥ 50% MCA stenosis. The measures of both hemodynamic properties were inversely correlated with the stenotic degree.
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