A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 Wuhan strain infection and also pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor binding domain and other domains, distal to the ACE2 receptor-interaction site. Collectively, our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that can be targeted by peptides and potentially other drug-like molecules. One-Sentence SummaryWe identify a conserved site on the SARS-CoV-2 spike that can be targeted by a broadly neutralizing macrocyclic peptide.

Clinical Significance of miR-21-5p in Predicting Occurrence and Progression of Uremic Vascular Calcification in Patients with End-Stage Renal Disease

Purpose@#Vascular calcification (VC) is a common complication of end-stage renal disease (ESRD). This study aimed to examine changes in the expression of miR-21-5p in ESRD patients with VC and to explore its clinical value in predicting the occurrence and progression of uremic VC. @*Materials and Methods@#120 ESRD patients were divided into patients without VC group (n=38) and patients with VC group (n=82). All patients were followed up for 2 years to evaluate VC progression. qRT-PCR was used to detect serum miR-21-5p levels.Receiver operating characteristic curves were constructed to assess diagnostic value. Kaplan-Meier and log-rank methods were utilized to calculate associations between VC progression and risk factors. @*Results@#Serum miR-21-5p levels were significantly higher in ESRD patients with VC than in those without VC and increased progressively with increasing disease severity. Serum miR-21-5p levels were able to distinguish patients with VC from those without VC, with an area under the curve value of 0.883, a sensitivity of 81.7%, and a specificity of 84.2%. After 2 years of follow-up, miR-21-5p expression had increased in patients with worse VC severity, compared with those with stable VC severity. Patients with high miR-21-5p levels were more likely to develop more severe VC, indicating an association between miR-21-5p and VC progression (log-rank p=0.002). Multivariable Cox regression analysis suggested that serum miR-21-5p is an independent predictive factor of VC progression in ESRD patients (hazard ratio=2.064, 95% confidence interval=1.225–3.478, p=0.006). @*Conclusion@#miR-21-5p is overexpressed in the serum of ESRD patients with VC. Our results suggest that overexpression of miR-21-5p is closely associated with VC progression.

Pyrolyzed biowastes deactivated potentially toxic metals and eliminated antibiotic resistant genes for healthy vegetable production.

Potentially toxic metals (PTEs) and antibiotic resistance genes (ARGs) present in bio-wastes were the major environmental and health risks for soil use. If pyrolyzing bio-wastes into biochar could minimize such risks had not been elucidated. This study evaluated PTE pools, microbial and ARGs abundances of wheat straw (WS), swine manure (SM) and sewage sludge (SS) before and after pyrolysis, which were again tested for soil amendment at a 2% dosage in a pot experiment with a vegetable crop of pak choi (Brassica campestris L.). Pyrolysis led to PTEs concentration in biochars but reduced greatly their mobility, availability and migration potential, as revealed respectively by leaching, CaCl2 extraction and risk assessment coding. In SM and SS after pyrolysis, gene abundance was removed by 4-5 orders for bacterial, by 2-3 orders for fungi and by 3-5 orders for total ARGs. With these material amended, PTEs available pool decreased by 25%-85% while all ARGs eliminated to background in the pot soil. Unlike a >50% yield decrease and a >30% quality decline with unpyrolyzed SM and SS, their biochars significantly increased biomass production and overall quality of pak choi grown in the amended soil. Comparatively, amendment of the biochars decreased plant PTEs content by 23-57% and greatly reduced health risk of pak choi, with total target hazard quotient values well below the guideline limit for subsistence diet by adult. Furthermore, biochar soil amendment enabled a synergic improvement on soil fertility, product quality, and biomass production as well as metal stabilization in the soil-plant system. Thus, biowastes pyrolysis and reuse in vegetable production could help build up a closed loop of production-waste-biochar-production, addressing not only circular economy but healthy food and climate nexus also and contributing to achieving the United Nations sustainable development goals.

Screening and research of homologous peptide with adenovirus receptor / 中国免疫学杂志

Objective:To screen the binding peptide against adenovirus type 7(Ad7) and evaluate the relevance with the ade-novirus receptor .Methods:Binding peptide against Ad 7 was screened by panning the phage display 12 peptides library .The antibody against the selected peptide was prepared and was used to study the binding to the membrane by immunofluorescence technique .Re-sults:Using Ad7 as the target protein , GTS09 peptide was selected from the phage display 12 peptides library by biopanning .GTS09-phage complex could significantly bind Ad 7, with the affinity constant up to 1.93 ×1010 L/mol;at the same time, immunofluorescence showed that antibody of GTS09 could specifically bind to membrane of 293 cell.Conclusion: Antibody against GTS09 peptide could specifically bind to membrane of 293 cell,which shows that the peptide may presumably have homology with the cell receptors of Ad 7.

Study on effect of fushenkeli on expression of TAK1 in human renal tubular epithelial cells and its possible mechanism / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the effects of fushenkeli on the expression of TAK1 in the proliferation of the renal tubular epithelial cells induced by TGF-beta1 and its possible mechanism.</p><p><b>METHOD</b>Human renal tubular epithelial (HK-2) cells were divided into five groups:blank control group, TGF-beta1 group (5 microg x L(-1)), intervention group 1 (5 microg x L(-1) of TGF-beta1 + 100 mg x L(-1) of fushenkeli), intervention group 2 (5 microg x L(-1) of TGF-beta1 + 500 mg x L(-1) of fushenkeli) and intervention group 3 (5 microg x L(-1) of TGF-beta1 + 1 g x L(-1) of fushenkeli). HK-2 proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay. Type IV collagen in the supernatants of the cultured HK-2 was detected by ELISA at 12, 24, 48 hours respectively. The protein and mRNA expressions of TAK1 was measured by Western blot and real-time quantitative PCR.</p><p><b>RESULT</b>1) The cell proliferation and the expression of type IV collagen were increased compared with the control group (P<0.05, P<0.01), but they were decreased in intervention group. 2) The expressions of protein and mRNA of TAK1 in TGF-beta1 group were upregulating significantly compared with control group (P<0.01), but they were downregulating in intervention group, especially in intervention group 3.</p><p><b>CONCLUSION</b>Fushenkeli could inhibits TAK1 expression induced by TGF-beta1 in the proliferation of HK-2 cell.</p>

Fosinopril down-regulates transforming growth factor-activated kinase 1 in rats with renal tubulointerstitial fibrosis / 第三军医大学学报

Objective To investigate the effect of fosinopril on the expression of transforming growth factor (TGF)-activated kinase 1 (TAK-1) in the kidney of rats with unilateral ureteral obstruction (UUO),and its protective effect on renal interstitial fibrosis (RIF).Methods UUO model was induced by ligating the left ureter in rats.A total of 72 male Sprague-Wistar rats were randomly divided into 3 groups:sham-operated group (n=24),UUO model group (n=24) and UUO+fosinopril group (n=24).The rats were treated with 10 mg/(kg?d) by gastric gavage in the fosinopril treated group from 2 d after the operation,and the rats were treated with the identical dose of normal saline in the other 2 groups.Eight rats of each group were sacrificed at 7,14 and 21 d after UUO.Pathological changes of the renal tissue were observed by HE and Masson staining,and the mRNA and protein expression of TAK1 was detected by in situ hybridization,real-time PCR and Western blot analysis.Results The renal interstitial damage index of UUO group was increased compared with that of the sham-operation group (P