Coupling of N7-methyltransferase and 3′-5′ exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading

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Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques

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Association of the colistin resistance gene mcr-1 with faecal pollution in water environments in Hanoi,Vietnam

Colistin is one of the antibiotics of last resort for human health. However, the dissemination of the plasmid-mediated colistin resistance gene mcr-1 is of great concern globally. In the One Health framework, the environment is an important component for managing antimicrobial resistance. However, little information is available concerning the prevalence of mcr-1 in water environments. We aimed to reveal the prevalence of mcr-1 in different water environments in Hanoi, Vietnam. Quantitative PCR was applied to detect mcr-1 in four urban drainages receiving untreated domestic wastewater, three rivers, five lakes and two groundwater samples. Urban drainages contained higher concentrations of mcr-1, suggesting that urban residents carry the gene. The class 1 integron-integrase gene was identified as a good surrogate of antibiotic resistance genes including mcr-1. A significant correlation was found between the levels of mcr-1 and the human-specific cross-assembly phage, which is an indicator of human faecal pollution. These results indicated that the primary source of mcr-1 in urban water environments is human faeces, which is consistent with the fact that most domestic wastewater is untreated in Hanoi. The control of untreated wastewater is critical for alleviating the spread of mcr-1 in water environments in Vietnam.     

Planktonic and sediment bacterial communities in an integrated mariculture system

An integrated multi-trophic aquaculture (IMTA) system, with one fish cage model surrounded by an island and shellfish rafts, was used in the current study. Planktonic and sediment bacterial communities in the IMTA system were monitored over four seasons in 2019. In both plankton and sediment samples, the most dominant phyla were Proteobacteria and Bacteroidota. Sediment bacterial samples were more similar and had higher levels of biodiversity than planktonic bacterial samples. Obvious seasonal variations were found in plankton samples, but not in sediment samples. No obvious inter-site variations in planktonic and sediment bacteria (fish cages, shellfish rafts and control sites) were found and the results suggested that no obvious impact of feeding operations in fish culture cage model on bacterial communities in the IMTA system was observed in this study. Based on the sequence data, some faecal indicator bacteria and potentially pathogenic bacterial species were detected. According to the results, the bacterial water quality in the IMTA system was acceptable. PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) analysis revealed that the primary difference in potential functional roles of planktonic and sediment bacteria was amino acid transport and metabolism, which was active in different seasons.     

Xinnaokang improves cecal microbiota and lipid metabolism to target atherosclerosis

This study aims to explore the potential mechanisms of Xinnaokang in atherosclerosis treatment. Firstly, the active components of Xinnaokang were analysed by HPLC, which contains ginsenoside Rg1, puerarin, tanshinone, notoginsenoside R1, ammonium glycyrrhizate and glycyrrhizin. Network pharmacology analysis showed there were 145 common targets of Xinnaokang, including the chemical stress, lipid metabolite, lipopolysaccharide, molecules of bacterial origin, nuclear receptor and fluid shear stress pathways. Then, the animal experiment showed that Xinnaokang reduced the body weight and blood lipid levels of atherosclerotic mice. Vascular plaque formation was increased in atherosclerotic mice, which was markedly reversed by Xinnaokang. In addition, Xinnaokang reduced CAV-1 expression and increased ABCA1, SREBP-1 and LXR expressions in the vasculature. Xinnaokang promoted SREBP-2 and LDLR expressions in the liver but decreased IDOL and PCSK9 expressions, indicating that Xinnaokang regulated lipid transport-related protein expression. Cecal microbiota diversity was reduced in atherosclerotic mice but increased after Xinnaokang treatment. Xinnaokang treatment also improved gut microbiota communities by enriching Actinobacteria, Bifidobacteriales and Bifidobacteriaceae abundances. Metabolic profile showed that Xinnaokang significantly reduced homogentisate, phenylacetylglycine, alanine and methionine expressions in the liver of atherosclerotic mice. Xinnaokang effectively alleviated atherosclerosis, and this effect might be linked with the altered features of the liver metabolite profiles and cecal microbiota.     

Identification of connexin43 in diabetic retinopathy and its downregulation by O-GlcNAcylation to inhibit the activation of glial cells

BackgroundDespite advances in the treatments of diabetic complications, proliferative diabetic retinopathy (PDR) still remains a major cause leading to visual loss, mainly because of the lack of pathological mechanisms and complicated protein expressions in vivo. Current study aimed to investigate the patterns of connexin43 (Cx43) changes and the possible interactions with O-GlcNAcylation in DR.MethodsClinical samples of vitreous and fibrovascular membranes were acquired from PDR patients during pars plana vitrectomy. Brown Norway rats were used to build diabetic animal models; to investigate the effects of O-GlcNAcylation on Cx43 expressions, total retinal O-GlcNAcylation was changed by intravitreal injections. Levels of protein expressions were examined by immunofluorescence staining and western blot.ResultsOur results revealed increased Cx43 expressions in a vessel-shape pattern followed by the distribution of glial fibrillary acidic protein (GFAP) in diabetic fibrovascular membranes. Similarly, Cx43 and GFAP expressions were elevated in PDR vitreous and diabetic animal retinas. Retinal O-GlcNAcylation was effectively regulated by intravitreal injections, and the increase of Cx43 and GFAP was significantly suppressed by O-GlcNAcylation inhibition under hyperglycemia conditions.ConclusionsWe systemically proved the changes of Cx43 with different retinal cells, and reported the effective methods to regulate retinal O-GlcNAcylation by intravitreal injections, and clearly illustrated the downregulated effects of O-GlcNAcylation inhibition on Cx43 and GFAP expressions.General significance:Targeting connexin43 in glial cells reveals a novel mechanism to understand the formation of diabetic fibrovascular membranes and offers a potential therapeutic strategy to interfere the development of PDR.     

GDF11 prevents the formation of thoracic aortic dissection in mice: Promotion of contractile transition of aortic SMCs

Thoracic aortic dissection (TAD) is an aortic disease associated with dysregulated extracellular matrix composition and de-differentiation of vascular smooth muscle cells (SMCs). Growth Differentiation Factor 11 (GDF11) is a member of transforming growth factor β (TGF-β) superfamily associated with cardiovascular diseases. The present study attempted to investigate the expression of GDF11 in TAD and its effects on aortic SMC phenotype transition. GDF11 level was found lower in the ascending thoracic aortas of TAD patients than healthy aortas. The mouse model of TAD was established by β-aminopropionitrile monofumarate (BAPN) combined with angiotensin II (Ang II). The expression of GDF11 was also decreased in thoracic aortic tissues accompanied with increased inflammation, arteriectasis and elastin degradation in TAD mice. Administration of GDF11 mitigated these aortic lesions and improved the survival rate of mice. Exogenous GDF11 and adeno-associated virus type 2 (AAV-2)-mediated GDF11 overexpression increased the expression of contractile proteins including ACTA2, SM22α and myosin heavy chain 11 (MYH11) and decreased synthetic markers including osteopontin and fibronectin 1 (FN1), indicating that GDF11 might inhibit SMC phenotype transition and maintain its contractile state. Moreover, GDF11 inhibited the production of matrix metalloproteinase (MMP)-2, 3, 9 in aortic SMCs. The canonical TGF-β (Smad2/3) signalling was enhanced by GDF11, while its inhibition suppressed the inhibitory effects of GDF11 on SMC de-differentiation and MMP production in vitro. Therefore, we demonstrate that GDF11 may contribute to TAD alleviation via inhibiting inflammation and MMP activity, and promoting the transition of aortic SMCs towards a contractile phenotype, which provides a therapeutic target for TAD.     

Role of the APOE ε2/ε3/ε4 Polymorphism in the Development of Primary Open-Angle Glaucoma: Evidence from a Comprehensive Meta-Analysis

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The association between the APOE ε2/ε3/ε4 polymorphism and the risk of POAG has been widely reported, but the results of previous studies remain controversial. To comprehensively evaluate the APOE ɛ2/ɛ3/ε4 polymorphism on the genetic risk for POAG, we performed a systematic review and meta-analysis of previously published studies. The PubMed and Web of Science databases were systematically searched to identify relevant studies. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Stratified analyses according to ethnicity and sensitivity analyses were also conducted for further confirmation. A total of nine studies were eligible for the meta-analysis, and these studies included data on 1928 POAG cases and 1793 unrelated match controls. The combined results showed that there were no associations between the APOE ε2/ε3/ε4 polymorphism and POAG risk in any of the 10 comparison models. The analysis that was stratified by ethnicity subgroups also failed to reveal a significant association. The sensitivity analysis confirmed the stability and reliability of the findings. There was no risk of publication bias. Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations.     

IPA-3 Inhibits the Growth of Liver Cancer Cells By Suppressing PAK1 and NF-κB Activation

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.