We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and ...healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.
An electrochemical asymmetric coupling of secondary acyclic amines with ketones via a Shono-type oxidation has been described, affording the corresponding amino acid derivatives with good to ...excellent diastereoselectivity and enantioselectivity. The addition of an N-oxyl radical as a redox mediator could selectively oxidize the substrate rather than the product, although their oxidation potential difference is subtle (about 13 mV). This electrochemical transformation proceeds in the absence of stoichiometric additives, including metals, oxidants, and electrolytes, which gives it good functional group compatibility. Mechanistic studies suggest that proton-mediated racemization of the product is prevented by the reduction of protons at the cathode.
Coal and gas outburst is a frequent dynamic disaster during underground coal mining activities. After about 150 years of exploration, the mechanisms of outbursts remain unclear to date. Studies on ...outburst mechanisms worldwide focused on the physicochemical and mechanical properties of outburst-prone coal, laboratory-scale outburst experiments and numerical modeling, mine-site investigations, and doctrines of outburst mechanisms. Outburst mechanisms are divided into two categories: single-factor and multi-factor mechanisms. The multi-factor mechanism is widely accepted, but all statistical phenomena during a single outburst cannot be explained using present knowledge. Additional topics about outburst mechanisms are proposed by summarizing the phenomena that need precise explanation. The most appealing research is the microscopic process of the interaction between coal and gas. Modern physical-chemical methods can help characterize the natural properties of outburst-prone coal. Outburst experiments can compensate for the deficiency of first-hand observation at the scene. Restoring the original outburst scene by constructing a geomechanical model or numerical model and reproducing the entire outburst process based on mining environment conditions, including stratigraphic distribution, gas occurrence, and geological structure, are important. Future studies can explore outburst mechanisms at the microscale.
METTL3 catalyzes the formation of N
-methyl-adenosine (m
A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in ...mammals. Here we generated germ cell-specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m
A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m
A modification in spermatogenesis and reproduction in mammals.
Poly(triarylamine) (PTAA)-wrapped single-walled carbon nanotubes (SWCNTs) functioned in a dual role as an efficient hole-transporting layer and electrode in perovskite solar cells (PSCs). Thanks to ...the well-matched energy level, increased hole-transporting mobility, and hydrophobicity rendered by dopant-free PTAA, this dual-role SWCNTs electrode applied-PSCs using dopant-free PTAA achieved a better efficiency and stability than reference standards using LiTFSI-doped Spiro-OMeTAD. This dopant-free PTAA-applied SWCNTs electrode is expected to not only give a solution for efficiently using the SWCNTs electrode in PSCs, but also unveil the mechanism of the interaction between the hole-transporting layer and SWCNTs.
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Platinum usually offers the most effective active center for hydrogen evolution reaction (HER), because of the optimal trade‐off between the adsorption and desorption of hydrogeN atoms (H*) on Pt ...atoms. Herein, we report an unusual result regarding the active center of a HER catalyst, which was synthesized by electrodepositing traces of Pt nanoparticles (NPs) into a porous nitrogen‐rich dodecahedron matrix derived from zeolitic imidazolate framework ZIF‐8. With an ultra‐low Pt loading of 2.76 μg cm−2, the N‐Pt‐bonded catalyst can produce a current density of 117 mA cm−2 for the HER in 1.0 m H2SO4 at an overpotential of 50 mV, whereas the commercial Pt/C (300 μg cm−2 Pt) can only reach 50 mA cm−2 under the same conditions. Cyclic voltammetry demonstrates that both the H* adsorption and the Pt oxidation are not allowed to occur on this catalyst, due to a full surface coverage of the trace Pt NPs by imidazole. The results from the specially designed experiments indicate that the imidazole N atoms may act as proton anchor‐sites for the HER due to their electron donor nature. Density functional theory calculations also support a catalytic HER mechanism centered at the Pt‐supported N active center, which needs a Gibbs free energy of H* absorption (ΔGH*) significantly smaller than the absolute value of ΔGH* on the Pt(111) surface. We hope that the results of this study will encourage the research on novel N‐centered catalysts for the HER.
Role reversal: Imidazole N atoms prove to be the real active center of a highly efficient ZIF‐8‐derived electrocatalyst for hydrogen evolution reaction (HER), even in the presence of trace Pt (a well‐known active center). Neither H* adsorption nor Pt oxidation can occur on the nonexposed Pt surface (fully covered by imidazole).
Inactivation of the p66Shc adaptor protein confers resistance to oxidative stress and protects mice from aging-associated vascular diseases. However, there is limited information about the negative ...regulating mechanisms of p66Shc expression in the vascular system.
In this study, we investigated the role of SIRT1, a class III histone deacetylase, in the regulation of p66Shc expression and hyperglycemia-induced endothelial dysfunction.
Expressions of p66Shc gene transcript and protein were significantly increased by different kinds of class III histone deacetylase (sirtuin) inhibitors in human umbilical vein endothelial cells and 293A cells. Adenoviral overexpression of SIRT1 inhibited high-glucose-induced p66Shc upregulation in human umbilical vein endothelial cells. Knockdown of SIRT1 increased p66Shc expression and also increased the expression levels of plasminogen activator inhibitor-1 expression, but decreased manganese superoxide dismutase expression in high-glucose conditions. However, knockdown of p66Shc significantly reversed the effects of SIRT1 knockdown. In addition, p66Shc overexpression significantly decreased manganese superoxide dismutase expression and increased plasminogen activator inhibitor-1 expression in high-glucose conditions, which were recovered by SIRT1 overexpression. Moreover, compared to streptozotocin-induced wild-type diabetic mice, endothelium-specific SIRT1 transgenic diabetic mice had decreased p66Shc expression at both the mRNA and the protein levels, improved endothelial function, and reduced accumulation of nitrotyrosine and 8-OHdG (markers of oxidative stress). We further found that SIRT1 was able to bind to the p66Shc promoter (-508 bp to -250 bp), resulting in a decrease in the acetylation of histone H3 bound to the p66Shc promoter region.
Our findings indicate that repression of p66Shc expression by SIRT1 contributes to the protection of hyperglycemia-induced endothelial dysfunction.
MiR-34a, a direct target of p53, has been shown to target several molecules associated with the cell cycle and cell survival pathways, and its dysregulation is implicated in cancer drug resistance or ...sensitivity in several human cancers. However, the correlation between miR-34a expression and chemoresistance has not been explored in HCC. In this study, we confirmed that miR-34a was significantly down-regulated in HCC tissues and HCC cell lines by qRT-PCR. HCC tissues with lower miR-34a expression displayed higher expression of Bcl-2 protein than those with high expression of miR-34a; therefore, an inverse correlation is evident between the miR-34a level and Bcl-2 expression. Moreover, patients with lower miR-34a expression had significantly poorer overall survival. Bioinformatics and luciferase reporter assays revealed that miR-34a binds the 3'-UTR of the Bcl-2 mRNA and represses its translation. Western blotting analysis and qRT-PCR confirmed that Bcl-2 is inhibited by miR-34a overexpression. Functional analyses indicated that the restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression. This study is the first to demonstrate that miR-34a induces sensitivity to the anti-tumor effect of sorafenib in human HCC cells, suggesting a potential role of miR-34a in the treatment of HCC.
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•Molecular mechanisms of hepatic insulin resistance in nonalcoholic fatty liver disease.•Lipid metabolism and inflammation are the key basic mechanisms of all mechanisms.•For the ...treatment of NAFLD, improving lipid metabolism and inflammatory drugs is a potential direction.
The prevalence of nonalcoholic fatty liver disease (NAFLD) in the general population is estimated at 25 %, and there is currently no effective treatment of NAFLD. Although insulin resistance (IR) is not the only factor causing the pathogenesis of NAFLD, hepatic IR has a cause-effective relationship with NAFLD. Improving hepatic IR is a potential therapeutic strategy to treat NAFLD. This review highlights the molecular mechanisms of hepatic IR in the development of NAFLD. Available data on potential drugs including glucagon-like peptide 1 receptor (GLP-1) agonists, peroxisome proliferator-activated receptor (PPAR-γ/α/δ) agonists, farnesoid X receptor (FXR) agonists, etc. are carefully discussed.
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A novel stearic-pillared MgAl layered double hydroxide (S-Mo/LDH) containing MoOx nanoparticles was successfully prepared by calcination-reconstruction, where MoOx nanoparticles were ...decorated onto the surface of the S-Mo/LDH by reducing the MoO42−-pillared LDH precursor (Mo-LDH). The microstructures, bonding states and surface properties were investigated by XRD, SEM, FT-IR, BET/BJH, WAC and TG-DTG, which confirmed that the interlayer MoO42− anion was grafted onto the brucite sheets to form MoOx nanoparticles during the calcination process of the Mo-LDH, and stearic anions were intercalated into the interlayers of the S-Mo/LDH. The performances of the flame-retardancy were improved by combining these properties of the individual materials of stearic, parent LDH and MoOx nanoparticles. In comparison to the Mo-LDH, the S-Mo/LDH demonstrated a more homogeneous dispersion in polypropylene (PP) matrix due to surface hydrophobicity. The incorporation of the S-Mo/LDH filter at 20 g∙100 g−1 loading provided an excellent fire resistance towards PP matrix, giving the high limited oxygen index (28.6%), vertical burning UL94 (V-0) and reduced total heat release (71.6% reduction in PHRR relative to neat PP). These remarkable properties indicated that the approach to improve flame retardancy of PP was a cost-effective, feasible and highly effective way.
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