Intermolecular Buchwald-Hartwig Reactions for Enantioselective Synthesis of Diverse Atropisomers: Rerouting the C-N Forming Mechanism to Substrate Oxygen-Assisted Reductive Elimination.

Axially chiral biaryls featuring a C-N axis are important functional molecules in diverse fields. The asymmetric Buchwald-Hartwig reaction represents a powerful strategy for these targets. Previous studies, however, have been predominantly restricted to intramolecular atroposelective coupling, likely due to the steric and entropic effects in the reductive elimination of Pd(II) species with sterically congested aryl and nitrogen groups. We now report two intermolecular Buchwald-Hartwig coupling systems of bulky NH lactams and halohydrocarbons enabled by rerouting the mechanism of C-N reductive elimination to one that accommodates sterically challenging substrates. Both atroposelective coupling systems exhibited functional group tolerance, excellent enantioselectivity, and high Z selectivity (if applicable), affording C-N atropisomeric biaryl and olefins through de novo construction of a C-N chiral axis. Experimental and computational studies were performed to elucidate the mechanism, and the switch of the reaction pathways is traced to the steric effect (ortho substituent) of the aryl halide substrate. A bulky 2,6-disubstituted aryl halide reorients the proximal lactamide ligand to its unusual O-ligation mode. With the amide oxygen participation, this intermediate undergoes C-N reductive elimination with an accessible barrier through a five-membered ring transition state, a pathway as well as a chiral induction mode that has been much underexplored in asymmetric catalysis.

Molecular Engineering to Regulate the Pseudo-Graphitic Structure of Hard Carbon for Superior Sodium Energy Storage.

Resin-derived hard carbons have shown great advantages in serving as promising anode materials for sodium-ion batteries due to their flexible microstructure tunability. However, it remains a daunting challenge to rationally regulate the pseudo-graphitic crystallite and defect of hard carbon toward advanced sodium storage performance. Herein, a molecular engineering strategy is demonstrated to modulate the cross-linking degree of phenolic resin and thus optimize the microstructure of hard carbon. Remarkably, the resorcinol endows resin with a moderate cross-linking degree, which can finely tune the pseudo-graphitic structure with enlarged interlayer spacing and restricted surface defects. As a consequence, the optimal hard carbon delivers a notable reversible capacity of 334.3 mAh g-1 at 0.02 A g-1, a high initial Coulombic efficiency of 82.1%, superior rate performance of 103.7 mAh g-1 at 2 A g-1, and excellent cycling durability over 5000 cycles. Furthermore, kinetic analysis and in situ Raman spectroscopy are performed to reveal the electrochemical advantage and sodium storage mechanism. This study fundamentally sheds light on the molecular design of resin-based hard carbons to advance sodium energy for scale-up applications.

Resolving Deactivation of Low-Spin Fe Sites by Redistributing Electron Density toward High-Energy Sodium Storage.

Prussian blue (PB) has been an emerging class of cathode material for sodium-ion batteries due to its low cost and high theoretical capacity. However, their working voltage and capacity are substantially restricted due to the deactivation of low-spin Fe sites. Herein, we demonstrate a universal strategy to activate the low-spin Fe sites of PB by hybridizing them with the π-π conjugated electronic conductors. The redistribution of electron density between π-π conjugated conductors and PB effectively promotes the participation of low-spin Fe sites in sodium storage. Consequently, the low-spin Fe-induced plateau is greatly aroused, resulting in a high specific capacity of 148.4 mAh g-1 and remarkable energy density of 444.2 Wh kg-1. In addition, the excellent structural stability enables superior cycling stability over 2500 cycles and outstanding rate performance. The work will provide fundamental insight into activating the low-spin Fe sites of PB for advanced battery technologies.

Biomass-Derived Hard Carbon with Interlayer Spacing Optimization toward Ultrastable Na-Ion Storage.

Hard carbons as a kind of nongraphitized amorphous carbon have been recognized as potential anode materials for sodium-ion batteries (SIBs) due to its large interlayer spacing. However, the issues in terms of onerous synthetic procedure and elusive working mechanism remains critical bottlenecks for practical implement. Herein, we report a facile production of tubular hard carbon through direct carbonization of platanus flosses (FHC) for the first time. Through optimizing the pyrolysis temperatures, the FHC obtained at 1300 °C possesses a key balance between the interlayer spacing and surface area, which can maintain the substantial active sites as well as reduce the irreversible sodium storage. Accordingly, it can deliver a reversible capacity of 324.6 mAh g-1 with a high initial Coulombic efficiency of 80%, superb rate property of 107.2 mAh g-1 at 2 A g-1, and long operating stability over 1000 cycles. Furthermore, the in situ Raman spectroscopic studies certify that sodium ions are stored in FHC following the "adsorption-insertion" mechanism. Our study could provide a promising route for large-scale development of the biomass-derived carbonaceous anodes for high-performance SIBs.

Recycling spent masks to fabricate flexible hard carbon anode toward advanced sodium energy storage.

The massive discard of spent masks during the COVID-19 pandemic imposes great environmental anxiety to the human society, which calls for a reliable and sustainable outlet to mitigate this issue. In this work, we demonstrate a green design strategy of recycling the spent masks to fabricate hard carbon fabrics toward high-efficient sodium energy storage. After a simple carbonization treatment, flexible hard carbon fabrics composed of interwoven microtubular fibers are obtained. When serving as binder-free anodes of sodium-ion batteries, a large Na-ion storage capacity of 280 mAh g-1 is achieved for the optimized sample. More impressively, the flexible anode exhibits an initial coulombic efficiency of as high as 86% and excellent rate/cycling performance. The real-life practice of the flexible hard carbon is realized in the full-cells. The present study affords an enlightening approach for the recycling fabrication of high value-added hard carbon materials from the spent masks for advanced sodium energy storage.

Silencing Gene-Engineered Injectable Hydrogel Microsphere for Regulation of Extracellular Matrix Metabolism Balance.

Extracellular matrix (ECM) metabolism balance is essential for maintaining tissue structure and function. However, the complex crosstalk between the ECM, resident cellular, and tissue microenvironment makes long-term maintenance of ECM metabolism balance in an abnormal microenvironment difficult to achieve. Herein, an injectable circRNA silencing-hydrogel microsphere (psh-circSTC2-lipo@MS) is constructed by grafting circSTC2 silencing genes-loaded 1,2-dioleoyl-3-trimethylammonium-propane/cholesterol/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOTAP/Chol/DOPE) cationic liposomes on methacrylated hyaluronic acid (HAMA) microspheres via amide bonds, which could silence pathological genes in nucleus pulposus (NP) cells to regulate ECM metabolism balance in the nutrient-restricted microenvironment, thereby inhibiting intervertebral disc (IVD) degeneration. HAMA microspheres prepared by microfluidics displayed good degradability, swellability, and injectability. And lipoplexes can be efficiently loaded and released for 27 d through chemical grafting. Cocultured under nutrient-restricted conditions for 72 h, psh-circSTC2-lipo@MS significantly promotes the synthesis of ECM-related proteins and inhibits the secretion of ECM catabolism-related proteases in NP cells. In the rat IVD nutrient-restricted model, local injection of psh-circSTC2-lipo@MS promotes ECM synthesis and restored NP tissue after 8 weeks. In summary, this study confirms that psh-circSTC2-lipo@MS as a safe and controllable targeted gene delivery system has great potential in regulating the ECM metabolism balance under an abnormal microenvironment.

Comprehensive Profile Analysis of Differentially Expressed circRNAs in Glucose Deprivation-Induced Human Nucleus Pulposus Cell Degeneration.

Nucleus pulposus (NP) is the core substance to maintain the homeostasis of intervertebral disc and stability of biomechanics. The insufficient supply of nutrition (especially glucose) is an important factor that leads to the degeneration of NP cells. circRNAs play an important role in the process of intervertebral disc degeneration (IDD) by regulating the functions of NP cells. However, glucose deprivation-related circRNAs and their functions in IDD have not been reported. In this study, the differentially expressed circRNAs in NP cells after 0, 6, 12, and 24 h of glucose deprivation culture were detected by a microarray assay. Besides, time series clustering analysis by STEM software obtained the differentially up- and downregulated circRNAs during glucose deficiency. Then, the main functions and pathways of up- and downregulated circRNAs were predicted by the functional enrichment analysis. By constructing the circRNA-miRNA regulatory network, the potential mechanisms of the most differentially expressed circRNAs were predicted. In addition, according to in vitro validation, circ_0075062 was upregulated in degenerating NP tissues and glucose deprivation-induced NP cell degeneration. Based on Sanger sequencing and RNase tolerance assay, circ_0075062 was the circular transcript. Interfering with circ_0075062 expression could potentially alleviate the imbalance of extracellular matrix (ECM) synthesis and degradation in the NP cells induced by glucose deprivation. Together, these findings help us gain a comprehensive understanding of the underlying mechanisms of IDD, and circ_0075062 may be a promising therapeutic target of IDD.

Integrating multiple microarray dataset analysis and machine learning methods to reveal the key genes and regulatory mechanisms underlying human intervertebral disc degeneration.

Intervertebral disc degeneration (IDD), a major cause of lower back pain, has multiple contributing factors including genetics, environment, age, and loading history. Bioinformatics analysis has been extensively used to identify diagnostic biomarkers and therapeutic targets for IDD diagnosis and treatment. However, multiple microarray dataset analysis and machine learning methods have not been integrated. In this study, we downloaded the mRNA, microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) expression profiles (GSE34095, GSE15227, GSE63492 GSE116726, GSE56081 and GSE67566) associated with IDD from the GEO database. Using differential expression analysis and recursive feature elimination, we extracted four optimal feature genes. We then used the support vector machine (SVM) to make a classification model with the four optimal feature genes. The ROC curve was used to evaluate the model's performance, and the expression profiles (GSE63492, GSE116726, GSE56081, and GSE67566) were used to construct a competitive endogenous RNA (ceRNA) regulatory network and explore the underlying mechanisms of the feature genes. We found that three miRNAs (hsa-miR-4728-5p, hsa-miR-5196-5p, and hsa-miR-185-5p) and three circRNAs (hsa_circRNA_100723, hsa_circRNA_104471, and hsa_circRNA_100750) were important regulators with more interactions than the other RNAs across the whole network. The expression level analysis of the three datasets revealed that BCAS4 and SCRG1 were key genes involved in IDD development. Ultimately, our study proposes a novel approach to determining reliable and effective targets in IDD diagnosis and treatment.

LncRNA PACER is down-regulated in osteoarthritis and regulates chondrocyte apoptosis and lncRNA HOTAIR expression.

LncRNA PACER is a chondrocyte inflammation-associated long non-coding RNA (lncRNA), and chondrocyte inflammation is involved in osteoarthritis (OA). We observed that plasma PACER was down-regulated, while plasma HOTAIR was up-regulated in OA patients. Altered plasma levels of PACER and HOTAIR distinguished OA patients from healthy controls. PACER and HOTAIR were inversely correlated in both OA patients and healthy controls. PACER overexpression mediated the down-regulation of HOTAIR, while HOTAIR overexpression did not significantly affect PACER. PACER overexpression led to inhibited, while HOTAIR overexpression led to promoted apoptosis of chondrocyte. HOTAIR overexpression attenuated the effects of PACER overexpression. Therefore, lncRNA PACER is down-regulated in OA and regulates chondrocyte apoptosis by down-regulating lncRNA HOTAIR.

p16INK4a inhibits the proliferation of osteosarcoma cells through regulating the miR-146b-5p/TRAF6 pathway.

Down-regulation of p16INK4a and miR-146b-5p contributes to tumorigenesis in osteosarcoma (OS). However, the correlation between p16INK4a and miR-146b-5p in OS proliferation remains largely unknown. In the present study, we demonstrated that miR-146b-5p expression was positively correlated with p16INK4a in OS, but inversely correlated with TNF receptor associated factor 6 (TRAF6) expression. Overexpression of miR-146b-5p dramatically suppressed OS cell proliferation. Mechanistically, we validated TRAF6 as a direct functional target of miR-146b-5p and found that miR-146b-5p overexpression significantly decreased the level of phosphorylated PI3k and Akt, which are the pivotal downstream effectors of TRAF6. Moreover, TRAF6 expression was positively correlated with Ki-67 but inversely correlated with miR-146b-5p expression. In OS cells, silencing of TRAF6 mimicked the anti-tumor effects of miR-146b-5p. p16INK4a is an important tumor suppressor gene frequently down-regulated in OS. We found that this inhibitory effect is associated with the suppression of the miR-146b-5p, and is mediated via up-regulating TRAF6 expression. Our findings identified p16INK4a and miR-146b-5p as tumor suppressors, and suggested p16INK4a, miR-146b-5p and TRAF6 as potential therapeutic candidates for malignant OS.

[Association between LMP2/LMP7 gene polymorphism and the infection of hepatitis B virus].

OBJECTIVE: To elucidate whether the antigen-processing gene (LMP2/LMP7) polymorphisms could influence the infection of hepatitis B virus. METHODS: Genomic DNA of 176 patients infected with HBV and 208 healthy volunteers were extracted from the peripheral blood leukocytes. Polymorphisms of LMP genes in HBV patients were determined by polymerase chain reaction-restriction fragment length polymorphism (RFLP), the controls by DNA sequencing. We used the software PHASE1.0 to construct the haplotypes of every individual. At last the unconditional Logistic regression model was used to analyze the statistical association of genotypes or haplotypes in two groups adjusted by gender and age. RESULTS: The distributions of LMP2 genes between cases and controls did not differ. However, LMP7 gene frequency in patients was higher than that in controls [odds ratio 2.11(95% confidence interval 1.36-3.26); 2.66 (95% confidence interval 1.17-6.02), heterogenous or homologous respectively]. Similarly, we found the haplotype combinated by R-K had a significant difference in two groups [odds ratio 1.81 (95% confidence interval 1.19-2.76)]. CONCLUSION: These findings suggest that polymorphisms of LMP2/LMP7 gene is one of the important host factors which independently affect on the infection of hepatitis B virus.

[Observation on therapeutic effect of chronic fatigue syndrome treated with coiling dragon needling and moving cupping on back].

OBJECTIVE: To compare the differences of therapeutic effect of chronic fatigue syndrome treated with the combined therapy of coiling dragon needling and cupping on back and the western medicine therapy with Prednisone. METHODS: Seventy-two cases were randomly divided into an acupuncture and cupping group (37 cases) and a Prednisone group (35 cases). In acupuncture and cupping group, Jiaji (EX-B 2) points of T1--L5 were applied with coiling dragon needling (once a day), combined with moving cupping on back (once every two days); in Prednisone group, Prednisone tablets were orally taken for 10 mg at 8:00 am. Seven days made one course, and 2 courses were carried on totally. FS-14 scale and BELL's chronic fatigue syndrome integral table were applied to evaluate the fatigue degree of patients before and after treatment, and the therapeutic effects of both groups were compared. RESULTS: After one course of treatment, the BELL's scores of both groups were obviously improved (both P < 0.01), but there was no significant difference between groups (P > 0.05); after two courses of treatment, the BELL's score in acupuncture and cupping group improved more obviously than that in Prednisone group, and the total effective rate of 91.9% (34/37) in acupuncture and cupping group was superior to that of 71.4% (25/35) in Prednisone group (P < 0.05). CONCLUSION: The therapeutic effect of chronic fatigue syndrome treated with coiling dragon needling and moving cupping on back is positive, superior to that of Prednisone with oral administration.

Multi-morphological self-assembled structures in water of a biodegradable ß-cyclodextrin-based copolymer.

A rigid-coil ß-cyclodextrin-poly (ɛ-caprolactone) (CD-PCL) copolymer was synthesized in which biodegradable flexible multi PCL arms were selectively connected onto the wide side of the rigid torus-shaped ß-CD through ring-opening polymerization (ROP) of ɛ-caprolactone (CL) and protection/deprotection technique of ß-cyclodextrin (ß-CD) via trimethylsilyl groups. (1)H NMR, FT-IR, and GPC analysis confirmed the "jellyfish-like" branched architecture of CD-PCL copolymers. The self-assembled structures in water of the amphiphilic CD-PCL copolymer were investigated by transmission electron microscopy (TEM), dynamic light scattering (DLC) and viscometry. The results showed that CD-PCL could self-assemble into multi-morphological aggregates such as spheres, rods, vesicles, vesicular clusters and vesicular network in water. Interestingly, hierarchical stripe structure was observed in the formed vesicular network, which was driven by the crystallization of PCL segment in micelles. Moreover, the inclusion ability of copolymer micelles with ferrocenecarboxylic acid was investigated by UV.

Association of the -183 polymorphism in the IFN-gamma gene promoter with hepatitis B virus infection in the Chinese population.

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that plays an important role in regulating cellular immune responses. Regulation of IFN-gamma expression is considered to be strictly controlled at the transcriptional level. Two single-nucleotide polymorphisms (SNPs) within the human IFN-gamma promoter (at positions -183 and -155) are considered to influence the promoter activity by altering the acting transcription factor-1 (AP-1) binding. We sought to assess the association between the SNPs of the IFN-gamma promoter and the host susceptibility to hepatitis B virus (HBV) infection, as well as its interaction with age and gender. No polymorphism at position-155 was detected in any of the participants, but a significant difference was found in the polymorphism at position -183 between the cases and controls (G/T and T/T vs. GG; P < 0.01, odds ratio (OR) = 4.50 (95% confidence interval (CI) = 2.23-9.09). A susceptibility analysis revealed a gradually increased trend of the OR value from the young to the old group (OR = 3.03, 4.17, and 5.56). Similarly, the association of the -183 polymorphism was markedly different in females (OR = 5.71). Our data suggest that the polymorphism at position -183 of the IFN-gamma gene promoter may be associated with susceptibility to HBV infection, and age and gender factors are coordinative risk factors.