Enantioselective Palladium(II)-Catalyzed Desymmetrizative Coupling of 7-Azabenzonorbornadienes with Alkynylanilines.

A PdII -catalyzed, domino enantioselective desymmetrizative coupling of 7-azabenzonorbornadienes with alkynylanilines is disclosed herein. This operationally simple transformation generates three covalent bonds and two contiguous stereocenters with excellent enantio- and diastereo-selectivity. The resulting functionalized indole-dihydronaphthalene-amine conjugates served as an appealing platform to streamline the diversity-oriented synthesis (DOS) of other valuable enantioenriched compounds. DFT calculations revealed that the two stabilizing non-covalent interactions contributed to the observed enantioselectivity.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Bazi Bushen alleviates skin senescence by orchestrating skin homeostasis in SAMP6 mice.

Bazi Bushen, a Chinese-patented drug with the function of relieving fatigue and delaying ageing, has been proven effective for extenuating skin senescence. To investigate the potential mechanism, senescence-accelerated mouse prone 6 (SAMP6) was intragastrically administered with Bazi Bushen for 9 weeks to induce skin homeostasis. Skin homeostasis is important in mitigating skin senescence, and it is related to many factors such as oxidative stress, SASP, apoptosis, autophagy and stem cell. In our study, skin damage in SAMP6 mice was observed using HE, Masson and SA-ß-gal staining. The content of hydroxyproline and the activities of SOD, MDA, GSH-PX and T-AOC in the skin were measured using commercial assay kits. The level of SASP factors (IL-6, IL-1ß, TNF-α, MMP2 and MMP9) in skin were measured using ELISA kits. The protein expressions of p16, p21, p53, Bax, Bcl-2, Cleaved caspase-3, LC3, p62, Beclin1, OCT4, SOX2 and NANOG were measured by western blotting. The expression of ITGA6 and COL17A1 was measured by immunofluorescence staining and western blotting. Our findings demonstrated that Bazi Bushen alleviated skin senescence by orchestrating skin homeostasis, reducing the level of oxidative stress and the expression of SASP, regulating the balance of apoptosis and autophagy and enhancing the protein expressions of ITGA6 and COL17A1 to improve skin structure in SAMP6 mice. This study indicated that Bazi Bushen could serve as a potential therapy for alleviating skin senescence.

Bazi Bushen maintains intestinal homeostasis through inhibiting TLR4/NFκB signaling pathway and regulating gut microbiota in SAMP6 mice.

BACKGROUND: Bazi Bushen is a Chinese patented medicine with multiple health benefits and geroprotective effects, yet, no research has explored its effects on intestinal homeostasis. In this study, we aimed to investigate the effect of Bazi Bushen on intestinal inflammation and the potential mechanism of gut microbiota dysbiosis and intestinal homeostasis in senescence-accelerated mouse prone 6 (SAMP6). The hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to assess the function of the intestinal mucosal barrier. The enzyme-linked immunosorbent assay (ELISA) and Western blotting were used to determine the level of intestinal inflammation. The aging-related ß-galactosidase (SA-ß-gal) staining and Western blotting were used to measure the extent of intestinal aging. The 16S ribosomal RNA (16S rRNA) was performed to analyze the change in gut microbiota composition and distribution. RESULTS: Bazi Bushen exerted remarkable protective effects in SAMP6, showing a regulated mucosal barrier and increased barrier integrity. It also suppressed intestinal inflammation through down-regulating pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) and inhibiting TLR4/NFκB signaling pathway (MYD88, p-p65, and TLR4). Bazi Bushen improved intestinal aging by reducing the area of SA-ß-gal-positive cells and the expression of senescence markers p16, p21, and p53. In addition, Bazi Bushen effectively rebuilt the gut microbiota ecosystem by decreasing the abundance of Bacteroides and Klebsiella, whiles increasing the ratio of Lactobacillus/Bacteroides and the abundance of Akkermansia. CONCLUSION: Our study shows that Bazi Bushen could serve as a potential therapy for maintaining intestinal homeostasis. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

A PDMS-based microneedle array electrode for long-term ECG recording.

To acquire high-quality electrocardiogram (ECG) signals, traditional Ag/AgCl wet electrodes used together with conductive gel can effectively reduce electrode-skin interface impedance (EII) in a short term. However, their weaknesses of poor flexibility and instability can no longer meet the long-term monitoring requirements of intelligent wearable devices. Owing to the flexible dry electrode without conductive gel, it is a good choice to solve the critical problem on drying-out of conductive gel. Therefore, we develop a flexible microneedle array electrode (FMAE) based on polydimethylsiloxane (PDMS) substrate, which obtains reliable bioelectrical signals by way of penetrating into the stratum corneum (SC) of the skin. The fabrication process, including silicon mold, twice PDMS shape-transferring and encapsulation, has advantages of low cost, repeatable production and good biocompatibility. Afterwards, by comparing the performance with different electrodes, impedance test results indicate that the impedance of FMAE are smaller and more stable, and ECG tests in long term and at resting/jogging states also verify that FMAE can obtain durable, stable and reliable signals. In conclusion, FMAE is promising in long-term ECG monitoring.

Catalytic Enantioselective Isocyanide-Based Reactions: Beyond Passerini and Ugi Multicomponent Reactions.

The development of catalytic enantioselective isocyanide-based reactions is currently of great interest because the resulting products are valuable in organic synthesis, pharmacological chemistry, and materials science. This review assembles and comprehensively summarizes the recent achievements in this rapidly growing area according to the reaction types. Special attention is paid to the advantages, limitations, possible mechanisms, and synthetic applications of each reaction. In addition, a personal outlook on the opportunities for further exploration is given at the end.

Diastereoselective Synthesis of 1,3-Diyne-Tethered Trifluoromethylcyclopropanes through a Sulfur Ylide Mediated Cyclopropanation/DBU-Mediated Epimerization Sequence.

A one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF3-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a DBU-mediated epimerization sequence is described in this work. This process is highly diastereoselective with broad substrate scope. Moreover, a series of synthetic transformations based on the diyne moieties were conducted smoothly, affording cyclopropanes featuring trifluoromethyl-substituted all-carbon quaternary centers.

Establishment of a Gene Signature to Predict Prognosis for Patients with Lung Adenocarcinoma.

Accumulating evidence indicates that the reliable gene signature may serve as an independent prognosis factor for lung adenocarcinoma (LUAD) diagnosis. Here, we sought to identify a risk score signature for survival prediction of LUAD patients. In the Gene Expression Omnibus (GEO) database, GSE18842, GSE75037, GSE101929, and GSE19188 mRNA expression profiles were downloaded to screen differentially expressed genes (DEGs), which were used to establish a protein-protein interaction network and perform clustering module analysis. Univariate and multivariate proportional hazards regression analyses were applied to develop and validate the gene signature based on the TCGA dataset. The signature genes were then verified on GEPIA, Oncomine, and HPA platforms. Expression levels of corresponding genes were also measured by qRT-PCR and Western blotting in HBE, A549, and PC-9 cell lines. The prognostic signature based on eight genes (TTK, HMMR, ASPM, CDCA8, KIF2C, CCNA2, CCNB2, and MKI67) was established, which was independent of other clinical factors. The risk model offered better discrimination between risk groups, and patients with high-risk scores tended to have poor survival rate at 1-, 3- and 5-year follow-up. The model also presented better survival prediction in cancer-specific cohorts of age, gender, clinical stage III/IV, primary tumor 1/2, and lymph node metastasis 1/2. The signature genes, moreover, were highly expressed in A549 and PC-9 cells. In conclusion, the risk score signature could be used for prognostic estimation and as an independent risk factor for survival prediction in patients with LUAD.

Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.

Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provides important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy-induced T-ALL, suggesting that such events occur at preferential sites in the noncoding genome.

Iodine-promoted radical alkyl sulfuration of imidazopyridines with dialkyl azo compounds and elemental sulfur.

Dialkyl azo compounds were found to be effective alkyl radical sources for direct alkyl sulfuration with imidazopyridines using elemental sulfur under metal-free conditions. Iodine, an inexpensive and mild reagent, could promote alkyl sulfuration. A variety of quaternary cyanoalkyl radicals were successfully coupled with elemental sulfur. A subsequent C-H sulfuration of imidazopyridines afforded a diverse array of imidazopyridine derivatives bearing cyanoalkylthio groups. The cyano group could be modified and further underwent condensation with 2-aminothiazole to afford an interesting heterocyclic amide. Control experiments showed that iodine could greatly suppress the self-coupling of cyanoalkyl radicals, thus making the sulfuration proceed smoothly.

In Vitro Immune Activation of Raw264.7 Cells by Nanodiamonds with Different Surface Chemistry.

In this study, three commercially available nanodiamonds (NDs) of similar size (about 5 nm in diameter) but with different surface chemistry (-COOH, -NH2 and -poly(ethylene glycol)) were used to study the toxicity and immune activation of Raw264.7 cells. Only ND-PEG is well dispersed in water and cell culture medium (about 10 nm in diameter), while ND-COOH and ND-NH2 only showed some aggregation, about 50 nm in water and about 100 nm in cell culture medium. The three NDs showed different zeta potentials in water but the difference disappeared in cell culture medium due to the surface adsorption of the proteins. The ND-PEG did not show any obvious signs of cytotoxicity or activation on Raw264.7 cells under tested conditions. The ND-COOH and ND-NH2 caused dose-dependent toxicity, with the amino group capped NDs being much more toxic compare to those of the carboxylic acid group at the same exposure conditions. ND-COOH induced a certain immune response in Raw264.7 cells, leading to a higher expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), especially with a significantly longer incubation time. ND-NH2 also induced significant expression of TNF-α and IL-6 in Raw264.7 cells at first, but this expression was reduced with a longer incubation time due to cell death.

Copper-Catalyzed Arylation of Remote C(sp3 )-H Bonds in Carboxamides and Sulfonamides.

Reported herein is an unprecedented copper-catalyzed arylation of remote C(sp3 )-H bonds. Stirring a trifluorotoluene solution of either N-fluorocarboxamides or N-fluorosulfonamides and arylboronic acids in the presence of a catalytic amount of copper(II) trifluoroacetylacetonate, 2,2'-bipyridine, and sodium tert-butoxide afforded the γ- and δ-C(sp3 )-H arylated carboxamides and sulfonamides, respectively, in good to high yields. Mechanistic studies indicate that the reaction might proceed through an amidyl radical generation, 1,5-hydrogen atom transfer (HAT), and copper-catalyzed cross-coupling of the resulting carbon radical with arylboronic acids.

Nickel-Catalyzed Reductive Dicarbofunctionalization of Alkenes.

An intermolecular, three-component reductive dicarbofunctionalization of alkenes is presented here. The combination of Ni catalysis with TDAE as final reductant enables the direct formation of Csp3-Csp3 and Csp3-Csp2 bonds across a variety of π-systems using two different electrophiles that are sequentially activated with exquisite selectivity under mild reaction conditions.

Anti-leukaemic activity of the TYK2 selective inhibitor NDI-031301 in T-cell acute lymphoblastic leukaemia.

Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI-031301 treatment and was responsible for NDI-031301-induced T-ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI-031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT-K1 T-ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T-ALL.

Hierarchical Branched Vanadium Oxide Nanorod@Si Nanowire Architecture for High Performance Supercapacitors.

Vanadium oxide (VOx ) nanorods are uniformly synthesized on dense Si nanowire arrays. This 3D hierarchical nanoarchitecture offers a novel high-performance supercapacitor electrode design with significantly improved specific capacitance and high-rate capability.

Cellulose-Based Nanomaterials for Energy Applications.

Cellulose is the most abundant natural polymer on earth, providing a sustainable green resource that is renewable, degradable, biocompatible, and cost effective. Recently, nanocellulose-based mesoporous structures, flexible thin films, fibers, and networks are increasingly developed and used in photovoltaic devices, energy storage systems, mechanical energy harvesters, and catalysts components, showing tremendous materials science value and application potential in many energy-related fields. In this Review, the most recent advancements of processing, integration, and application of cellulose nanomaterials in the areas of solar energy harvesting, energy storage, and mechanical energy harvesting are reviewed. For solar energy harvesting, promising applications of cellulose-based nanostructures for both solar cells and photoelectrochemical electrodes development are reviewed, and their morphology-related merits are discussed. For energy storage, the discussion is primarily focused on the applications of cellulose-based nanomaterials in lithium-ion batteries, including electrodes (e.g., active materials, binders, and structural support), electrolytes, and separators. Applications of cellulose nanomaterials in supercapacitors are also reviewed briefly. For mechanical energy harvesting, the most recent technology evolution in cellulose-based triboelectric nanogenerators is reviewed, from fundamental property tuning to practical implementations. At last, the future research potential and opportunities of cellulose nanomaterials as a new energy material are discussed.

γ-Functionalizations of Amines through Visible-Light-Mediated, Redox-Neutral C-C Bond Cleavage.

Cleavage of unstrained C-C bonds under mild, redox-neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible-light-mediated, γ-functionalization of amines. In situ generated C-centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp3 )-C(sp3 ), C(sp3 )-H and C(sp3 )-Br bonds, respectively.

Ferroelectric Polarization-Enhanced Photoelectrochemical Water Splitting in TiO2-BaTiO3 Core-Shell Nanowire Photoanodes.

The performances of heterojunction-based electronic devices are extremely sensitive to the interfacial electronic band structure. Here we report a largely enhanced performance of photoelectrochemical (PEC) photoanodes by ferroelectric polarization-endowed band engineering on the basis of TiO2/BaTiO3 core/shell nanowires (NWs). Through a one-step hydrothermal process, a uniform, epitaxial, and spontaneously poled barium titanate (BTO) layer was created on single crystalline TiO2 NWs. Compared to pristine TiO2 NWs, the 5 nm BTO-coated TiO2 NWs achieved 67% photocurrent density enhancement. By numerically calculating the potential distribution across the TiO2/BTO/electrolyte heterojunction and systematically investigating the light absorption, charge injection and separation properties of TiO2 and TiO2/BTO NWs, the PEC performance gain was proved to be a result of the increased charge separation efficiency induced by the ferroelectric polarization of the BTO shell. The ferroelectric polarization could be switched by external electric field poling and yielded PEC performance gain or loss based on the direction of the polarization. This study evidence that the piezotronic effect (ferroelectric or piezoelectric potential-induced band structure engineering) holds great promises in improving the performance of PEC photoelectrodes in addition to chemistry and structure optimization.

Nickel-Catalyzed Stereoselective Dicarbofunctionalization of Alkynes.

A nickel-catalyzed three-component reaction involving terminal alkynes, boronic acids, and alkyl halides is presented herein. Trisubstituted alkenes can be obtained in a highly regio- and stereocontrolled manner by the simultaneous addition of both aryl and alkyl groups across the triple bond in a radical-mediated process. The reaction, devoid of air- and moisture-sensitive organometallic reagents and catalysts, is operationally simple and offers a broad scope and functional-group tolerance.

Silver-Catalyzed Decarboxylative Radical Azidation of Aliphatic Carboxylic Acids in Aqueous Solution.

We report herein an efficient and general method for the decarboxylative azidation of aliphatic carboxylic acids. Thus, with AgNO3 as the catalyst and K2S2O8 as the oxidant, the reactions of various aliphatic carboxylic acids with tosyl azide or pyridine-3-sulfonyl azide in aqueous CH3CN solution afforded the corresponding alkyl azides under mild conditions. A broad substrate scope and wide functional group compatibility were observed. A radical mechanism is proposed for this site-specific azidation.