An efficient C-glycoside production platform enabled by rationally tuning the chemoselectivity of glycosyltransferases.

Despite the broad potential applications of C-glycosides, facile synthetic methods remain scarce. Transforming glycosyltransferases with promiscuous or natural O-specific chemoselectivity to C-glycosyltransferases is challenging. Here, we employ rational directed evolution of the glycosyltransferase MiCGT to generate MiCGT-QDP and MiCGT-ATD mutants which either enhance C-glycosylation or switch to O-glycosylation, respectively. Structural analysis and computational simulations reveal that substrate binding mode govern C-/O-glycosylation selectivity. Notably, directed evolution and mechanism analysis pinpoint the crucial residues dictating the binding mode, enabling the rational design of four enzymes with superior non-inherent chemoselectivity, despite limited sequence homology. Moreover, our best mutants undergo testing with 34 substrates, demonstrating superb chemoselectivities, regioselectivities, and activities. Remarkably, three C-glycosides and an O-glycoside are produced on a gram scale, demonstrating practical utility. This work establishes a highly selective platform for diverse glycosides, and offers a practical strategy for creating various types of glycosylation platforms to access pharmaceutically and medicinally interesting products.

Nickel-Catalyzed Cross-Coupling of Aziridines with Thioesters toward Atom-Economic Synthesis of ß-Sulfanyl Amides.

Thioesters have been recognized as a class of powerful bifunctional reagents, namely, great donors of acyl and sulfide moieties. However, such application in value-added synthesis is still very limited to date. Herein, a nickel-catalyzed cross-coupling reaction system of aziridines with thioesters was developed under redox-neutral and mild conditions. This catalytic method provides an atom-economic route for the synthesis of diverse ß-sulfanyl amide derivatives with wide substrate scope (43 examples), good functional group tolerance, and regioselectivity.

Photocatalytic manipulation of Ca2+ signaling for regulating cellular and animal behaviors via MOF-enabled H2O2 generation.

The in situ generation of H2O2 in cells in response to external stimulation has exceptional advantages in modulating intracellular Ca2+ dynamics, including high controllability and biological safety, but has been rarely explored. Here, we develop photocatalyst-based metal-organic frameworks (DCSA-MOFs) to modulate Ca2+ responses in cells, multicellular spheroids, and organs. By virtue of the efficient photocatalytic oxygen reduction to H2O2 without sacrificial agents, photoexcited DCSA-MOFs can rapidly trigger Ca2+ outflow from the endoplasmic reticulum with single-cell precision in a repeatable and controllable manner, enabling the propagation of intercellular Ca2+ waves (ICW) over long distances in two-dimensional and three-dimensional cell cultures. After photoexcitation, ICWs induced by DCSA-MOFs can activate neural activities in the optical tectum of tadpoles and thighs of spinal frogs, eliciting the corresponding motor behaviors. Our study offers a versatile optical nongenetic modulation technique that enables remote, repeatable, and controlled manipulation of cellular and animal behaviors.

B(C6F5)3-catalyzed regio- and stereoselective thiosulfonylation of terminal alkynes with thiosulfonates.

Herein, a metal-free main-group catalysis system for thiosulfonylation of terminal alkynes with thiosulfonates has been established by using commercially available B(C6F5)3 as a catalyst. The protocol provides a highly regio- and stereoselective route for the synthesis of diverse (E)-(ß)-arylthiolvinyl sulfones under mild conditions with 100% atom-economy and exceptional functional group compatibility.

Synthesis of gem-Difluorinated 1,4-Dienes via Nickel-Catalyzed Three-Component Coupling of (Trifluoromethyl)alkenes, Alkynes, and Organoboronic Acids.

Herein, a nickel-catalyzed defluorinative three-component coupling of trifluoromethyl alkenes, internal alkynes, and organoboronic acids is presented. The protocol provides a highly efficient and selective route for the synthesis of structurally diverse gem-difluorinated 1,4-dienes under mild conditions. Mechanistic studies suggest that C-F bond activation proceeds probably through the oxidative cyclization of trifluoromethyl alkenes with Ni(0) species, sequential addition to alkynes, and ß-fluorine elimination.

Nickel-Catalyzed Desulfonylative Reductive Cross-Coupling of Aryl Sulfones with Aryl Bromides.

Herein, a nickel catalysis system for desulfonylative C(sp2)-C(sp2) reductive cross-coupling reactions of aryl sulfone derivatives with a range of aryl bromides has been established to form diverse biaryl compounds. The complex Ar-Ni(II)-SO2CF3 bearing a phosphine ligand through oxidative addition of aryl sulfone to Ni(0) species was isolated and confirmed by an X-ray, which provides solid evidence for the understanding of the C(Ar)-SO2 bond activation and reaction mechanism.

C(sp2)-C(sp2) Reductive Cross-Coupling of Triarylphosphines with Aryl Halides by Palladium/Nickel Co-catalysis.

Herein, we report the first general C(sp2)-C(sp2) reductive cross-coupling reaction of diverse triarylphosphines with a wide range of aryl halides by palladium/nickel co-catalysis. This protocol offers a unique route for the synthesis of biaryl compounds via the activation of inert C(Ar)-P bonds. The mechanistic studies demonstrate that the formation of the phosphonium salts in situ plays a key role in the catalytic cycle.

Rooted in earth, rooted in community: Aging in rural houses of northern China.

Northern China has experienced unprecedented urbanization over the past several decades, with younger Chinese moving to cities while leaving the lion's share of the older population in rural areas. This study explores how this structural change creates unique opportunities and challenges for older adults living in rural houses, which informs their everyday practices, the meanings of homes, and their subsequent housing choices. We examined the housing experiences of rural older adults through a field study conducted in Heilongjiang province. The study employed qualitative in-depth interviews with thirty-two older adults who live or have lived in rural housing, along with systematic documentation of their houses through photography and hand drawings captured from the field. We analyzed the interview narratives and images using the Glaserian grounded theory method to allow a high level of flexibility and conceptualization. The study identified five core categories of residential experiences: (1) houses as sites of production; (2) the earth/dwelling relationship; (3) social life in interstitial spaces; (4) the house as a means to preserve agency in old age and; (5) the burdensome house. These features were directly linked to the older adults' senses of home and their subsequent housing choices. The rural houses offered a strong sense of agency and belonging to rural older adults, but the city's expansion, the changing household registration system, and their aging bodies forced rural older adults to engage in constant reevaluation of their houses, informing their residential choices. We discuss the study's theoretical contributions and offer insights into policies and future planning for residential areas in both rural and urban areas by comparing the spatial configurations of rural dwellings with their urban apartment counterparts.

Cascade of C(sp2)-H Addition to Carbonyl and C(sp2)-CN/C(sp2)-H Coupling Enabled by Brønsted Acid: Construction of Benzo[a]carbazole Frameworks.

Herein, we report an unprecedented cascade reaction of C(sp2)-H addition to carbonyl and the C(sp2)-CN/C(sp2)-H coupling of 2-(2-oxo-2-arylethyl)benzonitriles with indoles enabled by commercially available TsOH·H2O. The protocol represents the first metal-free C(sp2)-CN/C(sp2)-H coupling, affording a new route for the synthesis of various benzo[a]carbazole derivatives with a broad substrate scope, high yields, and simple conditions.

A Probe into the Intervention Mechanism of Yiqi Huayu Jiedu Decoction on TLR4/NLRP3 Signal Pathway in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome (ARDS) Rats.

BACKGROUND: This study discusses the anti-inflammatory mechanism of Yiqi Huayu Jiedu decoction (YQHYJD) and studies the intervening effect of YQHYJD on the inflammatory cytokines in acute respiratory distress syndrome (ARDS) rats by inhibiting the TLR4/NLRP3 signal pathway. The aim of the probe is to provide evidence to support the identification of therapeutic targets in Chinese medicine treatment, which broadens the alternatives for the treatment of ARDS. METHOD: A lipopolysaccharide (LPS)-induced ARDS model group is established on rats by tail vein injection. A medicine group is established on ARDS rats by prophylactic administration using YQHYJD. Materials are collected, and tests are conducted according to experimental processes. RESULT: The rats in the medicine group gained weight compared with those in the ARDS model group. Pathological sections from the medicine group indicated improved condition in terms of pulmonary and interstitial edema in the lung tissues of rats compared with that from the ARDS model group. The percentage of neutrophil of the medicine group was significantly brought down compared with that of the ARDS model group (P < 0.001). Enzyme-linked immunosorbent assay (ELISA) was used to detect the changes in the level of inflammatory cytokines. It was observed that the levels of IL-1ß and IL-18 in serum of the medicine group significantly decreased (P < 0.001 and P < 0.01), the contents of TLR4 and NLRP3 in bronchoalveolar lavage fluid (BALF) of the medicine group decreased, and the contents of TLR4 and NLRP3 in lung tissue homogenate of the medicine group significantly decreased (P < 0.05, P < 0.001, P < 0.01, and P < 0.05). In further mass spectrum identification of the proteins from the same animal groups, it was observed that the expressions of inflammatory proteins TNFRSF1, LBP, and NOS2 of the medicine group were reduced. The differences were statistically significant. CONCLUSIONS: The pharmacological action of YQHYJD's anti-inflammatory mechanism is closely associated with the regulation of inflammatory cytokines TLR4, NLRP3, IL-1ß, IL-18, TNFRSF1, LBP, and NOS2 on the TLR4/NLRP3 signal pathway.

Electron-deficient boron-based catalysts for C-H bond functionalisation.

In contrast to transition metal-catalysed C-H functionalisation, highly efficient construction of C-C and C-X (X = N, O, S, B, Si, etc.) bonds through metal-free catalytic C-H functionalisation remains one of the most challenging tasks for synthetic chemists. In recent years, electron-deficient boron-based catalyst systems have exhibited great potential for C-H bond transformations. Such emerging systems may greatly enrich the chemistry of C-H functionalisation and main-group element catalysis, and will also provide enormous opportunities in synthetic chemistry, materials chemistry, and chemical biology. This article aims to give a timely comprehensive overview to recognise the current status of electron-deficient boron-based catalysis in C-H functionalisation and stimulate the development of more efficient catalytic systems.

Alleviation of Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats by Yiqi Huayu Jiedu Decoction: A Tandem Mass Tag-Based Proteomics Study.

BACKGROUND: To study the effect of Yiqi Huayu Jiedu Decoction (YQHYJD) on protein expression in the lung tissue of acute respiratory distress syndrome (ARDS) rats and to explore the underlying molecular therapeutic mechanism of YQHYJD. METHODS: Sprague Dawley rats were administered with YQHYJD by oral gavage for 1 week. The rats were injected with lipopolysaccharide (LPS) to induce ARDS. The lung injury was assessed pathologically. Differentially expressed proteins (DEPs) were screened by quantitative proteomics and analyzed using bioinformatic tools, such as Metascape and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapper. DEPs were verified by parallel reaction monitoring (PRM). RESULTS: YQHYJD alleviated the LPS-induced pathological damage of lung tissue in rats. There were 134 DEPs among the YQHYJD treatment and model groups. The Genomes pathway analyses revealed that the DEPs were closely related to immune system pathway. The mass spectrometry analysis revealed that YQHYJD exhibits a protective effect on lung tissue by significantly upregulating hematopoietic cell kinase (Hck), phospholipid phosphatase 3 (Plpp3), myristoylated-alanine rich C-kinase substrate (Marcks), and Actin-related protein 2/3 complex subunit 2 (Arpc2), which are related to Fc gamma receptor-mediated phagocytosis pathway. CONCLUSION: YQHYJD can alleviate the lung injury of ARDS rats by regulating the Fc gamma receptor-mediated phagocytosis pathway, which is related to immune system.

Study on Intervention Mechanism of Yiqi Huayu Jiedu Decoction on ARDS Based on Network Pharmacology.

BACKGROUND: Yiqi Huayu Jiedu (YQHYJD) is a traditional Chinese medicine decoction made up of eight traditional Chinese medicines. Although YQHYJD is effectively used to prevent and treat ARDS/acute lung injury (ALI) in rats, the molecular mechanisms supporting its clinical application remain elusive. The purpose of the current study was to understand its lung protective effects at the molecular level using network pharmacology approach. METHODS: In an ARDS animal model, the beneficial pharmacological activities of YQHYJD were confirmed by reduced lung tissue damage levels observed on drug treated rats versus control group. We then proposed a network analysis to discover the key nodes based on drugs and disease network. Subsequently, we analyzed interaction networks and screened key targets. Using Western blot to detect the expression level of key targets, the intervention effect of changes in expression level of key targets on ARDS was evaluated. RESULTS: Pathway enrichment analysis of highly ranked genes showed that ErbB pathways were highly related to ARDS. Finally, western blot results showed decreased level of the AKT1 and KRAS/NRAS/HRAS protein in the lung after treatment which confirmed the hypothesis. CONCLUSION: In conclusion, our results suggest that YQHYJD can exert lung tissue protective effect against the severe injury through multiple pathways, including the endothelial cells permeability improvement, inflammatory reaction inhibition, edema, and lung tissue hemorrhage reduction.

Radical C-N Borylation of Aromatic Amines Enabled by a Pyrylium Reagent.

Herein, we report a radical borylation of aromatic amines through a homolytic C(sp2 )-N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (Sc Pyry-OTf) thus priming the amino group for reactivity. The combination of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2 )-N bond and forges a new C(sp2 )-B bond. The unique non-planar structure of the pyridinium intermediate, provides the necessary driving force for the aryl radical formation. The method permits borylation of a wide variety of aromatic amines indistinctively of the electronic environment.

Ni-Catalyzed Reductive Liebeskind-Srogl Alkylation of Heterocycles.

Herein we present a Ni-catalyzed alkylation of C-SMe with alkyl bromides for the decoration of heterocyclic frameworks. The protocol, reminiscent to the Liebeskind-Srogl coupling, makes use of simple C(sp2)-SMe to be engaged in a reductive coupling. The reaction is suitable for a preponderance of highly valuable heterocyclic motifs. In addition to cyclic bromides, noncyclic alkyl bromides are well accommodated with exquisite levels of retention over isomerization. The protocol is scalable and permits orthogonal couplings in the presence of other functionalization handles.

B(C6 F5 )3 /Amine-Catalyzed C(sp)-H Silylation of Terminal Alkynes with Hydrosilanes: Experimental and Theoretical Studies.

Transition metal catalyzed C-H functionalization of organic compounds has proved to be a useful atom-efficient strategy in organic synthesis. In contrast, main-group-element-based catalytic processes for C-H functionalization have remained underexplored to date. Reported herein is the catalytic C(sp)-H silylation of a wide range of terminal alkynes with hydrosilanes by using a combination of B(C6 F5 )3 and an organic base such as triethylenediamine (DABCO). This protocol constitutes the first example of boron-catalyzed C(sp)-H functionalization, offering a convenient route for the synthesis of a variety of alkynylsilanes. Experimental and computational studies have revealed that DABCO plays two crucial roles (Lewis base and Brønsted base) in this catalytic transformation.

Selective Functionalization of Aminoheterocycles by a Pyrylium Salt.

The functionalization of aminoheterocycles by using a pyrylium tetrafluoroborate reagent (Pyry-BF4 ) is presented. This reagent efficiently condenses with a great variety of heterocyclic amines and primes the C-N bond for nucleophilic aromatic substitution. More than 60 examples for the formation of C-O, C-N, C-S, or C-SO2 R bonds are disclosed herein. In contrast to C-N activation through diazotization and polyalkylation, this method is characterized by its mild conditions and impressive functional-group tolerance. In addition to small-molecule derivatization, Pyry-BF4 allows the introduction of functional groups in a late-stage fashion to furnish highly functionalized structures.

α-C-H Alkylation of Methyl Sulfides with Alkenes by a Scandium Catalyst.

The C-H addition of sulfides to alkenes is an atom-efficient route for the functionalization and modification of sulfide compounds through C-C bond formation, but this transformation is highly challenging. We report here the regioselective α-C(sp3)-H addition of a wide range of methyl sulfides to a variety of olefins and dienes by a half-sandwich scandium catalyst. This protocol provides a unique route for the synthesis of diverse sulfide derivatives through C-C bond formation at a sulfur-adjacent carbon atom in a 100% atom efficient fashion.

B(C6F5)3-Catalyzed C-Si/Si-H Cross-Metathesis of Hydrosilanes.

The substituent redistribution of hydrosilanes on silicon through C-Si and Si-H bond cleavage and reformation is of great interest and importance, but this transformation is usually difficult to achieve in a selective fashion. By using electron-rich aromatic hydrosilanes, we have achieved for the first time the selective C-Si/Si-H bond homo- and cross-metathesis of a series of hydrosilanes in the presence of a boron catalyst B(C6F5)3. This protocol features simple reaction conditions, high chemoselectivity, wide substrate scope, and high functionality tolerance, offering a new pathway for the synthesis of multisubstituted functional silanes.

Boron-Catalyzed Aromatic C-H Bond Silylation with Hydrosilanes.

Metal-free catalytic C-H silylation of a series of aromatic compounds such as N,N-disubstituted anilines with various hydrosilanes has been achieved for the first time using commercially available B(C6F5)3 as a catalyst. This protocol features simple and neutral reaction conditions, high regioselectivity, wide substrate scope (up to 40 examples), Si-Cl bond compatibility, and no requirement for a hydrogen acceptor.