Divergence among rice cultivars reveals roles for transposition and epimutation in ongoing evolution of genomic imprinting.

Parent-of-origin-dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin-specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA-producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions-the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution.

Spontaneous Symmetry Breaking of Achiral Molecules Leading to the Formation of Homochiral Superstructures that Exhibit Mechanoluminescence.

Chirality, with its intrinsic symmetry-breaking feature, is frequently utilized in the creation of acentric crystalline functional materials that exhibit intriguing optoelectronic properties. On the other hand, the development of chiral crystals from achiral molecules offers a solution that bypasses the need for enantiopure motifs, presenting a promising alternative and thereby expanding the possibilities of the self-assembly toolkit. Nevertheless, the rational design of achiral molecules that prefer spontaneous symmetry breaking during crystallization has so far been obscure. In this study, we present a series of six achiral molecules, demonstrating that when these conformationally flexible molecules adopt a cis-conformation and engage in multiple non-covalent interactions along a helical path, they collectively self-assemble into chiral superstructures consisting of single-handed supramolecular columns. When these homochiral supramolecular columns align in parallel, they form polar crystals that exhibit intense luminescence upon grinding or scraping. We therefore demonstrate our molecular design strategy could significantly increase the likelihood of symmetry breaking in achiral molecular synthons during self-assembly, offering a facile access to novel chiral crystalline materials with unique optoelectronic properties.

Ion Pair Catalyst - Pentanidinium.

In this account, we further describe our already developed N-sp2 hybrid guanidinium as an efficient phase-transfer catalyst and ion pair catalysis based on N-sp2 hybrid pentanidinium and its application in some new reactions. The sp3 hybrid quaternary ammonium salt has a tetrahedral structure, which means that three sides of it can be effectively steric, allowing the remaining side to be close to the substrate. However, the sp2 hybrid ammonium salt allows the substrate to form ion pairs from both directions respectively, so it is a greater challenge to control the stereoselectivity of the reaction. Van der Waals forces, such as hydrogen bonds and π - π ${\pi -\pi }$ interactions, have been used to make electrophiles approach from a certain direction, leading to a higher enantioselectivity. Based on the above idea, we designed an N-sp2 hybrid phase-transfer catalyst, pentanidinium. Pentanidinium has five conjugated nitrogen atoms, one of which has a formal positive charge, which is necessary for it to become an ion pair catalyst. We have confirmed that pentanidinium can catalyze α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins, desymmetrization of pro-chiral sulfinate to afford enantioenriched sulfinate esters. Pentanidinium with side chain structure changes can also be catalyzed efficiently with enantioconvergent halogenophilic nucleophilic substitution, including azidation and thioesterification. In the reaction catalyzed by pentanidinium, it always attracts us with the advantages of low catalytic load and good enantioselectivity.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

Periodontitis-induced neuroinflammation impacts dendritic spine immaturity and cognitive impairment.

OBJECTIVE: This study investigated the spinal changes in ligature-induced periodontitis and the role of periodontitis in cognitive impairment. METHODS: Twenty mice were randomized into the control and chronic periodontitis (CP) groups, with the latter receiving ligature-induced periodontitis. Cognitive performance was assessed by fear conditioning test. Periodontal inflammation and alveolar bone resorption were evaluated by micro-computed tomography and histopathology. The hippocampal microglial activation was evaluated by immunohistochemistry (IHC). The expressions of hippocampal cytokines (TNF-α, iNOS, IL-1ß, IL-4, IL-10, and TREM2) were measured by reverse transcription-polymerase chain reaction. The morphology and density of the dendritic spines were determined by Golgi-Cox staining. RESULTS: The CP mice reported significant inflammatory cell infiltration and alveolar bone resorption, with marked increases in cytokine levels (TNF-α, iNOS, IL-1ß, and TREM2) in the brain. Moreover, the CP mice showed significantly reduced freezing to the conditioned stimulus in the cued and contextual tests, indicating impaired memory. Further analyses revealed, in the hippocampus of the CP mice, enhanced microglial activation, decreased dendritic spine density, and increased proportion of thin dendritic spines. CONCLUSIONS: Periodontitis-induced neuroinflammation may impair the cognitive function by activating hippocampal microglia and inducing dendritic spine immaturity.

Design, synthesis, and biological evaluation of benzoheterocyclic sulfoxide derivatives as quorum sensing inhibitors in Pseudomonas aeruginosa.

Six series of benzoheterocyclic sulfoxide derivatives were designed and synthesised as Pseudomonas aeruginosa (P. aeruginosa) quorum sensing inhibitors in this paper. We experimentally demonstrated that 6b significantly inhibited the formation of P. aeruginosa PAO1 biofilm without affecting the growth. Further mechanistic studies showed that 6b affected the luminescence of quorum sensing reported strain PAO1-lasB-gfp and the production of P. aeruginosa PAO1 elastase virulence factor which was regulated by las system. These experimental results indicate that 6b acts as a quorum sensing inhibitor mainly through the las system. Furthermore, silico molecular docking studies demonstrated that 6b and the P. aeruginosa quorum sensing receptor LasR were molecularly bound via hydrogen bonding interactions. Preliminary structure-activity relationship and docking studies illustrated that 6b shows great promise as anti-biofilm compounds for further studies in order to solve the problem of microbial resistance in future.

Design, Synthesis, and Biological Evaluation of Phenyloxadiazole Sulfoxide Derivatives as Potent Pseudomonas aeruginosa Biofilm Inhibitors.

With the development of antimicrobial agents, researchers have developed new strategies through key regulatory systems to block the expression of virulence genes without affecting bacterial growth. This strategy can minimize the selective pressure that leads to the emergence of resistance. Quorum sensing (QS) is an intercellular communication system that plays a key role in the regulation of bacterial virulence and biofilm formation. Studies have revealed that the QS system controls 4-6% of the total number of P. aeruginosa genes, and quorum sensing inhibitors (QSIs) could be a promising target for developing new prevention and treatment strategies against P. aeruginosa infection. In this study, four series of phenyloxadiazole and phenyltetrazole sulfoxide derivatives were synthesized and evaluated for their inhibitory effects on P. aeruginosa PAO1 biofilm formation. Our results showed that 5b had biofilm inhibitory activity and reduced the production of QS-regulated virulence factors in P. aeruginosa. In addition, silico molecular docking studies have shown that 5b binds to the P. aeruginosa QS receptor protein LasR through hydrogen bond interaction. Preliminary structure-activity relationship and docking studies show that 5b has broad application prospects as an anti-biofilm compound, and further research will be carried out in the future to solve the problem of microbial resistance.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis.

Pyrazolones and pyrazoles, featuring nitrogen-nitrogen bonds, are two of the most important classes of heterocycles, owing to their widespread occurrence in medicinal chemistry and functional materials. The last decade has witnessed a rapid increase in the construction of chiral pyrazolone and pyrazole derivatives, with the application of pyrazolone derivatives as powerful synthons. Since our last review in 2018, a large number of new achievements has emerged in this area, requiring a timely update. Thus, this review summarizes these elegant achievements based on the multiple reactive sites of different pyrazolone synthons. In addition, important mechanisms and interesting biological investigations relating to the corresponding products are also discussed.

The Molecular Architecture of Pseudomonas aeruginosa Quorum-Sensing Inhibitors.

The survival selection pressure caused by antibiotic-mediated bactericidal and bacteriostatic activity is one of the important inducements for bacteria to develop drug resistance. Bacteria gain drug resistance through spontaneous mutation so as to achieve the goals of survival and reproduction. Quorum sensing (QS) is an intercellular communication system based on cell density that can regulate bacterial virulence and biofilm formation. The secretion of more than 30 virulence factors of P. aeruginosa is controlled by QS, and the formation and diffusion of biofilm is an important mechanism causing the multidrug resistance of P. aeruginosa, which is also closely related to the QS system. There are three main QS systems in P. aeruginosa: las system, rhl system, and pqs system. Quorum-sensing inhibitors (QSIs) can reduce the toxicity of bacteria without affecting the growth and enhance the sensitivity of bacterial biofilms to antibiotic treatment. These characteristics make QSIs a popular topic for research and development in the field of anti-infection. This paper reviews the research progress of the P. aeruginosa quorum-sensing system and QSIs, targeting three QS systems, which will provide help for the future research and development of novel quorum-sensing inhibitors.

DBU Promoted Polysubstituted Arene Formation via a Michael Addition/Cyclization/Elimination Cascade Reaction.

The straightforward construction of polysubstituted arenes is essential in both synthetic chemistry and medicinal chemistry. Herein, we reported a DBU promoted Michael addition/cyclization/elimination cascade reaction between vinylogous malononitrile derivatives and chlorinated nitrostyrenes for the synthesis of polysubstituted arenes. The method features mild reaction conditions, wide substrate scope and high yield. Interestingly, preliminary study of the enantioselective version of this cascade was conducted to give chiral biaryl atropisomers with up to 40% ee through center-to-axial chirality transfer strategy.

Advances of α-activated cyclic isothiocyanate for the enantioselective construction of spirocycles.

The efficient and enantioselective synthesis of pharmaceutically important spirocycles has attracted the focus of organic and medicinal chemists. In this context, with the excellent reactivity of α-activated isothiocyanate as formal 1,3-dipoles in the (3 + 2) cyclization process, the cyclic isothiocyanates featuring important pharmacophores, such as oxindole, pyrazolone, and indanone moieties, have emerged as powerful precursors to access a variety of spirocycles with highly structural diversities. In addition, the facile transformations of these spirocycles have shown potential applications in drug design. This review will cover the recent advances of α-activated cyclic isothiocyanates in the enantioselective construction of spirocycles since 2015, and the applications of corresponding products in organic and medicinal chemistry.

2-Activated 1,3-enynes in enantioselective synthesis.

The rapid enantioselective synthesis of valuable building blocks and pharmaceutically important compounds from easily accessible precursors is one of the major areas of focus in organic chemistry. In this context, 2-activated 1,3-enyne has emerged as a powerful synthon in recent years for the efficient synthesis of enantioenriched furans, allenes, 4-H-pyrans, and 4-isoxazolines, which are privileged scaffolds in bioactive compounds and natural products. This review will cover the history of the development of 2-activated 1,3-enyne in enantioselective synthesis along with the corresponding mechanisms, which may motivate further development in this area to forge more complex and valuable molecules.

The Structural Diversity of Marine Microbial Secondary Metabolites Based on Co-Culture Strategy: 2009-2019.

Marine microorganisms have drawn great attention as novel bioactive natural product sources, particularly in the drug discovery area. Using different strategies, marine microbes have the ability to produce a wide variety of molecules. One of these strategies is the co-culturing of marine microbes; if two or more microorganisms are aseptically cultured together in a solid or liquid medium in a certain environment, their competition or synergetic relationship can activate the silent biosynthetic genes to produce cryptic natural products which do not exist in monocultures of the partner microbes. In recent years, the co-cultivation strategy of marine microbes has made more novel natural products with various biological activities. This review focuses on the significant and excellent examples covering sources, types, structures and bioactivities of secondary metabolites based on co-cultures of marine-derived microorganisms from 2009 to 2019. A detailed discussion on future prospects and current challenges in the field of co-culture is also provided on behalf of the authors' own views of development tendencies.

A fluorescent immunosensor for determination and imaging of circulating tumor cells based on a bifunctional DNA nanomachine.

A fluorescent platform was developed for the determination and visualization of circulating tumor cells by a toehold-mediated bifunctional DNA nanomachine. In the presence of target tumor cells, the DNA nanomachine was activated. Multiple DNA products were formed, including dendritic DNA products and double-strand DNA products. Dendritic DNA products bound to their target cells for the visualization, while double-strand DNA products were released for the determination of tumor cells. At fluorescence excitation and emission wavelengths of 530 and 550 nm, this method could detect as low as 43 cells/mL (S/N = 3) with a linear range of 100 to 10,000 cells/mL. In clinical hydrothorax samples, this platform exhibited high reliability with a recovery of 93 to 116%. At the fluorescence excitation and emission wavelengths of 490 and 515 nm, the specificity and biocompatibility of this method were further verified by tumor cells imaging. Furthermore, the robustness of the toehold-mediated bifunctional DNA nanomachine was demonstrated by the specific gene mutation detection in single-cell analysis. Graphical abstract Schematic illustration of the fluorescent immunosensor for determination and imaging of circulating tumor cells. The method is based on aptamer-based recognition and toehold-mediated bifunctional DNA nanomachine.

Ultrahigh Elastic Strain Energy Storage in Metal-Oxide-Infiltrated Patterned Hybrid Polymer Nanocomposites.

Modulus of resilience, the measure of a material's ability to store and release elastic strain energy, is critical for realizing advanced mechanical actuation technologies in micro/nanoelectromechanical systems. In general, engineering the modulus of resilience is difficult because it requires asymmetrically increasing yield strength and Young's modulus against their mutual scaling behavior. This task becomes further challenging if it needs to be carried out at the nanometer scale. Here, we demonstrate organic-inorganic hybrid composite nanopillars with one of the highest modulus of resilience per density by utilizing vapor-phase aluminum oxide infiltration in lithographically patterned negative photoresist SU-8. In situ nanomechanical measurements reveal a metal-like high yield strength (∼500 MPa) with an unusually low, foam-like Young's modulus (∼7 GPa), a unique pairing that yields ultrahigh modulus of resilience, reaching up to ∼24 MJ/m3 as well as exceptional modulus of resilience per density of ∼13.4 kJ/kg, surpassing those of most engineering materials. The hybrid polymer nanocomposite features lightweight, ultrahigh tunable modulus of resilience and versatile nanoscale lithographic patternability with potential for application as nanomechanical components which require ultrahigh mechanical resilience and strength.

Organocatalytic Enantioselective Protonation for Photoreduction of Activated Ketones and Ketimines Induced by Visible Light.

The first catalytic asymmetric photoreduction of 1,2-diketones and α-keto ketimines under visible light irradiation is reported. A transition-metal-free synergistic catalysis platform harnessing dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst and a non-covalent chiral organocatalyst is effective for these transformations. With the flexible use of a chiral Brønsted acid or base in H+ transfer interchange to control the elusive enantioselective protonation, a variety of chiral α-hydroxy ketones and α-amino ketones were obtained with high yields and enantioselectivities.

Catalytic Asymmetric Conjugate Addition and Sulfenylation of Diarylthiazolidin-2,4-diones.

This work reports the first application of diarylthiazolidin-2,4-diones as nucleophiles in asymmetric catalysis. By utilizing chiral amino acid-based (thio)urea-tertiary amines as the catalysts, we successively established asymmetric conjugate addition to nitroolefins and sulfenylation to N-(sulfanyl)-succinimides of diarylthiazolidin-2,4-diones. Two series of biologically important 5-aryl-5-substituted thiazolidin-2,4-diones were obtained with high enantio- and diastereoselectivities (up to >99% ee and >19:1 dr). The enantioenriched adducts were found to show satisfactory anticancer activities against three different cancer cell lines using the MTT assay. All of these successes depended on the development of a general and expedient synthetic strategy to provide diverse 5H-thiazolidin-2,4-diones.

Dipeptide-Based Chiral Tertiary Amine-Catalyzed Asymmetric Conjugate Addition Reactions of 5H-Thiazol/Oxazol-4-Ones.

Highly enantio- and chemo-selective 1,4-conjugate addition process of 5H-thiazol-4-ones with maleimides or 1,4-naphthoquinones, and 5H-oxazol-4-ones with maleimides were performed under a dipeptide-based tertiary amine (DP-UAA) catalyst. A series of valuable N,S- and N,O-containing heterocyclic compounds with excellent enantio- and disastereo-selectivities (up to >99% ee, > 20:1 dr) were attained.