A new label‐free sensing mechanism is demonstrated experimentally by monitoring the whispering‐gallery mode broadening in microcavities. It is immune to both noise from the probe laser and ...environmental disturbances, and is able to remove the strict requirement for ultra‐high‐Q mode cavities for sensitive nanoparticle detection. This ability to sense nanoscale objects and biological analytes is particularly crucial for wide applications.
The site‐selective functionalization of unactivated C(sp3)−H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp3)−H alkylation of amino ...acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp3)−H bonds. Experimental studies revealed that C−H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C−H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C−H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp3)−H activation.
The site‐selective δ‐C(sp3)−H alkylation of amino acids and peptides with maleimides is enabled by a palladium catalyst. C−H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C−H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle generated by δ‐C−H activation. The selectivity can be explained by the Curtin–Hammett principle. PA=picolinamide.
Ribosomally synthesized and post‐translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450‐catalyzed RiPPs ...stand out as a unique but underexplored family. Herein, we introduce a rule‐based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co‐occurrence and co‐conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450‐catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp‐Trp‐Tyr (one C−C and two C−N bonds), Tyr‐Trp (C−C bond), Trp‐Trp (C−N bond), and His‐His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non‐native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.
P450 enzymes are highly effective catalysts, yet little research has been conducted on their ability to modify ribosomal peptides. Now uncharted bacterial cytochrome P450s responsible for the macrocyclization of ribosomal peptides have been discovered by sequence‐ and 3D‐structure‐based genome mining. These P450s exhibit diverse catalytic capabilities, catalyzing aromatic crosslinking by forming C−C, C−N, and C−O bonds.
Plant trichomes serve as a highly suitable model for investigating cell differentiation at the single‐cell level. The regulatory genes involved in unicellular trichome development in Arabidopsis ...thaliana have been intensively studied, but genes regulating multicellular trichome development in plants remain unclear. Here, we characterized Cucumis sativus (cucumber) trichomes as representative multicellular and unbranched structures, and identified Micro‐trichome (Mict), using map‐based cloning in an F₂ segregating population of 7,936 individuals generated from a spontaneous mict mutant. In mict plants, trichomes in both leaves and fruits, are small, poorly developed, and denser than in the wild type. Sequence analysis revealed that a 2,649‐bp genomic deletion, spanning the first and second exons, occurred in a plant‐specific class I homeodomain‐leucine zipper gene. Tissue‐specific expression analysis indicated that Mict is strongly expressed in the trichome cells. Transcriptome profiling identified potential targets of Mict including putative homologs of genes known in other systems to regulate trichome development, meristem determinacy, and hormone responsiveness. Phylogenic analysis charted the relationships among putative homologs in angiosperms. Our paper represents initial steps toward understanding the development of multicellular trichomes.
Ultrahigh‐Q optical whispering gallery microcavities are promising platforms for fundamental studies and applied photonics. A new type of on‐chip microcavity is experimentally realized, which ...supports both highly unidirectional emission and ultra‐high‐Q factors exceeding 100 million in near infrared. By doping erbium, the unidirectional‐emission lasing is observed in 1550 nm band with the threshold as low as 2 μW.
This work focuses on investigating the self-healing characteristics and mechanism of Engineered Geopolymer Composites using fly ash and metakaolin as the precursors (MFA-EGCs). The hardened specimens ...were preloaded to different tensile strain levels followed by exposure to air and wet-dry cycles allowing for self-healing. Apart from the cracking characteristics, tensile properties were studied together with chemical and microstructural analyses. The results revealed a pronounced multiple cracking pattern and strain-hardening behavior for the MFA-EGCs. The number of cracks decreases significantly after the self-healing. High recovery ratios of the tensile strains and the ultimate tensile strengths were found, with some studied specimens showing even better tensile properties than the control specimens. It seems that air exposure is more favorable for the self-healing of the MFA-EGCs compared with exposure to the wet-dry cycles. Based on the results from SEM-EDS, XRD and FT-IR, it was concluded that amorphous aluminosilicate phases are the main healing products.
Background:
The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have ...beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance.
Methods:
Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips.
Results:
Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL-1, miR-540-3p, and a downregulation of miR-338-5p.
Conclusion:
Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts.
As the key intermediate phase of crystalline calcium carbonate biominerals, amorphous calcium carbonate (ACC) remains mysterious in its structures because of its long‐range disorder and instability. ...We herein report the synthesis of ACC nanospheres in a water‐deficient organic solvent system. The obtained ACC nanospheres are very stable under dry conditions. Cryo‐TEM reveals that each nanospheres consists of smaller nanosized clusters. We further demonstrate that these clusters can precipitate on other substrates to form an ultrathin ACC coating, which should be an ACC cluster monolayer. The results demonstrate that the presence of small ACC clusters as the subunits of larger aggregates is inherent to ACC synthesized in water‐alcohol system but not induced by polymer additives.
Amorphous calcium carbonate(ACC) nanoparticles are synthesized in water‐deficient ethanol solution. The nanoparticles consist of tiny clusters as revealed by cryo‐TEM. ACC can aggregate on templates such as graphene oxide nanosheets. These findings provide a theoretical basis for controlled synthesis of ACC and a strategy to fabricate ultrathin mineral coatings on different substrates.
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. ...Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
•The phase-field regularized cohesive zone model is combined with X-ray computed tomography imaging.•Mesoscopic heterogeneities and inelasticities are both considered to realistically model failure ...in concrete.•Numerical results given by the proposed method are independent of the mesh and length scale parameter.•The influence of mesoscopic heterogeneities on the peak load and crack pattern of concrete is investigated.
Crack nucleation and propagation in concrete is significantly affected by mesoscopic heterogeneities, resulting in distinct failure modes and mechanical behavior. In this work, the phase-field regularized cohesive zone model (PF-CZM) is combined with the X-ray computed tomography (XCT) imaging technique and applied to the modeling of mesoscopic cracking in concrete. More specifically, the in situ XCT image is employed to build the finite element discretization of concrete meso-structure, and the PF-CZM with the Cornelissen et al. (1986) softening law is adopted to model the interfacial transition zone (ITZ) and the matrix. The combined XCT and PF-CZM method is validated by Monto Carlo simulations of concrete samples under uniaxial tension. The influence of mesoscopic heterogeneities on the peak load and crack pattern is then investigated with respect to three- and four-point bending beams with various pre-notch depths. Numerical results show that, as the combined XCT and PF-CZM method takes mesoscopic heterogeneities and material inelasticities into account simultaneously, it is very promising for the modeling of damage and failure in concrete.
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