Activity

We discover that analysis in the frozen-hydrated state yields a 10,000 fold increase in signal intensity for polar molecules, such as amino acid, which has important implications for SIMS imaging of metabolites and pharmaceuticals.Optically triggered twisted intramolecular charge transfer (TICT) states in donor-acceptor chromophores form the molecular basis for designing bioimaging probes that sense polarity, microviscosity, and pH in vivo. However, a lack of predictive understanding of the “twist” localization precludes a rational design of TICT-based dyes. Here, using femtosecond stimulated Raman spectroscopy, we reveal a distinct Raman signature of the TICT state for a stilbazolium-class mitochondrial staining dye. Resonance-selective probing of 4-N,N-diethylamino-4″-N’-methyl-stilbazolium tosylate (DEST) tracks the excited-state structure of the dye as it relaxes to a TICT state on a picosecond time scale. The appearance of a remarkably blue-shifted C=C stretching mode at 1650 cm-1 in the TICT state is attributed to the “twist” of a single bond adjacent to the ethylenic π-bridge in the DEST backbone based on detailed electronic structure calculations and vibrational mode analysis. Our work demonstrates that the π-bridge, connecting the donor and acceptor moieties, influences the spatial location of the “twist” and offers a new perspective for designing organelle-specific probes through cogent tuning of backbone dynamics.Enzymes are an important class of biomacromolecules which catalyze many metabolic processes in living systems. Nanomaterials can be synthesized with tailored sizes as well as desired surface modifications, thus acting as promising enzyme regulators. Fluorescent gold nanoclusters (AuNCs) are a representative class of ultrasmall nanoparticles (USNPs) with sizes of ∼2 nm, smaller than most of proteins including enzymes. In this work, we chose α-chymotrypsin (ChT) and AuNCs as the model system. Activity assays and inhibition kinetics studies showed that dihydrolipoic acid (DHLA)-coated AuNCs (DHLA-AuNCs) had a high inhibitory potency (IC50 = 3.4 μM) and high inhibitory efficacy (>80%) on ChT activity through noncompetitive inhibition mechanism. In distinct contrast, glutathione (GSH)-coated AuNCs (GSH-AuNCs) had no significant inhibition effects. Fluorescence spectroscopy, agarose gel electrophoresis and circular dichroism (CD) spectroscopy were conducted to explore the underlying mechanisms. A two-step interaction model was proposed. First, both DHLA-AuNCs and GSH-AuNCs might be bound to the positively charged sites of ChT through electrostatic forces. Second, further hydrophobic interactions occurred between three tyrosine residues of ChT and the hydrophobic carbon chain of DHLA, leading to a significant structural change thus to deactivate ChT on the allosteric site. On the contrary, no such interactions occurred with GSH of zwitterionic characteristic, which explained no inhibitory effect of GSH-AuNCs on ChT. To the best of our knowledge, this is the first example of the allosteric inhibition of ChT by nano regulators. These findings provide a fundamental basis for the design and development of nano regulators.SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a non-receptor protein tyrosine phosphatase that removes tyrosine phosphorylation. Functionally, SHP2 serves as an important hub to connect several intracellular oncogenic signaling pathways, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, and PD-1/PD-L1 pathways. Mutations and/or overexpression of SHP2 have been associated with genetic developmental diseases and cancers. Because of the role of SHP2 plays in many diseases, the development of inhibitors targeting the catalytic site in SHP2 has been pursued for more than a decade, but none has advanced to clinical development. Recent discovery of allosteric inhibitors has inspired a novel approach to selectively target SHP2 via the non-catalytic site. To date, four SHP2 allosteric inhibitors have entered clinical trials for the treatment of solid tumors. This review will provide a summary of the physiological and biological functions of SHP2 and discuss the development of non-allosteric/allosteric SHP2 inhibitors in recent years.The development of new routes or materials to realize superlubricity under high contact pressure can result in energy-saving and reduction of emissions. In this study, superlubricity (μ = 0.0017) under extreme pressure (717 MPa, more than twice the previously reported liquid superlubricity) between the frictional pair of Si3N4/sapphire was achieved by prerunning-in with a H3PO4 (HP) solution followed by lubrication with an aqueous solution consisting of poly(vinyl alcohol) (PVA) and sodium chloride (NaCl). learn more Under the same test condition, the aqueous PVA lubricant did not show superlubricity. Results of X-ray photoelectron spectroscopy and Raman spectroscopy indicate the formation of a PVA-adsorbed film at the frictional interface after lubrication with PVA but not after lubrication with PVA/NaCl, indicating competitive adsorption between hydrated Na+ ions and PVA molecules. The hydrated Na+ ions adsorbed preferentially to the solid surfaces, causing the transformation of the shear interface from a polymer film/polymer film to a solid/polymer film. Meanwhile, the hydrated Na+ ions also produced hydration repulsion force and induced low shear stress between the solid surfaces. Furthermore, NaCl increased the viscosity of the polymer lubricant, enhanced the hydrodynamic effect between interfaces, and decreased direct contact between the friction pair, causing a further reduction in friction. Thus, the superlubricity of the PVA/NaCl mixture is attributed to the combination of hydration and hydrodynamic effects. This study provides a novel route and mechanism for achieving extreme-pressure superlubricity at the macroscale, through the synergistic lubricating effect of hydrated ions and a polymer solution, propelling the industrial application of superlubricity.A dipyrrin-supported nickel catalyst (AdFL)Ni(py) (AdFL 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile.