Pi-class glutathione S-transferase (GSTP1) is a detoxification enzyme that is highly expressed in various types of cancer cells and is a promising target for cancer imaging and therapy. Ps-TAc, an ...acetylated derivative of the GSTP1-specific fluorogenic substrate Ps-TG, is attracting attention as an effective GSTP1 fluorescent probe, and has been successfully used to visualize intracellular GSTP1 activity. Ps-TAc is a prodrug type fluorescent probe in which the phenolic hydroxyl group of Ps-TG is acetylated and thus is susceptible to nonspecific hydrolysis, potentially compromising its ability to detect GSTP1 activity. Here, we describe the development of a highly selective fluorogenic GSTP1 substrate that is membrane permeable and does not involve esterification and show its application to live-cell imaging and FACS analysis. We designed and synthesized several compounds with benzylsulfone substituents instead of the mesyl group of Ps-TG and tested their fluorescence activation by GSTP1 catalysis in vitro and in cellulo. Of the test compounds, Ps-TG3 was the most suitable for the visualization of intracellular GSTP1 activity because the signal from living cells increased significantly when MK-571, an inhibitor of multidrug resistance proteins (MRPs), was simultaneously loaded. The results obtained by co-loading Ps-TG3 and MK571 into GSTP1-nonexpressing cells suggest that Ps-TG3 can be a substrate for MRPs. The usefulness of Ps-TG3 was demonstrated by fluorescence imaging of several cancer cell cultures and FACS analysis of lymphoma cells. The results presented here suggest that Ps-TG3, in combination with MK571, is useful for visualizing and detecting intracellular GSTP1 activity in cancer cells that highly express GSTP1.
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•Ps-TG3, a hydrophobic analogue of Ps-TG, is developed.•Ps-TG3 is a new fluorescent probe for detecting GSTP1 activity.•Ps-TG3 with MK571 enables highly sensitive detection of intracellular GSTP1 activity.
Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito ...control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated.
Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S-transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti. The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4',6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein.
Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We synthesized a series of new intrinsically stretchable block copolymers (BCPs) in linear AB-type, ABA-type, and star-shaped architectures composed of oligosaccharide (MH) and flexible poly(n-butyl ...acrylate) (PBA) blocks for the application in field-effect transistor memory. The BCP thin films are used as the charge trapping layers in the memory devices where the BCPs phase separate into ordered MH microdomains in soft PBA matrices. The MH microdomain works as the charge-trapping sites while the soft PBA matrix provides a stretchability. In particular, the BCPs of the ABA-type and star-shaped architectures with the end MH blocks not only show superior memory performances but also form physical networks that impart mechanical resilience to the thin films such that they can endure 100% strain without formation of cracks. The mobilities and the memory windows of the devices are nearly constant even when the charge trapping layers are stretched and released at 50% strain for 1000 cycles. This work highlights the importance of the molecular architectures on the BCPs intended for stretchable electronic materials.
The effect of intramolecular cross-linking in an amphiphilic block copolymer (BCP) system was systematically investigated in terms of its thermal properties, critical micelle concentration (CMC), and ...aqueous self-assembly. A series of linear BCPs consisting of poly(ethylene glycol) (PEG) as a hydrophilic block and poly(ε-caprolactone- co -7-allyloxepan-2-one) (P(CL- co -ACL)) as a hydrophobic block were prepared by the ring-opening copolymerization of ε-caprolactone (CL) and 7-allyloxepan-2-one (ACL) using poly(ethylene glycol)monomethyl ether as an initiator. The intramolecular olefin metathesis reaction in the P(CL- co -ACL) block was subsequently carried out under various conditions to prepare the cross-linked BCPs with different degrees of cross-linking. The thermal analysis confirmed that the linear P(CL- co -ACL) block was found to crystallize, while the cross-linked one showed no crystallinity. In addition, glass transition temperature of the P(CL- co -ACL) block increased upon cross-linking. On the other hand, the intramolecular cross-linking had no significant influence on the CMC. The self-assembled micelles were prepared from the obtained BCPs and their size and morphology were investigated. For the BCPs with relatively short PEG chains, the micellar size decreased from 36.6 nm to 16.7 nm as the degree of cross-linking of the P(CL- co -ACL) block increased. On the other hand, the BCPs with relatively long PEG chains showed a change in the micellar morphology from spherical micelles to short worm and large compound micelles upon cross-linking.
We report the synthesis, morphology, and photophysical properties of new conjugated rod-coil block copolymers consisting of poly2,7-(9,9-dihexylfluorene) (PF) conjugated rods and soft poly( n -butyl ...acrylate) (PBA) coils for stretchable light-emitting device applications. The PF- b -PBA thin films could form obvious self-assembled nanofibrillar structures after the solvent annealing treatment. Besides this, both the deformability and optical properties of block copolymers were controllable by varying the PF/PBA ratio. The annealed PF 4k - b -PBA 7k thin film exhibited pure blue emission with a high photoluminescence quantum yield of over 22.5% under 100% strain, validating the excellent stretchability and promising stability. Furthermore, a stretchable and fluorescent PF- b -PBA based microporous template with tunable regularity can be fabricated through the breath figure method. These results demonstrated that the novel intrinsically deformable and luminescent rod-coil block copolymers could have versatile applications in stretchable light-emitting devices.
Discrete block co-oligomers (BCOs) are gaining considerable attention due to their potential to form highly ordered ultrasmall nanostructures suitable for lithographic templates. However, laborious ...synthetic routes present a major hurdle to the practical application. Herein, we report a readily available discrete BCO system that is capable of forming various self-assembled nanostructures with ultrasmall periodicity. Click coupling of propargyl-functionalized sugars (containing 1-7 glucose units) and azido-functionalized terpenoids (containing 3, 4, and 9 isoprene units) afforded the discrete and monodisperse BCOs with a desired total degree of polymerization and block ratio. These BCOs microphase separated into lamellar, gyroid, and cylindrical morphologies with the domain spacing (d) of 4.2-7.5 nm. Considering easy synthesis and rich phase behavior, presented BCO systems could be highly promising for application to diverse ~4-nm nanofabrications.
A comprehensive examination of the synthesis of single-chain nanoparticles (SCNPs) from statistical copolymers of n -butyl methacrylate (BMA) and 3-butenyl methacrylate (3BMA), i.e. , P(BMA- co ...-3BMA)s, via the intramolecular olefin metathesis reaction under high dilution conditions is described. The olefin metathesis reaction of P(BMA- co -3BMA) using Grubbs’ 2 nd generation catalyst in CH 2 Cl 2 efficiently gave the corresponding SCNPs under mild conditions. We achieved the size-controlled synthesis of the SCNPs by adjusting the following factors: (1) the olefin content in the precursor, (2) the molecular weight of the precursor, and (3) the solvent quality of the reaction medium. The hydrodynamic radius and the intrinsic viscosity of the resultant SCNPs were investigated by DLS and viscometric measurements, respectively, which provided further evidence of SCNP formation with controlled diameters. Furthermore, the above-established intramolecular olefin metathesis approach was successfully applied to poly(acrylate), poly(styrene), and poly(ester) precursors, which proved that the present approach could be applied to a wide range of olefin-containing precursors to give SCNPs with various functional groups.
This paper is concerned with robust principal component analysis (PCA) based on spatial sign and spatial rank vectors. The most common PC approach is based on the eigenvectors of the sample ...covariance matrix; however, this approach is known to be sensitive to outliers. Several robust alternatives based on spatial sign and spatial rank vectors have been discussed including Kendall’s tau or Marden’s rank and Spearman’s rank matrices. Our aims in this paper are to investigate properties of PCA based on Spearman’s rank matrix from theoretical and practical view points and to compare the performance of PCA based on these robust alternatives. A concentration inequality for an estimator of Spearman’s rank matrix is derived, which reveals consistency of the estimator. The influence functions for eigenvalues and eigenvectors of Spearman’s rank matrix are examined which establish the asymptotics for PCA based on Spearman’s rank matrix. Monte Carlo simulations and application to a real dataset show that the performance of PCA using Spearman’s rank matrix is comparable to or sometime better than that of Kendall’s tau and Marden’s rank matrices.
Developing an efficient and versatile process to transform a single linear polymer chain into a shape‐defined nanoobject is a major challenge in the fields of chemistry and nanotechnology to ...replicate sophisticated biological functions of proteins and nucleic acids in a synthetic polymer system. In this study, we performed one‐shot intrablock cross‐linking of linear block copolymers (BCPs) to realize single‐chain nanoparticles (SCNPs) with two chemically compartmentalized domains (Janus‐shaped SCNPs). Detailed structural characterizations of the Janus‐shaped SCNP composed of polystyrene‐block‐poly(glycolic acid) revealed its compactly folded conformation and compartmentalized block localization, similar to the self‐folded tertiary structures of natural proteins. Versatility of the one‐shot intrablock cross‐linking was demonstrated using several different BCP precursors. In addition, the Janus‐shaped SCNP produce miniscule microphase‐separated structures.
A one‐shot intrablock cross‐linking protocol was demonstrated to achieve a rapid and facile synthesis of single‐chain nanoparticles (SCNPs) with two chemically compartmentalized domains (Janus‐shaped SCNPs) from the various diblock copolymers bearing one particular cross‐linkable functionality across the entire polymer chain. Janus‐shaped SCNP produce significantly small microphase‐separated structure.
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