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In previous work, we reported on iridium(III) (Ir(III)) complex-peptide hybrids as amphiphilic conjugates (IPH-ACs) and triptycene-peptide hybrids as amphiphilic conjugates (TPH-ACs) and found that these hybrid compounds containing three cationic KK(K)GG peptide units through C 6 -C 8 alkyl linkers induce paraptosis II, which is one of the nonapoptotic programmed cell death (PCD) types in Jurkat cells and different from previously reported paraptosis. The details of that study revealed that the paraptosis II induced by IPH-ACs (and TPH-ACs) proceeds via a membrane fusion or tethering of the endoplasmic reticulum (ER) and mitochondria, and Ca 2+ transfer from the ER to mitochondria, which results in a loss of mitochondrial membrane potential ( ΔΨ m ) in Jurkat cells. However, the detailed mechanistic studies of paraptosis II have been conducted only in Jurkat cells. In the present work, we decided to conduct mechanistic studies of paraptosis II in HeLa-S3 and A549 cells as well as in Jurkat cells to study the general mechanism of paraptosis II. Simultaneously, we designed and synthesized new TPH-ACs functionalized with peptides that contain cyclohexylalanine, which had been reported to enhance the localization of peptides to mitochondria. We found that TPH-ACs containing cyclohexylalanine promote paraptosis II processes in Jurkat, HeLa-S3 and A549 cells. The results of the experiments using fluorescence Ca 2+ probes in mitochondria and cytosol, fluorescence staining agents of mitochondria and the ER, and inhibitors of paraptosis II suggest that TPH-ACs induce Ca 2+ increase in mitochondria and the membrane fusion between the ER and mitochondria almost simultaneously, suggesting that our previous hypothesis on the mechanism of paraptosis II should be revised.

The antimicrobial properties of anodic porous alumina (APA) formed by the anodization of Al substrates were evaluated. APA surfaces with needle-like projections fabricated under controlled preparation conditions exhibited high antibacterial activity against Escherichia coli and Staphylococcus aureus . In antibacterial tests using APA with different interpore distances, all APA surfaces showed high antibacterial activity against E. coli , regardless of the interpore distance. In the case of S. aureus , in contrast, the smaller the interpore distance in APA is, the higher the antibacterial activity. These results indicate that different bacterial species require different optimal surface structures for antimicrobial activity. The needle-like projections formed on the surface of APA became finer as the interpore distance decreased; the finer the projections, the more efficiently the soft cell membrane of S. aureus is disrupted and the higher the antibacterial activity. On an APA with an interpore distance of 60 nm, the colony formation rate of S. aureus and E. coli was reduced to less than 1/100,000 compared to that of a nonanodized Al substrate. The fabrication process described in this article is expected to make it possible to impart antimicrobial properties to the surfaces of various Al products.

Oligonucleotides are short nucleic acids that serve as one of the most promising classes of drug modality. However, attempts to establish a physicochemical evaluation platform of oligonucleotides for acquiring a comprehensive view of their properties have been limited. As the chemical stability and the efficacy as well as the solution properties at a high concentration should be related to their higher-order structure and intra-/intermolecular interactions, their detailed understanding enables effective formulation development. Here, the higher-order structure and the thermodynamic stability of the thrombin-binding aptamer (TBA) and four modified TBAs, which have similar sequences but were expected to have different higher-order structures, were evaluated using ultraviolet spectroscopy (UV), circular dichroism (CD), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). Then, the relationship between the higher-order structure and the solution properties including solubility, viscosity, and stability was investigated. The impact of the higher-order structure on the antithrombin activity was also confirmed. The higher-order structure and intra-/intermolecular interactions of the oligonucleotides were affected by types of buffers because of different potassium concentrations, which are crucial for the formation of the G-quadruplex structure. Consequently, solution properties, such as solubility and viscosity, chemical stability, and antithrombin activity, were also influenced. Each instrumental analysis had a complemental role in investigating the higher-order structure of TBA and modified TBAs. The utility of each physicochemical characterization method during the preclinical developmental stages is also discussed.

Cu nanoclusters exhibit distinctive physicochemical properties and hold significant potential for multifaceted applications. Although Cu nanoclusters are synthesized by reacting Cu ions and reducing agents by covering their surfaces using organic protecting ligands or supporting them inside porous materials, the synthesis of surface-exposed Cu nanoclusters with a controlled number of Cu atoms remains challenging. This study presents a solid-state reduction method for the synthesis of Cu nanoclusters employing a ring-shaped polyoxometalate (POM) as a structurally defined and rigid molecular nanoreactor. Through the reduction of Cu 2+ incorporated within the cavity of a ring-shaped POM using H 2 at 140 °C, spectroscopic studies and single-crystal X-ray diffraction analysis revealed the formation of surface-exposed Cu nanoclusters with a defined number of Cu atoms within the cavities of POMs. Furthermore, the Cu nanoclusters underwent a reversible redox transformation within the cavity upon alternating the gas atmosphere (i.e., H 2 or O 2 ). These Cu nanoclusters produced active hydrogen species that can efficiently hydrogenate various functional groups such as alkenes, alkynes, carbonyls, and nitro groups using H 2 as a reductant. We expect that this synthesis approach will facilitate the development of a wide variety of metal nanoclusters with high reactivity and unexplored properties.

Although the use of biodegradable plastics is suitable for unrecoverable, single-use plastic, their high production cost and much lower variety compared to commodity plastics limit their application. In this study, we developed a new polymer with potential biodegradability, poly(ketone/ester), synthesized from propylene and carbon monoxide. Propylene and carbon monoxide are easily available at low costs from fossil resources, and they can also be derived from biomass. Using an atom insertion reaction to the main chain of the polymer, the main-chain editing of the polymer molecule proceeded with up to 89% selectivity for atom insertion over main-chain cleavage.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles ( 5a - h , 6 , and 7a - e ) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a , 5d , and 5e can effectively inhibit both targets. 5a , 5d , and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

The rapid amplification and sensitive detection of α-synuclein (αSyn) seeds is an efficient approach for the early diagnosis of Parkinson's disease. Ultrasonication stands out as a promising method for the rapid amplification of αSyn seeds because of its robust fibril fragmentation capability. However, ultrasonication also induces the primary nucleation of αSyn monomers, deteriorating the seed detection sensitivity by generating seed-independent fibrils. In this study, we show that an addition of surfactants to the αSyn monomer solution during αSyn seed detection under ultrasonication remarkably improves the detection sensitivity of the αSyn seeds by a factor of 100-1000. Chemical kinetic analysis reveals that these surfactants reduce the rate of primary nucleation while promoting the fragmentation of the αSyn fibrils under ultrasonication. These effects are attributed to the modification of the ultrasonic cavitation surface by the surfactants. Our study enhances the utility of ultrasonication in clinical assays targeting αSyn seeds as the Parkinson's disease biomarker.

Supported particulate noble-metal catalysts are widely used in industrial catalytic reactions. However, these metal species, whether in the form of nanoparticles or highly dispersed entities, tend to aggregate during reactions, leading to a reduced activity or selectivity. Addressing the frequent necessity for the replacement of industrial catalysts remains a significant challenge. Herein, we demonstrate the feasibility of the 'regenerable catalytic system' exemplified by selective catalytic oxidation of ammonia (NH 3 -SCO) employing Ag/Al 2 O 3 catalysts. Results demonstrate that our highly dispersed Ag catalyst (Ag HD) maintains >90% N 2 selectivity at 80% NH 3 conversion and >80% N 2 selectivity at 100% NH 3 conversion after enduring 5 cycles of reducible aggregation and oxidative dispersion. Moreover, it consistently upholds over 98% N 2 selectivity at 100% NH 3 conversion after 10 cycles of Ar treatment. During the aggregation-dispersion process, the Ag HD catalyst intentionally aggregated into Ag nanoparticles (Ag NP) after H 2 reduction and exhibited remarkable regenerable capabilities, returning to the Ag HD state after calcination in the air. This structural evolution was characterized through in situ transmission electron microscopy, atomically resolved high-angle annular dark-field scanning transmission electron microscopy, and X-ray absorption spectroscopy, revealing the on-site oxidative dispersion of Ag NP. Additionally, in situ diffuse reflectance infrared Fourier transform spectroscopy provided insights into the exceptional N 2 selectivity on Ag HD catalysts, elucidating the critical role of NO + intermediates. Our findings suggest a sustainable and cost-effective solution for various industry applications.

In research focused on protein-protein interaction (PPI) inhibitors, the optimization process to achieve both high inhibitory activity and favorable physicochemical properties remains challenging. Our previous study reported the discovery of novel and bioavailable Keap1-Nrf2 PPI inhibitor 8 which exhibited moderate in vivo activity in rats. In this work, we present our subsequent efforts to optimize this compound. Two distinct approaches were employed, targeting high energy water molecules and Ser602 as "hot spots" from the anchor with good aqueous solubility, metabolic stability, and membrane permeability. Through ligand efficiency (LE)-guided exploration, we identified two novel inhibitors 22 and 33 with good pharmacokinetics (PK) profiles and more potent in vivo activities, which appear to be promising chemical probes among the existing inhibitors.

Organic-polyoxometalate (POM) hybrids have recently attracted considerable interest because of their distinctive properties and wide-ranging applications. For the construction of organic-POM hybrids, porphyrins are promising building units owing to their optical properties and reactivity, including strong visible-light absorption and subsequent singlet-oxygen ( 1 O 2 *) generation. However, the practical utilization of porphyrins as photocatalysts and photosensitizers is often hindered by their own degradation by 1 O 2 *. Therefore, there is a substantial demand for the development of porphyrin-derived photocatalysts with both high efficiency and durability. Herein, we present a porphyrin-polyoxotungstate molecular hybrid featuring a face-to-face stacked porphyrin dimer ( I ) fastened by four lacunary polyoxotungstates. Hybrid I exhibited remarkable efficiency and durability in photocatalytic aerobic oxidation reactions, and the selective oxidation of various dienes, alkenes, sulfides, and amines proceeded using just 0.003 mol % of the catalyst. Mechanistic investigations suggested that the high activity of I stems from the efficient generation of 1 O 2 *, resulting from the heavy-atom effect of POMs. Furthermore, despite its high efficiency in 1 O 2 * generation compared to free porphyrins, I exhibited superior durability against 1 O 2 *-induced degradation under photoirradiation.

An unexplored material of copper boride has been realized recently in two-dimensional form at a (111) surface of the fcc copper crystal. Here, one-dimensional (1-D) boron growth was observed on the Cu(110) surface, as probed by atomically resolved scanning probe microscopy. The 1-D copper boride was composed of quasi-periodic atomic chains periodically aligned parallel to each other, as confirmed by Fourier transform analysis. The 1-D growth unexpectedly proceeded across surface steps in a self-assembled manner and extended over several 100 nm. The long-range formation of a 1-D quasi-periodic structure on a surface has been theoretically modeled as a 1-D quasi-crystal and the predicted conditions matched the structural parameters obtained by the experimental work here. The quasi-periodic 1-D copper boride system enabled a way to examine 1-D quasi-crystallinity on an actual material.

BaTiO 3 -CaTiO 3 and SrTiO 3 -BaTiO 3 core-shell nanocubes were synthesized through the surface reconstruction of BaTiO 3 nanocubes, which involved the reaction of titanium oxide with Ca(OH) 2 , Sr(OH) 2 , or Sr(OH) 2 ·8H 2 O in water at 100 °C. The core-shell structure comprised a BaTiO 3 nanocube core and a CaTiO 3 or SrTiO 3 shell. The outermost layer with a perovskite structure also comprised CaTiO 3 or SrTiO 3 , and its thickness was several hundred picometers. The thinnest layer was constructed of only one layer of CaTiO 3 or SrTiO 3 . This is the first presented work on a core-shell nanocube with the outermost layer consisting of only CaTiO 3 or SrTiO 3 surrounding the BaTiO 3 nanocube. The shells of CaTiO 3 and SrTiO 3 comprise a layer thickness of only one unit cell of ∼0.4 nm (400 pm). Thus, we demonstrate new research on nanocube surfaces on the picometer scale.

Poly( N -isopropylacrylamide) (pNIPAm) undergoes a hydrophilicity/hydrophobicity change around its lower critical solution temperature (LCST). Therefore, pNIPAm-based polymer nanoparticles (NPs) shrink above their LCST and swell below their LCST. Although temperature responsiveness is an important characteristic of synthetic polymers in drug and gene delivery, few studies have investigated the temperature-responsive catch and release of low-molecular-weight drugs (LMWDs) as their affinity to the target changes. Since LMWDs have only a few functional groups, preparation of NPs with high affinity for LMWDs is hard compared with that for peptides and proteins. However, LMWDs such as anticancer drugs often have a stronger effect than peptides and proteins. Therefore, the development of NPs that can load and release LMWDs is needed for drug delivery. Here, we engineered pNIPAm-based NPs that capture paclitaxel (PTX), an anticancer LMWD that inhibits microtubules, above their LCST and release it below their LCST. The swelling transition of the NPs depended on their hydrophobic monomer structure. NPs with swelling ratios (=NP size at 25 °C/NP size at 37 °C) exceeding 1.90 released captured PTX when cooled to below their LCST by changing the affinity for PTX. On the other hand, NPs with a swelling ratio of only 1.14 released melittin. Therefore, optimizing the functional monomers of temperature-responsive NPs is essential for the catch and release of the target in a temperature-dependent manner. These results can guide the design of stimuli-responsive polymers that catch and release their target molecules., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

In large bicycloalkanes, several in/out forms exist, wherein substituents on the bridgehead atoms are oriented either outside or inside the cage. The relative stability between the in,out and twist-out,out forms, which can interconvert through homeomorphic conversion, was found to depend upon the cage size. The in,out form demonstrated thermodynamic stability in the smaller C10 derivative, whereas the twist-out,out form prevailed in the larger derivatives of C14 and C18 plausibly as a result of dispersion forces among the chains.

The Ba 2 RE 1- x Ce x TaO 6 (RE = La, Gd, Y; 0 ≤ x ≤ 1) pigments were synthesized by a conventional solid-state reaction method to develop environmentally friendly reddish inorganic pigments. The host was the double-perovskite-type Ba 2 RETaO 6 (RE: rare-earth elements), and the color source was Ce 3+ . All Ba 2 RE 1- x Ce x TaO 6 samples were obtained in a single-phase form as solid solutions. Rietveld refinement analysis of the Ba 2 RETaO 6 (RE = La, Ce, Gd, and Y) samples revealed that the average bond length between RE 3+ and O depends on the ionic radius of RE 3+ , and the shorter the RE-O length, the stronger the crystal field surrounding Ce 3+ . A photon energy at the maximum 4f-5d absorption of Ce 3+ depended on the weighted average ionic radius ( r RE ) at the RE 3+ site (i.e., the crystal field energy around the Ce 3+ ions). In response to this phenomenon, the sample color was changed in order to orange, red, pink, and violet with a decrease in the r RE value, and a hue angle ( h °) was roughly linearly related to that. For validation of the tendency, we demonstrated the synthesis and characterization of Ba 2 La 0.5- y Y y Ce 0.5 TaO 6 to obtain a more reddish color. As we exactly expected, a more reddish color was obtained while maintaining a high C value. Furthermore, the h ° values for y = 0.1 and 0.2 were in good agreement with our estimation. In light of the above results, by controlling the intensity of the crystal field surrounding Ce 3+ and/or the concentration of Ce 3+ , the optical absorption wavelength and absorption intensity of the Ba 2 RE 1- x Ce x TaO 6 system can be changed to adjust the color.

We developed a multichannel wireless quartz-crystal-microbalance (QCM) biosensor for mechanically studying the on-surface aggregation reaction of α-synuclein (α-syn). We find a quite unusual change in the resonant frequency that eventually exceeds the baseline, which has never been observed during seeding aggregation reaction. By incorporating a growth-to-percolation theory for fibril elongation reaction, we have favorably reproduced this unusual response and found that it can be explained only with formation of an ultrastiff fibril network. We also find that the stiffness of the fibril network grown from artificially prepared twist-type seeds is significantly higher than that from rod-type seeds. Furthermore, the stiffnesses of fibril networks grown from seeds derived from brain tissues of Parkinson's disease (PD) and multiple system atrophy (MSA) patients show a very similar trend to those of rod and twist seeds, respectively, indicating that fibrils from MSA patients are stiffer than those from PD.

Fluorination of oximes with the relatively mild diethylaminosulfur trifluoride/tetrahydrofuran (DAST-THF) system affords imidoyl fluorides. These compounds were isolated, and their structures were confirmed by X-ray single-crystal structure analysis. Reaction of imidoyl fluorides with various nucleophiles efficiently afforded amides, amidines, thioamides, and amine derivatives in high yields. Furthermore, one-pot reaction of in situ generated imidoyl fluorides from oximes was also applicable to efficient synthesis of these products. The oxime stereochemistry and acid-labile protecting group remained intact in this system.

Although catalytic dehydrogenative aromatization from cyclohexanones and NH 3 is an attractive synthetic method for primary anilines, using a hydrogen acceptor was indispensable to achieve satisfactory levels of selectivity in liquid-phase organic synthetic systems without photoirradiation. In this study, we developed a highly selective synthesis of primary anilines from cyclohexanones and NH 3 via efficient acceptorless dehydrogenative aromatization heterogeneously catalyzed by an Mg(OH) 2 -supported Pd nanoparticle catalyst in which Mg(OH) 2 species are also deposited on the Pd surface. The basic sites of the Mg(OH) 2 support effectively accelerate the acceptorless dehydrogenative aromatization via concerted catalysis, suppressing the formation of secondary amine byproducts. In addition, the deposition of Mg(OH) 2 species inhibits the adsorption of cyclohexanones on the Pd nanoparticles to suppress phenol formation, achieving the desired primary anilines with high selectivity., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor 7 with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully provided the lead compound 25 , which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting 25 , which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Neighboring group participation involving a 6-membered ring structure is rare, despite the privilege of 6-membered ring transition structures in organic chemistry. We examined the putative role of a 6-membered cyclic intermediate with neighboring group participation of nitrogen cation in syn -migration of peri -ester indanone oximes. Direct observation of a peri -methyl ester-iminylium intermediate in solution by means of 1 H NMR supported the existence of the 6-membered cation intermediate. Density functional theory (DFT) calculations also supported the intervention of this intermediate in the rearrangement and indicated that it has a planar structure stabilized by electron delocalization.

The primary coordination sphere of the multinuclear cofactor (Mn 4 CaO x ) in the oxygen-evolving complex (OEC) of photosystem II is absolutely conserved to maintain its structure and function. Recent time-resolved serial femtosecond crystallography identified large reorganization of the primary coordination sphere in the S 2 to S 3 transition, which elicits a cascade of events involving Mn oxidation and water molecule binding to a putative catalytic Mn site. We examined how the crystallographic fields, created by transient conformational states of the OEC at various time points, affect the thermodynamics of various isomers of the Mn cluster using DFT calculations, with an aim of comprehending the functional roles of the flexible primary coordination sphere in the S 2 to S 3 transition and in the recovery of the S 2 state. The results show that the relative movements of surrounding residues change the size and shape of the cavity of the cluster and thereby affect the thermodynamics of various catalytic intermediates as well as the ability to capture a new water molecule at a coordinatively unsaturated site. The implication of these findings is that the protein dynamics may serve to gate the catalytic reaction efficiently by controlling the sequence of Mn oxidation/reduction and water binding/release. This interpretation is consistent with EPR experiments; g ∼ 5 and g ∼ 3 signals obtained after near-infrared (NIR) excitation of the S 3 state at 4 K and a g ∼ 5 only signal produced after prolonged incubation of the S 3 state at 77 K can be best explained as originating from water-bound S 2 clusters ( S total = 7/2) under a S 3 ligand field, i.e., the immediate one-electron reduction products of the oxyl-oxo ( S total = 6) and hydroxo-oxo ( S total = 3) species in the S 3 state.

A reliable strategy for the construction of trans -fused bicyclo[ n .3.0] skeletons was explored by utilizing photoinduced cyclization of acylsilanes bearing a boronate. The substrates having an acylsilane and a boronate in a 1,2- trans relationship were prepared via hydroboration of cycloalkene derivatives. The desired cyclization was efficiently promoted by photoirradiation to give the trans -fused bicyclo[ n .3.0] derivatives as a single diastereomer. It is noteworthy that this methodology enables the efficient construction of a highly strained trans -5-5 ring system.

The ring-shaped polyoxometalate (POM) [P 8 W 48 O 184 ] 40- contains a large cavity and is an attractive inorganic multidentate ligand for accumulating metal cations. Until now, several multinuclear metal cores are constructed within the {P 8 W 48 } framework in aqueous solvents. However, it is still challenging to control the number and arrangement of introduced metal cations because of the numerous coordination sites inside the {P 8 W 48 } framework. In this study, we developed a novel approach for the selective synthesis of several multinuclear copper-containing ring-shaped POMs in organic solvents using methoxy groups as organic protecting ligands for the reactive coordination sites. Reacting a tetra- n -butylammonium (TBA) salt of [P 8 W 48 O 184 ] 40- ( P8W48 ) with 4 and 8 equiv of copper(II) acetate in the presence of methanol (MeOH), tetra- and octacopper cores were incorporated into the cavity to form TBA 11 H 13 [Cu 4 (H 2 O) 4 P 8 W 48 O 176 (OCH 3 ) 8 ]·28H 2 O·3CH 3 NO 2 ( Cu4 ) and TBA 14 H 2 [Cu 8 (H 2 O) 12 P 8 W 48 O 176 (OCH 3 ) 8 ]·24H 2 O·CH 3 CN ( Cu8 ), respectively. For both structures, methoxy groups served as protecting ligands and temporarily inactivated vacant coordination sites. Without MeOH, dodeca- and hexadecacopper cores were constructed inside the cavity to form TBA 14 H 2 [Cu 12 (H 2 O) 16 P 8 W 48 O 184 ]·4H 2 O ( Cu12 ) and TBA 16 H 8 [Cu 16 (OH) 16 (H 2 O) 4 P 8 W 48 O 184 ]·12H 2 O·C 3 H 6 O ( Cu16 ), respectively. The arrangement of copper ions on the same {P 2 W 12 } units could be controlled by the input number of copper ions. Moreover, all four POMs could be synthesized from P8W48 by the stepwise addition of 4 equiv of copper(II) acetate, clarifying the introduction process.

We report on the design and synthesis of triptycene-peptide hybrids (TPHs), 5 , syn - 6 , and anti - 6 , which are conjugates of a triptycene core unit with two or three cationic KKKGG peptides (K: lysine and G: glycine) through a C 8 alkyl chain. It was discovered that syn - 6 and anti - 6 induce paraptosis, a type of programmed cell death (PCD), in Jurkat cells (leukemia T-lymphocytes). Mechanistic studies indicate that these TPHs induce the transfer of Ca 2+ from the endoplasmic reticulum (ER) to mitochondria, a loss of mitochondrial membrane potential (ΔΨ m ), tethering of the ER and mitochondria, and cytoplasmic vacuolization in the paraptosis processes.

We previously reported that a cyclometalated iridium (Ir) complex-peptide hybrid (IPH) 4 functionalized with a cationic KKKGG peptide unit on the 2-phenylpyridine ligand induces paraptosis, a relatively newly found programmed cell death, in cancer cells (Jurkat cells) via the direct transport of calcium (Ca 2+ ) from the endoplasmic reticulum (ER) to mitochondria. Here, we describe that CGP37157, an inhibitor of a mitochondrial sodium (Na + )/Ca 2+ exchanger, induces paraptosis in Jurkat cells via intracellular pathways similar to those induced by 4 . The findings allow us to suggest that the induction of paraptosis by 4 and CGP37157 is associated with membrane fusion between mitochondria and the ER, subsequent Ca 2+ influx from the ER to mitochondria, and a decrease in the mitochondrial membrane potential ( ΔΨ m ). On the contrary, celastrol, a naturally occurring triterpenoid that had been reported as a paraptosis inducer in cancer cells, negligibly induces mitochondria-ER membrane fusion. Consequently, we conclude that the paraptosis induced by 4 and CGP37157 (termed paraptosis II herein) proceeds via a signaling pathway different from that of the previously known paraptosis induced by celastrol, a process that negligibly involves membrane fusion between mitochondria and the ER (termed paraptosis I herein).

We studied the Z / E preference of N -phenylthioacetamide (thioacetanilide) derivatives in various solvents by means of 1 H NMR spectroscopy, as well as molecular dynamics (MD) and other computational analyses. Our experimental results indicate that the Z / E isomer preference of secondary (NH)thioamides of N -phenylthioacetamides shows substantial solvent dependency, whereas the corresponding amides do not show solvent dependency of the Z / E isomer ratios. Detailed study of the solvent effects based on molecular dynamics simulations revealed that there are two main modes of hydrogen (H)-bond formation between solvent and (NH)thioacetamide, which influence the Z / E isomer preference of (NH)thioamides. DFT calculations of NH-thioamide in the presence of one or two explicit solvent molecules in the continuum solvent model can effectively mimic the solvation by multiple solvent molecules surrounding the thioamide in MD simulations and shed light on the precise nature of the interactions between thioamide and solvent. Orbital interaction analysis showed that, counterintuitively, the Z / E preference of NH-thioacetamides is mainly determined by steric repulsion, while that of sterically congested N -methylthioacetamides is mainly determined by thioamide conjugation.

We focused on identifying a catalytic active site structure at the atomic level and elucidating the mechanism at the elementary reaction level of liquid-phase organic reactions with a heterogeneous catalyst. In this study, we experimentally and computationally investigated efficient C-H bond activation for the selective aerobic α,β-dehydrogenation of saturated ketones by using a Pd-Au bimetallic nanoparticle catalyst supported on CeO 2 (Pd/Au/CeO 2 ) as a case study. Detailed characterization of the catalyst with various observation methods revealed that bimetallic nanoparticles formed on the CeO 2 support with an average size of about 2.5 nm and comprised a Au nanoparticle core and PdO nanospecies dispersed on the core. The formation mechanism of the nanoparticles was clarified through using several CeO 2 -supported controlled catalysts. Activity tests and detailed characterizations demonstrated that the dehydrogenation activity increased with the coordination numbers of Pd-O species in the presence of Au(0) species. Such experimental evidence suggests that a Pd(II)-(μ-O)-Au(0) structure is the true active site for this reaction. Based on density functional theory calculations using a suitable Pd 1 O 2 Au 12 cluster model with the Pd(II)-(μ-O)-Au(0) structure, we propose a C-H bond activation mechanism via concerted catalysis in which the Pd atom acts as a Lewis acid and the adjacent μ-oxo species acts as a Brønsted base simultaneously. The calculated results reproduced the experimental results for the selective formation of 2-cyclohexen-1-one from cyclohexanone without forming phenol, the regioselectivity of the reaction, the turnover-limiting step, and the activation energy., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Intraperitoneal chemotherapy demonstrates potential applicability in the treatment of peritoneally disseminated ovarian cancer because the disseminated tumors can directly receive exposure to high concentrations of anticancer drugs. However, a considerable proportion of drugs, particularly micromolecular and hydrophilic drugs, such as cisplatin (CDDP), are often excreted through glomerular filtration for a short period. To effectively deliver CDDP into peritoneally disseminated ovarian cancer tissues, we developed an alginate (AL)-based hybrid system in which a CDDP-loaded AL nanogel (AL/CDDP-nanogel) was encapsulated in an injectable AL-hydrogel cross-linked with calcium ions. This system enabled the sustained release of CDDP from the AL/CDDP-nanogel/AL-hydrogel hybrid for over a week. Herein, we constructed a peritoneally disseminated ovarian cancer mouse model using ovarian cancer cell lines with KRAS mutations (ID8-KRAS: KRAS G12V ). The AL/CDDP-nanogel/AL-hydrogel hybrid system showed significant antitumor activity in vivo . This therapy may be considered a novel strategy for the treatment of advanced-stage ovarian cancer with KRAS mutations.

Ultrasonication has been recently adopted in amyloid-fibril assays because of its ability to accelerate fibril formation, being promising in the early stage diagnosis of amyloidoses in clinical applications. Although applications of this technique are expanding in the field of protein science, its effects on the aggregation reactions of amyloidogenic proteins are poorly understood. In this study, we comprehensively investigated the morphology and structure of resultant aggregates, kinetics of fibril formation, and seed-detection sensitivity under ultrasonication using β 2 -microglobulin and compared these characteristics under shaking, which has been traditionally adopted in amyloid-fibril assays. To discuss the ultrasonic effects on the amyloid-fibril formation, we propose the half-time heat map, which describes the phase diagram of the aggregation reaction of amyloidogenic proteins. The experimental results show that ultrasonication greatly promotes fibril formation, especially in dilute monomer solutions, induces short-dispersed fibrils, and is capable of detecting ultra-trace-concentration seeds with a detection limit of 10 fM. Furthermore, we indicate that ultrasonication highly alters the energy landscape of an aggregation reaction due to the effect of ultrasonic cavitation. These insights contribute not only to our understanding of the effects of agitation on amyloidogenic aggregation reactions but also to their effective application in the clinical diagnosis of amyloidoses.

An efficient stepwise synthesis method for discovering new heteromultinuclear metal clusters using a robotic workflow is developed where numerous reaction conditions for constructing heteromultinuclear metal oxo clusters in polyoxometalates (POMs) were explored using a custom-built automated platform. As a result, new nonanuclear tetrametallic oxo clusters {FeMn 4 }Lu 2 A 2 in TBA 5 [(A-α-SiW 9 O 34 ) 2 FeMn 4 O 2 {Lu(acac) 2 } 2 A 2 ] ( II ; A = Ag, Na, K; TBA = tetra- A ; A = Ag, Na, K; TBA = tetra- n -butylammonium; acac = acetylacetonate) were discovered by the installation of diamagnetic metal cations A + into a paramagnetic {FeMn 4 }Lu 2 unit in TBA 7 [(A-α-SiW 9 O 34 ) 2 FeMn 4 O 2 {Lu(acac) 2 } 2 ] ( I ). POMs II , 40.0 K; A , 40.3 K; II , 26.7 K) compared with that of the parent Ag (19.7 K). Importantly, these clusters with unique properties were constructed as designed by a step of the predictable sequential multistep reactions with the time-efficient platform.II Na , 40.3 K; II K , 26.7 K) compared with that of the parent I (19.7 K). Importantly, these clusters with unique properties were constructed as designed by a step of the predictable sequential multistep reactions with the time-efficient platform.

The adsorption of POMs on Rh/SiO 2 in water solvent under strongly reductive conditions was investigated. Aqueous solutions of α-Keggin type silicotungstate and silicovanadotungstates were mixed with Rh/SiO 2 at 393-473 K under 1 MPa of H 2 . Monovanadium-substituted silicotungstate, α-SiVW 11 O 40 5- (SiVW 11 ), was more readily adsorbed than nonsubstituted silicotungstate, α-SiW 12 O 40 ). After adsorption at 433 K, SiVW 4- (SiW 12 ). After adsorption at 433 K, SiVW 11 was desorbed from Rh/SiO 2 by oxidation with Br 2 water without change of the Keggin structure, as evidenced by 51 V NMR. Trivanadium-substituted silicotungstate, α-1,2,3-SiV 3 W 9 O 40 did not maintain the Keggin structure. The very high temperature for adsorption (473 K) also led to the decomposition of the Keggin structure of SiVW 7- , was not stable, and the desorbed species from Rh/SiO 2 by oxidation with Br 2 did not maintain the Keggin structure. The very high temperature for adsorption (473 K) also led to the decomposition of the Keggin structure of SiVW 11 . An increase in the concentration of SiVW 11 in the liquid phase gave a saturation of the amount of desorbable SiVW 11 , up to five SiVW 11 anions per one Rh particle with a 3 nm size. The elemental analysis and W L 3 -edge extended X-ray absorption fine structure of Rh/SiO 2 after the adsorption of SiVW 11 showed that a part of SiVW 11 was decomposed and irreversibly adsorbed as metallic W species incorporated into the surface of Rh metal particles. The amount of decomposed SiVW 11 was almost the same as that of SiVW 11 adsorbed as the original Keggin structure. The desorbable SiVW 11 was probably bonded on the W atom incorporated on the Rh metal particles as the two-electron-reduced form (α-SiV III W 11 O 40 7- ).

The [3 + 2]-cycloaddition reaction between N -tosylaziridines and α,β-unsaturated ketones was promoted with lithium iodide. The reaction proceeded under mild conditions to provide N -tosylpyrrolidines. Quaternary carbon-possessing 3,3-disubstituted pyrrolidines including spiro compounds were afforded in high yields. A simple procedure with easy to handle reagents makes this reaction concise. The intramolecular version of this reaction was applied to synthesize tropane skeletons.

Time evolution of the microscopic wetting velocity of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMI-TFSI) or water on a micrometer-scale line-patterned surface with a poly(3-sulfopropyl methacrylate) brush and a hydrophobic perfluoroalkyl monolayer was precisely measured by direct observation using optical microscopy and a selective dyeing method over a long period (178 days). When a liquid droplet was placed on the dyed line-patterned brush surface, the liquid penetrated and spread into the polymer brush layer, forming a precursor thin film that extended beyond the macroscopic contact line. The elongation proceeded in two stages by an adiabatic process followed by a diffusive process. The elongation distance X increased with time in proportion to t 2.6 for water and t 0.81 for EMI-TFSI during the adiabatic process. In a diffusive process, the advancing velocity of the precursor film was markedly reduced to be expressed as X ∝ t 0.66 for water and X ∝ t 0.21 for EMI-TFSI, indicating that the diffusive process was affected by the energy dissipation of the wetting system. The high viscosity and the strong molecular interaction of EMI-TFSI with the polymer brush gave a large entropy change during the wetting process to result in a slower spreading velocity.

Macrocage molecules with a bridged π-electron system could be assumed as crystalline molecular gyrotops because of the structural similarity and the rotatable π-electron system. In this study, 1,2-difluoro-3,6-phenylene-bridged macrocages were designed and synthesized as crystalline molecular gyrotops with a dipolar rotor. The thermal ring dynamics of the dipolar rotor in the crystal were investigated by solid-state NMR and dielectric spectroscopy. The gyrotop that was surrounded by three C14-alkyl chains exhibited an exchange between two stationary positions in the crystalline state. In contrast, the gyrotop cage consisting of C18 chains exhibited no dynamics in the crystalline state. Although the corresponding phenylene derivatives exhibit a facile rotational motion of the phenylene group in the crystalline state, the dynamics of each derivative was observed to be different. The reason for this difference is ascribed to the difference in the bulkiness between the fluorine and hydrogen atoms in the rotor.

We developed adaptive optical (AO) two-photon excitation microscopy by introducing a spatial light modulator (SLM) in a commercially available microscopy system. For correcting optical aberrations caused by refractive index (RI) interfaces at a specimen's surface, spatial phase distributions of the incident excitation laser light were calculated using 3D coordination of the RI interface with a 3D ray-tracing method. Based on the calculation, we applied a 2D phase-shift distribution to a SLM and achieved the proper point spread function. AO two-photon microscopy improved the fluorescence image contrast in optical phantom mimicking biological specimens. Furthermore, it enhanced the fluorescence intensity from tubulin-labeling dyes in living multicellular tumor spheroids and allowed successful visualization of dendritic spines in the cortical layer V of living mouse brains in the secondary motor region with a curved surface. The AO approach is useful for observing dynamic physiological activities in deep regions of various living biological specimens with curved surfaces., Competing Interests: The authors declare no competing financial interest., (© 2020 The Authors. Published by American Chemical Society.)

In the present study, we propose a rare-event sampling method called anomaly detection parallel cascade selection molecular dynamics (ad-PaCS-MD). The original PaCS-MD was designed to generate conformational transition pathways from a given reactant to a product when the latter is known a priori . As an extension of the original method, ad-PaCS-MD has been designed to efficiently search transition pathways from a given reactant without referring to a given product. In ad-PaCS-MD, rarely occurring but essential states (configurations) of proteins for the transitions are identified based on the degrees of an anomaly. In more detail, ad-PaCS-MD adopts an algorithm called an anomaly detection generative adversarial network (anoGAN) as a measure for detecting rarely occurring states to be resampled. Here, the essential configurations with higher degrees of the anomaly are selected with anoGAN and intensively resampled by restarting short-time MD simulations from the selected configurations. By repeating the detections and resampling of configurations with the higher degrees of the anomaly, ad-PaCS-MD automatically and efficiently promotes the rare events and gives a wide range of the free energy landscape by combining with the Markov state model construction. As demonstrations, open-closed transitions of two globular proteins (T4 lysozyme and maltose-binding protein) were promoted with ad-PaCS-MD by referring only to the given starting configurations. In each demonstration, ad-PaCS-MD promoted the large-amplitude open-closed transitions with nanosecond-order simulation times. In conclusion, our demonstrations showed a higher conformational sampling efficiency for ad-PaCS-MD than conventional MD (CMD) because CMD required computational costs of more than microsecond-order simulation times to promote the rare events.

Multielectron reaction electrode materials using partial oxygen redox can be potentially used as cathodes in lithium-ion batteries, as they offer numerous advantages, including high reversible capacity and energy density and low cost. Here, a reversible three-electron reaction is demonstrated utilizing topotactic phase transition between antifluorite and rocksalt in a cation-disordered antifluorite-type cubic Li 6 CoO 4 cathode. This cubic phase is synthesized by a simple mechanochemical treatment of conventionally prepared tetragonal Li 6 CoO 4 . It displays a reversible capacity of 487 mAh g -1 , a high value because of a reversible three-electron reaction using Co 2+ /Co 3+ , Co 3+ /Co 4+ , and O 2- /O 2 2- redox, occurring without O 2 gas evolution. The mechanochemical treatment is assumed to reduce its lattice distortion by cation-disordering and facilitate a reversible topotactic phase transition between antifluorite and rocksalt structures via a dynamic cation pushing mechanism.

Amyloid fibrils are formed by denatured proteins when the supersaturation of denatured proteins is broken by agitation, such as ultrasonication, or by seeding, although the detailed mechanism of how solubility and supersaturation regulate amyloid formation remains unclear. To further understand the mechanism of amyloid formation, we examined α-synuclein (α-syn) amyloid formation at varying concentrations of SDS, LPA, heparin, or NaCl at pH 7.5. Amyloid fibrils were formed below or around the critical micelle concentrations (CMCs) of SDS (2.75 mM) and LPA (0.24 mM), although no fibrils were formed above the CMCs. On the other hand, amyloid fibrils were formed with 0.01-2.5 mg/mL of heparin and 0.5-1.0 M NaCl, and amyloid formation was gradually suppressed at higher concentrations of heparin and NaCl. To reproduce these concentration-dependent effects of additives, we constructed two models: (i) the ligand-binding-dependent solubility-modulation model and (ii) the cosolute-dependent direct solubility-modulation model, both of which were used by Tanford and colleagues to analyze the additive-dependent conformational transitions of proteins. The solubility of α-syn was assumed to vary depending on the concentration of additives either by the decreased solubility of the additive-α-syn complex (model i) or by the direct regulation of α-syn solubility (model ii). Both models well reproduced additive-dependent bell-shaped profiles of acceleration and inhibition observed for SDS and LPA. As for heparin and NaCl, participation of amorphous aggregates at high concentrations of additives was suggested. The models confirmed that solubility and supersaturation play major roles in driving amyloid formation in vitro , furthering our understanding of the pathogenesis of amyloidosis in vivo .

The myo -inositol-1-phosphate synthase (MIPS) ortholog Ari2, which is encoded in the aristeromycin biosynthetic gene cluster, catalyzes the formation of five-membered cyclitol phosphate using d-fructose 6-phosphate (F6P) as a substrate. To understand the stereochemistry during the Ari2 reaction in vivo , we carried out feeding experiments with (6 S )-d-[6- 2 H 1 ]- and (6 R )-d-[6- 2 H 1 ]glucose in the aristeromycin-producing strain Streptomyces citricolor . We observed retention of the 2 H atom of (6 S )-d-[6- 2 H 1 ]glucose and no incorporation of the 2 H atom from (6 R )-d-[6- 2 H 1 ]glucose in aristeromycin. This indicates that Ari2 abstracts the pro-R proton at C6 of F6P after oxidation of C5-OH by nicotinamide adenine dinucleotide (NAD + ) to generate the enolate intermediate, which then attacks the C2 ketone to form the C-C bond via aldol-type condensation. The reaction of Ari2 with (6 S )-d-[6- 2 H 1 ]- and (6 R )-d-[6- 2 H 1 ]F6P in vitro exhibited identical stereochemistry compared with that observed during the feeding experiments. Furthermore, analysis of the crystal structure of Ari2, including NAD + as a ligand, revealed the active site of Ari2 to be similar to that of MIPS of Mycobacterium tuberculosis , supporting the similarity of the reaction mechanisms of Ari2 and MIPS.

Silver nanoclusters have attracted scientific interest due to their properties and applications. However, practical synthetic methods to access these materials are still limited mainly due to the low stability. Here, we report a controlled assembly strategy for fabricating atomically precise silver nanoclusters using polyoxometalates (POMs) as structure-directing as well as functionalizing units. A trefoil-propeller-shaped {Ag 27 } 17+ nanocluster was synthesized by assembling reactive nanoclusters supported by open-Dawson-type POMs [Si 2 W 18 O 66 ] 16- . The {Ag 27 } 17+ nanocluster possessed 10 delocalized valence electrons and showed unprecedented ultrastability in solutions. The cluster showed unique {Ag 27 }-to-POM charge transfer bands in the visible light region.

A Ru II -NH 3 complex, 2 , was oxidized through a proton-coupled electron transfer (PCET) mechanism with a Ce IV complex in water at pH 2.5 to generate a Ru V ═NH complex, 5 . Complex 5 was characterized with various spectroscopies, and the spin state was determined by the Evans method to be S = 1/2. The reactivity of 5 in substrate C-H oxidation was scrutinized in acidic water, using water-soluble organic substrates such as sodium ethylbenzene-sulfonate (EBS), which gave the corresponding 1-phenylethanol derivative as the product. In the substrate oxidation, complex 5 was converted to the corresponding Ru III -NH 3 complex, 3 . The formation of 1-phenylethanol derivative from EBS and that of 3 indicate that complex 5 as the oxidant does not perform nitrogen-atom transfer, in sharp contrast to other high-valent metal-imido complexes reported so far. Oxidation of cyclobutanol by 5 afforded only cyclobutanone as the product, indicating that the substrate oxidation by 5 proceeds through a hydride-transfer mechanism. In the kinetic analysis on the C-H oxidation, we observed kinetic isotope effects (KIEs) on the C-H oxidation with use of deuterated substrates and remarkably large solvent KIE (sKIE) in D 2 O. These positive KIEs indicate that the rate-determining step involves not only cleavage of the C-H bond of the substrate but also proton transfer from water molecules to 5 . The unique hydride-transfer mechanism in the substrate oxidation by 5 is probably derived from the fact that the Ru IV -NH 2 complex ( 4 ) formed from 5 by 1e - /1H + reduction is unstable and quickly disproportionates into 3 and 5 .

Our NMR, IR/Raman, CD spectroscopic, and X-ray crystallographic studies, as well as accelerated molecular dynamics simulations, showed that alternating hybrid α/β-peptides containing a bicyclic β-proline surrogate form unique extended curved folds, regardless of the peptide length and solvent environment. It is suggested that extended β/PPII structures are preferred in the insulating α-alanine moieties between the rigid bicyclic β-proline structures. These hybrid peptides inhibit p53-MDM2 and p53-MDMX protein-protein interactions.

The chiral bisphosphine dioxide-catalyzed asymmetric conjugate reduction of acyclic β,β-disubstituted α,β-unsaturated ketones with trichlorosilane affords saturated ketones having a stereogenic carbon center at the carbonyl β-position with high enantioselectivities. Because the E/Z -isomerizations of enone substrates occur concomitantly, reduction products with the same absolute configurations are obtained from either ( E )- or ( Z )-enones. Conjugate reduction is accelerated in the presence of an electron-rich aryl group at the β-position of the enone owing to its carbocation-stabilizing ability. Computational studies were also conducted in order to elucidate the origin of the observed enantioselectivity. The regio- and enantioselective reductions of dienones were realized and applied to the syntheses of ar -turmerone, turmeronol A, mutisianthol, and jungianol, which are optically active sesquiterpenes.

The catalytic cycle of allylic arylation in water catalyzed by linear polystyrene-stabilized Pd or PdO nanoparticles (PS-PdNPs or PS-PdONPs) was investigated. Stoichiometric stepwise reactions indicated that the reaction did not proceed stepwise on the surface of the catalyst. In the case of the reaction with PS-PdNPs, the leached Pd species is the catalytically active species and the reaction takes place through a similar reaction pathway accepted in the case of a complex catalyst. In contrast, allylic arylation using PS-PdONPs as a catalyst occurs via a Pd (II) catalytic cycle., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

With 2-pyridyl benzoates as acylating agents and Zn(OAc) 2 as a catalyst, 1,2-diols, 1,3-diols, and catechol were selectively monoacylated. Furthermore, the highly enantioselective desymmetrization of meso -tartrates was achieved for the first time, utilizing 2-pyridyl esters and NiBr 2 /AgOPiv/Ph-BOX in CH 3 CN or CuCl 2 /AgOPiv/Ph-BOX in EtOAc catalyst systems (up to 96% ee). The latter catalyst system was also effective for the kinetic resolution of dibenzyl dl-tartrate.