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A Si-based negative electrode for lithium-ion batteries (LIBs) is produced from methanol solutions of single-nanometer-size B and P co-doped Si nanoparticles (NPs) by drop-coating the solution on a substrate in air without using binders and conductive additives. Stable charge–discharge cycles are observed for films produced from Si NPs in the size range from less than 2 to 12.5 nm in diameter. It is shown that the performance and stability of the electrodes depend strongly on the size. The initial capacity increases with the size, while the stability decreases. The optimum diameter is ∼7 nm. In the electrode made from 7 nm diameter B and P co-doped Si NPs, the capacity is ∼3300 mAh/g and the Coulombic efficiency is ∼97% at a charge–discharge rate of 0.2C rate. [ABSTRACT FROM AUTHOR]

The photothermal heating properties of perfectly spherical crystalline silicon nanoparticles having Mie resonances in the visible range are studied under different illumination wavelengths by using the Raman scattering peak as a nanothermometer. Analytical calculations reveal that the magnetic quadrupole (MQ) Mie mode is the most suitable mode for photothermal heating. The experimentally obtained size and illumination wavelength dependence of the temperature rise agrees quantitatively with numerical simulations, and the heating efficiency reaches up to 381 K/(mW/μm2) when the illumination wavelength of 633 nm matches the MQ resonance. Conversely, tuning the illumination wavelength to a relatively nonabsorbing mode, such as the electric dipole (ED) mode, can significantly reduce the heating effect. In this context, the ED mode functions as a practically heating-less nanoantenna, promoting the surface-enhanced fluorescence of nearby dye molecules, while high-Q modes, e.g., MQ and electric quadrupole (EQ) modes, serve as an optical heating platform. Furthermore, the photothermal heating and Raman thermometry of silicon nanoparticles in water and in cancer cells are demonstrated. [ABSTRACT FROM AUTHOR]

Resonance Raman spectra of the reduced carbon monoxide- (CO-) bound form of heme enzyme, indoleamine 2,3-dioxygenase (IDO), which catalyzes dioxygenation of L-Trp (tryptophan), yielding N-formylkynurenine is measured in order to gain insights into the active site environment of [O.sub.2]. Significantly higher anharmonicity of the Fe-CO stretching oscillator compared to those of oxygen carrier proteins is observed to be a specific character of IDO and might be responsible for the unique reactivity of this enzyme.

Several ONIOM calculations are conducted to explain the reaction mechanisms and the chemistry of various different heme dioxygenases. The presence of dual oxidants is shown to be the main factor responsible for the observed dioxygenase reactivity of the compounds.

A series of single and double mutants are prepared by site-directed mutagenesis focusing on the Arg73 and Arg84 residues of CYP105A1 from Streptomyces griseolus in order to obtain the hyperactive vitamin [D.sub.3] hydroxylase. The structural analyses of single and double mutants have shown that the amino acid residues at positions 73 and 84 have affected the location and conformation of the bound compound in the reaction site and those in the transient binding site.

Density functional calculations are used for proposing a new mechanism for dioxygen activation in indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase heme systems. The effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are examined.

The crystal structure of a highly active mutant (R84A) of CYP105A1 from Streptomyces griseolus in complex and not in complex with 1[alpha], 25-dihydroxyvitamin [D.sub.3] is reported.

The evaluation of the role of two heme propionate side chains, attached at the 6 and 7 positions of the heme framework in sperm whale myoglobin revealed the 6-propionate to contribute for the stabilization of the bound [O.sub.2] where as the 7-propionate was found to be important for regulation of the Fe-His bond.

Single crystals of sperm whale myoglobin reconstituted with 13,16-dicarboxyethyl-2,7-diethyl-3,6,12,17-tetramethylporphycenatoiron(III) are obtained in the imidazole buffer and the three-dimensional (3D) structure has indicated that the iron porphycene is located in the normal position of the heme pocket. The increase in the peroxidase activity and the formation of the stable compound III in myoglobin with iron porphycene mainly arise from the strong coordination of the Fe-His93 bond.

The heme environmental structures of cytoglobin and neuroglobin in the ligand-bound and ligand-dissociated forms are characterized and the findings are discussed in relation to their ligand binding properties. Ligand binding could be controlled by both the distal structure and the proximal ligand in association with the dynamic motion of the protein part.

A photoresponsive molecular switch made up of an aluminum porphyrin and an olefin to be used in controlling the reaction of carbon dioxide and an epoxide through the light-induced structural change, photoisomerization, of the olefin is described. The switch is composed of a reaction site, reaction control site, and a photocontrol site. Aluminum porphyrin and stilbazole were selected as components of the molecular switch since the photoswitchable complexation of a base to a metalloporphyrin.

Research was conducted to examine the crystal structure of human D-dopachrome tautomerase, a homologue of macrophage migration inhibitory factor, at 1.54 angstrom resolution. Human D-dopachrome tautomerase cDNA was cloned and overexpressed in Escherichia coli, followed by purification, crystallization and preliminary crystallographic analysis. Results indicate significant differences in the environment around the potential active site, the intersubunit contacts and charge distribution on the molecular surface.

CYP1O5A1 from Streptomyces griseolus has the capability of converting vitamin D3 (VD3) to its active form, lct,25-dihydroxyvitamin D3 (la,25(OH)2D3) by a two-step hydroxylation reaction. Our previous structural study has suggested that Arg73 and Arg84 are key residues for the activitie~ of CYPIO5AI. In this study, we prepared a series of single and double mutants by site-directed mutagenesis focusing on these two residues of CYP1O5A1 to obtain the hyperactive vitamin D3 hydroxylase. R84F mutation altered the substrate specificity that gives preference to the hi-hydroxylation of 25-hydroxyvitamin D3 over the 25-hydroxylation of Ia-hydroxyvitamin D3, opposite to the wild type and ot~ier mutants. The double mutant R73V1R84A exhibited 435- and 110-fold higher kcat/Km values for the 25-hydroxylation of la-hydroxyvitamin D3 and la-hydroxylation of 25-hydroxyvitamin D3, respectively, c4mpared with the wild-type enzyme. These values notably exceed those of CYP27A1, which is the physiolpgically essential VD3 hydroxylase. Thus, we successfully generated useful enzymes of altered substratp preference and hyperactivity. Structural and kinetic analyses of single and double mutants suggest that the amino acid residues at positions 73 and 84 affect the location and conformation of the bound compoupd in the reaction site and those in the transient binding site, respectively. [ABSTRACT FROM AUTHOR]

Vitamin D3 (VD3), a prohormone in mammals, plays a crucial role in the maintenance of calcium and phosphorus concentrations in serum. Activation of VD3 requires 25-hydroxylation in the liver and 1α-hydroxylation in the kidney by cytochrome P450 (CYP) enzymes. Bacterial CYP105A1 converts VD3 into 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in two independent reactions, despite its low sequence identity with mammalian enzymes (<21% identity). The present study determined the crystal structures of a highly active mutant (R84A) of CYP105A1 from Streptomyces griseolus in complex and not in complex with 1α,25(OH)2D3. The compound 1α,25(OH)2D3 is positioned 11 Å from the iron atom along the I helix within the pocket. A similar binding mode is observed in the structure of the human CYP2R1 -VD3 complex, indicating a common substrate-binding mechanism for 25-hydroxylation. A comparison with the structure of wild-type CYP105A1 suggests that the loss of two hydrogen bonds in the R84A mutant increases the adaptability of the B′ and F helices, creating a transient binding site. Further mutational analysis of the active site reveals that 25- and 1α-hydroxylations share residues that participate in these reactions. These results provide the structural basis for understanding the mechanism of the two-step hydroxylation that activates VD3. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 23-dioxygenase (TDO) are heme-containing dioxygenases and catalyze oxidative cleavage of the pyrrole ring of L-tryptophan. On the basis of three recent crystal structures of these heme-containing dioxygenases, two new mechanistic pathways were proposed by several groups. Both pathways start with electrophilic addition of the Fe(ll)-bound dioxygen concerted with proton transfer (oxygen ene-type reaction), followed by either formation of a dioxetane intermediate or Criegee-type rearrangement. However, density functional theory (DFT) calculations do not support the proposed concerted oxygen ene-type and Criegee-type rearrangement pathways. On the basis of DFT calculations, we propose a new mechanism for dioxygen activation in these heme systems. The mechanism involves (a) direct electrophilic addition of the Fe(ll)-bound oxygen to the C2 or C3 position of the indole in a closed-shell singlet state or (b) direct radical addition of the Fe(lll)-superoxide to the 02 position of the indole in a triplet (or open-shell singlet) state. Then, a radical-recombination or nearly barrierless charge-recombination step from the resultant diradical or zwitterionic intermediates, respectively, proceeds to afford metastable dioxetane intermediates, followed by ring-opening of the dioxetanes. Alternatively, homolytic 0-0 bond cleavage from the diradical intermediate followed by oxo attack and facile C2-C3 bond cleavage could compete with the dioxetane formation pathway. Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied. [ABSTRACT FROM AUTHOR]

Optical magnetic dipole (MD) emission predominantly relies on emitters with significant MD transitions, which, however, rarely exist in nature. Here, we propose a strategy to transform electric dipole (ED) emission to a magnetic one by elegantly coupling an ED emitter to a silicon nanoparticle exhibiting a strong MD resonance. This emission mode transformation enables an artificially ideal magnetic dipole source with an MD purity factor of up to 99%. The far-field emission patterns of such artificial MD sources were experimentally measured, which unambiguously resolved their magnetic-type emission origin. This study opens the path to achieving ideal magnetic dipole emission with nonmagnetic emitters, largely extending the availability of magnetic light emitters conventionally limited by nature. Beyond the fundamental significance in science, we anticipate that this study will also facilitate the development of magnetic optical nanosource and enable potential photonic applications relying on magnetic light emission.

A tumor microenvironment (TME)-responsive nanoprobe composed of a fluorescent dye-decorated silicon (Si) nanosphere core and a thin MnO 2 shell is proposed for simple and intelligent detection of cancer cells. The Si nanosphere core with diameters of 100-200 nm provides environment-independent Mie scattering imaging, while, simultaneously, the MnO 2 shell provides the capability to switch the on/off state of the dye fluorescence reacted to the glutathione (GSH) and/or H 2 O 2 levels in a cancer cell. Si-MnO 2 core-shell nanosphere probes are fabricated in a solution-based process from crystalline Si nanosphere cores. The fluorescence switching under exposure to GSH is demonstrated, and the mechanism is discussed based on detailed optical characterizations including single-particle spectroscopy. Different types of human cells are incubated with the nanoprobes, and a proof of concept experiment is performed. From the combination of the robust scattering images and GSH- and H 2 O 2 -sensitive fluorescence images, the feasibility of cancer cell detection by the multimodal nanoprobes is demonstrated.

Cathodoluminescence spectroscopy performed in an electron microscope has proven a versatile tool for analyzing the near- and far-field optical response of plasmonic and dielectric nanostructures. Nevertheless, the transition radiation produced by electron impact is often disregarded in the interpretation of the spectra recorded from resonant nanoparticles. Here we show, experimentally and theoretically, that transition radiation can by itself generate distinct resonances that, depending on the time-of-flight of the electron beam inside the particle, can result from constructive or destructive interference in time. Superimposed on the eigenmodes of the investigated structures, these resonances can distort the recorded spectrum and lead to potentially erroneous assignment of modal characters to the spectral features. We develop an intuitive analogy that helps distinguish between the two contributions. As an example, we focus on the case of silicon nanospheres and show that our analysis facilitates the unambiguous interpretation of experimental measurements on Mie-resonant nanoparticles.

Successful development of targeted therapeutics aimed at the elimination of diseased cells relies on the target properties and the therapeutics that target them. Currently, target properties have been evaluated through antibody-dependent semiquantitative approaches such as flow cytometry, Western blotting, or microscopy. Since antibodies can alter target properties following binding, antibody-dependent approaches provide at best skewed measurements for target intrinsic properties. To circumvent, here we attempted to develop an antibody-free targeted mass spectrometry-based (ATM) strategy to measure the surface densities and the intrinsic rates ( K int ) of CD38 internalization in multiple myeloma cell lines. Using cell-surface biotinylation in conjunction with differential mass tagging to separate inward CD38 molecules from the outbound and nascent ones, the ATM approach revealed diversities in measured CD38 K int values of 0.239 min -1 S.E. ± 0.076, 0.109 min -1 S.E. ± 0.032, and 0.058 min -1 S.E. ± 0.001 for LP1, NCIH929, and MOLP8 cell lines, respectively. Together with CD38 surface densities, intrinsic K int values aligned well with the tumor penetration model and supported the outcomes for tumor regression in mouse xenografts upon drug treatment. Additionally, the ATM approach can evaluate molecules with fast K int as we determined for CTLA4 protein. We believe that the ATM approach has the potential to evaluate diverse cell-surface targets as part of the pharmacological assessment in drug discovery.

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2- d ]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d , which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d , which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b ( TAK-931 ) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.