Metallic State of a Mixed-Sequence Oligomer Salt That Models Doped PEDOT Family.

Modern organic conductors are typically low-molecular-weight or polymer-based materials. Low-molecular-weight materials can be characterized using crystallographic information, allowing structure-conductivity relationships to be established and conduction mechanisms to be understood. However, controlling their conductive properties through molecular structural modulation is often challenging because of their relatively narrow conjugate areas. In contrast, polymer-based materials have highly π-conjugated structures with wide molecular-weight distributions, and their structural inhomogeneity makes characterizing their structures difficult. Thus, we focused on the less-explored intermediate, i.e., single-molecular-weight oligomers that model doped poly(3,4-ethylenedioxythiophene) (PEDOT). The dimer and trimer models provided clear structures; however, the short oligomers led to much lower conductivities (<10-3 S cm-1) than that of doped PEDOT. Herein, we elongated the oligomer to a tetramer through geometrical tuning based on a mixed sequence. The "P-S-S-P" sequence (S: 3,4-ethylenedithiothiophene; P: 3,4-(2',2'-dimethypropylenedioxy)thiophene) with twisted S-S enhanced the solubility and chemical stability. The subsequent oxidation process planarized the oligomer and expanded the conjugate area. Interestingly, the sequence involving sterically bulky outer P units allowed the doped oligomer to form a pitched π-stack in the single-crystal form. This enabled the inclusion of excess counter anions, which modulated the band filling. The combined effects of conjugate area expansion and band-filling modulation significantly increased the room-temperature conductivity to 36 S cm-1. This is the highest value reported for a single-crystalline oligomer conductor. Furthermore, a metallic state was observed above room temperature in a single-crystalline oligoEDOT for the first time. This unique mixed-sequence strategy for oligomer-based conductors enabled the precise control of conductive properties.

Spin-Polarized Radicals with Extremely Long Spin-Lattice Relaxation Time at Room Temperature in a Metal-Organic Framework.

The generation of spin polarization is key in quantum information science and dynamic nuclear polarization. Polarized electron spins with long spin-lattice relaxation times (T1) at room temperature are important for these applications but have been difficult to achieve. We report the realization of spin-polarized radicals with extremely long T1 at room temperature in a metal-organic framework (MOF) in which azaacene chromophores are densely integrated. Persistent radicals are generated in the MOF by charge separation after photoexcitation. Spin polarization of a triplet generated by photoexcitation is successfully transferred to the persistent radicals. Pulse electron spin resonance measurements reveal that the T1 of the polarized radical in the MOF is as long as 214 µs with a relatively long spin-spin relaxation time T2 of the radicals of up to 0.98 µs at room temperature. The achievement of extremely long spin polarization in MOFs with nanopores accessible to guest molecules will be an important cornerstone for future highly sensitive quantum sensing and efficient dynamic nuclear polarization.

Clarifying the Electronic Structure of Anion-Templated Silver Nanoclusters by Optical Absorption Spectroscopy and Theoretical Calculation.

Electronic structures of anion-templated silver nanoclusters (Ag NCs) are not well understood compared to conventional, template-free Ag NCs. In this study, we synthesized three new anion-templated Ag NCs, namely [S@Ag17(S-4CBM)15(PPh3)5]0, [S@Ag18(S-4CBM)16(PPh3)8]0, and [Cl@Ag18(S-4CBM)16(PPh3)8][PPh4], where S-4CBM = 4-chlorobenzene methanethiolate, and single-crystal X-ray crystallography revealed that they have S@Ag6, S@Ag10, and Cl@Ag10 cores, respectively. Investigation of their electronic structures by optical spectroscopy and theoretical calculations elucidated the following unique features: (1) their electronic structures are different from those of template-free Ag NCs described by the superatomic concept; (2) optical absorption in the range of 550-400 nm for S2--templated Ag NCs is attributed to the charge transitions from S2--templated Ag-cage orbitals to the s-shaped orbital in the S2- moiety; (3) the Cl--templated Ag NCs can be viewed as [Cl@Ag18(S-4CBM)16(PPh3)8]0[PPh4]0 rather than the ion pair [Cl@Ag18(S-4CBM)16(PPh3)8]-[PPh4]+; and (4) singlet-coupled singly occupied orbitals are involved in the optical absorption of the Cl--templated Ag NC.

Conformational ensemble of a multidomain protein explored by Gd3+ electron paramagnetic resonance.

Despite their importance in function, the conformational state of proteins and its changes are often poorly understood, mainly because of the lack of an efficient tool. MurD, a 47-kDa protein enzyme responsible for peptidoglycan biosynthesis, is one of those proteins whose conformational states and changes during their catalytic cycle are not well understood. Although it has been considered that MurD takes a single conformational state in solution as shown by a crystal structure, the solution nuclear magnetic resonance (NMR) study suggested the existence of multiple conformational state of apo MurD in solution. However, the conformational distribution has not been evaluated. In this work, we investigate the conformational states of MurD by the use of electron paramagnetic resonance (EPR), especially intergadolinium distance measurement using double electron-electron resonance (DEER) measurement. The gadolinium ions are fixed on specific positions on MurD via a rigid double-arm paramagnetic lanthanide tag that has been originally developed for paramagnetic NMR. The combined use of NMR and EPR enables accurate interpretation of the DEER distance information to the structural information of MurD. The DEER distance measurement for apo MurD shows a broad distance distribution, whereas the presence of the inhibitor narrows the distance distribution. The results suggest that MurD exists in a wide variety of conformational states in the absence of ligands, whereas binding of the inhibitor eliminates variation in conformational states. The multiple conformational states of MurD were previously implied by NMR experiments, but our DEER data provided structural characterization of the conformational variety of MurD.

Tetramethyltetrathiafulvalene [(NbOF4)-]∞: One-Dimensional Charge Transfer Salt with an Infinite Anion Chain.

An unusual valence one-dimensional (1D) molecular charge transfer salt (TMTTF)(NbOF4) [TMTTF = tetramethyltetrathiafulvalene] with infinite anion chains was prepared. To understand the crystal structure and electronic states of the (TMTTF)(NbOF4) salt, we performed synchrotron X-ray diffraction, electron spin resonance, and static magnetization measurements. There is only one independent TMTTF molecule in the unit cell of (TMTTF)(NbOF4). The TMTTF1+ cation radicals stack to form 1D columns. The effective charge of the TMTTF molecule in the crystal was estimated to be +1. The electric charge of TMTTF donors is compensated by the infinite anion chains [(NbOF4)-]∞. The magnetic susceptibility of (TMTTF)(NbOF4) is 4 × 10-4 emu/mol at room temperature and shows weak temperature dependence above 60 K. However, some deviation appears below 60 K. The temperature dependence of the spin susceptibility shows a noticeable enhancement below 60 K. Below 5 K, the magnetization curve as a function of the magnetic field deviates from the straight line and shows a saturation tendency. The experimental results can be reproduced well with the S = 2 spin system at 2 K. The detailed analysis of the crystal structure and anomalous low-temperature magnetic state magnetic properties of (TMTTF)(NbOF4) are discussed.

Controlled Dimerization and Bonding Scheme of Icosahedral M@Au12 (M=Pd, Pt) Superatoms.

Targeted syntheses of MM'Au36 (PET)24 (M, M'=Pd, Pt; PET=SC2 H4 Ph) were achieved by hydride-mediated fusion reactions between [MAu8 (PPh3 )8 ]2+ and [M'Au24 (PET)18 ]- . Single-crystal X-ray diffraction analysis indicated that the products have bi-icosahedral MM'Au21 cores composed of M@Au12 and M'@Au12 superatoms. Although the MM'Au21 superatomic molecules correspond to O2 in terms of the number of valence electrons (12 e), the distances between the icosahedrons were larger than that in the bi-icosahedral Au23 core of Au38 (PET)24 corresponding to F2 and the spin state was singlet. These counterintuitive results were explained by a "bent bonding model" based on tilted (non-orthogonal) bonding interaction between the 1P superatomic orbitals of M@Au12 and M'@Au12 superatoms.

Understanding Doping Effects on Electronic Structures of Gold Superatoms: A Case Study of Diphosphine-Protected M@Au12 (M = Au, Pt, Ir).

Dopants into ligand-protected Au superatoms have been hitherto limited to group X-XII elements (Pt, Pd, Ag, Cu, Hg, and Cd). To expand the scope of the dopants to the group IX elements, we synthesized unprecedented [IrAu12(dppe)5Cl2]+ [IrAu12; dppe = 1,2-bis(diphenylphosphino)ethane] and [PtAu12(dppe)5Cl2]2+ (PtAu12) and compared their electronic structures with that of [Au13(dppe)5Cl2]3+ (Au13). Single-crystal X-ray diffractometry, 31P{1H} NMR, and Ir L3-edge extended X-ray absorption fine structure analysis of IrAu12 revealed that the single Ir atom is located at the center of the icosahedral IrAu12 core. Electrochemical analysis demonstrated that the energy levels of the highest occupied molecular orbitals are upshifted in the order of Au13 < PtAu12 < IrAu12. This trend was qualitatively explained in such a manner that the jellium core potential at the central position becomes shallower by replacing Au+ with Pt0 and further with Ir-. IrAu12 underwent reversible redox reactions between the charge states of 1+ and 2+. The gradual increase of the energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital in the order of Au13 < PtAu12 < IrAu12 was observed by electrochemical measurement and optical spectroscopy. This study provides a simple guiding principle to tune the electronic structures of heterometal-doped superatoms.

Aryl hydrocarbon receptor control of a disease tolerance defence pathway.

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.

Stoichiometric Formation of Open-Shell [PtAu24(SC2H4Ph)18]- via Spontaneous Electron Proportionation between [PtAu24(SC2H4Ph)18]2- and [PtAu24(SC2H4Ph)18]0.

[PtAu24(SC2H4Ph)18]0 ([PtAu24]0) was fully and selectively converted to [PtAu24]-, having an open electronic structure with seven valence electrons, upon the addition of an equiamount of NaBH4. Stoichiometric production of [PtAu24]- by the reaction between an equal amount of [PtAu24]0 and [PtAu24]2- revealed that the above reaction proceeds via the spontaneous electron transfer (ET) from [PtAu24]2- nascently reduced by H--mediated reduction to [PtAu24]0 remaining in the solution. Theoretical calculation suggested that the driving force of this novel ET reaction was the larger adiabatic electron affinity of [PtAu24]0 compared to that of [PtAu24]-, partly associated with reduction-induced relief of the Jahn-Teller strain. We propose that ET proceeds via the dimer complex of [PtAu24]2- and [PtAu24]0 formed through the aurophilic interaction between Au(I) sites in the surface layer.

A Peptoid with Extended Shape in Water.

The term "peptoids" was introduced decades ago to describe peptide analogues that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo(N-substituted glycine) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible, and ensuring a defined shape in water is difficult. This conformational flexibility severely limits the biological application of oligo-NSG. Here, we propose oligo(N-substituted alanine) (oligo-NSA) as a peptoid that forms a defined shape in water. The synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies, and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. This new class of peptoid achieves the constrained conformation without any assistance of N-substituents and serves as a scaffold for displaying functional groups in well-defined three-dimensional space in water, which leads to effective biomolecular recognition.

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice.

BACKGROUND: In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. METHODS: Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS: Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.

Successive Dimensional Transition in (TMTTF)_{2}PF_{6} Revealed by Synchrotron X-ray Diffraction.

A quasi-one-dimensional organic charge-transfer salt (TMTTF)_{2}PF_{6} undergoes a multistep phase transition as the temperature decreases. One of these transitions is called a "structureless transition," and these detailed structures were unknown for many years. With synchrotron x-ray diffraction, we observed a slight structural difference owing to the effect of charge-order transition between two TMTTF molecules in a dimer, which corresponds to the charge transfer δ_{CO}=0.20e. The two-dimensional Wigner crystallization was determined from an electron density analysis using core differential Fourier synthesis. Furthermore, we found that the ground state due to tetramerization, called the spin Peierls phase, is a three-dimensional transition with interchain correlation.

Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells.

Autoimmune neuroinflammation, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity, is believed to result from immune tolerance dysfunction leading to demyelination and substantial neurodegeneration. We previously showed that CNS-restricted expression of hepatocyte growth factor (HGF), a potent neuroprotective factor, reduced CNS inflammation and clinical deficits associated with EAE. In this study, we demonstrate that systemic HGF treatment ameliorates EAE through the development of tolerogenic dendritic cells (DCs) with high expression levels of glucocorticoid-induced leucine zipper (GILZ), a transcriptional repressor of gene expression and a key endogenous regulator of the inflammatory response. RNA interference-directed neutralization of GILZ expression by DCs suppressed the induction of tolerance caused by HGF. Finally, adoptive transfer of HGF-treated DCs from wild-type but not GILZ gene-deficient mice potently mediated functional recovery in recipient mice with established EAE through effective modulation of autoaggressive T cell responses. Altogether, these results show that by inducing GILZ in DCs, HGF reproduces the mechanism of immune regulation induced by potent immunomodulatory factors such as IL-10, TGF-ß1, and glucocorticoids and therefore that HGF therapy may have potential in the treatment of autoimmune dysfunctions.

Negative Impact of Hypoxia on Tryptophan 2,3-Dioxygenase Function.

Tryptophan is an essential amino acid for hosts and pathogens. The liver enzyme tryptophan 2,3-dioxygenase (TDO) provokes, by its ability to degrade tryptophan to N-formylkynurenine, the precursor of the immune-relevant kynurenines, direct and indirect antimicrobial and immunoregulatory states. Up to now these TDO-mediated broad-spectrum effector functions have never been observed under hypoxia in vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO and ex vivo murine TDO functions under different oxygen conditions and show that TDO-induced restrictions of clinically relevant pathogens (bacteria, parasites) and of T cell proliferation are abrogated under hypoxic conditions. We pinpointed the loss of TDO efficiency to the reduction of TDO activity, since cell survival and TDO protein levels were unaffected. In conclusion, the potent antimicrobial as well as immunoregulatory effects of TDO were substantially impaired under hypoxic conditions that pathophysiologically occur in vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens.

Bronchioalveolar morphogenesis of human bronchial epithelial cells depending upon hepatocyte growth factor.

Lung alveolar regeneration occurs in adult human lungs as a result of proliferation, differentiation and alveolar morphogenesis of stem cells. It is increasingly being believed that bronchial epithelial cells (BECs) have a potential as stem cells, because they are potent to differentiate into multiple central and peripheral lung cell types in three-dimensional (3D) cultures, and they develop multiple foci with well-differentiated histogenesis after transformed into neoplastic cells. In this study, we investigated morphogenic abilities of HBE135 human BECs immortalized by E6/E7 oncogene in 3D cultures. When HBE135 cells were cultured alone or co-cultured with endothelial cells, the cells formed spherical colonies without branching. However, in co-culture with lung fibroblast MRC-9 cells, HBE135 cells formed colonies with bronchioalveolar-like complex branching, suggesting that MRC-9-derived soluble factor(s) are responsible for the branching formation. MRC-9 cells, not endothelial cells, were found to highly express hepatocyte growth factor (HGF), a soluble molecule involved in liver and kidney regeneration. An anti-HGF neutralizing antibody severely suppressed the complex branching formation, but addition of HGF could not sufficiently compensate the morphogenic effects of MRC-9 cells, suggesting that MCR-9-derived HGF was necessary but insufficient for the bronchioalveolar structure formation. Immunohistochemistry revealed that Met, a cognate receptor for HGF, was highly expressed and phosphorylated in neoplastic BECs from lung adenocarcinomas with well-differentiated, not poorly differentiated, histogenesis. These results are consistent with the notion that BECs have an aspect of stem cells. This aspect appears to become manifest through HGF-Met signalling pathway activation.

Creation of Superheterojunction Polymers via Direct Polycondensation: Segregated and Bicontinuous Donor-Acceptor π-Columnar Arrays in Covalent Organic Frameworks for Long-Lived Charge Separation.

By developing metallophthalocyanines and diimides as electron-donating and -accepting building blocks, herein, we report the construction of new electron donor-acceptor covalent organic frameworks (COFs) with periodically ordered electron donor and acceptor π-columnar arrays via direct polycondensation reactions. X-ray diffraction measurements in conjunction with structural simulations resolved that the resulting frameworks consist of metallophthalocyanine and diimide columns, which are ordered in a segregated yet bicontinuous manner to form built-in periodic π-arrays. In the frameworks, each metallophthalocyanine donor and diimide acceptor units are exactly linked and interfaced, leading to the generation of superheterojunctions-a new type of heterojunction machinery, for photoinduced electron transfer and charge separation. We show that this polycondensation method is widely applicable to various metallophthalocyanines and diimides as demonstrated by the combination of copper, nickel, and zinc phthalocyanine donors with pyrommellitic diimide, naphthalene diimide, and perylene diimide acceptors. By using time-resolved transient absorption spectroscopy and electron spin resonance, we demonstrated that the COFs enable long-lived charge separation, whereas the metal species, the class of acceptors, and the local geometry between donor and acceptor units play roles in determining the photochemical dynamics. The results provide insights into photoelectric COFs and demonstrate their enormous potential for charge separation and photoenergy conversions.

Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA.

Photoelectric covalent organic frameworks: converting open lattices into ordered donor-acceptor heterojunctions.

Ordered one-dimensional open channels represent the typical porous structure of two-dimensional covalent organic frameworks (COFs). Here we report a general synthetic strategy for converting these open lattice structures into ordered donor-acceptor heterojunctions. A three-component topological design scheme was explored to prepare electron-donating intermediate COFs, which upon click reaction were transformed to photoelectric COFs with segregated donor-acceptor alignments, whereas electron-accepting buckyballs were spatially confined within the nanochannels via covalent anchoring on the channel walls. The donor-acceptor heterojunctions trigger photoinduced electron transfer and allow charge separation with radical species delocalized in the π-arrays, whereas the charge separation efficiency was dependent on the buckyball content. This new donor-acceptor strategy explores both skeletons and pores of COFs for charge separation and photoenergy conversion.

Contributions of tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase to the conversion of D-tryptophan to nicotinamide analyzed by using tryptophan 2,3-dioxygenase-knockout mice.

We investigated the contribution percentage of tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) to the conversion of D-tryptophan to nicotinamide in TDO-knockout mice. The calculated percentage conversions indicated that TDO and IDO oxidized 70 and 30%, respectively, of the dietary L-tryptophan. These results indicate that both TDO and IDO biosynthesize nicotinamide from D-tryptophan and L-tryptophan in mice.

Three distinct redox states of an oxo-bridged dinuclear ruthenium complex.

A series of [{(terpy)(bpy)Ru}(µ-O){Ru(bpy)(terpy)}](n+) ([RuORu](n+), terpy=2,2';6',2''-terpyridine, bpy=2,2'-bipyridine) was systematically synthesized and characterized in three distinct redox states (n=3, 4, and 5 for Ru(II,III)2, Ru(III,III)2, and Ru(III,IV)2, respectively). The crystal structures of [RuORu](n+) (n=3, 4, 5) in all three redox states were successfully determined. X-ray crystallography showed that the Ru-O distances and the Ru-O-Ru angles are mainly regulated by the oxidation states of the ruthenium centers. X-ray crystallography and ESR spectra clearly revealed the detailed electronic structures of two mixed-valence complexes, [Ru(III)ORu(IV)](5+) and [Ru(II)ORu(III)](3+), in which each unpaired electron is completely delocalized across the oxo-bridged dinuclear core. These findings allow us to understand the systematic changes in structure and electronic state that accompany the changes in the redox state.