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Supplementary Figure 3 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Supplementary Figure 2 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Supplementary Figure 4 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Supplementary Figure Legends 1-5 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Supplementary Figure 5 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

Supplementary Figure 1 from Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor–Activating Mutations

The generation of spin polarization is key in quantum information science and dynamical 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 triplet generated by photoexcitation are successfully transferred to the persistent radicals. Pulse ESR measurements reveal that the T1 of the polarized radical in the MOF is as long as 274 s 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.

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.

Quantum sensing using molecular qubits is expected to provide excellent sensitivity due to the proximity of the sensor to the target analyte. However, many molecular qubits are used at cryogenic temperatures, and how to make molecular qubits respond to specific analytes remains unclear. Here, we propose a new quantum sensor design in which the coherence time changes in response to a variety of analytes at room temperature. We used the photoexcited triplet, which can be initialized at room temperature, as qubits and introduce them to a metal–organic framework that can flexibly change its pore structure in response to guest adsorption. By changing the local molecular density around the triplet qubits by adsorption of a specific analyte, the mobility of the triplet qubit can be changed, and the coherence time can be made responsive.

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.

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 synthesi...

Structural parameters in quasi-one-dimensional organic conductors ${(\mathrm{TMTTF})}_{2}X$ ($X=\mathrm{Nb}{\mathrm{F}}_{6}, \mathrm{As}{\mathrm{F}}_{6}, \mathrm{P}{\mathrm{F}}_{6}$, and Br) are investigated by synchrotron x-ray diffraction. The temperature dependences of the crystal structures differ significantly between octahedral and monatomic anion systems, corresponding to the presence or absence of a charge-ordering transition. Changes in temperature and chemical pressure control the dimensionality of the lattice and the degree of dimerization. Furthermore, the antiferromagnetic and spin-Peierls ground states in this system depend on the spin frustration due to transfer integral paths between the one-dimensional chain molecules.

[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. Sto...

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.

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.

This work introduces a direct determination method of an orbital state in materials, using synchrotron X-ray diffraction and an electron density analysis.

The utilization of near-infrared light is an important objective for the high-efficiency utilization of solar energy. Here, we describe a new class of a near-infrared light-induced electron transfer system using a distorted phthalocyanine as a photosensitizer. We revealed that the appropriate modification of distorted phthalocyanine affords a near-infrared absorbing dye with high photostability and long excitation lifetime, and a near-infrared light-induced electron transfer system was successfully established using the dye. The mechanistic investigation clarified that the electron transfer system works via a dynamic quenching mechanism. The system generated a long-lived anion radical species of the dye upon near-infrared light irradiation (>750 nm).

[PtAu

$1T\ensuremath{-}\mathrm{TiS}{\mathrm{e}}_{2}$ has a semimetallic band structure at room temperature and undergoes phase transition to a triple-$q$ charge-density wave (CDW) state with a commensurate superlattice structure $(2a\ifmmode\times\else\texttimes\fi{}2a\ifmmode\times\else\texttimes\fi{}2c)$ below ${T}_{c}\ensuremath{\approx}200\phantom{\rule{0.16em}{0ex}}\mathrm{K}$ at ambient pressure. This phase transition is caused by cooperative phenomena involving electron-phonon and electron-hole (excitonic) interactions, and cannot be described by a standard CDW framework. By Cu intercalation or the application of pressure, this phase-transition temperature is suppressed and superconductivity (SC) appears. However, it is not clear what kind of order parameters are affected by these two procedures. We investigated the crystal structure of $\mathrm{C}{\mathrm{u}}_{x}\mathrm{TiS}{\mathrm{e}}_{2}$ and pressurized $1T\ensuremath{-}\mathrm{TiS}{\mathrm{e}}_{2}$ around the SC state by synchrotron x-ray diffraction on single crystals. In the high-temperature phase, the variations of structural parameters for the case of Cu intercalation and application of pressure are considerably different. Moreover, the relationship between the critical points of the CDW phase transition and the SC dome are also different for the two cases. The excitonic interaction appears to play an important role in the $P\ensuremath{-}T$ phase diagram of $1T\ensuremath{-}\mathrm{TiS}{\mathrm{e}}_{2}$, but not in the $x\ensuremath{-}T$ phase diagram.

The phase transition phenomenon in a semimetallic $1T\ensuremath{-}\mathrm{TiS}{\mathrm{e}}_{2}$ has attracted attention as an excitonic insulator. However, as the phase transition accompanying superlattice peaks has the $q$ vector connecting the Fermi surfaces of the three-dimensional shape of hole and electron pockets, it also assumes the charge density wave (CDW) state owing to the electron--phonon interaction. To understand the electronic state at the low temperature, control of the chemical potential was attempted by electronic doping through $\mathrm{C}{\mathrm{u}}^{+}$ intercalation. Physical properties measurements and synchrotron x-ray diffraction experiments in $\mathrm{C}{\mathrm{u}}_{x}\mathrm{TiS}{\mathrm{e}}_{2}$ ($x=0--0.35$) were performed. The phase transition was determined to occur as a cooperative phenomenon between the honeycomb lattice type CDW corresponding to the nesting vector and the ordered state of the $\mathrm{C}{\mathrm{u}}^{+}$ ions between $\mathrm{TiS}{\mathrm{e}}_{2}$ layers at a specific doping amount ($x=1/3$). The behavior of $\mathrm{C}{\mathrm{u}}^{+}$ ions in highly doped regions suggests the occurrence of a two-dimensional liquid-solid state transition based on the temperature dependence of the x-ray diffuse scattering.

New, spin-labeled nucleosides, and an efficient synthetic route for a modified uridine amidite, were developed. The spin-labeled part was the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) group, which was linked via an alkynyl chain at the 5 position of uridine. Three typical protecting groups, the t-butyldimethylsilyl (TBDMS) group at 2′, the dimethoxytrityl (DMTr) group at 5′, and the phosphoramidite group at 3′, were introduced to produce an automated nucleic acid synthesizer. The TEMPO group at the 5 position in the uridine structure affected introduction of bulky protecting groups, such as the DMTr group at the 5′ position and the TBDMS group at the 2′ position. The electron paramagnetic resonance (EPR) data revealed a nitroxyl radical in the structure of synthetic nucleoside compounds; however, RNA produced by automated synthesis using a TEMPO-linked uridine phosphoramidite building block was EPR silent.

The physical properties of molecular crystals are governed by the frontier orbitals of molecules. A molecular orbital, which is formed by superposing the atomic orbitals of constituent elements, has complicated degrees of freedom in the crystal because of the influence of electron correlation and crystal field. Therefore, in general, it is difficult to experimentally observe the whole picture of a frontier orbital. Here, we introduce a new method called &ldquo, core differential Fourier synthesis&rdquo, (CDFS) using synchrotron X-ray diffraction to observe the valence electron density in materials. By observing the valence electrons occupied in molecular orbitals, the orbital state can be directly determined in a real space. In this study, we applied the CDFS method to molecular materials such as diamond, C60 fullerene, (MV)I2, and (TMTTF)2X. Our results not only demonstrate the typical orbital states in some materials, but also provide a new method for studying intramolecular degrees of freedom.

A series of three-coordinate monovalent nickel halide complexes bearing N-heterocyclic carbene (NHC) ligands, i.e., NiCl(IPr)(L) [L = pyridine, P(OPh)3, bis(diphenylphosphino)butane (dppb), IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], NiX(IMes)(PPh3) (X = Cl and Br, IMes = 1,3-bis(mesityl)imidazol-2-ylidene), were prepared. The complexes were identified using NMR spectroscopy, superconducting quantum interference device (SQUID), and X-ray crystallography. Additionally, ESR spectra of NiCl(IPr)(pyridine) were taken in toluene. These complexes had three-coordinate Y-shaped geometries in both the solid and solution states. The compounds containing IPr showed equilibrium between the monomeric and dimeric forms, with liberation of ligands. Addition of 1,2-bis(diphenylphosphino)ethane and 1,3-bis(diphenylphosphino)propane to the dinickel(I) IPr complex instead of dppb resulted in heterolytic cleavage to nickel(0) and nickel(II) species. Catalysis of Suzuki cross-coupling and Buchwald–Hartwig aminati...

Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme involved in tumor malignancy. However, the regulatory mechanism underlying its involvement remains largely uncharacterized. The present study aimed to investigate the hypothesis that NK4, an antagonist of hepatocyte growth factor (HGF), can regulate IDO and to characterize the signaling mechanism involved. Following successful transfection of the human ovarian cancer cell line SKOV-3 (which constitutively expresses IDO) with an NK4 expression vector, we observed that NK4 expression suppressed IDO expression; furthermore, NK4 expression did not suppress cancer cell growth in vitro [in the absence of natural killer (NK) cells], but did influence tumor growth in vivo. In addition, NK4 enhanced the sensitivity of cancer cells to NK cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. In an effort to clarify the mechanisms by which NK4 interacts with IDO, we performed investigations utilizing various biochemical inhibitors. The results of these investigations were as follows. First, c-Met (a receptor of HGF) tyrosine kinase inhibitor PHA-665752, and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both suppress IDO expression. Second, enhanced expression of PTEN (a known tumor suppressor) via negative regulation within a PI3K-AKT pathway, inhibits IDO expression. Conversely, neither the MEK1/2 inhibitor U0126 nor the STAT3 inhibitor WP1066 affects IDO expression. These results suggest that NK4 inhibits IDO expression via a c-Met-PI3K-AKT signaling pathway.

Sugarcane vinegar is produced in various countries of southern Asia. It is also a niche product of the Kagoshima and Okinawa Prefectures in Japan. Turbid compounds are sometimes found in sugarcane vinegar, thereby lowering the market value. In this study, the turbid compounds were precipitated with a 1:2 (v/v) volume of ethanol, and they were identified as α-1,6-glucan using enzymatic digestion tests and 13C nuclear magnetic resonance analysis. Moreover, Lactobacillus nagelii was isolated from sugarcane juice, and it produced α-1,6-glucan when grown with sugar. The turbid compounds found in sugarcane vinegar were assumed to be α-1,6-glucan produced from sugar by lactic acid bacteria that exist in sugarcane juice.

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 hypoxiain vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO andex vivomurine 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 occurin vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens.

Nowadays, for the estimation of traffic demand or people flow, modelling route choice activity in road networks is an important task and many algorithms have been developed to generate route choice sets. However, developing an algorithm based on a small amount of data that can be applied generally within a metropolitan area is difficult. This is because the characteristics of road networks vary widely. On the other hand, recently, the collection of people movement data has lately become much easier, especially through mobile phones. Lately, most mobile phones include GPS functionality. Given this background, we propose a data-oriented algorithm to generate route choice sets using mobile phone GPS data. GPS data contain a number of measurement errors; hence, they must be adjusted to account for these errors before use in advanced people movement analysis. However, this is time-consuming and expensive, because an enormous amount of daily data can be obtained. Hence, the objective of this study is to develop an algorithm that can easily manage GPS data. Specifically, at first movement data from all GPS data are selected by calculating the speed. Next, the nearest roads in the road network are selected from the GPS location and count such data for each road. Then An algorithm based on the GSP (Gateway Shortest Path) algorithm is proposed, which searches the shortest path through a given gateway. In the proposed algorithm, the road for which the utilization volume calculated by GPS data is large is selected as the gateway. Thus, route choice sets that are based on trends in real GPS data are generated. To evaluate the proposed method, GPS data from 0.7 million people a year in Japan and DRM (Digital Road Map) as the road network are used. DRM is one of the most detailed road networks in Japan. Route choice sets using the proposed algorithm are generated and the cover rate of the utilization volume of each road under evaluation is calculated. As a result, the proposed route generation algorithm and GPS data cleaning process work well and a huge variety of routes that have high potential to be used in the real world can be generated.

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.