Spontaneous-Spin-Polarized 2D π-d Conjugated Frameworks Towards Enhanced Oxygen Evolution Kinetics.

Alternative strategies to design sustainable-element-based electrocatalysts enhancing oxygen evolution reaction (OER) kinetics are demanded to develop affordable yet high-performance water-electrolyzers for green hydrogen production. Here, it is demonstrated that the spontaneous-spin-polarized 2D π-d conjugated framework comprising abundant elements of nickel and iron with a ratio of Ni:Fe = 1:4 with benzenehexathiol linker (BHT) can improve OER kinetics by its unique electronic property. Among the bimetallic NiFex:y-BHTs with various ratios with Ni:Fe = x:y, the NiFe1:4-BHT exhibits the highest OER activity. The NiFe1:4-BHT shows a specific current density of 140 A g-1 at the overpotential of 350 mV. This performance is one of the best activities among state-of-the-art non-precious OER electrocatalysts and even comparable to that of the platinum-group-metals of RuO2 and IrO2. The density functional theory calculations uncover that introducing Ni into the homometallic Fe-BHT (e.g., Ni:Fe = 0:1) can emerge a spontaneous-spin-polarized state. Thus, this material can achieve improved OER kinetics with spin-polarization which previously required external magnetic fields. This work shows that a rational design of 2D π-d conjugated frameworks can be a powerful strategy to synthesize promising electrocatalysts with abundant elements for a wide spectrum of next-generation energy devices.

On-the-fly kinetic Monte Carlo simulations with neural network potentials for surface diffusion and reaction.

We develop an adaptive scheme in the kinetic Monte Carlo simulations, where the adsorption and activation energies of all elementary steps, including the effects of other adsorbates, are evaluated "on-the-fly" by employing the neural network potentials. The configurations and energies evaluated during the simulations are stored for reuse when the same configurations are sampled in a later step. The present scheme is applied to hydrogen adsorption and diffusion on the Pd(111) and Pt(111) surfaces and the CO oxidation reaction on the Pt(111) surface. The effects of interactions between adsorbates, i.e., adsorbate-adsorbate lateral interactions, are examined in detail by comparing the simulations without considering lateral interactions. This study demonstrates the importance of lateral interactions in surface diffusion and reactions and the potential of our scheme for applications in a wide variety of heterogeneous catalytic reactions.

AJICAP Second Generation: Improved Chemical Site-Specific Conjugation Technology for Antibody-Drug Conjugate Production.

The site-directed chemical conjugation of antibodies remains an area of great interest and active efforts within the antibody-drug conjugate (ADC) community. We previously reported a unique site modification using a class of immunoglobulin-G (IgG) Fc-affinity reagents to establish a versatile, streamlined, and site-selective conjugation of native antibodies to enhance the therapeutic index of the resultant ADCs. This methodology, termed "AJICAP", successfully modified Lys248 of native antibodies to produce site-specific ADC with a wider therapeutic index than the Food and Drug Administration-approved ADC, Kadcyla. However, the long reaction sequences, including the reduction-oxidation (redox) treatment, increased the aggregation level. In this manuscript, we aimed to present an updated Fc-affinity-mediated site-specific conjugation technology named "AJICAP second generation" without redox treatment utilizing a "one-pot" antibody modification reaction. The stability of Fc affinity reagents was improved owing to structural optimization, enabling the production of various ADCs without aggregation. In addition to Lys248 conjugation, Lys288 conjugated ADCs with homogeneous drug-to-antibody ratio of 2 were produced using different Fc affinity peptide reagent possessing a proper spacer linkage. These two conjugation technologies were used to produce over 20 ADCs from several combinations of antibodies and drug linkers. The in vivo profile of Lys248 and Lys288 conjugated ADCs was also compared. Furthermore, nontraditional ADC production, such as antibody-protein conjugates and antibody-oligonucleotide conjugates, were achieved. These results strongly indicate that this Fc affinity conjugation approach is a promising strategy for manufacturing site-specific antibody conjugates without antibody engineering.

Detection of impurities in dietary supplements containing L-tryptophan.

Impurities in nine dietary supplements containing L-tryptophan were evaluated using an HPLC methodology. In five tested products, the total impurities were higher than the thresholds described in the Food Chemical Codex or implemented in the EU for pharmaceutical grade L-tryptophan. In addition, liquid chromatography-mass spectrometry was used to specifically test for the presence of 1,1'-ethylidenebis-L-tryptophan (EBT). None of the tested products contained detectable amounts of EBT. High amounts of unidentified impurities in some dietary supplements point to potential health risks.

Collective bath coordinate mapping of "hierarchy" in hierarchical equations of motion.

The theory of hierarchical equations of motion (HEOM) is one of the standard methods to give exact evaluations of the dynamics as coupled to harmonic oscillator environments. However, the theory is numerically demanding due to its hierarchy, which is the set of auxiliary elements introduced to capture the non-Markovian and non-perturbative effects of environments. When system-bath coupling becomes relatively strong, the required computational resources and precision move beyond the regime that can be currently handled. This article presents a new representation of HEOM theory in which the hierarchy is mapped into a continuous space of a collective bath coordinate and several auxiliary coordinates as the form of the quantum Fokker-Planck equation. This representation gives a rigorous time evolution of the bath coordinate distribution and is more stable and efficient than the original HEOM theory, particularly when there is a strong system-bath coupling. We demonstrate the suitability of this approach to treat vibronic system models coupled to environments.

Chemical Site-Specific Conjugation Platform to Improve the Pharmacokinetics and Therapeutic Index of Antibody-Drug Conjugates.

To overcome a lack of selectivity during the chemical modification of native non-engineered antibodies, we have developed a technology platform termed "AJICAP" for the site-specific chemical conjugation of antibodies through the use of a class of IgG Fc-affinity reagents. To date, a limited number of antibody-drug conjugates (ADCs) have been synthesized via this approach, and no toxicological study was reported. Herein, we describe the compatibility and robustness of AJICAP technology, which enabled the synthesis of a wide variety of ADCs. A stability assessment of a thiol-modified antibody synthesized by AJICAP technology indicated no appreciable increase in aggregation or decomposition upon prolonged storage, indicating that the unexpectedly stable thiol intermediate has a great potential intermediate for payload or linker screening or large-scale manufacturing. Payload conjugation with this stable thiol intermediate generated several AJICAP-ADCs. In vivo xenograft studies indicated that the AJICAP-ADCs displayed significant tumor inhibition comparable to benchmark ADC Kadcyla. Furthermore, a rat pharmacokinetic analysis and toxicology study indicated an increase in the maximum tolerated dose, demonstrating an expansion of the AJICAP-ADC therapeutic index, compared with stochastic conjugation technology. This is the first report of the therapeutic index estimation of site-specific ADCs produced by utilizing Fc affinity reagent conjugation. The described site-specific conjugation technology is a powerful platform to enable next-generation ADCs through reduced heterogeneity and enhanced therapeutic index.

Extending nudged elastic band method to reaction pathways involving multiple spin states.

There are diverse reactions including spin-state crossing, especially the reactions catalyzed by transition metal compounds. To figure out the mechanisms of such reactions, the discussion of minimum energy intersystem crossing (MEISC) points cannot be avoided. These points may be the bottleneck of the reaction or inversely accelerate the reactions by providing a better pathway. It is of great importance to reveal their role in the reactions by computationally locating the position of the MEISC points together with the reaction pathway. However, providing a proper initial guess for the structure of the MEISC point is not as easy as that of the transition state. In this work, we extended the nudged elastic band (NEB) method for multiple spin systems, which is named the multiple spin-state NEB method, and it is successfully applied to find the MEISC points while optimizing the reaction pathway. For more precisely locating the MEISC point, a revised approach was adopted. Meanwhile, our examples also suggest that special attention should be paid to the criterion to define an image optimized as the MEISC point.

Constraint structure optimization to a specific minimum using ionization energy.

A structure optimization method with ionization energy constraint is developed to explore structures with specific ionization energy. The Levine-Coe-Martínez penalty function (J Phys Chem B 2008, 112, 405) was adopted, and the penalty function includes a predefined core-ionization energy and inner-shell ionization energy. For an SN 2 reaction, isomerization of a platinum complex, a proton transfer reaction, and carbon monoxide adsorption on a palladium cluster, the present method was tested, and the targeted energy minima were obtained as designated by the input ionization energy. The shape of the objective function, the parameters in the penalty function, and structural changes during the optimization process were discussed. An automated parameter setting and possible problems are discussed for future direction. © 2018 Wiley Periodicals, Inc.

Facile and Efficient Chemoenzymatic Semisynthesis of Fc-Fusion Compounds for Half-Life Extension of Pharmaceutical Components.

The formation of Fc-fusions, in which biologically active molecules and the Fc fragment of antibodies are linked to each other, is one of the most efficient and successful half-life extension technologies to be developed and applied to peptide and protein pharmaceuticals thus far. Fc-fusion compounds are generally produced by recombinant methods. However, these cannot be applied to artificial middle molecules, such as peptides with non-natural amino acids, unnatural cyclic peptides, or pharmaceutical oligonucleotides. Here, we developed a simple, efficient, semisynthetic method for Fc-fusion production involving our previously developed enzymatic N-terminal extension reaction (i.e., NEXT-A reaction) and strain-promoted azide-alkyne cycloaddition, achieving quantitative conversion and high selectivity for the N-terminus of the Fc protein. An Fc-fusion compound prepared by this method showed comparable biological activity to that of the original peptide and a long-circulating plasma half-life. Thus, the proposed method is potentially applicable for the conjugation of a wide range of pharmaceutical components.

Distinct ionic adsorption sites in defective Prussian blue: a 3D-RISM study.

Ferric hexacyanoferrate (FeHCF) or Prussian blue (PB) exhibits selective alkali ion adsorption and has great potential for use in various applications. In the present work, alkali ion (Li+, Na+, K+, and Cs+) and water configurations in defective PB (d-PB) were studied by using the statistical mechanics of molecular liquids. The three-dimensional (3D) distribution functions of the ions and water were determined by solving the 3D-reference interaction site model (RISM) equation of systems of a unit lattice of d-PB in electrolyte solutions, i.e., LiCl, NaCl, KCl, and CsCl. The results show the difference in the ion-water configurations and distributions between small (Li+ and Na+) and large ions (K+ and Cs+). The adsorption sites of Li+ and Na+ are located off-center and lie on the diagonal axis. By contrast, the larger ions, K+ and Cs+, are adsorbed at the center of the unit cell. The degree of dehydration due to the adsorption of alkali ions indicates that there was no water exchange during Li+ and Na+ adsorption, whereas two and three water molecules were removed after adsorption of K+ or Cs+ in the unit cell.

Experimental and theoretical study of multinuclear indium-oxo clusters in CHA zeolite for CH4 activation at room temperature.

We have carried out an experimental and theoretical study of CHA-zeolite supported indium (In)-oxo clusters that promote CH4 activation at room temperature. X-ray absorption fine structure (XAFS) measurements indicate the formation of multinuclear In-oxo clusters by the O2 activation of the In(i)-exchanged CHA zeolite prepared through reductive solid-state ion exchange (RSSIE). The structure of the In-oxo clusters and their locations were investigated in detail using ab initio thermodynamic analysis. The redox properties of the In species during RSSIE and the formation of the In-oxo clusters were also studied by temperature programmed reaction and in situ XAFS measurements. The reaction of CH4 on the O2-activated In-CHA zeolite was monitored using IR spectroscopy where adsorbed formic acid was generated at room temperature. The adsorption and C-H activation of CH4 on our plausible model of the In-oxo clusters were theoretically investigated using density functional theory calculations. We found that CH4 is likely to adsorb and react more easily on dinuclear In-oxo ions than on monomeric In-oxo ions and that the C-H bond cleavage reaction occurs via a heterolytic pathway rather than a homolytic pathway. This study reveals the potential of multinuclear In-oxo clusters as active sites for the transformation of CH4 to oxygenates under mild reaction conditions.

Theoretical Study on the C-H Activation of Methane by Liquid Metal Indium: Catalytic Activity of Small Indium Clusters.

The mechanism of C-H activation of methane by liquid indium, which is the first step of the dehydrogenative conversion of methane to higher hydrocarbons, was investigated using density functional theory calculations. In the first-principle molecular dynamics trajectory at the experimental temperature (1200 K), low-coordinated indium atoms continuously appear on the disordered liquid surface. The C-H cleavage is endothermic on clean surfaces, while the low-coordinated indium atoms reduce the endothermicity significantly. In small indium clusters, which are models of low-coordinated atoms on a surface, the calculated activation energy is much smaller than that on the clean surface. The energy level of the methane C-H σ* orbital is reduced by the interaction with the indium 5pσ orbitals. In2 shows the lowest activation energy and exothermicity in the C-H bond cleavage.

The neonicotinoids acetamiprid and imidacloprid impair neurogenesis and alter the microglial profile in the hippocampal dentate gyrus of mouse neonates.

Acetamiprid (ACE) and imidacloprid (IMI) are widely used neonicotinoid pesticides. They bind selectively to insect nicotinic acetylcholine receptors (nAChRs) and are considered non-hazardous to mammals. Few studies have assessed the activation of vertebrate nAChRs and the neurodevelopmental toxicity following in utero or neonatal exposure to neonicotinoids; therefore, we evaluated the effects of ACE or IMI exposure on neurogenesis and microglial profiles in the developing hippocampal dentate gyrus (DG) of mouse neonates. Mice were exposed to ACE, IMI (both 5 mg/kg/day) or nicotine (0.5 mg/kg/day) from postnatal day (P)12 to P26 by oral gavage. On P27, brains were removed, and neurogenesis and microglial activation in the hippocampal DG were examined via immunohistochemistry. A reduction in neurogenesis in the hippocampal DG of neonates following ACE, IMI and nicotine treatment was found. Additionally, neonicotinoid-exposed newborns showed an increase in the number of amoeboid-type and activated M1-type microglia. These results suggest that exposure to ACE and IMI impairs neurogenesis and alters microglial profiles in the developing hippocampal DG following oral dosing in an early postnatal period. A better understanding of the potential effects of these pesticides on human infant health is an important goal of our research.

[Three Cases of Resectable Advanced Gastric Cancer Treated with Neoadjuvant Chemotherapy].

Three patients diagnosed with HER2-negative resectable advanced gastric cancer with extensive regional lymph node metastases were treated with neoadjuvant chemotherapy(NAC), followed by gastrectomy with D2lymph node dissection. One patient received four 21-day courses of S-1 plus oxaliplatin(G-SOX), and pathological effect(PE)was Grade 3. Two patients received four 21-day courses of capecitabine plus oxaliplatin(CapeOX), and each PE was Grade 2and Grade 1a, respectively. One patient in poor PE was with recurrent liver and peritoneal metastases. This suggested that for resectable advanced gastric cancer with extensive regional lymph node metastases, NAC by SOX or CapeOX was effective for some patients.

Formation of a New, Strongly Basic Nitrogen Anion by Metal Oxide Modification.

Development of new hybrid materials having unique and unprecedented catalytic properties is a challenge for chemists, and heterogeneous-homogeneous hybrid catalysts have attracted much attention because of the preferable and exceptional properties that are highly expected to result from combination of the components. Base catalysts are widely used in organic synthesis as key materials, and a new class of base catalysts has made a large impact from academic and industrial viewpoints. Here, a principle for creating a new strong base by hybridization of homogeneous and heterogeneous components is presented. It is based on the modification of organic compounds with metal oxides by using the acid-base property of metal oxides. Based on kinetic and DFT studies, combination of CeO2 and 2-cyanopyridine drastically enhanced the basicity of 2-cyanopyridine by a factor of about 109 (∼9 by pKa (in CH3CN)), and the pKa was estimated to be ∼21, which locates it in the superbase category. 2-Cyanopyridine and CeO2 formed a unique adsorption complex via two interaction modes: (i) coordinative interaction between the Ce atom of CeO2 and the N atom of the pyridine ring in 2-cyanopyridine, and (ii) covalent interaction between the surface O atom of CeO2 and the C atom of the CN group in 2-cyanopyridine by addition of the lattice oxygen of CeO2 to the CN group of 2-cyanopyridine. These interactions established a new, strongly basic site of N- over the CeO2 surface.

Catalytic Cyclopropanation by Myoglobin Reconstituted with Iron Porphycene: Acceleration of Catalysis due to Rapid Formation of the Carbene Species.

Myoglobin reconstituted with iron porphycene catalyzes the cyclopropanation of styrene with ethyl diazoacetate. Compared to native myoglobin, the reconstituted protein significantly accelerates the catalytic reaction and the kcat/Km value is 26-fold enhanced. Mechanistic studies indicate that the reaction of the reconstituted protein with ethyl diazoacetate is 615-fold faster than that of native myoglobin. The metallocarbene species reacts with styrene with the apparent second-order kinetic constant of 28 mM-1 s-1 at 25 °C. Complementary theoretical studies support efficient carbene formation by the reconstituted protein that results from the strong ligand field of the porphycene and fewer intersystem crossing steps relative to the native protein. From these findings, the substitution of the cofactor with an appropriate metal complex serves as an effective way to generate a new biocatalyst.

[A Case of HER2-Positive Unresectable Gastric Cancer with Multiple Lymph Node and Liver Metastases Controlled Effectively by Combination Chemotherapy with Capecitabine, Oxaliplatin, and Trastuzumab].

A 77-year-old woman was diagnosed with HER2-positive unresectable gastric cancer with multiple lymph node and liver metastases(cT3-4, cN3, cM1[HEP, LYM], cStage IV ). Four courses of combination chemotherapy with capecitabine, oxaliplatin, and trastuzumab(XELOX plus Tras)were administered. Though all lesions showed a complete or partial response, anorexia and body weight loss appeared because of the stenosis in the primary gastric lesion. After another course, these symptoms became worse and she underwent laparoscopic gastrojejunostomy. She progressed favorably after the surgery, her anorexia improved and her weight increased. Thirty-four days after the surgery, the same chemotherapy was continued. At present, the metastases are well controlled 12months after the initial treatment. It is suggested that XELOX plus Tras is an effective chemotherapy regimen for HER2-positive unresectable gastric cancer.

Spin-Blocking Effect in CO and H2 Binding Reactions to Molybdenocene and Tungstenocene: A Theoretical Study on the Reaction Mechanism via the Minimum Energy Intersystem Crossing Point.

Potential energy profiles and electronic structural interpretation of the CO and H2 binding reactions to molybdenocene and tungstenocene complexes [MCp2] (M = Mo and W, Cp = cycropentadienyl) were studied using density functional theory calculations and ab initio multiconfigurational electronic structure calculations. Experimentally observed slow H2 binding was reasonably explained in terms of the spin-blocking effect. Electronic structural analysis at the minimum-energy intersystem crossing point (MEISCP) revealed that the singly occupied molecular orbital's π-bonding/σ-antibonding character in the M-CO/H2 moiety determines the energy levels of the MEISCP. Analysis of the reaction coordinate showed that the singlet-triplet gap significantly depends on the Cp-M-Cp angle. Therefore, not only the metal-ligand distance but also the Cp-M-Cp angle is an important reaction coordinate to reach the MEISCP, the transition state of H2 binding. The role of spin-orbit coupling is also discussed.

Electronic Polarization Effect of the Water Environment in Charge-Separated Donor-Acceptor Systems: An Effective Fragment Potential Model Study.

The electronic polarization (POL) of the surrounding environment plays a crucial role in the energetics of charge-separated systems. Here, the mechanism of POL in charge-separated systems is studied using a combined quantum mechanical and effective fragment potential (QM/EFP) method. In particular, the POL effect caused by charge separation (CS) is investigated at the atomic level by decomposition into the POL at each polarizability point. The relevance of the electric field generated by the CS is analyzed in detail. The model systems investigated are Na+-Cl- and guanine-thymine solvated in water. The dominant part of the POL arises from solvent molecules close to the donor (D) and acceptor (A) units. At short D-A distances, the electric field shows both positive and negative interferences. The former case enhances the POL energy. At longer distances, the interference is weakened, and the local electric field determines the POL energy.

Blast resistance of CC-NB-LRR protein Pb1 is mediated by WRKY45 through protein-protein interaction.

Panicle blast 1 (Pb1) is a panicle blast resistance gene derived from the indica rice cultivar "Modan." Pb1 encodes a coiled-coil-nucleotide-binding site-leucine-rich repeat (CC-NB-LRR) protein and confers durable, broad-spectrum resistance to Magnaporthe oryzae races. Here, we investigated the molecular mechanisms underlying Pb1-mediated blast resistance. The Pb1 protein interacted with WRKY45, a transcription factor involved in induced resistance via the salicylic acid signaling pathway that is regulated by the ubiquitin proteasome system. Pb1-mediated panicle blast resistance was largely compromised when WRKY45 was knocked down in a Pb1-containing rice cultivar. Leaf-blast resistance by Pb1 overexpression (Pb1-ox) was also compromised in WRKY45 knockdown/Pb1-ox rice. Blast infection induced higher accumulation of WRKY45 in Pb1-ox than in control Nipponbare rice. Overexpression of Pb1-Quad, a coiled-coil domain mutant that had weak interaction with WRKY45, resulted in significantly weaker blast resistance than that of wild-type Pb1. Overexpression of Pb1 with a nuclear export sequence failed to confer blast resistance to rice. These results suggest that the blast resistance of Pb1 depends on its interaction with WRKY45 in the nucleus. In a transient system using rice protoplasts, coexpression of Pb1 enhanced WRKY45 accumulation and increased WRKY45-dependent transactivation activity, suggesting that protection of WRKY45 from ubiquitin proteasome system degradation is possibly involved in Pb1-dependent blast resistance.