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The general principles of discrete, large self-assemblies composed of numerous components are not unveiled and the artificial formation of such entities is a challenging topic. In metal-organic cages, design strategies for tuning the coordination directions in multitopic ligands by the bend and twist angles were previously developed to solve this problem. In this study, the importance of remote geometric communications between components is emphasized, realizing several types of metal-organic assemblies based on dihedral angle control in multitopic ligands although they have the same coordination directions. Self-assembly of a tritopic ligand with dihedral angles θ = 36.5° and a cis-protected Pd(II) ion affords M 9 L 6 and M 12 L 8 cages as kinetic and thermodynamic products, respectively, whereas an M 12 L 8 sheet is formed when θ = 90°. Geometric analyses of strains in the subcomponent rings reveals that remote geometric communications among neighboring multitopic ligands through coordination bonds are key for large assemblies., (© 2024. The Author(s).)

The development of nonfullerene acceptors (NFAs), represented by ITIC, has contributed to improving the power conversion efficiency (PCE) of organic solar cells (OSCs). Although tuning the electronic structures to reduce the exciton binding energy (E b ) is considered to promote photocharge generation, a rational molecular design for NFAs has not been established. In this study, we designed and developed two ITIC-based NFAs bearing spiro-substituted bithiophene or biphenyl units (named SpiroT-DCI and SpiroF-DCI) to tune the frontier molecular orbital (FMO) distribution of NFAs. While the highest occupied molecular orbitals (HOMOs) of SpiroF-DCI and ITIC are delocalized in the main π-conjugated framework, the HOMO of SpiroT-DCI is distributed on the bithiophene unit. Reflecting this difference, SpiroT-DCI exhibits a smaller E b than either SpiroF-DCI or ITIC, and exhibits greater external quantum efficiency in single-component OSCs. Furthermore, SpiroT-DCI shows improved PCEs for bulk-heterojunction OSCs with a donor of PBDB-T, compared with that of either SpiroT-DCI or ITIC. Time-resolved spectroscopy measurements show that the photo-induced intermolecular charge separation is effective even in pristine SpiroT-DCI films. This study highlights the introduction of spiro-substituted bithiophene units that are effective in tuning the FMOs of ITIC, which is desirable for reducing the E b and improving the PCE in OSCs., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The power conversion efficiency (PCE) of organic photovoltaics (OPVs) has reached more than 19% due to the rapid development of non-fullerene acceptors (NFAs). To compete with the PCEs (26%) of commercialized silicon-based inorganic photovoltaics, the drawback of OPVs should be minimized. This drawback is the intrinsic large loss of open-circuit voltage; however, a general approach to this issue remains elusive. Here, we report a discovery regarding highly efficient NFAs, specifically ITIC. We found that charge-transfer (CT) and charge dissociation (CD) can occur even in a neat ITIC film without the donor layer. This is surprising, as these processes were previously believed to take place exclusively at donor/acceptor heterojunctions. Femtosecond time-resolved visible to mid-infrared measurements revealed that in the neat ITIC layers, the intermolecular CT immediately proceeds after photoirradiation (<0.1 ps) to form weakly-bound excitons with a binding energy of 0.3 eV, which are further dissociated into free electrons and holes with a time-constant of 56 ps. Theoretical calculations indicate that stacking faults in ITIC ( i.e. , V-type molecular stacking) induce instantaneous intermolecular CT and CD in the neat ITIC layer. In contrast, J-type stacking does not support such CT and CD. This previously unknown pathway is triggered by the larger dipole moment change on the excited state generated at the lower symmetric V-type molecular stacking of ITIC. This is in sharp contrast with the need of sufficient energy offset for CT and CD at the donor-acceptor heterojunction, leading to the significant voltage loss in conventional OPVs. These results demonstrate that the rational molecular design of NFAs can increase the local dipole moment change on the excited state within the NFA layer. This finding paves the way for a groundbreaking route toward the commercialization of OPVs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Rotaxane cross-linkers enhance the toughness of the resulting rotaxane cross-linked polymers through a stress dispersion effect, which is attributed to the mobility of the interlocked structure. To date, the compositional diversity of rotaxane cross-linkers has been limited, and the poor compatibility of these cross-linkers with peptides and proteins has made their use in such materials challenging. The synthesis of a rotaxane composed of peptides may result in a biodegradable cross-linker that is compatible with peptides and proteins, allowing the fortification of polypeptides and proteins and ultimately leading to the development of innovative materials that possess excellent mechanical properties and biodegradability. However, the chemical synthesis of all-peptide-based rotaxanes has remained elusive because of the absence of strong binding motifs in peptides, which prevents an axial peptide from penetrating a cyclic peptide. Here, we synthesized all-peptide-based rotaxanes using an active template method for proline-containing cyclic peptides. The results of molecular dynamics simulations suggested that cyclic peptides with an expansive inner cavity and carbonyl oxygens oriented toward the center are favorable for rotaxane synthesis. This rotaxane synthesis method is expected to accelerate the synthesis of peptides and proteins with mechanically interlocked structures, potentially leading to the development of peptide- and protein-based materials with unprecedented functionalities.

The difluorination reaction of alkenes catalyzed by molecular iodine was revealed for the first time. This difluorination reaction affords a simple and practical experimental method and can be applied to many aliphatic and aromatic alkenes bearing synthetically useful functional groups, such as ester, amide, hydroxy, and aryl groups. Preliminary mechanistic studies of this alkene difluorination suggest the existence of two catalytic cycles: the IF-driven cycle and the catalytic cycle by the IF adduct.

A series of ferrocene(Fc)-bridged pentacene(Pc)-dimers [Fc-Ph(2,n)-(Pc) 2 : n=number of phenylene spacers] were synthesized to examine the tortional motion effect of Fc-terminated phenylene linkers on strongly coupled quintet multiexciton ( 5 TT) formation through intramolecular singlet fission (ISF). Fc-Ph(2,4)-(Pc) 2 has a relatively small electronic coupling and large conformational flexibility according to spectroscopic and theoretical analyses. Fc-Ph(2,4)-(Pc) 2 exhibits a high-yield 5 TT together with quantitative singlet TT ( 1 TT) generation through ISF. This demonstrates a much more efficient ISF than those of other less flexible Pc dimers. The activation entropy in 1 TT spin conversion of Fc-Ph(2,4)-(Pc) 2 is larger than those of the other systems due to the larger conformational flexibility associated with the torsional motion of the linkers. The torsional motion of linkers in 1 TT is attributable to weakened metal-ligand bonding in the Fc due to hybridization of the hole level of Pc to Fc in 1 TT unpaired orbitals., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Precise engineering of excited-state interactions between an organic conjugated molecule and a two-dimensional semiconducting inorganic nanosheet, specifically the manipulation of charge-transfer excited (CTE) states, still remains a challenge for state-of-the-art photochemistry. Herein, we report a long-lived, highly emissive CTE state at structurally well-defined hetero-nanostructure interfaces of photoactive pyrene and two-dimensional MoS 2 nanosheets via an N -benzylsuccinimide bridge (Py-Bn-MoS 2 ). Spectroscopic measurements reveal that no charge-transfer state is formed in the ground state, but the locally-excited (LE) state of pyrene in Py-Bn-MoS 2 efficiently generates an unusual emissive CTE state. Theoretical studies elucidate the interaction of MoS 2 vacant orbitals with the pyrene LE state to form a CTE state that shows a distinct solvent dependence of the emission energy. This is the first example of organic-inorganic 2D hetero-nanostructures displaying mixed luminescence properties by an accurate design of the bridge structure, and therefore represents an important step in their applications for energy conversion and optoelectronic devices and sensors., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Quantum light is increasingly recognized as a promising resource for developing optical measurement techniques. Particular attention has been paid to enhancing the precision of the measurements beyond classical techniques by using nonclassical correlations between quantum entangled photons. Recent advances in the quantum optics technology have made it possible to manipulate spectral and temporal properties of entangled photons, and photon correlations can facilitate the extraction of matter information with relatively simple optical systems compared to conventional schemes. In these respects, the applications of entangled photons to time-resolved spectroscopy can open new avenues for unambiguously extracting information on dynamical processes in complex molecular and materials systems. Here, we propose time-resolved spectroscopy in which specific signal contributions are selectively enhanced by harnessing nonclassical correlations of entangled photons. The entanglement time characterizes the mutual delay between an entangled twin and determines the spectral distribution of photon correlations. The entanglement time plays a dual role as the knob for controlling the accessible time region of dynamical processes and the degrees of spectral selectivity. In this sense, the role of the entanglement time is substantially equivalent to the temporal width of the classical laser pulse. The results demonstrate that the application of quantum entangled photons to time-resolved spectroscopy leads to monitoring dynamical processes in complex molecular and materials systems by selectively extracting desired signal contributions from congested spectra. We anticipate that more elaborately engineered photon states would broaden the availability of quantum light spectroscopy., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

The biomimetic design of a transition metal complex based on the iron(iv)-oxo porphyrin π-cation radical species in cytochrome P450 enzymes has been studied extensively. Herein, we translate the functions of this iron(iv)-oxo porphyrin π-cation radical species to an α-ketoacyl phosphonium species comprised of non-metal atoms and utilize it as a light-activated oxygenation auxiliary for ortho -selective oxygenation of anilines. Visible light irradiation converts the α-ketoacyl phosphonium species to the excited state, which acts as a transiently generated oxidant. The intramolecular nature of the process ensures high regioselectivity and chemoselectivity. The auxiliary is easily removable. A one-pot protocol is also described., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We identified a ternary hybrid catalyst system composed of an acridinium photoredox catalyst, a thiophosphoric imide (TPI) catalyst, and a titanium complex catalyst that promoted an intermolecular addition reaction of organic molecules with various ketones through sp 3 C-H bond activation. The thiyl radical generated via single-electron oxidation of TPI by the excited photoredox catalyst abstracted a hydrogen atom from organic molecules such as toluene, benzyl alcohol, alkenes, aldehydes, and THF. The thus-generated carbon-centered radical species underwent addition to ketones and aldehydes. This intrinsically unfavorable step was promoted by single-electron reduction of the intermediate alkoxy radical by catalytically generated titanium(III) species. This reaction provided an efficient and straightforward route to a broad range of tertiary alcohols and was successfully applied to late-stage functionalization of drugs or their derivatives. The proposed mechanism was supported by both experimental and theoretical studies.

Background: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation., Methods: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed., Results: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m 2 , the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05)., Conclusions: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients., (© 2023. The Author(s).)

COA-Cl is a newly synthesized adenosine analogue that exhibits various physiological activities. Its angiogenic, neurotropic, and neuroprotective potencies make it promising for the development of medicines. In this study, we show Raman spectroscopic study of COA-Cl to elucidate molecular vibrations and related chemical properties. Density functional theory calculations were combined with the Raman spectroscopic data to understand the details of each vibrational mode. Comparative analysis with adenine, adenosine, and other nucleic acid analogues enabled identification of unique Raman peaks originating from the cyclobutane moiety and chloro group of COA-Cl. This study provides fundamental knowledge and crucial insights for further development of COA-Cl and related chemical species.

We propose a new hybrid approach combining quantum chemistry and statistical mechanics of liquids for calculating the nuclear magnetic resonance (NMR) chemical shifts of solvated molecules. Based on the reference interaction site model self-consistent field with constrained spatial electron density distribution (RISM-SCF-cSED) method, the electronic structure of molecules in solution is obtained, and the expression for the nuclear magnetic shielding tensor is derived as the second-order derivative of the Helmholtz energy of the solution system. We implemented a method for calculating chemical shifts and applied it to an adenine molecule in water, where hydrogen bonding plays a crucial role in electronic and solvation structures. We also performed the calculations of 17 O chemical shifts, which showed remarkable solvent dependence. While converged results could not be sometimes obtained using the conventional method, in the present framework with RISM-SCF-cSED, an adequate representation of electron density is guaranteed, making it possible to obtain an NMR shielding constant stably. This introduction of cSED is key to extending the method's applicability to obtain the chemical shift of various chemical species. The present demonstration illustrates our approach's superiority in terms of numerical robustness and accuracy.

The spread of abnormal opacity on chest computed tomography (CT) has been reported as a predictor of coronavirus disease 2019 (COVID-19) severity; however, the relationship between CT findings and prognosis in patients with severe COVID-19 remains unclear. The objective of this study was to evaluate the extent of abnormal opacity on chest CT and its association with prognosis in patients with COVID-19 in a critical care medical center, using a simple semi-quantitative method. This single-center case-control study included patients diagnosed with severe COVID-19 pneumonia who were admitted to a critical care center. The diagnosis of COVID-19 was based on positive results of a reverse transcription polymerase chain reaction test. All patients underwent non-contrast whole-body CT upon admission. Six representative axial chest CT images were selected for each patient to evaluate the extent of lung lesions. The percentage of the area involved in the representative CT images was visually assessed by 2 radiologists and scored on 4-point scale to obtain the bedside CT score, which was compared between patients who survived and those who died using the Mann-Whitney U test. A total of 63 patients were included in this study: 51 survived and 12 died after intensive treatment. The inter-rater reliability of bedside scores between the 2 radiologists was acceptable. The median bedside CT score of the survival group was 12.5 and that of the mortality group was 16.5; the difference between the 2 groups was statistically significant. The degree of opacity can be easily scored using representative CT images in patients with severe COVID-19 pneumonia, without sophisticated software. A greater extent of abnormal opacity is associated with poorer prognosis. Predicting the prognosis of patients with severe COVID-19 could facilitate prompt and appropriate treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fluorinated analogs of polyhedral hydrocarbons have been predicted to localize an electron within their cages upon reduction. Here, we report the synthesis and characterization of perfluorocubane, a stable polyhedral fluorocarbon. The key to the successful synthesis was the efficient introduction of multiple fluorine atoms to cubane by liquid-phase reaction with fluorine gas. The solid-state structure of perfluorocubane was confirmed using x-ray crystallography, and its electron-accepting character was corroborated electrochemically and spectroscopically. The radical anion of perfluorocubane was examined by matrix-isolation electron spin resonance spectroscopy, which revealed that the unpaired electron accepted by perfluorocubane is located predominantly inside the cage.

Nitration of benzene is a representative aromatic substitution reaction related to the σ-complex (arenium ion or "Wheland" intermediate) concept. This reaction is typically carried out in a mixed acid solution to generate nitronium ions, and how solvent molecules play roles in the reaction has been of great interest. Here we will shed new light on the reaction, namely the electronic structure and the microscopic insights of the solvation, which have been rarely discussed so far. We studied this process using the reference interaction site model-self consistent field with constrained spatial electron density distribution (RISM-SCF-cSED) method, considering sulfuric acid or water molecules as a solvent. In this method, the electronic structure of the solute and the solvation structure are self-consistently determined based on quantum chemistry and statistical mechanics of molecular liquids. The solvation free energy surfaces in solution and solvation structures were verified. In the bond formation process of benzene and nitronium ions, the solvation structure by sulfuric acid molecules drastically changes and the solvation effect on the free energy is quite large. We revealed largely contributing resonance structures in the π-electron system of the σ-complex in gas and solution phases by analysing the valence electronic structures.

We present a methodology for analyzing chemical bonds embedded in the electronic wave function of molecules, especially in terms of spin correlations or so-called "local spin." In this paper, based on biorthogonal second quantization, the spin correlation functions of molecules are naturally introduced, which enables us to extract local singlet and local triplet elements from the wave function. We also clarify the relationship between these spin correlations and traditional chemical concepts, i.e., resonance structures. Several chemical reactions, including the intramolecular radical cyclization and the formation of preoxetane, are demonstrated to verify the analysis method numerically.

The NMR chemical shifts of hydride and fluoride ions in the solution phase are evaluated from the first principle. The cluster structure in the first solvation shell is calculated by density functional theory and MP2 theory, and the solvent effect around the cluster is considered by PCM and RISM-SCF-SEDD methods. The obtained shifts are analyzed in terms of electronic structure and solvent effects and are compared with available experimental data. The fluoride ion is deshielded in the presence of solvent molecules compared to the isolated state due to a larger paramagnetic contribution from the 2p orbital. On the other hand, there is no such change for the hydride ion. The paramagnetic and diamagnetic contributions are slightly changed due to the solvation, but they are canceled out. As a result, the chemical shift of the hydride ion is less affected by the solvent than that of the fluoride ion. The increased diamagnetic contribution of hydride ion dissolved in the solvent is attributed to the change in electron density coupled with microscopic solvation.

We developed organocatalyst systems to promote the cleavage of stable C-H bonds, such as formyl, α-hydroxy, and benzylic C-H bonds, through a hydrogen atom transfer (HAT) process without the use of exogenous photosensitizers. An electronically tuned thiophosphoric acid, 7,7'-OMe-TPA, was assembled with substrate or co-catalyst N -heteroaromatics through hydrogen bonding and π-π interactions to form electron donor-acceptor (EDA) complexes. Photoirradiation of the EDA complex induced stepwise, sequential single-electron transfer (SET) processes to generate a HAT-active thiyl radical. The first SET was from the electron-rich naphthyl group of 7,7'-OMe-TPA to the protonated N -heteroaromatics and the second proton-coupled SET (PCET) from the thiophosphoric acid moiety of 7,7'-OMe-TPA to the resulting naphthyl radical cation. Spectroscopic studies and theoretical calculations characterized the stepwise SET process mediated by short-lived intermediates. This organocatalytic HAT system was applied to four different carbon-hydrogen (C-H) functionalization reactions, hydroxyalkylation and alkylation of N -heteroaromatics, acceptorless dehydrogenation of alcohols, and benzylation of imines, with high functional group tolerance.

The ground state and excited state electronic properties of chlorophyll (Chl) a and Chl b in diethyl ether, acetone, and ethanol solutions are investigated using quantum mechanical and molecular mechanical calculations with density functional theory (DFT) and time-dependent DFT (TDDFT). Although the DFT/TDDFT methods are widely used, the electronic structures of molecules, especially large molecules, calculated with these methods are known to be strongly dependent on the functionals and the parameters used in the functionals. Here, we optimize the range-separated parameter, μ, of the CAM-B3LYP functional of Chl a and Chl b to reproduce the experimental excitation energy differences of these Chl molecules in solution. The optimal values of μ for Chl a and Chl b are smaller than the default value of μ and that for bacteriochlorophyll a, indicating the change in the electronic distribution, i.e., an increase in electron delocalization, within the molecule. We find that the electronic distribution of Chl b with an extra formyl group is different from that of Chl a. We also find that the polarity of the solution and hydrogen bond cause the decrease in the excitation energies and the increase in the widths of excitation energy distributions of Chl a and Chl b. The present results are expected to be useful for understanding the electronic properties of each pigment molecule in a local heterogeneous environment, which will play an important role in the excitation energy transfer in light-harvesting complex II.

Fluorination reaction of alkenes with iodine and HF·pyridine complex (pyr·9HF) was performed under mild conditions in the presence of K 2 S 2 O 8 or Na 2 S 2 O 8 as an oxidant. Aliphatic and aromatic alkenes underwent iodofluorination to give the iodofluorinated products with high regioselectivity. The substitution reactions of the iodofluorinated product by nitrogen, sulfur, and oxygen nucleophiles indicated further applications as a building block for synthesis of 2-fluoroalkyl-substituted compounds.

The α-acids contained in hops are one of the ingredients of beer. The isomerization of α-acids produces iso-α-acids, the main source of bitterness in beer. In this study, the isomerization mechanism of the α-acid, cohumulone, was elucidated by using density functional theory in conjunction with the polarizable continuum model or 3D-RISM integral equation theory of liquids. The calculated reaction diagram is consistent with experimental results; the activation free energy difference between the cis and trans isomers is in good agreement with the experimental estimate. The activation energy difference results from solvation energy. Additionally, a calculation of NMR chemical shifts showed that the proton position of isocohumulone is different from that proposed previously. The effect of Mg 2+ cation on the isomerization was also investigated. Both the activation and reaction free energy are stabilized by the presence of Mg 2+ , which is consistent with experimental results. Water solvation reduces the activation free energy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

With the advent of antiretroviral therapy (ART), the prognosis of people infected with human immunodeficiency virus (HIV) has improved, and the frequency of HIV-related central nervous system (CNS) diseases has decreased. Nevertheless, mortality from HIV-related CNS diseases, including those associated with ART (e.g., immune reconstitution inflammatory syndrome) remains significant. Magnetic resonance imaging (MRI) can improve the outlook for people with HIV through early diagnosis and prompt treatment. For example, HIV encephalopathy shows a diffuse bilateral pattern, whereas progressive multifocal leukoencephalopathy, HIV-related primary CNS lymphoma, and CNS toxoplasmosis show focal patterns on MRI. Among the other diseases caused by opportunistic infections, CNS cryptococcosis and CNS tuberculosis have extremely poor prognoses unless diagnosed early. Immune reconstitution inflammatory syndrome shows distinct MRI findings from the offending opportunistic infections. Although distinguishing between HIV-related CNS diseases based on imaging alone is difficult, in this review, we discuss how pattern recognition approaches can contribute to their early differentiation., (© 2021. The Author(s).)

2-(2'-Hydroxyphenyl)-benzothiazole (HBT) has been widely studied for use as a system for excited-state intramolecular proton transfer. However, the mechanism underlying the solvent dependency of HBT fluorescence spectra remains unclear. In this study, the HBT photochemical process in the S 1 state was analysed using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The excited-state intramolecular proton transfer in the enol form of HBT was found to depend on the hydrogen-bond acceptability of the solvent. The twisting of the keto form of HBT is determined by whether HBT acts as a hydrogen-bond acceptor or donor. A specific stacking structure of the enol form of HBT was found to decrease the S 1 → S 0 transition energy, which corresponds to the experimental fluorescence spectra in a DMSO/H 2 O solution mixture.

The resonance theory is still very useful in understanding the valence electron structure. However, such a viewpoint is not usually obtained by general-purpose quantum chemical calculations, instead requires rather special treatment such as valence bond methods. In this study, we propose a method based on second quantization to analyze the results obtained by general-purpose quantum chemical calculations from the local point of view of electronic structure and analyze diazadiboretidine and the tautomerization of formamide. This method requires only the "PS"-matrix, consisting of the density matrix (P-matrix) and overlap matrix, and can be computed with a comparable load to that of Mulliken population analysis. A key feature of the method is that, unlike other methods proposed so far, it makes direct use of the results of general-purpose quantum chemical calculations., (© 2021 Wiley Periodicals LLC.)

This article proposes an ab initio quantum chemical method to evaluate the effective electronic coupling that determines the rate of superexchange electron transfer in donor-bridge-acceptor (D-B-A) systems. The method utilizes the fragment charge difference to define electronic diabatic states and to apply an electrostatic potential in a form of a uniform potential difference that mimics solvation effects on the relative energies of the electronic states. The two-state generalized Mulliken-Hush method is used to obtain the effective electronic coupling as the nondiagonal element of the effective Hamiltonian that is derived based on the Green's function approach and the quasi-degenerate perturbation theory. A theoretical basis is provided for the dependence of the calculated effective electronic coupling on the applied potential and for how to find the optimal potential to give the desired effective electronic coupling that coincides with the result of the minimum energy splitting method. The method is applied to typical D-B-A molecules and gives the effective electronic couplings in reasonable agreement with the experimental estimates.

A new method for calculating nuclear magnetic shielding in solutions is developed based on the reference interaction site model self-consistent field (RISM-SCF) with spatial electron density distribution (SEDD). In RISM-SCF-SEDD, the electrostatic interaction between the solute and the solvent is described by considering the spread of electron to obtain more realistic electronic structure in solutions. It is thus expected to allow us to predict more quantitative chemical shifts of a wide variety of chemical species in solutions. In this study, the method is applied to a water molecule in water and is validated by examining the dependence of the solvent temperature and density on chemical shifts. The dependence of solvent species is also investigated, and more accurate results are obtained for polar solvents compared to the previous RISM-SCF study. Another application example of this method is the 15 N chemical shifts of two azines in water, which is difficult to predict with the polarizable continuum model (PCM). Our results are in good agreement with the previous quantum mechanical/molecular mechanics study and experimental results. It is also shown that our method gives more realistic results for methanol and acetone than the PCM.

Objective: Pathologic features of atherosclerotic plaques on CT are not established. We compared CT values among pathologically confirmed plaque constituents and evaluated their ability to distinguish plaque constituents., Methods: 50 histopathological images of carotid endarterectomy samples from 10 males and 2 females (age 54-74 years, average 65.9 years) were examined. We compared pre-operative CT [pre-contrast (CT-P), early post-contrast phase (CT-E), delayed post-contrast phase (CT-D)] of lipid-rich necrotic core (NC) and fibrous tissue (F) plaque components with pathological images. The ability of features to differentiate plaque components using several discrimination techniques were compared., Results: CT values of NC and F were 36 ± 13, 45 ± 11 (mean ± standard deviation, Hounsfield unit, HU), 41 ± 17, 69 ± 18, and 44 ± 16, 70 ± 13 in CT-P ( p < 0.01), CT-E ( p < 0.0001), and CT-D ( p < 0.0001), respectively. The threshold, sensitivity, and accuracy for distinguishing NC from F were 44 HU, 74%, and 68%; 55 HU, 85%, and 85%; and 63 HU, 92%, and 84% in CTP, CT-E, and CT-D, respectively. CT-P had lower accuracy than CT-E and CT-D (both p < 0.05), but CT-E and CT-D were similar. CT-E and CT-D yielded 90 and 91% sensitivity and accuracy, respectively in linear discrimination analysis., Conclusion: In both pre- and post-contrast CT, CT values were lower in NC than F. Although values overlapped, using two-phase post-contrast CTs improved discrimination ability., Advances in Knowledge: Our findings may help to establish computer-aided diagnosis of vulnerable atherosclerotic plaques in future.

Light absorbed by light-harvesting antennae is transferred to the reaction center (RC). The excitation energy transfer (EET) to the RC is known to proceed with nearly perfect quantum yield. However, understanding of EET is still limited at the molecular level. Here, we examine the dynamics in the Fenna-Matthews-Olson (FMO) protein by developing an efficient molecular dynamics simulation that can properly describe the electronic properties of bacteriochlorophylls. We find that the FMO protein consists of sites with heterogeneous fluctuations extending from fast to slow modulation. We also find that efficient EETs are facilitated by site-dependent fluctuations that enhance the resonance condition between neighboring sites with large site energy differences and circumvent exciton trapping on the pathway to the RC. Knowledge of site-dependent fluctuations is an important component of understanding optimization of EET in photosynthetic systems.

We investigate the effects of water addition on a highly stereocontrolled fluorination of dienamine generated by α-branched enals and 6'-hydroxy-9-amino-9-deoxy- epi -quinidine with N -fluorobenzenesulfonimide (NFSI) in the presence of Brønsted acid both experimentally and theoretically. It is experimentally found that water addition to organic solvent significantly shortens the reaction time whereas excessive water addition decreases the enantiomeric excess. The results calculated with three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) method are in good agreement with the experimental ones. It is revealed that the shortness of reaction time is caused by the reactant destabilization and that the decrease in enantiomeric excess is due to the difference of hydration free energy between two transition states.

Purpose: To evaluate the uterine kinetics in each phase of the menstrual cycle when observed in detail using cine-mode magnetic resonance imaging (MRI) of sagittal and transverse plane images., Methods: Seven volunteers with a history of multiple natural pregnancies and deliveries were enrolled from January 2017 to May 2017. The kinetic parameters (depth, frequency, and direction) of uterine muscle contractions were evaluated in cine-mode MRI., Results: Strong contractions from the uterine cornua to cervix were detected during menstruation. In the late follicular phase, the frequency of opposing contractions from the cervix and uterine cornua increased. Immediately before ovulation, contractions from the cervix reached the uterine fundus. After ovulation, opposing contractions returned. These contractions gradually decreased in the mid-luteal phase, while fine contractions from the cervix to the middle of the uterine body were frequently observed until 7 days after ovulation. Few contractions were observed in the implantation phase., Conclusions: Our data suggest that the uterine kinetics change in each phase of the menstrual cycle in accordance with the purpose of the uterus in each phase. Further, cine-mode MRI studies of each phase are needed to assess the relationships between uterine kinetics and infertility., Competing Interests: Conflict of interest: The authors declare no conflict of interest. Human rights statements and informed consent: All the procedures were followed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the principles of the Helsinki Declaration of 1964 and its later amendments. The protocol of this research project was approved by the institutional review board of Soranomori Clinic. Informed consent was obtained from all volunteers for the examinations and in this study. Additional informed consent was obtained from all volunteers for which identifying information is included in this article. Animal studies: This article does not contain any studies with animal subjects performed by the any of the authors., (© 2019 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

On our quest for new bioactive molecules from marine sources, two cyclic imines ( 1 , 2 ) were isolated from a dinoflagellate extract, inhibiting the growth of the respiratory syncytial virus (RSV). Compound 1 was identified as a known molecule portimine, while 2 was elucidated to be a new cyclic imine, named kabirimine. The absolute stereochemistry of 1 was determined by crystallographic work and chiral derivatization, whereas the structure of 2 was elucidated by means of spectroscopic analysis and computational study on all the possible isomers. Compound 1 showed potent cytotoxicity (CC 50 < 0.097 µM) against HEp2 cells, while 2 exhibited moderate antiviral activity against RSV with IC 50 = 4.20 µM (95% CI 3.31-5.33).

Magnesium ions (Mg 2+ ) are crucial for various biological processes. A bacterial Mg 2+ channel, MgtE, tightly regulates the intracellular Mg 2+ concentration. Previous X-ray crystal structures showed that MgtE forms a dimeric structure composed of a total of 10 transmembrane α helices forming a central pore, and intracellular soluble domains constituting a Mg 2+ sensor. The ion selectivity for Mg 2+ over Ca 2+ resides at a central cavity in the transmembrane pore of MgtE, involving a conserved aspartate residue (Asp432) from each monomer. Here, we applied ion-exchange-induced difference FTIR spectroscopy to analyze the interactions between MgtE and divalent cations, Mg 2+ and Ca 2+ . Using site-directed mutagenesis, vibrational bands at 1421 (Mg 2+ ), 1407 (Mg 2+ ), ∼1440 (Ca 2+ ), and 1390 (Ca 2+ ) cm -1 were assigned to symmetric carboxylate stretching modes of Asp432, involved in the ion coordination. Conservative modifications of the central cavity by Asp432Glu or Ala417Leu mutations resulted in the disappearance of the Mg 2+ -sensitive carboxylate bands, suggesting a highly optimized geometry for accommodating a Mg 2+ ion. The dependency of the vibrational changes on Mg 2+ and Ca 2+ concentrations revealed the presence of a two different classes of binding sites: a high affinity site for Mg 2+ ( K d ≈ 0.3 mM) with low Ca 2+ affinity ( K d ≈ 80 mM), and a medium affinity site for Mg 2+ ( K d ≈ 2 mM) and Ca 2+ ( K d ≈ 6 mM), tentatively assigned to the central cavity and the sensor domain, respectively. With the aid of molecular dynamics simulation and normal-mode analysis by quantum chemistry, we confirm that changes in carboxylate bands of the high affinity binding site originate from Asp432 in the central cavity.

The energy conversion of oxygenic photosynthesis is triggered by primary charge separation in proteins at the photosystem II reaction center. Here, we investigate the impacts of the protein environment and intramolecular vibrations on primary charge separation at the photosystem II reaction center. This is accomplished by combining the quantum dynamic theories of condensed phase electron transfer with quantum chemical calculations to evaluate the vibrational Huang-Rhys factors of chlorophyll and pheophytin molecules. We report that individual vibrational modes play a minor role in promoting charge separation, contrary to the discussion in recent publications. Nevertheless, these small contributions accumulate to considerably influence the charge separation rate, resulting in subpicosecond charge separation almost independent of the driving force and temperature. We suggest that the intramolecular vibrations complement the robustness of the charge separation in the photosystem II reaction center against the inherently large static disorder of the involved electronic energies.

Background and Purpose: Urgent diagnosis of acute Stanford type A aortic dissection (AAD) in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) is sometimes challenging. We assessed predictive values for markers of AAD in patients with AIS or TIA., Methods: Consecutive patients with AIS or TIA with AAD who presented to our emergency room within 4.5 hours of symptom onset between 2007 and 2014 were compared with patients without AAD seen between 2012 and 2014., Results: Data were obtained for 24 patients with AIS or TIA with AAD (15 women; mean age, 75 ± 12 years) and 812 patients without AAD (305 women; mean age, 73 ± 12 years). Compared with patients without AAD, patients with AAD displayed significantly higher systolic blood pressure (SBP) laterality (30 ± 20 mm Hg versus 12 ± 11 mm Hg), initial D-dimer concentration (median 38.1 µg/mL versus 1.3 µg/mL), and mediastinal width-to-chest width (M/C) ratio on x-ray (.35 ± .05 versus .29 ± .05), and more frequently showed common carotid artery (CCA) dissection on carotid ultrasonography (84% versus 1%) and pericardial effusion on echocardiography (43% versus 0%). Sensitivity and specificity to identify AAD were 80% and 75% for SBP laterality 17 mm Hg or greater; 100% and 86% for D-dimer concentration 4.1 µg/mL or greater; 75% and 76% for M/C ratio .32 or greater; 84% and 99% for CCA dissection; and 43% and 100% for pericardial effusion, respectively., Conclusions: High D-dimer level may provide the most reliable screening test for AAD in patients with AIS or TIA. CCA dissection on ultrasonography appears to represent the most disease-specific finding and shows acceptable sensitivity., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Triglyceride deposit cardiomyovasculopathy (TGCV) is an intractable cardiovascular disease for which a specific treatment is urgently required. In TGCV, adipose triglyceride lipase (ATGL) deficiency results in the abnormal intracellular metabolism of long-chain fatty acid (LCFA) which leads to TG deposition. Medium-chain triglycerides have been used as an important functional food for various human diseases. To address the potential activities of tricaprin, a medium-chain triglyceride, on cardiac dysfunctions of TGCV, we examined the effects of tricaprin diet on Atgl knock out (KO) mice, an animal model for TGCV. Cardiac imaging tests showed that the tricaprin diet reduced TG accumulation, resulting from improvement of LCFA metabolism, and improved left ventricular function in Atgl KO mice compared to that in mice fed the control diet. In conclusion, tricaprin improved myocardial abnormality in the TGCV model, thus, it may be useful for the treatment of patients with TGCV.

Objective: To assess sex-specific differences regarding use of conventional risks and coronary artery calcification (CAC) to detect coronary artery disease (CAD) using coronary CT angiography (CCTA)., Methods: The Nationwide Gender-specific Atherosclerosis Determinants Estimation and Ischemic Cardiovascular Disease Prospective Cohort study is a prospective, multicentre, nationwide cohort study. Candidates with suspected CAD aged 50-74 years enrolled from 2008 to 2012. The outcome was obstructive CAD defined as any stenosis ≥50% by CCTA. We constructed logistic regression models for obstructive CAD adjusted for conventional risks (clinical model) and CAC score. Improvement in discrimination beyond risks was assessed by C-statistic; net reclassification index (NRI) for CAD probability of low (<30%), intermediate (30%-60%) and high (≥60%); and risk stratification capacity., Results: Among 991 patients (456 women, 535 men; 65.2 vs 64.4 years old), women had lower CAC scores (median, 4 vs 60) and lower CAD prevalence (21.7% vs 37.0%) than men. CAC significantly improved model discrimination compared with clinical model in both sexes (0.66-0.79 in women vs 0.61-0.83 in men). The NRI for women was 0.33, which was much lower than that for men (0.71). Adding CAC to clinical model had a larger benefit in terms of moving an additional 43.3% of men to the most determinant categories (high or low risk) compared with -1.4% of women., Conclusions: The addition of CAC to a prediction model based on conventional variables significantly improved the classification of risk in suspected patients with CAD, with sex differences influencing the predictive ability., Trial Registration Number: UMIN-CTR Clinical Trial: UMIN000001577., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Canonical K + channels are tetrameric and highly K + -selective, whereas two-pore-domain K + (K2P) channels form dimers, but with a similar pore architecture. A two-pore-domain potassium channel TWIK1 (KCNK1 or K2P1) allows permeation of Na + and other monovalent ions, resulting mainly from the presence of Thr-118 in the P1 domain. However, the mechanistic basis for this reduced selectivity is unclear. Using ion-exchange-induced difference IR spectroscopy, we analyzed WT TWIK1 and T118I (highly K + -selective) and L228F (substitution in the P2 domain) TWIK1 variants and found that in the presence of K + ions, WT and both variants exhibit an amide-I band at 1680 cm -1 This band corresponds to interactions of the backbone carbonyls in the selectivity filter with K + , a feature very similar to that of the canonical K + channel KcsA. Computational analysis indicated that the relatively high frequency for the amide-I band is well explained by impairment of hydrogen bond formation with water molecules. Moreover, concentration-dependent spectral changes indicated that the K + affinity of the WT selectivity filter was much lower than those of the variants. Furthermore, only the variants displayed a higher frequency shift of the 1680-cm -1 band upon changes from K + to Rb + or Cs + conditions. High-speed atomic force microscopy disclosed that TWIK1's surface morphology largely does not change in K + and Na + solutions. Our results reveal the local conformational changes of the TWIK1 selectivity filter and suggest that the amide-I bands may be useful "molecular fingerprints" for assessing the properties of other K + channels., (© 2018 Tsukamoto et al.)

Background: Living systems are characterized by the dynamic assembly and disassembly of biomolecules. The dynamical ordering mechanism of these biomolecules has been investigated both experimentally and theoretically. The main theoretical approaches include quantum mechanical (QM) calculation, all-atom (AA) modeling, and coarse-grained (CG) modeling. The selected approach depends on the size of the target system (which differs among electrons, atoms, molecules, and molecular assemblies). These hierarchal approaches can be combined with molecular dynamics (MD) simulation and/or integral equation theories for liquids, which cover all size hierarchies., Scope of Review: We review the framework of quantum mechanical/molecular mechanical (QM/MM) calculations, AA MD simulations, CG modeling, and integral equation theories. Applications of these methods to the dynamical ordering of biomolecular systems are also exemplified., Major Conclusions: The QM/MM calculation enables the study of chemical reactions. The AA MD simulation, which omits the QM calculation, can follow longer time-scale phenomena. By reducing the number of degrees of freedom and the computational cost, CG modeling can follow much longer time-scale phenomena than AA modeling. Integral equation theories for liquids elucidate the liquid structure, for example, whether the liquid follows a radial distribution function., General Significance: These theoretical approaches can analyze the dynamic behaviors of biomolecular systems. They also provide useful tools for exploring the dynamic ordering systems of biomolecules, such as self-assembly. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The structural stability of a cytochrome c domain-swapped dimer compared with that of the monomer was investigated by molecular dynamics (MD) simulations and by three-dimensional reference interaction site model (3D-RISM) theory. The structural fluctuation and structural energy of cytochrome c were treated by MD simulations, and the solvation thermodynamics was treated by 3D-RISM theory. The domain-swapped dimer state is slightly less stable than the monomer state, which is consistent with experimental observations; the total free energy difference is calculated as 25 kcal mol -1 . The conformational change and translational/rotational entropy change contribute to the destabilization of the dimer, whereas the hydration and vibrational entropy contribute to the stabilization. Further analyses on the residues located at the hinge loop for swapping were conducted, and the results reveal details at the molecular level of the structural and interaction changes upon dimerization.

Two new sesterterpenoids, 1 and 2, were isolated from the sponge Luffariella variabilis . Their planar structures were characterized with spectroscopic analyses. The sole chiral center of compound 1 was elucidated as 12 R by comparing observed and calculated optical rotation values. The configurations of compound 2 were determined by NMR and electronic circular dichroism (ECD) studies. Furthermore, compound 2 showed cytotoxicity at IC 50 1.0 µM against NBT-T2 cells., Competing Interests: The authors declare no conflict of interest.

Extrauterine choriocarcinoma in the fallopian tube is very rare and is often diagnosed and treated as an ectopic tubal pregnancy. A 34-year-old woman who initially became pregnant after infertility treatment using ovulation induction with clomiphene citrate and intrauterine insemination was later diagnosed with an extrauterine choriocarcinoma in the left fallopian tube. Because of suspected left ectopic tubal pregnancy based on ultrasonography findings and a high level of β-human chorionic gonadotropin (β-hCG; 7054.3 mIU/mL), the patient underwent diagnostic laparoscopy at a gestational age of 6 weeks. Left salpingectomy was performed based on the operative diagnosis of an ectopic tubal pregnancy. No signs of tubal rupture or leakage of contents from the fallopian tube were observed during the operation. Her serum β-hCG dropped to 10.3 mIU/mL at 15 days postoperatively. Histopathology demonstrated an extrauterine choriocarcinoma in the removed fallopian tube, and the patient was referred to a regional oncologic hospital to receive additional adjuvant chemotherapy. This case indicates that conservative treatment for ectopic pregnancy should be chosen carefully, and that histopathology diagnosis and appropriate β-hCG monitoring following treatment are important not only to diagnose persistent ectopic pregnancy, but also to rule out the possibility of a tubal choriocarcinoma., (Copyright © 2017 AAGL. Published by Elsevier Inc. All rights reserved.)

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

Cardiac magnetic resonance (MR) imaging with late gadolinium enhancement (LGE) is used to detect and assess the myocardial damage seen with a variety of cardiomyopathies. Gadolinium-based contrast material accumulates in the expanded interstitial space of the myocardium. Areas with LGE correspond to replacement fibrosis, fibrofatty change, epithelioid granuloma, inflammatory cell infiltration, cardiomyocyte necrosis, and amyloid deposition-conditions that represent a focal increase in interstitial space. Areas without LGE correspond to interstitial or plexiform fibrosis, mildly degenerated cardiomyocytes, inflammatory cell infiltration, and diffuse amyloid deposition-conditions that represent diffuse increases in interstitial space. LGE MR imaging cannot depict these diffuse changes and does not enable quantitative evaluation of this increased interstitial space because on inversion-recovery MR images, the inversion time is adjusted to null the signal from normal-appearing or the least enhancing regions of the myocardium. Thus, the absence of LGE does not always indicate normal myocardial tissue. The use of current T1 mapping techniques enables one to overcome these drawbacks of LGE imaging, detect diffuse myocardial abnormalities, and perform quantitative analysis of the interstitial space. The authors describe the histopathologic and corresponding cardiac MR imaging findings of hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, giant cell myocarditis, and cardiac amyloidosis-mainly those seen on LGE MR images-as assessed by using whole-heart specimens obtained from autopsy or transplantation. © RSNA, 2017.