The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation.

The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo.

Ultrafine Spatial Modulation of Diazapyrene-Based Two-Dimensional Conjugated Covalent Organic Frameworks.

Tailormade bottom-up synthesis of covalent organic frameworks (COFs) from various functional building blocks offer not only tunable topology and pore size but also multidimensional properties. High crystallinity is one of the prerequisites for their structures and associated physicochemical properties. Among different π-conjugated motifs for constructing COFs, pyrene-based tetragonal structures are effective in achieving highly ordered and crystalline states. In the present research, we demonstrated that the substitution of pyrene with 2,7-diazapyrene produces nearly "flat" structures of two-dimensional (2D) COF layers by controlling the torsional angle of linker molecules. Featuring finite pore diameters and excellent thermodynamic stability of ∼500 °C, ordered face-to-face (slipped AA) stacking arrangements were produced. Extended electrical conjugation spanning 2D frames with modest optical bandgaps (Eg) of ∼2.1 eV shows the planar character of diazapyrene-based COFs. The stacking of the conjugated 2D frames with small Eg values is also beneficial for the formation of highly stable conducting pathways in the crystalline state, which was confirmed by the results of the microwave conductivity measurements. Nitrogen centers in diazapyrene units also play a key role as the active sites for proton transfer, and the maximum proton conductivity of σ = 10-2 S cm-1 was achieved along the cocontinuous nanopore structures surrounded by the active sites. Results show that tetragonal COFs based on diazapyrene can be used as a highly crystalline two-dimensional material with special electrical and proton-conducting capabilities.

Nuclear quantum and H/D isotope effects on aromaticity: path integral molecular dynamics study.

Aromaticity is an important concept in organic chemistry, and thus, many theoretical and experimental studies have been conducted so far. However, the majority of theoretical studies have concentrated on the aromaticity of the stationary point structures. Herein, the influence of nuclear quantum fluctuation (nuclear quantum effects: NQEs) and thermal fluctuation on the aromaticity of benzene have been analyzed by path integral molecular dynamics (PIMD) simulation. The PIMD simulations revealed that the NQEs affected not only the C-H bonds but also the C-C bonds. The HOMA and NICS calculations demonstrated that the aromaticity decreased due to the NQEs of carbon atoms, attributed to an increase in the contribution from specific vibrational modes strongly correlated with benzene's aromaticity.

Nuclear quantum effects on the intramolecular hydrogen bonds in biuret and biguanide.

We focus on the unique aspects of biuret and biguanide, which form six-membered ring structures via intramolecular hydrogen bonds. The proton donor and acceptor atoms differ between biuret and biguanide, leading to varying energy barrier heights for proton transfer. We performed path integral molecular dynamics (PIMD) simulations for biuret and biguanide to investigate the correlation between proton transfer and the degree of the delocalization of π-electrons in the six-membered ring framework structure. The results indicate that the π-electrons in the framework structure are delocalized regardless of the ease of intramolecular proton transfer.

Location of the Shared Proton in Proton-Bound Dimer Compound of Hydrogen Sulfate and Formate: Path Integral Molecular Dynamics Study.

The structure of the proton-bound dimer compound of hydrogen sulfate and formate has been studied by considering nuclear quantum effects (NQEs) using the path integral molecular dynamics method. This study unveiled the location of the shared proton and answered the following question: "Is the shared proton localized on either an anion or located around the center of two anions?" We have elucidated that the shared proton is distributed in the region beyond the transition state due to the NQEs, even though the shared proton did not completely overcome the transition state for the proton shuttle.

Molecular Mechanism of SLC6A8 Dysfunction with c.1699T > C (p.S567P) Mutation in Cerebral Creatine Deficiency Syndromes.

Cerebral creatine deficiency syndromes (CCDS) are neurodevelopmental disorders caused by a decrease in creatine levels in the central nervous system (CNS) due to functional mutations in creatine synthetic enzymes or creatine transporter (CRT/SLC6A8). Although SLC6A8 mutations have been reported to be the most frequent cause of CCDS, sufficient treatment for patients with CCDS harboring SLC6A8 mutations has not yet been achieved. This study aimed to elucidate the molecular mechanism of SLC6A8 dysfunction caused by the c. 1699T > C missense mutation, which is thought to induce dysfunction through an unidentified mechanism. A study on SLC6A8-expressing oocytes showed that the c.1699T > C mutation decreased creatine uptake compared to that in wild-type (WT) oocytes. In addition, a kinetics study of creatine uptake revealed that the c.1699T > C mutation reduced the maximum uptake rate but not Michaelis-Menten constant. In contrast, the c.1699T > C mutation did not attenuate SLC6A8 protein levels or alter its cellular localization. Based on the SLC6A8 structure in the AlphaFold protein structure database, it is possible that the c.1699T > C mutation alters the interaction between the S567 and Y143 residues of SLC6A8, leading to decreased creatine transport function. These findings contribute to the understanding of the pathology of CCDS and to the development of strategies for CCDS treatment.

Nuclear quantum effects in phase transition between Ice VII and Ice X.

The theoretical modeling of high-pressure ice remains challenging owing to the complexity in accurately reflecting its properties attributable to nuclear quantum effects. To explore the nuclear quantum effects of the phase transition between Ice VII and Ice X, we introduce an approach based on ab initio path-integral molecular dynamics. The results indicate that quantum effects facilitate the phase transition, with the observed isotope effects consistent with the experimental outcomes. We demonstrate that quantum effects manifest differently across ice phases: In Ice VII, quantum effects reduce the pressure through the centralization of protons. In contrast, in Ice X, quantum effects increase the pressure owing to the increased kinetic energy of zero-point vibration.

Theoretical study of short-range exchange interaction based on semiconductor dielectric function model toward time-dependent dielectric density functional theory.

This study explores various models of semiconductor dielectric functions, with a specific emphasis on the large wavenumber spectrum and the derivation of the screened exchange interaction. Particularly, we discuss the short-range effect of the screened exchange potential. Our investigation reveals that the short-range effect originating from the high wavenumber spectrum is contingent upon the dielectric constant of the targeted system. To incorporate dielectric-dependent behaviors concerning the short-range aspect into the dielectric density functional theory (DFT) framework, we utilize the local Slater term and the Yukawa-type term, adjusting the ratio between these terms based on the dielectric constant. Additionally, we demonstrate the efficacy of the time-dependent dielectric DFT method in accurately characterizing the electronic structure of excited states in dyes and functional molecules. Several theoretical approaches have incorporated parameters dependent on the system to elucidate short-range exchange interactions. Our theoretical analysis and discussions will be useful for those studies.

Nuclear quantum and H/D isotope effects on intramolecular hydrogen bond in curcumin.

Curcumin and its derivatives possess intramolecular low-barrier hydrogen bonds for intramolecular proton transfer. The π-delocalization in the OCCCO framework of the hydrogen bond in these compounds is reorganized concomitantly with the proton transfer. To characterize the hydrogen bond and π-delocalization, we performed path integral molecular dynamics simulations, revealing that although the proton migration and reorganization of the π-delocalized structure showed a positive correlation, the correlation was weak.

Direct Elucidation of the Vibrationally Averaged Structure of Benzene: A Path Integral Molecular Dynamics Study.

Path integral molecular dynamics (PIMD) simulations for C6H6, C6D6, and C6T6 have been carried out to directly estimate the distribution of projected C-H(D,T) bond lengths onto the principal axis plane. The average values of raw C-H(D,T) bond lengths obtained from PIMD simulations are in the order of ⟨RC-H⟩ > ⟨RC-D⟩ > ⟨RC-T⟩ due to the anharmonicity of the potential energy curve. However, the projected C-H(D,T) bond lengths are almost the same as those reported by Hirano et al. [J. Mol. Struct. 2021, 1243, 130537]. Our PIMD simulations directly and strongly support the explanation by Hirano et al. for the experimental observations that almost the same projected C-H(D) bond lengths are found for C6H6 and C6D6. The PIMD simulations also predicted the same projected bond lengths for C6T6 as those of C6H(D)6. In addition to the previous local mode analysis, the present PIMD simulations predicted, for benzene isotopologues, that the vibrationally averaged structure is planar but non-flat.

A path integral molecular dynamics study on the muoniated xanthene-thione molecule.

A positive Mu is a useful tool for investigating the spin density of radical species. The theoretical estimation of its behavior in a molecule requires the inclusion of a quantum effect due to the small mass of muonium. Herein, we performed ab initio a path integral molecular dynamics (PIMD) simulation, which accurately included a multi-dimensional quantum effect, for muoniated 9H-xanthene-9-thione (µXT). Our results showed that the quantum effect significantly increased the hyperfine coupling constant (HFCC) value of µXT, which qualitatively improved the calculated HFCC value, compared to the experimental one. In the PIMD simulation, the bond length between muonium and sulfur in µXT is longer than that between hydrogen and sulfur in a hydrogenated 9H-xanthene-9-thione (HXT), leading to a spin density transfer from XT (9H-xanthene-9-thione) to muonium due to neutral dissociations. Additionally, we found that the S-Mu bond in µXT prefers a structure perpendicular to the molecular plane, where the interaction between Mu and the singly occupied molecular orbital of µXT is the strongest. These structural changes resulted in a larger HFCC value in the PIMD simulation of µXT.

Stability and bonding nature of positronic lithium molecular dianion.

We studied the stability of a system consisting of a positron (e+) and two lithium anions, [Li-; e+; Li-], using first-principles quantum Monte Carlo calculations combined with the multi-component molecular orbital method. While diatomic lithium molecular dianions Li22- are unstable, we found that its positronic complex can form a bound state with respect to the lowest energy decay into the dissociation channel Li2- and a positronium (Ps). The [Li-; e+; Li-] system has the minimum energy at the internuclear distance of ∼3 Å, which is close to the equilibrium internuclear distance of Li2-. At the minimum energy structure both an excess electron and a positron are delocalized as orbiting around the Li2- molecular anion core. A dominant feature of such a positron bonding structure is described as the Ps fraction bound to Li2-, unlike the covalent positron bonding scheme for the electronically isovalent [H-; e+; H-] complex.

A comprehensive theoretical study of positron binding and annihilation properties of hydrogen bonded binary molecular clusters.

We studied the positron binding and annihilation of hydrogen bonded binary molecular clusters containing small inorganic molecules such as water, hydrogen fluoride, ammonia, hydrogen sulfide, hydrogen chloride, and phosphine, using first-principles calculation. While unimolecular systems of these species mostly exhibit no or very small positron binding energies (positron affinities), we found that all of their hydrogen bonding clusters have greater positive positron affinities. The permanent dipole moment enhanced by the formation of the intermolecular hydrogen bond acts as a dominant parameter to bind a positron for a given proton donor, whereas it is insufficient for reproducing the dependence of the positron affinity on substitutions of the proton donor. By multiple regression analyses with inherent properties of the clusters, we found a reasonable model with additional effective parameters represented by, particularly, the number of hydrogen atoms free from the hydrogen bond. By density analyses for the single-particle and electron-positron collision probabilities, we revealed that these effective parameters are associated with the electronic structure changes induced by the hydrogen bond and positron binding, which have important roles to enhance the electron-positron contact densities due to the proton-screening effect.

A path integral molecular dynamics study on the NH4+ rotation in NH4+⋯XH2 (X = Be or Mg) dihydrogen bond systems.

The nuclear quantum effects (NQEs) in dihydrogen bond (DHB) complexes, i.e., NH4+⋯BeH2 and NH4+⋯MgH2, have been investigated using multicomponent quantum mechanics (MC_QM) calculations and path integral molecular dynamics (PIMD) simulation. The MC_QM method considers the NQEs, whereas PIMD considers both the NQEs and the thermal effects. The linear C3v structure is maintained in the optimized structures obtained by the static MP2 and MC_MP2 calculations, whereas the average structures obtained by the PIMD simulation are nonlinear. The strong DHB interaction in NH4+⋯MgH2 suppresses the fluctuation in the Hδ+NMg and Hδ-MgN angles, and hence, the NH4+ rotation did not occur in the simulation of NH4+⋯MgH2. The analysis of the radius of gyration revealed that the nuclear quantum fluctuation in the perpendicular direction is suppressed by the formation of the DHB complex, whereas that in the parallel direction is slightly enhanced in both the Hδ+ and Hδ- nuclei.

Theoretical investigations of positron affinities and their structure-dependent properties of carbon dioxide clusters (CO2)n (n = 1-5).

Although positron binding to van der Waals intermolecularly bonded clusters of non-polar carbon dioxide (CO2) molecules was experimentally suggested, the positron binding feature has been poorly understood. We investigated positron affinities (PAs) by means of multi-component configuration interaction calculations for various structures of (CO2)n (n = 1-5) obtained by the single-component artificial force induced reaction (SC-AFIR) method. Our calculations showed that CO2 monomers do not bind a positron, whereas positron affinities for clusters tend to increase with an increase in the cluster size. Our regression analyses for determining PAs with electrostatic and structural properties of conformations revealed a significant conformer effect due to which structural characteristics such as flatness may have a strong influence on PA for loosely bound positronic complexes of (CO2)n.

Hydrogen/Deuterium Transfer from Anisole to Methoxy Radicals: A Theoretical Study of a Deuterium-Labeled Drug Model.

Recently, deuterium-labeled drugs, such as deutetrabenazine, have attracted considerable attention. Consequently, understanding the reaction mechanisms of deuterium-labeled drugs is crucial, both fundamentally and for real applications. To understand the mechanisms of H- and D-transfer reactions, in this study, we used deuterated anisole as a deutetrabenazine model and computationally considered the nuclear quantum effects of protons, deuterons, and electrons. We demonstrated that geometrical differences exist in the partially and fully deuterated methoxy groups and hydrogen-bonded structures of intermediates and transition states due to the H/D isotope effect. The observed geometrical features and electronic structures are ascribable to the different nuclear quantum effects of protons and deuterons. Primary and secondary kinetic isotope effects (KIEs) were calculated for H- and D-transfer reactions from deuterated and undeuterated anisole, with the calculated primary KIEs in good agreement with the corresponding experimental data. These results reveal that the nuclear quantum effects of protons and deuterons need to be considered when analyzing the reaction mechanisms of H- and D-transfer reactions and that a theoretical approach that directly includes nuclear quantum effects is a powerful tool for the analysis of H/D isotope effects in H- and D-transfer reactions.

Transport Characteristics of Placenta-Derived Extracellular Vesicles and Their Relevance to Placenta-to-Maternal Tissue Communication.

The placenta, a unique organ that helps maintain a healthy pregnancy, plays a pivotal role in maternal adaptation to pregnancy and releases extracellular vesicles (EVs), autacoids, and hormones. EVs are membranous vesicles released by all types of cells, including placental trophoblasts, which are involved in intracellular communication by delivering their cargo, such as proteins, nucleic acids, and lipids, to the targeted cells in a neighboring or distant location. Recently, an increasing number of publications have reported that EVs secreted from the placenta into maternal circulation deliver their cargo to maternal organs and mediate placenta-to-maternal communication during pregnancy. This review provides an overview of the transport mechanism of placenta-derived EVs to maternal organs.

Contribution of monocarboxylate transporter 12 to blood supply of creatine on the sinusoidal membrane of the hepatocytes.

Creatine (Cr)/phosphocreatine has the ability to buffer the high-energy phosphate, thereby contributing to intracellular energy homeostasis. As Cr biosynthetic enzyme deficiency is reported to increase susceptibility to colitis under conditions of inflammatory stress, Cr is critical for maintaining intestinal homeostasis under inflammatory stress. Cr is mainly produced in the hepatocytes and then distributed to other organs of the body by the circulatory system. Since monocarboxylate transporter 9 (MCT9) and monocarboxylate transporter 12 (MCT12) have been reported to accept Cr as a substrate, these transporters are proposed as candidates for Cr efflux transporter in the liver. The aim of this study was to elucidate the transport mechanism on Cr supply from the hepatocytes. Immunohistochemical staining of the rat liver sections revealed that both MCT9 and MCT12 were localized on the sinusoidal membrane of the hepatocytes. In the transport studies using Xenopus laevis oocyte expression system, [14C]Cr efflux from MCT9- or MCT12-expressing oocytes was significantly greater than that from water-injected oocytes. [14C]Cr efflux from primary cultured hepatocytes was significantly decreased following MCT12 mRNA knockdown, whereas this efflux was not decreased after mRNA knockdown of MCT9. Based on the extent of MCT12 protein downregulation and Cr efflux after knockdown of MCT12 in primary cultured rat hepatocytes, the contribution ratio of MCT12 in Cr efflux was calculated as 76.4%. Our study suggests that MCT12 substantially contributes to the efflux of Cr at the sinusoidal membrane of the hepatocytes.NEW & NOTEWORTHY Our study is the first to identify the role of monocarboxylate transporter 12 (MCT12) as a transporter of creatine (Cr) in the liver. MCT12 was found to significantly contribute to the efflux of Cr on the sinusoidal membrane of the hepatocytes. Since hepatocytes are known to be involved in creatine biosynthesis, the present findings can be beneficial for the regulation of Cr biosynthesis and supply.

A theoretical study on solvatofluorochromic asymmetric thiazolothiazole (TTz) dyes using dielectric-dependent density functional theory.

In this work, the excitation energies of asymmetric thiazolothizaole (TTz) dye molecules have been theoretically studied using dielectric-dependent density functional theory (DFT). In the dielectric-dependent DFT approach, the ratio (fraction) of the nonlocal Hartree exchange term incorporated into the DFT exchange-correlation functional is a system-dependent parameter, which is inversely proportional to the dielectric constant of the target material. The dielectric-dependent DFT method is closely related to the Coulomb hole and screened exchange (COHSEX) approximation in the GW method and therefore has been applied to crystalline systems with periodic boundary conditions, such as semiconductors and inorganic materials. By focusing on the solvatofluorochromic phenomena of asymmetric TTz dyes, we show that excitation energy calculations obtained from the dielectric-dependent DFT method can reproduce the corresponding experimental UV-vis absorption and emission spectra of dyes in solvents.

Theoretical investigation of the enhancement of positron affinity by the vibration and dimerization of non-polar carbon disulfide.

The positronic bound state for the non-polar carbon disulfide (CS2) has been experimentally identified, although previous theoretical investigations, which were dedicated to studying the positronic CS2 monomer, could not reasonably reproduce the experimentally measured positron affinity. In the present study, we performed analysis of the vibrational averaged positron affinity for the positronic CS2 dimer, [C2S4; e+], using the Hartree-Fock and configuration interaction levels of the multi-component molecular orbital method combined with the self-consistent field level of the vibrational variational Monte Carlo method. We demonstrated that the equilibrium structure of the non-polar C2S4 can have the positronic bound state with a positron affinity of about 46.18 meV in the configuration interaction level, while this is 0 meV in the Hartree-Fock level. Furthermore, by taking into account the vibrational effect, we succeeded in reproducing the resonant positron kinetic energies lying close to the experimental value, where the vibrational averaged positron affinity becomes greater with an increased dipole moment and dipole polarizability. We also showed possible mechanisms to effectively enhance the resonant positron capture for [C2S4; e+], associated with both the infrared active and infrared inactive vibrational modes.