Inverse Versus Normal Behavior of Interactions, Elucidated Based on the Dynamic Nature with QTAIM Dual-Functional Analysis.

In QTAIM dual-functional analysis, Hb(rc) is plotted versus Hb(rc) - Vb(rc)/2 for the interactions, where Hb(rc) and Vb(rc) are the total electron energy densities and potential energy densities, respectively, at the bond critical points (BCPs) on the interactions in question. The plots are analyzed by the polar (R, θ) coordinate representation for the data from the fully optimized structures, while those from the perturbed structures around the fully optimized structures are analyzed by (θp, κp). θp corresponds to the tangent line of the plot, and κp is the curvature; θ and θp are measured from the y-axis and y-direction, respectively. The normal and inverse behavior of interactions is proposed for the cases of θp > θ and θp < θ, respectively. The origin and the mechanism for the behavior are elucidated. Interactions with θp < θ are typically found, although seldom for [F-I-∗-F]-, [MeS-∗-TeMe]2+, [HS-∗-TeH]2+ and CF3SO2N-∗-IMe, where the asterisks emphasize the existence of BCPs in the interactions and where [Cl-Cl-∗-Cl]- and CF3SO2N-∗-BrMe were employed as the reference of θp > θ. The inverse behavior of the interactions is demonstrated to arise when Hb(rc) - Vb(rc)/2 and when the corresponding Gb(rc), the kinetic energy densities at BCPs, does not show normal behavior.

Dynamic and Static Nature of XH-∗-π and YX-∗-π (X = F, Cl, Br, and I; Y = X and F) in the Distorted π-System of Corannulene Elucidated with QTAIM Dual Functional Analysis.

The dynamic and static nature of the XH-∗-π and YX-∗-π (X = F, Cl, Br, and I; Y = X and F) interactions in the distorted π-system of corannulene (π(C20H10)) is elucidated with a QTAIM dual functional analysis (QTAIM-DFA), where asterisks emphasize the presence of bond critical points (BCPs) on the interactions. The static and dynamic nature originates from the data of the fully optimized and perturbed structures, respectively, in QTAIM-DFA. On the convex side, H in F-H-∗-π(C20H10) and each X in Y-X-∗-π(C20H10) join to C of the central five-membered ring in π(C20H10) through a bond path (BP), while each H in X-H-∗-π(C20H10) does so to the midpoint of C=C in the central five-membered ring for X = Cl, Br, or I. On the concave side, each X in F-X-∗-π(C20H10) also joins to C of the central five-membered ring with a BP for X = H, Cl, Br, and I; however, the interactions in other adducts are more complex than those on the convex side. Both H and X in X-H-∗-π(C20H10) (X = Cl and Br) and both Fs in F-F-∗-π(C20H10) connect to the three C atoms in each central five-membered ring (with three BPs). Two, three, and five BPs were detected for the Cl-Cl, I-H, Br-Br, and I-I adducts, where some BPs do not stay on the central five-membered ring in π(C20H10). The interactions are predicted to have a vdW to CT-MC nature. The interactions on the concave side seem weaker than those on the convex side for X-H-∗-π(C20H10), whereas the inverse trend is observed for Y-X-∗-π(C20H10) as a whole. The nature of the interactions in the π(C20H10) adducts of the convex and concave sides is examined in more detail, employing the adducts with X-H and F-X placed on their molecular axis together with the π(C24H12) and π(C6H6) adducts.

Mild heat stimulation facilitates muscle hypertrophy in C2C12 and mouse satellite cells through myokine release to the culture medium.

Mild heat stimulation is defined as a stimulation that occurs several degrees above optimal cell culture or body temperatures. Muscle hypertrophy in C2C12 cells is reportedly facilitated by 39 °C mild heat stimulation. However, the underlying molecular mechanisms by which 39 °C mild heat stimulation promotes muscle hypertrophy remains elusive. In this study, we aimed at understanding the details of these mechanisms. First, we found that 39 °C mild heat stimulation has little or no effect on Myogenesis-Related Factor (MRF) expression both in C2C12 and mouse primary satellite cells. Therefore, we hypothesized that 39 °C mild heat stimulation promotes muscle hypertrophy through myokines, essential components in myogenesis. Interestingly, we observed muscle hypertrophy in the group cultured at 37 °C in conditioned medium from 39 °C compared to the group cultured at 37 °C in conditioned medium from 37 °C in the case of both C2C12 and mouse primary satellite cells. These results suggest that 39 °C mild heat stimulation promotes muscle hypertrophy through myokines, once released in the culture medium. Finally, we identified Decorin as a hypertrophy-inducing myokine candidate. Therefore, in this study, we demonstrated that 39 °C mild heat stimulation contributes to muscle hypertrophy through enhancing Decorin gene expression in C2C12 and mouse primary satellite cells.

Insulin-like growth factor-1 induces IRE1-XBP1-dependent endoplasmic reticulum biogenesis in bovine mammary epithelial cells.

Insulin-like growth factor-1 (IGF-1) plays a key role in proliferation and galactopoiesis in mammary epithelial cells (MEC), but its definitive functions on endoplasmic reticulum (ER) during protein synthesis remain unknown. The present study aimed to elucidate the effects of IGF-1 on ER biogenesis in MEC in vitro and examined the expression of ER biogenesis-associated genes in the mammary gland during early lactation. We treated mammary alveolar cells-large T antigen cells (immortalized bovine MEC line established via stable transfection with simian virus-40 large T-antigen) with IGF-1 and examined ER biogenesis using the fluorescence intensity of an ER tracker and quantitative real-time PCR. We found IGF-1 significantly increased ER tracker staining and upregulated mRNA levels of ER biogenesis-related genes, such as CHKA (choline kinase α), PCYT1A (choline-phosphate cytidylyltransferase A), and SURF4 (surfeit locus protein 4). We focused on unfolded protein response to explore molecular mechanisms by which IGF-1 induces ER biogenesis. We found IGF-1 significantly increased mRNA levels of the XBP1 splicing form (XBP1s). Based on western blot analysis, IGF-1 induced the expression of (inositol-requiring kinase 1 α) protein, upstream of XBP1s, and phosphorylated-IRE1α. The inhibition of IRE1 endoribonuclease activity with 4-methylumbelliferone 8-carbaldehyde (4µ8C) significantly suppressed the increase in ER tracker fluorescence and ER biogenesis-related gene expression induced by IGF-1. Also, IGF-1-induced XBP1s and ER biogenesis-associated gene expression was inhibited by rapamycin, an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), indicating that IRE1-XBP1 activation by IGF-1 is mediated by mTORC1. Moreover, to clarify the expression of XBP1s and ER biogenesis-associated genes expression under normal physiological conditions, mammary gland tissue from biopsies of dairy cows during late gestation and lactation were analyzed. In vivo data highlighted the significant increases in the mRNA levels of XBP1s and ER biogenesis-related genes in mammary gland tissue immediately after calving through 6 wk of lactation. The mRNA levels of IGF1R (IGF-1 receptor) in mammary glands increased during 6 wk of lactation. Therefore, the present study indicated for the first time that IGF-1 induces ER biogenesis by activating the IRE1-XBP1 axis under the regulation of mTORC1 in bovine MEC line.

Intrinsic Dynamic and Static Nature of Halogen Bonding in Neutral Polybromine Clusters, with the Structural Feature Elucidated by QTAIM Dual-Functional Analysis and MO Calculations.

The intrinsic dynamic and static nature of noncovalent Br-∗-Br interactions in neutral polybromine clusters is elucidated for Br4-Br12, applying QTAIM dual-functional analysis (QTAIM-DFA). The asterisk (∗) emphasizes the existence of the bond critical point (BCP) on the interaction in question. Data from the fully optimized structures correspond to the static nature of the interactions. The intrinsic dynamic nature originates from those of the perturbed structures generated using the coordinates derived from the compliance constants for the interactions and the fully optimized structures. The noncovalent Br-∗-Br interactions in the L-shaped clusters of the Cs symmetry are predicted to have the typical hydrogen bond nature without covalency, although the first ones in the sequences have the vdW nature. The L-shaped clusters are stabilized by the n(Br)→σ*(Br-Br) interactions. The compliance constants for the corresponding noncovalent interactions are strongly correlated to the E(2) values based on NBO. Indeed, the MO energies seem not to contribute to stabilizing Br4 (C2h) and Br4 (D2d), but the core potentials stabilize them, relative to the case of 2Br2; this is possibly due to the reduced nuclear-electron distances, on average, for the dimers.

Effects of fatty acids on inducing endoplasmic reticulum stress in bovine mammary epithelial cells.

Fatty acids play important roles in the regulation of endoplasmic reticulum (ER) stress-induced apoptosis in different cells. Currently, the effects of fatty acids on bovine mammary epithelial cells (MEC) remain unknown. Our study examined bovine MEC viability and measured unfolded protein response (UPR)-related gene and protein expressions following fatty acid treatments. To evaluate the role of fatty acids, we treated MAC-T cells (a line of MEC) with 100 to 400 µM of saturated (palmitic and stearic acid) and unsaturated (palmitoleic, oleic, linoleic, and linolenic acid) fatty acids and 1 to 5 mM of short- and medium-chain fatty acids (acetic, propionic, butyric, and octanoic acid). Thereafter, we determined UPR-related gene expression using quantitative real-time PCR. Palmitic acid stimulated expression of XBP1s, ATF4, ATF6A, and C/EBP homologous protein (CHOP). Stearic acid increased expression of XBP1s and CHOP and decreased expression of ATF4 and ATF6A. Results of Western blot analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that palmitic and stearic acid reduced MAC-T cell viability and induced extreme ER stress by increasing the protein expression of ER stress markers, such as phospho-PKR-like endoplasmic reticulum kinase, phospho-eIF2α, cleaved CASP-3, and CHOP. Among unsaturated long-chain fatty acids, palmitoleic acid increased expression of ATF4 and ATF6A. Oleic acid increased expression of XBP1s, ATF4, and ATF6A. Linoleic and linolenic acids increased expression of XBP1s, ATF4, and ATF6A but decreased expression of XBP1s and ATF6A at the highest dose. Although palmitoleic, oleic, and linoleic acid decreased CHOP expression, only palmitoleic acid increased MAC-T cell viability. Therefore, unsaturated long-chain fatty acids did not induce severe ER stress. Acetic, propionic, and butyric acids decreased expression of ATF4, ATF6A, and CHOP and increased XBP1s expression. Although only octanoic acid increased ATF4 and ATF6A expressions, it lowered expression of XBP1s and CHOP. Although fatty acid treatment did not increase the levels of ER stress proteins, butyric and octanoic acids reduced cell viability, possibly because of early differentiation. These results suggest that saturated fatty acids play important roles in MEC viability by inducing severe ER stress compared with unsaturated fatty acids. In addition, acetic and propionic acids (short- and medium-chain fatty acids) reduced ER stress. Therefore, the present study reflects the new insight that serum fatty acid concentration plays an important role in maintaining the lactation physiology of dairy cows.

IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts.

In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1-XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1-XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1-XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1-XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

Behavior of the E-E' Bonds (E, E' = S and Se) in Glutathione Disulfide and Derivatives Elucidated by Quantum Chemical Calculations with the Quantum Theory of Atoms-in-Molecules Approach.

The nature of the E-E' bonds (E, E' = S and Se) in glutathione disulfide (1) and derivatives 2-3, respectively, was elucidated by applying quantum theory of atoms-in-molecules (QTAIM) dual functional analysis (QTAIM-DFA), to clarify the basic contribution of E-E' in the biological redox process, such as the glutathione peroxidase process. Five most stable conformers a-e were obtained, after applying the Monte-Carlo method then structural optimizations. In QTAIM-DFA, total electron energy densities Hb(rc) are plotted versus Hb(rc) - Vb(rc)/2 at bond critical points (BCPs), where Vb(rc) are potential energy densities at BCPs. Data from the fully optimized structures correspond to the static nature. Those containing perturbed structures around the fully optimized one in the plot represent the dynamic nature of interactions. The behavior of E-E' was examined carefully. Whereas E-E' in 1a-3e were all predicted to have the weak covalent nature of the shared shell interactions, two different types of S-S were detected in 1, depending on the conformational properties. Contributions from the intramolecular non-covalent interactions to stabilize the conformers were evaluated. An inverse relationship was observed between the stability of a conformer and the strength of E-E' in the conformer, of which reason was discussed.

The role of unfolded protein response in differentiation of mammary epithelial cells.

The accumulation of misfolded proteins in the ER provokes ER stress by increasing the demand for energy, chaperones, and other proteins that are needed to fold client proteins or to degrade unfoldable secretory cargo. This stress activates a signaling network called the unfolded protein response (UPR). However, recent accumulated data suggested that the UPR also provides important signals for regulating cell differentiation and maturation. However, the relationship between UPR and mammary gland development has not been fully elucidated. To define the involvement of the UPR in mammary gland development, mammary glands were collected from non-pregnant mice, at days 5, 10 and 15 of pregnancy, at days 1 and 7 of lactation, and the expression patterns of UPR-related genes were determined by real-time PCR. We found that the mRNA expression of ATF4 and XBP1 significant increased during pregnancy. Moreover, we found that both ATF4 and XBP1 proteins are expressed in mammary epithelial cells by immunohistological analysis. In order to know the role of ATF4 and XBP1 in the differentiation of mammary epithelial cell, we performed gene knockdown experiment using HC11 cells. We found that ATF4 or XBP1 knockdown suppressed the mRNA expression of beta-casein and lactogenic hormone receptor in differentiating HC11 cells. Our results demonstrate that XBP1 and ATF4, which are UPR-related transcription factors, directly or indirectly participate in cell differentiation mechanisms through the regulation of the expression of lactogenic hormone receptors in mouse mammary epithelial cells.

Relativistic Effect on 1 J(M,C) in Me4 M, Me3 M- , Ph4 M, and Ph3 M- (M=Pb, Sn, Ge, Si, and/or C): Role of s-Type Lone Pair Orbitals in the Distinct Effect for the Anionic Species.

Indirect one-bond nuclear spin-spin couplings between M and C [1 J(M,C)] in Me4 M, Me3 M- , Ph4 M, and Ph3 M- (M=Pb, Sn, Ge, Si, C) are analyzed with consideration of the relativistic effect and by employing Slater-type basis sets. The evaluated total values 1 JTL (M,C) reproduced the observed values with some systematic calculation errors. Fermi contact terms 1 JFC (M,C) contribute predominantly to 1 JTL (M,C) (≈99 %). A distinct relativistic effect on 1 J(Pb,C) is predicted for Me3 Pb- and Ph3 Pb- . The mechanisms for the distinct effect are elucidated by using the comparison between Me3 Pb- and Me4 Pb as an example. The contributions to 1 JFC (M,C) [or 1 JSD+FC (M,C), where SD denotes the spin-dipolar term] are decomposed into those of occupied orbitals and occupied-to-unoccupied transitions. The s-type lone-pair orbitals are demonstrated to contribute to the distinct relativistic effect on 1 J(Pb,C) of Me3 Pb- (and Ph3 Pb- ). The results are in sharp contrast to the cases of 1 J(M,C) for M atoms lighter than Pb, such as Si, and are explained by the s character of the M-C bonds. This treatment enables visualization and clear recognition the origin of the nuclear couplings for the species exhibiting a relativistic effect.

Linear Four-Chalcogen Interactions in Radical Cationic and Dicationic Dimers of 1,5-(Dichalcogena)canes: Nature of the Interactions Elucidated by QTAIM Dual Functional Analysis with QC Calculations.

The dynamic and static nature of extended hypervalent interactions of the BE···AE···AE···BE type are elucidated for four center-seven electron interactions (4c-7e) in the radical cationic dimers (1·+) and 4c-6e in the dicationic dimers (12+) of 1,5-(dichalcogena)canes (2: AE(CH2CH2CH2)2BE: AE, BE = S, Se, Te, and O). The quantum theory of atoms-in-molecules dual functional analysis (QTAIM-DFA) is applied for the analysis. Total electron energy densities Hb(rc) are plotted versus Hb(rc) - Vb(rc)/2 [= (ℏ2/8m)∇2ρb(rc)] at bond critical points (BCPs) of the interactions, where Vb(rc) values show potential energy densities at BCPs. Data from the fully optimized structures correspond to the static nature of the interactions. Those from the perturbed structures around the fully optimized ones are also plotted, in addition to those of the fully optimized ones, which represent the dynamic nature of interactions. The BE···AE-AE···BE interactions in 12+ are stronger than the corresponding ones in 1·+, respectively. On the one hand, for 12+ with AE, BE = S, Se, and Te, AE···AE are all classified by the shared shell interactions and predicted to have the weak covalent nature, except for those in 1a2+ (AE = BE = S) and 1d2+ (AE = BE = Se), which have the nature of regular closed shell (r-CS)/trigonal bipyramidal adduct formation through charge transfer (CT-TBP). On the other hand, AE···BE are predicted to have the nature of r-CS/molecular complex formation through charge transfer for 1a2+, 1b2+ (AE = Se; BE = S), and 1d2+ or r-CS/CT-TBP for 1c2+ (AE = Te; BE = S), 1e2+ (AE = Te; BE = Se), and 1f2+ (AE = BE = Te). The BE···AE-AE···BE interactions in 1·+ and 12+ are well-analyzed by applying QTAIM-DFA.

Behavior of Halogen Bonds of the Y-X⋠⋠⋠π Type (X, Y=F, Cl, Br, I) in the Benzene π System, Elucidated by Using a Quantum Theory of Atoms in Molecules Dual-Functional Analysis.

The nature of halogen bonds of the Y-X-✶-π(C6 H6 ) type (X, Y=F, Cl, Br, and I) have been elucidated by using the quantum theory of atoms in molecules (QTAIM) dual-functional analysis (QTAIM-DFA), which we proposed recently. Asterisks (✶) emphasize the presence of bond-critical points (BCPs) in the interactions in question. Total electron energy densities, Hb (rc ), are plotted versus Hb (rc )-Vb (rc )/2 [=(h(2) /8m)∇(2) ρb (rc )] for the interactions in QTAIM-DFA, in which Vb (rc ) are potential energy densities at the BCPs. Data for perturbed structures around fully optimized structures were used for the plots, in addition to those of the fully optimized ones. The plots were analyzed by using the polar (R, θ) coordinate for the data of fully optimized structures with (θp , κp ) for those that contained the perturbed structures; θp corresponds to the tangent line of the plot and κp is the curvature. Whereas (R, θ) corresponds to the static nature, (θp , κp ) represents the dynamic nature of the interactions. All interactions in Y-X-✶-π(C6 H6 ) are classified by pure closed-shell interactions and characterized to have vdW nature, except for Y-I-✶-π(C6 H6 ) (Y=F, Cl, Br) and F-Br-✶-π(C6 H6 ), which have typical hydrogen-bond nature without covalency. I-I-✶-π(C6 H6 ) has a borderline nature between the two. Y-F-✶-π(C6 H6 ) (Y=Br, I) were optimized as bent forms, in which Y-✶-π interactions were detected. The Y-✶-π interactions in the bent forms are predicted to be substantially weaker than those in the linear F-Y-✶-π(C6 H6 ) forms.

Mechanistic Studies on the Generation and Properties of Superelectrophilic Singlet Carbenes from Bis(perfluoroalkanesulfonyl)bromonium Ylides.

Pyrolysis of bis(perfluoroalkanesulfonyl)bromonium ylides in various olefins results in highly stereospecific formation of cyclopropanes via unimolecular decomposition. Product analysis, kinetic study, substituent effects, and theoretical study revealed the generation of singlet bis(perfluoroalkanesulfonyl)carbenes stabilized by intramolecular coordination of sulfonyl oxygen.

Dynamic and static behavior of the H...π and E...π interactions in EH2 adducts of benzene π-system (E = O, S, Se and Te), elucidated by QTAIM dual functional analysis.

Dynamic and static behavior of the interactions in the EH2 adducts of a benzene π-system (E = O, S, Se and Te) is elucidated by applying QTAIM-DFA (QTAIM dual functional analysis). Two types of H-*-π and E-*-π interactions are detected in the adducts, where the asterisk (*) emphasizes the existence of the bond critical point (BCP) on the interaction in question. Total electron energy densities Hb(rc) are plotted versus Hb(rc) -Vb(rc)/2 [=(ℏ(2)/8m)∇(2)ρb(rc)] at BCPs in QTAIM-DFA, where Vb(rc) are the potential energy densities at BCPs. Data from the fully optimized structures are analyzed by polar (R, θ) coordinate representation. Each plot for an interaction, containing data from the perturbed structures with those of the fully optimized one, shows a specific curve, which provides important information. The plot is expressed by (θp, κp): θp corresponds to the tangent line for the plot and κp is the curvature. θ and θp are measured from the y-axis and y-direction, respectively. Moreover, (R, θ) corresponds to the static nature, (θp, κp) represents the dynamic nature of interactions. While θ classifies the interaction in question, θp characterizes it. Both values are less than 90° for all H-*-π and E-*-π interactions examined in this study; therefore, they are all classified by the pure closed-shell interactions and predicted to have the character of vdW nature. However, it is suggested that E-*-π has the nature of the stronger interaction than the case of H-*-π for dynamic behavior in the same species evaluated at the MP2 and M06-2X levels. The nature of the interactions is well analyzed and specified by applying QTAIM-DFA.

Transannular E···E' Interactions in Neutral, Radical Cationic, and Dicationic Forms of cyclo-[E(CH2CH2CH2)2E'] (E, E' = S, Se, Te, and O) with Structural Feature: Dynamic and Static Behavior of E···E' Elucidated by QTAIM Dual Functional Analysis.

The nature of the transannular E-∗-E' interactions in neutral, radical cationic, and dicationic forms of cyclo-E(CH2CH2CH2)2E' (1) (E, E' = S, Se, Te, and O) (1, 1(•+), and 1(2+), respectively) is elucidated by applying QTAIM dual functional analysis (QTAIM-DFA). Hb(rc) are plotted versus Hb(rc) - Vb(rc)/2 for the data of E-∗-E' at BCPs in QTAIM-DFA, where ∗ emphasizes the existence of BCP. Plots for the fully optimized structures are analyzed by the polar coordinate (R, θ) representation. Those containing the perturbed structures are by (θp, κp): θp corresponds to the tangent line of the plot, and κp is the curvature. While (R, θ) describes the static nature, (θp, κp) represents the dynamic nature of interactions. The nature is well-specified by (R, θ) and (θp, κp). E-∗-E' becomes stronger in the order of 1 < 1(•+) < 1(2+), except for O-∗-O. While E-∗-E' (E, E' = S, Se, and Te) in 1(2+) are characterized as weak covalent bonds, except for S-∗-Te (MC nature through CT) and Se-∗-Te (TBP nature through CT), O-∗-E' seems more complex. The behavior of E-∗-E' in 1(2+) is very close to that of cyclo-E(CH2CH2CH2)E' (E, E' = S, Se, Te, and O), except for O-∗-O.

Dynamic and static behavior of hydrogen bonds of the X-H···π type (X = F, Cl, Br, I, RO and RR'N; R, R' = H or Me) in the benzene π-system, elucidated by QTAIM dual functional analysis.

Dynamic and static behavior of the X-H-*-π interactions in X-H-*-π(C6H6) (X = F, Cl, Br, I, HO, MeO, H2N, MeHN and Me2N) is elucidated by QTAIM-DFA (QTAIM dual functional analysis), which we proposed recently, as the first step to clarify various types of X-H-*-π interactions. The asterisk * emphasizes the existence of the bond critical point (BCP) on the interaction in question. Total electron energy densities (H(b)(r(c))) are plotted versus H(b)(r(c)) - V(b)(r(c))/2 [=(ℏ(2)/8m)∇(2)ρ(b)(r(c))] at BCPs in QTAIM-DFA, where V(b)(r(c)) are potential energy densities at BCPs. In our treatment, data for the perturbed structures around the fully optimized ones are employed, in addition to those for the fully optimized structures. Data from the fully optimized structures are analyzed by the polar coordinate (R, θ) representation. Each plot for an interaction, containing data from the perturbed structures, shows a specific curve, which provides important information. The plot is expressed by (θ(p), κ(p)): θ(p) corresponds to the tangent line of the plot and κ(p) is the curvature. θ and θ(p) are measured from the y-axis and the y-direction, respectively. While (R, θ) correspond to the static nature, (θ(p), κ(p)) represent the dynamic nature of interactions. The nature of the X-H-*-π(C6H6) interactions is well specified by (R, θ) and (θ(p), κ(p)). All interactions, examined in this work, are classified by the pure closed shell interactions and predicted to have the van der Waals nature.

System-level identification of transcriptional circuits underlying mammalian circadian clocks.

Mammalian circadian clocks consist of complexly integrated regulatory loops, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E' boxes, DBP/E4BP4 binding elements and RevErbA/ROR binding elements in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E' boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E' boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.

Intrinsic dynamic and static natures of APn--X+--BPn σ(3c-4e) type interactions (APn = BPn = N, P, As and Sb; X = H, F, Cl, Br and I) in bicyclo[3.3.3] and bicyclo[4.4.4] systems and their behaviour, elucidated with QTAIM dual functional analysis.

The intrinsic dynamic and static natures of APn--X+--BPn (APn = BPn: N, P, As and Sb; X = H, F, Cl, Br and I) in 1a+-8c+ were elucidated with the quantum theory of atoms-in-molecules dual functional analysis (QTAIM-DFA). Species 1a+-8c+ were formed by incorporating X+ between APn and BPn of APn(CH2CH2CH2)3BPn (1-4) and APn(CH2CH2CH2CH2)3BPn (5-8). The relative stabilities between the symmetric and nonsymmetric structures along with their transition states were investigated. Various natures from typical hydrogen bonds (t-HB) to classical covalent bonds were predicted for the APn-X/BPn-X interactions in APn--X+--BPn with QTAIM-DFA. The secondary interactions of H-H and X-C were also detected. The vdW to molecular complexes through charge transfer natures were predicted for them. Natural bond orbital analysis clarified that the CT terms were caused by not only n(APn)→ σ*(X-BPn) but also σ(APn-C)→σ*(X-BPn), σ(APn-C/BPn-C)→np(X+) and n(X)→ns(Pn+). The direction and magnitude of the p-character of n(APn) were the factors that determined the types of donor-acceptor interactions. Estimating the order of the interaction strengths was attempted. The σ(3c-4e) characters of APn--X+--BPn were also examined by analysing the charge distributions on APn--X+--BPn. These results would provide fundamentally important insight into designing molecules with high functionality containing X+ in symmetric and nonsymmetric structures.

Origin of 17O NMR chemical shifts based on molecular orbital theory: paramagnetic terms of the pre-α, α and ß effects from orbital-to-orbital transitions, along with the effects from vinyl, carbonyl and carboxyl groups.

17O NMR chemical shifts (δ(O)) were analysed based on the molecular orbital (MO) theory, using the diamagnetic, paramagnetic and total absolute magnetic shielding tensors (σd(O), σp(O) and σt(O), respectively). O2- was selected as the standard for the analysis. An excellent relationship was observed between σd(O) and the charges on O for O6+, O4+, O2+, O0 and O2-. The data from H2O, HO+, HO- and H3O+ were on the correlation line. However, such relationship was not observed for the oxygen species, other than above. The pre-α, α and ß effects were evaluated bases on σt(O), where the pre-α effect arises from the protonation to a lone pair orbital on O2-, for an example. The 30-40 ppm and 20-40 ppm (downfield shifts) were predicted for the pre-α and ß effects, respectively, whereas the values for the α effect was very small in magnitude, where the effect from the hydrogen bond formation should be considered. Similarly, the carbonyl effect in H2C[double bond, length as m-dash]O and the carboxyl effects in H(HO)C[double bond, length as m-dash]O were evaluated from MeOH, together with H2C[double bond, length as m-dash]CHOH from CH3CH2OH. Very large downfield shifts of 752, 425 and 207 ppm were predicted for H2C[double bond, length as m-dash]O*, H(HO)C[double bond, length as m-dash]O* and H(HO*)C[double bond, length as m-dash]O, respectively, together with the 81 ppm downfield shift for H2C[double bond, length as m-dash]CHO*H. The origin of the effect were visualized based on the occupied-to-unoccupied orbital transitions. As a result, the origin of the 17O NMR chemical shifts (δ(17O)) can be more easily imaged and understand through the image of the effects. The results would help to understand the role of O in the specific position of a compound in question and the mechanisms to arise the shift values also for the experimental scientists. The aim of this study is to establish the plain rules founded in theory for δ(17O), containing the origin, which has been achieved through the treatments.

Extremely stable system of 1-haloselanyl-anthraquinones: experimental and theoretical investigations.

Highly stable selanyl halides, 1-ATQSeX (X = I (1), Br (2) and Cl (3)), were prepared. The structures of 1, 2, 6 (1-ATQSeX: X = Me) and 7 (1-ATQBr) were determined. QC calculations were performed on 1-3, 4 (X = F), 5 (X = H), 6, 7 and 8 (X = SeATQ-1). The O⋯Se distances in 1-4 from the sum of the vdW radii of the atoms (Δr(Se, O1)) were less than -1 Å, in magnitude, which must be the driving force for the high stability. The O-*-Se interactions seem stronger in the order of 1 < 2 < 3 < 4. The intrinsic dynamic and static natures of O⋯Se and/or Se⋯X in 1-8 are elucidated by QTAIM dual functional analysis (QTAIM-DFA). The Se-*-I, Se-*-Br, Se-*-Cl and Se-*-F interactions in 1-4 are predicted to have the natures of covalent, TBP with CT, TBP with CT, and typical HB with covalency, respectively, whereas O-*-Ses in 1-4 are all predicted to have the nature of MC with CT. The Se-*-H, Se-*-CMe and Se-*-Se interactions in 5, 6 and 8 are all predicted to have the covalent nature, while O-*-Ses in 5, 6 and 8 are all predicted to have the nature of typical HB with no covalency. The E(2) values of 1-6 and 8 are calculated with NBO analysis, and correlate excellently with Δr(Se, O1), except for Se-*-F, for which E(2) is evaluated to be much larger. The E(2) values also correlate very well with Cii-1 for all Se-*-X in 1-4, although data from 5, 6 and 8 deviated from the correlation, where Cii is the diagonal element of the compliance (force) constant for the internal vibrations. The behaviour of the interactions is further examined based on the QTAIM-DFA parameters of θ and θp. The stabilizing effect is further confirmed by the calculations with the ν(CO) values analyzed carefully.