Ensemble dynamics and information flow deduction from whole-brain imaging data.

The recent advancements in large-scale activity imaging of neuronal ensembles offer valuable opportunities to comprehend the process involved in generating brain activity patterns and understanding how information is transmitted between neurons or neuronal ensembles. However, existing methodologies for extracting the underlying properties that generate overall dynamics are still limited. In this study, we applied previously unexplored methodologies to analyze time-lapse 3D imaging (4D imaging) data of head neurons of the nematode Caenorhabditis elegans. By combining time-delay embedding with the independent component analysis, we successfully decomposed whole-brain activities into a small number of component dynamics. Through the integration of results from multiple samples, we extracted common dynamics from neuronal activities that exhibit apparent divergence across different animals. Notably, while several components show common cooperativity across samples, some component pairs exhibited distinct relationships between individual samples. We further developed time series prediction models of synaptic communications. By combining dimension reduction using the general framework, gradient kernel dimension reduction, and probabilistic modeling, the overall relationships of neural activities were incorporated. By this approach, the stochastic but coordinated dynamics were reproduced in the simulated whole-brain neural network. We found that noise in the nervous system is crucial for generating realistic whole-brain dynamics. Furthermore, by evaluating synaptic interaction properties in the models, strong interactions within the core neural circuit, variable sensory transmission and importance of gap junctions were inferred. Virtual optogenetics can be also performed using the model. These analyses provide a solid foundation for understanding information flow in real neural networks.

Synthesis of All-Peptide-Based Rotaxane from a Proline-Containing Cyclic Peptide.

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.

Open-boundary cluster model with a parameter-free complex absorbing potential.

In quantum chemical calculations of heterogeneous structures in solids, e.g., when an impurity is located on the surface, the conventional cluster model is insufficient to describe the electronic structure of substrates due to its finite size. The open-boundary cluster model (OCM) overcomes this problem by performing cluster calculations under the outgoing-wave boundary condition. In this method, a complex absorbing potential (CAP) is used to impose the boundary condition, but the CAP used in the previous studies required parameter optimization based on the complex variational principle. This study proposes and applies a parameter-free CAP to OCM calculations. This approach makes it possible to uniquely determine the band-specific CAP based on the surface Green's function theory. Using this CAP, we conducted OCM calculations of the tight-binding model of a one-dimensional semi-infinite chain, and we found that the calculated density of states agreed with the exact one. Surface states of the Newns-Anderson-Grimley model were also computed using the CAP, and the projected density of states on the adsorbed atom was successfully reproduced.

Recent developments and applications of reference interaction site model self-consistent field with constrained spatial electron density (RISM-SCF-cSED): A hybrid model of quantum chemistry and integral equation theory of molecular liquids.

The significance of solvent effects in electronic structure calculations has long been noted, and various methods have been developed to consider this effect. The reference interaction site model self-consistent field with constrained spatial electron density (RISM-SCF-cSED) is a hybrid model that combines the integral equation theory of molecular liquids with quantum chemistry. This method can consider the statistically convergent solvent distribution at a significantly lower cost than molecular dynamics simulations. Because the RISM theory explicitly considers the solvent structure, it performs well for systems where hydrogen bonds are formed between the solute and solvent molecules, which is a challenge for continuum solvent models. Taking advantage of being founded on the variational principle, theoretical developments have been made in calculating various properties and incorporating electron correlation effects. In this review, we organize the theoretical aspects of RISM-SCF-cSED and its distinctions from other hybrid methods involving integral equation theories. Furthermore, we carefully present its progress in terms of theoretical developments and recent applications.

Computational dielectric spectroscopy on solid-solution interface by time-dependent voltage applied molecular dynamics simulation.

A frequency-dependent dielectric constant characterizes the dielectric response of a medium and also represents the time scale of system's collective dynamics. Although it is valuable not only academically but also practically for developing advanced devices, getting the value of a solution at the interface with a solid or electrode surface is challenging both experimentally and computationally. Here, we propose a computational method that imitates the dielectric spectroscopy and AC impedance measurement. It combines a time-dependent voltage applied molecular dynamics simulation with an equivalent circuit representation of a system composed of a solution confined between two identical electrodes. It gives the frequency-dependent dielectric constants of the bulk solution and the interface simultaneously. Unlike the conventional method, it does not require computation of a dipole autocorrelation function and its Fourier transformation. Application of the method on a system of water confined between polarizable Pt electrodes gives the static dielectric constant and the relaxation time of the bulk water in good agreement with previous simulation results and experimental values. In addition, it gives a much smaller static dielectric constant at the interface, consistent with previous observations. The outline of the dielectric dispersion curve of the interface seems similar to that of the bulk, but the relaxation time is several times faster.

Nonfullerene Acceptors Bearing Spiro-Substituted Bithiophene Units in Organic Solar Cells: Tuning the Frontier Molecular Orbital Distribution to Reduce Exciton Binding Energy.

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 (Eb) 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 Eb 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 Eb and improving the PCE in OSCs.

Factors influencing the prognosis of patients with acute cerebral infarction who received usual care: a multicenter prospective cohort study.

[Purpose] The prognostic factors for patients with acute stroke who received usual care (mobilization ≥48 h after admission) remain unclear. This study aimed to investigate the prognostic factors that predict functional outcomes using evaluations performed immediately after onset in patients with acute cerebral infarction who received usual care from admission until discharge. [Participants and Methods] Participants with acute cerebral infarction admitted to five acute care hospitals in Tokyo and Saitama, Japan and prescribed physical therapy were included. Participants information, functional evaluations, and progress were recorded during the first physical therapy session, mobilization, and discharge. Participants who received usual care were assigned to either the good- or poor-outcome group based on the Modified Rankin Scale at discharge. [Results] In total, 161 Participants receiving usual care (mobilization ≥48 h after admission) were included. Reinfarction and the First National Institutes of Health Stroke Scale score were identified as independent predictors of functional outcome at hospital discharge in participants who received usual care (median, 22.0 d). The cutoff NIHSS score was 4. [Conclusion] Our results provided evidence that the National Institutes of Health Stroke Scale score and reinfarction are useful predictors of functional outcomes in participants who received usual care.

WormTensor: a clustering method for time-series whole-brain activity data from C. elegans.

BACKGROUND: In the field of neuroscience, neural modules and circuits that control biological functions have been found throughout entire neural networks. Correlations in neural activity can be used to identify such neural modules. Recent technological advances enable us to measure whole-brain neural activity with single-cell resolution in several species including [Formula: see text]. Because current neural activity data in C. elegans contain many missing data points, it is necessary to merge results from as many animals as possible to obtain more reliable functional modules. RESULTS: In this work, we developed a new time-series clustering method, WormTensor, to identify functional modules using whole-brain activity data from C. elegans. WormTensor uses a distance measure, modified shape-based distance to account for the lags and the mutual inhibition of cell-cell interactions and applies the tensor decomposition algorithm multi-view clustering based on matrix integration using the higher orthogonal iteration of tensors (HOOI) algorithm (MC-MI-HOOI), which can estimate both the weight to account for the reliability of data from each animal and the clusters that are common across animals. CONCLUSION: We applied the method to 24 individual C. elegans and successfully found some known functional modules. Compared with a widely used consensus clustering method to aggregate multiple clustering results, WormTensor showed higher silhouette coefficients. Our simulation also showed that WormTensor is robust to contamination from noisy data. WormTensor is freely available as an R/CRAN package https://cran.r-project.org/web/packages/WormTensor .

A Catalytic Alkylation of Ketones via sp3 C-H Bond Activation.

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 sp3 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.

A prospective randomized study of multimodal analgesia combined with single injection transversus abdominis plane block versus epidural analgesia against postoperative pain after laparoscopic colon cancer surgery.

PURPOSE: Transversus abdominis plane (TAP) block is a safe, effective, and promising analgesic procedure, but TAP block only cannot overcome postoperative pain. We conducted a prospective randomized study to evaluate postoperative pain control using multimodal analgesia (MA) combined with a single injection TAP block compared with epidural analgesia (EA) after laparoscopic colon cancer surgery. METHODS: Sixty-seven patients scheduled for elective laparoscopic colon cancer surgery were enrolled in this study and randomized into EA and MA groups. The primary endpoint was the frequency of additional analgesic use until postoperative day (POD) 2. The VAS score, blood pressure, time to bowel movement, time to mobilization, postoperative complications, and length of hospital stay were also compared between the two groups. RESULTS: Sixty-four patients (EA group, n = 33; MA group, n = 31) were analyzed. The patient characteristics did not differ markedly between the two groups. The frequency of additional analgesic use was significantly lower in the MA group than in the EA group (P < 0.001), whereas the VAS score did not differ markedly between the two groups. The postoperative blood pressure on the day of surgery was significantly lower in the MA group than in the EA group (P = 0.016), whereas urinary retention was significantly higher in the EA group than in the MA group (P < 0.001). CONCLUSION: MA combined with a single injection TAP block after laparoscopic colon cancer surgery may be comparable to EA in terms of analgesia and superior to EA in terms of urinary retention.

Theoretical and computational methodologies for understanding coordination self-assembly complexes.

This perspective highlights three theoretical and computational methods to capture the coordination self-assembly processes at the molecular level: quantum chemical modeling, molecular dynamics, and reaction network analysis. These methods cover the different scales from the metal-ligand bond to a more global aspect, and approaches that are best suited to understand the coordination self-assembly from different perspectives are introduced. Theoretical and numerical researches based on these methods are not merely ways of interpreting the experimental studies but complementary to them.

Raman Spectroscopic and DFT Study of COA-Cl and Its Analogues.

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.

A geminal theory based on the generalized electron pairing.

As in the hierarchy of the Hartree-Fock theory in terms of spin symmetry, the extension of spin functions in a theory of two-electron units or geminal, was developed in this study. A trial wave function is constructed as an antisymmetrized product of geminals, in which singlet and triplet two-electron functions are fully mixed. We present a variational optimization method for this generalized pairing wave function in the strong orthogonality condition. The present method is considered an extension of the antisymmetrized product of strongly orthogonal geminals or perfect pairing generalized valence bond methods, maintaining the compactness of the trial wave function. The obtained broken-symmetry solutions were similar to the unrestricted Hartree-Fock wave functions in terms of spin contamination while giving lower energy due to the inclusion of the electron correlation effect in geminals. The degeneracy of the obtained broken-symmetry solutions in the Sz space is reported for the tested four-electron systems.

Predictive factors for walking in acute stroke patients: a multicenter study using classification and regression tree analysis.

[Purpose] Walking ability should be predicted as early as possible in acute stroke patients. The purpose is to construct a prediction model for independent walking from bedside assessments using classification and regression tree analysis. [Participants and Methods] We conducted a multicenter case-control study with 240 stroke patients. Survey items included age, gender, injured hemisphere, the National Institute of Health Stroke Scale, the Brunnstrom Recovery Stage for lower extremities, and "turn over from a supine position" from the Ability for Basic Movement Scale. The National Institute of Health Stroke Scale items, such as language, extinction, and inattention, were grouped under higher brain dysfunction. We used the Functional Ambulation Categories to classify patients into independent (four or more the Functional Ambulation Categories; n=120) and dependent (three or fewer the Functional Ambulation Categories; n=120) walking groups. A classification and regression tree analysis was used to create a model to predict independent walking. [Results] The Brunnstrom Recovery Stage for lower extremities, "turn over from a supine position" from the Ability for Basic Movement Scale, and higher brain dysfunction were the splitting criteria for classifying patients into four categories: Category 1 (0%), severe motor paresis; Category 2 (10.0%), mild motor paresis and could not turn over; Category 3 (52.5%), with mild motor paresis, could turn over, and had higher brain dysfunction; and Category 4 (82.5%), with mild motor paresis, could turn over, and no higher brain dysfunction. [Conclusion] We constructed a useful prediction model for independent walking based on the three criteria.

Upacicalcet Is a Novel Secondary Hyperparathyroidism Drug that Targets the Amino Acid Binding Site of Calcium-Sensing Receptor .

The human calcium-sensing receptor (CaSR) is a G protein-coupled receptor that maintains extracellular Ca2+ homeostasis by regulating the secretion of parathyroid hormone. Upacicalcet is a novel positive allosteric modulator of CaSR that is used for the treatment of secondary hyperparathyroidism. In the present study, to clarify the binding site of upacicalcet to CaSR, we conducted binding studies and agonistic activity studies in HEK-293T cells expressing human CaSR (intact and mutant) and an in silico docking-simulation analysis. As a result, upacicalcet competed with L-tryptophan and was thought to affect the amino acid binding site. In addition, the effects of substitutions at the amino acid binding site on the binding abilities to upacicalcet as well as the effects on receptor function as measured using inositol-1 monophosphate accumulation were examined. Upacicalcet interacted with several CaSR residues that constitute the amino acid binding site. Based on these results, we performed an in silico analysis and obtained a binding mode, consistent with the in vitro study results. Our study revealed that upacicalcet is a novel secondary hyperparathyroidism drug that targets the amino acid binding site of CaSR. Upacicalcet is expected to become a new treatment option for secondary hyperparathyroidism because the binding site differs from that of conventional drugs; consequently, it may be effective for patients who are not sensitive to conventional drugs, and it may have a superior safety profile. SIGNIFICANCE STATEMENT: Upacicalcet interacts with several residues that constitute the amino acid binding site of the calcium-sensing receptor (CaSR) and shows a potent positive allosteric activity. This mechanism differs from those of conventional drugs. Therefore, upacicalcet can be regarded as a novel secondary hyperparathyroidism drug that acts on the amino acid binding site of CaSR.

A catalyzed E/Z isomerization mechanism of stilbene using para-benzoquinone as a triplet sensitizer.

Sensitizer molecules affect not only the quantum yield but also the selectivity of photochemical reactions. For an appropriate design of sensitized photochemical processes, we need to elucidate the reaction mechanism in detail. Here we investigated the mechanism of photoisomerization of stilbene via the triplet state with a para-benzoquinone sensitizer using density functional theory. In general, the isomerization of stilbene via the triplet state exhibits (Z)-selectivity (cis-selectivity); however, the para-benzoquinone sensitizer changes it to (E)-selectivity (trans-selectivity). The calculations showed that stilbene and para-benzoquinone form stable exciplexes having a preoxetane structure. The E/Z isomerization occurred via this exciplex, in which para-benzoquinone acted as a photocatalyst rather than a sensitizer only providing excitation energy. The spin-density distribution of the exciplex differed from the isolated stilbene in the triplet state. Therefore, the stilbene moiety could take (E)-conformation in the exciplex. The intermolecular charge-transfer drove the exciplex formation. This specific reaction mechanism originated from the electron-accepting ability of para-benzoquinone in the triplet state.

Cyclization or bridging: which occurs faster is the key to the self-assembly mechanism of Pd6L3 coordination prisms.

The self-assembly processes of Pd6L3 coordination prisms consisting of cis-protected Pd(II) complexes and porphyrin-based tetratopic ligands with four 3-pyridyl or 4-pyridyl groups (L) were investigated by experimental and numerical methods, QASAP (quantitative analysis of self-assembly process) and NASAP (numerical analysis of self-assembly process), respectively. It was found that contrary to common intuition macrocyclization takes place faster than the bridging reaction in the prism assembly and that the bridging reaction occurring before the macrocyclization tends to produce kinetically trapped species. A numerical simulation demonstrates that the relative magnitude of the rate constants between the macrocyclization and the bridging reaction is the key factor that determines whether the self-assembly leads to the thermodynamically most stable prism or to kinetically trapped species. Finding the key elementary reactions that largely affect the selection of the major assembly pathway is helpful to rationally control the products under kinetic control via modulation of the energy landscape.

Solvation in nitration of benzene and the valence electronic structure of the Wheland intermediate.

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.

Self-consistent construction of grand potential functional with hierarchical integral equations and its application to solvation thermodynamics.

The construction of the density functional for grand potential is fundamental in understanding a broad range of interesting physical phenomena, such as phase equilibrium, interfacial thermodynamics, and solvation. However, the knowledge of a general functional accurately describing the many-body correlation of molecules is far from complete. Here, we propose a self-consistent construction of the grand potential functional based on the weighted density approximation (WDA) utilizing hierarchical integral equations. Different from our previous study [T. Yagi and H. Sato, J. Chem. Phys. 154, 124113, (2021)], we apply the WDA to the excess Helmholtz free energy functional rather than the bridge functional. To assess the performance of the present functional, we apply it to the solvation thermodynamics of Lennard-Jones fluids. Compared to the modified Benedict-Webb-Rubin equation of state, the present functional qualitatively predicts the liquid-vapor equilibrium. The solvation free energy obtained from the present functional provides a much better agreement with the Monte Carlo simulation result than the hypernetted chain functionals. It constitutes a general starting point for a systematic improvement in the accuracy of the grand potential functional.

Accelerated constant-voltage quantum mechanical/molecular mechanical method for molecular systems at electrochemical interfaces.

The structure and electronic properties of a molecule at an electrochemical interface are changed by interactions with the electrode surface and the electrolyte solution, which can be significantly modulated by an applied voltage. We present an efficient self-consistent quantum mechanics/molecular mechanics (QM/MM) approach to study a physisorbed molecule at a metal electrode-electrolyte interface under the constant-voltage condition. The approach employs a classical polarizable double electrode model, which enables us to study the QM/MM system in the constant-voltage ensemble. A mean-field embedding approximation is further introduced in order to overcome the difficulties associated with statistical sampling of the electrolyte configurations. The results of applying the method to a test system indicate that the adsorbed molecule is no less or slightly more polarized at the interface than in the bulk electrolyte solution. The geometry of the horizontally adsorbed molecule is modulated by their electrostatic interactions with the polarizable electrode surfaces and also the interactions with cations attracted toward the interface when the adsorbate is reduced. We also demonstrate that the approach can be used to quantitatively evaluate the reorganization energy of a one electron reduction reaction of a molecule in an electrochemical cell.