Effects of oxidized LDL versus IL-1ß/TNF-ɑ/INFÉ£ on human gingival mesenchymal stem cells properties.

AIMS: Oxidized low-density lipoprotein (oxLDL) is an important player in the course of metabolic inflammatory diseases. oxLDL was identified in the gingival crevicular fluid, denoting possible associations between oxLDL-induced inflammation and periodontal disease. The current investigation compared for the first-time direct effects of oxLDL to a cytokine cocktail of IL-1ß/TNF-ɑ/INF-γ on gingival mesenchymal stem cells' (G-MSCs) attributes. METHODS: Human third passage G-MSCs, isolated from connective tissue biopsies (n = 5) and characterized, were stimulated in three groups over 7 days: control group, cytokine group (IL-1ß[1 ng/mL], TNF-α[10 ng/mL], IFN-γ[100 ng/mL]), or oxLDL group (oxLDL [50 µg/mL]). Next Generation Sequencing and KEGG pathway enrichment analysis, stemness gene expression (NANOG/SOX2/OCT4A), cellular proliferation, colony-formation, multilinear potential, and altered intracellular pathways were investigated via histochemistry, next-generation sequencing, and RT-qPCR. RESULTS: G-MSCs exhibited all mesenchymal stem cells' characteristics. oxLDL group and cytokine group displayed no disparities in their stemness markers (p > .05). Next-generation-sequencing revealed altered expression of the TXNIP gene in response to oxLDL treatment compared with controls (p = .04). Following an initial boosting for up to 5 days by inflammatory stimuli, over 14 day, cellular counts [median count ×10-5 (Q25/Q75)] were utmost in control - [2.6607 (2.0804/4.5357)], followed by cytokine - [0.0433 (0.0026/1.4215)] and significantly lowered in the oxLDL group [0.0274 (0.0023/0.7290); p = .0047]. Osteogenic differentiation [median relative Ca2+ content(Q25/Q75)] was significantly lower in cytokine - [0.0066 (0.0052/0.0105)] compared to oxLDL - [0.0144 (0.0108/0.0216)] (p = .0133), with no differences notable for chondrogenic and adipogenic differentiation (p > .05). CONCLUSIONS: Within the current investigation's limitations, in contrast to cytokine-mediated inflammation, G-MSCs appear to be minimally responsive to oxLDL-mediated metabolic inflammation, with little negative effect on their differentiation attributes and significantly reduced cellular proliferation.

AB-G0W0: A practical G0W0 method without frequency integration based on an auxiliary boson expansion.

Common G0W0 implementations rely on numerical or analytical frequency integration to determine the G0W0 self-energy, which results in a variety of practical complications. Recently, we have demonstrated an exact connection between the G0W0 approximation and equation-of-motion quantum chemistry approaches [J. Tölle and G. Kin-Lic Chan, J. Chem. Phys. 158, 124123 (2023)]. Based on this connection, we propose a new method to determine G0W0 quasiparticle energies, which completely avoids frequency integration and its associated problems. To achieve this, we make use of an auxiliary boson (AB) expansion. We name the new approach AB-G0W0 and demonstrate its practical applicability in a range of molecular problems.

Accelerating Analytic-Continuation GW Calculations with a Laplace Transform and Natural Auxiliary Functions.

We present a simple and accurate GW implementation based on a combination of a Laplace transform (LT) and other acceleration techniques used in post-self-consistent field quantum chemistry, namely, natural auxiliary functions and the frozen-core approximation. The LT-GW approach combines three major benefits: (a) a small prefactor for computational scaling, (b) easy integration into existing molecular GW implementations, and (c) significant performance improvements for a wide range of possible applications. Illustrating these advantages for systems consisting of up to 352 atoms and 7412 basis functions, we further demonstrate the benefits of this approach combined with an efficient implementation of the Bethe-Salpeter equation.

Triplet Excitation-Energy Transfer Couplings from Subsystem Time-Dependent Density-Functional Theory.

We present an implementation of triplet excitation-energy transfer (TEET) couplings based on subsystem-based time-dependent density-functional theory (sTDDFT). TEET couplings are systematically investigated by comparing "exact" and approximate variants of sTDDFT. We demonstrate that, while sTDDFT utilizing explicit approximate non-additive kinetic energy (NAKE) density functionals is well-suited for describing singlet EET processes, it is inadequate for characterizing TEET. However, we show that projection-based embedding (PbE)-based sTDDFT addresses the challenges faced by NAKE-sTDDFT and emerges as a promising method for accurately describing electronic couplings in TEET processes. We also introduce the mixed PbE-/NAKE-embedding procedure to investigate the TEET effects in solvated pairs of chromophores. This approach offers a good balance between accuracy and efficiency, enabling comprehensive studies of TEET processes in complex environments.

Block2: A comprehensive open source framework to develop and apply state-of-the-art DMRG algorithms in electronic structure and beyond.

block2 is an open source framework to implement and perform density matrix renormalization group and matrix product state algorithms. Out-of-the-box it supports the eigenstate, time-dependent, response, and finite-temperature algorithms. In addition, it carries special optimizations for ab initio electronic structure Hamiltonians and implements many quantum chemistry extensions to the density matrix renormalization group, such as dynamical correlation theories. The code is designed with an emphasis on flexibility, extensibility, and efficiency and to support integration with external numerical packages. Here, we explain the design principles and currently supported features and present numerical examples in a range of applications.

Effect of Hyperbaric Oxygen and Inflammation on Human Gingival Mesenchymal Stem/Progenitor Cells.

The present study explores for the first time the effect of hyperbaric oxygen (HBO) on gingival mesenchymal stem cells' (G-MSCs) gene expression profile, intracellular pathway activation, pluripotency, and differentiation potential under an experimental inflammatory setup. G-MSCs were isolated from five healthy individuals (n = 5) and characterized. Single (24 h) or double (72 h) HBO stimulation (100% O2, 3 bar, 90 min) was performed under experimental inflammatory [IL-1ß (1 ng/mL)/TNF-α (10 ng/mL)/IFN-γ (100 ng/mL)] and non-inflammatory micro-environment. Next Generation Sequencing and KEGG pathway enrichment analysis, G-MSCs' pluripotency gene expression, Wnt-/ß-catenin pathway activation, proliferation, colony formation, and differentiation were investigated. G-MSCs demonstrated all mesenchymal stem/progenitor cells' characteristics. The beneficial effect of a single HBO stimulation was evident, with anti-inflammatory effects and induction of differentiation (TLL1, ID3, BHLHE40), proliferation/cell survival (BMF, ID3, TXNIP, PDK4, ABL2), migration (ABL2) and osteogenic differentiation (p < 0.05). A second HBO stimulation at 72 h had a detrimental effect, significantly increasing the inflammation-induced cellular stress and ROS accumulation through HMOX1, BHLHE40, and ARL4C amplification and pathway enrichment (p < 0.05). Results outline a positive short-term single HBO anti-inflammatory, regenerative, and differentiation stimulatory effect on G-MSCs. A second (72 h) stimulation is detrimental to the same properties. The current results could open new perspectives in the clinical application of short-termed HBO induction in G-MSCs-mediated periodontal reparative/regenerative mechanisms.

Which Physical Phenomena Determine the Ionization Potential of Liquid Water?

Understanding and predicting the properties of molecular liquids from the corresponding properties of the individual molecules is notoriously difficult because there is cooperative behavior among the molecules in the liquid. This is particularly relevant for water, where even the most fundamental molecular properties, such as the dipole moment, are radically different in the liquid compared to the gas phase. In this work, we focus on the ionization potential (IP) of liquid water by dissecting its individual contributions from the individual molecules making up the liquid. This is achieved by using periodic subsystem DFT, a state-of-the-art electronic structure method based on density embedding. We identify and evaluate four important electronic contributions to the IP of water: (1) mean-field, evaluated at the Hartree-Fock level; (2) electronic correlation, incorporated via DFT and wave function-based methods; (3) interaction with and (4) polarization of the environment, both evaluated ab initio with density embedding. Furthermore, we analyze their impact on the IP relative to the structural fluctuation of liquid water, revealing unexpected, hidden correlations, confirming that the broadening of the photoelectron spectra is mostly caused by intermolecular interactions confined in the first solvation shell.

Toll-like receptor expression profile of stem/progenitor cells from human exfoliated deciduous teeth.

BACKGROUND: Stem/progenitor cells from human exfoliated deciduous teeth (SHED) show remarkable pluripotent, regenerative, and immunological capacities. During in vivo regenerative processes, there could be the presence of SHED in the surrounding inflammatory microenvironment, through toll-like receptors (TLRs). AIM: The aim of this paper was to present a characteristic TLR expression profile on SHED for the first time. DESIGN: Cells were harvested from extracted primary teeth (n = 10), anti-STRO-1 immunomagnetically sorted and cultivated, through colony-forming units (CFUs). SHED were examined for mesenchymal stem/progenitor cell traits, including the expression of clusters of differentiation (CDs) 14, 34, 45, 73, 90, 105, and 146, and their multilineage differentiation aptitude. TLRs 1-10 expression was investigated for SHED in uninflamed and inflamed (25 ng/mL IL-1ß, 103 U/mL IFN-γ, 50 ng/mL TNF-α, and 3 × 103 U/mL IFN-α; SHED-i) microenvironmental conditions. RESULTS: SHED were negative for CDs 14, 34, and 45, but were positive for CDs 73, 90, 105, and 146, and demonstrated characteristic multilineage differentiation. In an uninflamed microenvironment, SHED expressed TLRs 1, 2, 3, 4, 6, 8, 9, and 10. The inflammatory microenvironment downregulated TLR7 significantly on gene level and upregulated TLR8 on gene and protein levels (p < .05; Wilcoxon signed-rank test). CONCLUSION: There appears to be a unique TLR expression profile on SHED, which could modulate their immunological and regenerative abilities in oral tissue engineering approaches.

Exact relationships between the GW approximation and equation-of-motion coupled-cluster theories through the quasi-boson formalism.

We describe the relationship between the GW approximation and various equation-of-motion (EOM) coupled-cluster (CC) theories. We demonstrate the exact equivalence of the G0W0 approximation and the propagator theory for an electron-boson problem in a particular excitation basis. From there, we establish equivalence within the quasi-boson picture to the IP+EA-EOM unitary CC propagator. We analyze the incomplete description of screening provided by the standard similarity-transformed IP+EA-EOM-CC and the recently introduced G0W0 Tamm-Dancoff approximation. We further consider the approximate decoupling of IP and EA sectors in EOM-CC treatments and devise the analogous particle-hole decoupling approach for the G0W0 approximation. Finally, we numerically demonstrate the exact relationships and magnitude of the approximations in the calculations of a set of molecular ionization potentials and electron affinities.

Thymoquinone-Mediated Modulation of Toll-like Receptors and Pluripotency Factors in Gingival Mesenchymal Stem/Progenitor Cells.

Thymoquinone (TQ), the key active component of Nigella sativa (NS), demonstrates very promising biomedical anti-inflammatory, antioxidant, antimicrobial and anticancer properties. Several investigations have inspected the modulative activities of TQ on different stem/progenitor cell types, but its possible role in the regulation of gingival mesenchymal stem/progenitor cells (G-MSCs) has not yet been characterized. For the first time, this study investigates the effects of TQ on G-MSCs' stemness and Toll-like receptor expression profiles. G-MSCs (n = 5) were isolated, sorted via anti-STRO-1 antibodies and then disseminated on cell culture dishes to create colony-forming units (CFUs), and their stem/progenitor cell attributes were characterized. TQ stimulation of the G-MSCs was performed, followed by an examination of the expression of pluripotency-related factors using RT-PCR and the expression profiles of TLRs 1−10 using flowcytometry, and they were compared to a non-stimulated control group. The G-MSCs presented all the predefined stem/progenitor cells' features. The TQ-activated G-MSCs displayed significantly higher expressions of TLR3 and NANOG with a significantly reduced expression of TLR1 (p < 0.05, Wilcoxon signed-rank test). TQ-mediated stimulation preserves G-MSCs' pluripotency and facilitates a cellular shift into an immunocompetent-differentiating phenotype through increased TLR3 expression. This characteristic modulation might impact the potential therapeutic applications of G-MSCs.

Automated Generation of Optimized Auxiliary Basis Sets for Long-Range-Corrected TDDFT Using the Cholesky Decomposition.

Range-separated hybrid functionals making use of a smooth separation of the Coulomb operator in terms of the error function and its complement have proven to be a valuable tool for improving Kohn-Sham density functional theory (DFT) calculations. This holds in particular for obtaining accurate excitation energies from linear-response time-dependent DFT. Evaluating the long-range exchange contributions represents one of the most time-consuming tasks in such calculations. Prefitted auxiliary basis sets can be employed to speed up this step. Here, we present a way to generate auxiliary basis sets optimized to fit the long-range exchange contributions only, contrary to the common optimization strategies on the basis of the full Coulomb operator. For this purpose, we use the atomic Cholesky decomposition technique. The basis sets are generated on-the-fly using the specific range-separation parameter defined in the exchange-correlation functional. We obtain excitation energies and oscillator strengths which are of similar or better accuracy than those obtained with conventional resolution-of-the-identity auxiliary basis sets while drastically reducing the number of auxiliary functions required. This is demonstrated for the QUESTDB#5 benchmark set. In addition, we outline the benefits of this approach in sequences of calculations employing varying range-separation parameters, as is the case in the optimally tuned range-separation strategy. Finally, we illustrate the efficiency of this approach for real-world examples, namely, a chlorophyll tetramer from photosystem II and a carotenoid-porphyrin-C60 triad.

The Seamless Connection of Local and Collective Excited States in Subsystem Time-Dependent Density Functional Theory.

The theoretical understanding of photoinduced processes in multichromophoric systems requires, as an essential ingredient, the possibility of accurately describing their electronically excited states. However, the size of these systems often prohibits the usage of conventional electronic-structure methods, so that often multiscale approaches based on phenomenologically motivated models are employed. In contrast, subsystem time-dependent density functional theory (sTDDFT) allows for a subsystem-based ab initio description of multichromophoric systems and therefore allows for, in principle, an exact description of photoinduced processes. This Perspective aims to outline the theoretical foundations and commonly used practical realizations as well as to illustrate benefits of recent developments and open issues in the field of sTDDFT. Prospective, potential future applications and possible methodological developments are discussed.

Subsystem-Based GW/Bethe-Salpeter Equation.

Subsystem Density-Functional Theory and its extension to excited states, namely, subsystem Time-Dependent Density-Functional Theory, have been proven to be efficient and accurate fragmentation approaches for ground and excited states. In the present study we extend this approach to the subsystem-based description of total systems by means of GW and the Bethe-Salpeter equation (BSE). For this, we derive the working equations starting from a subsystem-based partitioning of the screened-Coulomb interaction for an arbitrary number of subsystems. Making use of certain approximations, we develop a parameter-free approach in which environmental screening contributions are effectively included for each subsystem. We demonstrate the applicability of these approximations by comparing quasi-particle energies and excitation energies from subsystem-based GW/BSE calculations to the supermolecular reference. Furthermore, we demonstrate the computational efficiency and the usefulness of this method for the description of photoinduced processes in complex chemical environments.

Electronic couplings for photo-induced processes from subsystem time-dependent density-functional theory: The role of the diabatization.

Subsystem time-dependent density-functional theory (sTDDFT) making use of approximate non-additive kinetic energy (NAKE) functionals is known to be capable of describing excitation energy transfer processes in a variety of applications. Here, we show that sTDDFT, especially when combined with projection-based embedding (PbE), can be employed for the entire range of photo-induced electronic couplings essential for modeling photophysical properties of complex chemical and biological systems and therefore represents a complete toolbox for this class of problems. This means that it is capable of capturing the interaction/coupling associated with local- and charge-transfer (CT) excitons. However, this requires the choice of a reasonable diabatic basis. We therefore propose different diabatization strategies of the virtual orbital space in PbE-sTDDFT and show how CT excitations can be included in sTDDFT using NAKE functionals via a phenomenological approach. Finally, these electronic couplings are compared to couplings from a multistate fragment excitation difference (FED)-fragment charge difference (FCD) diabatization procedure. We show that both procedures, multistate FED-FCD and sTDDFT (with the right diabatization procedure chosen), lead to an overall good agreement for the electronic couplings, despite differences in their general diabatization strategy. We conclude that the entire range of photo-induced electronic couplings can be obtained using sTDDFT (with the right diabatization procedure chosen) in a black-box manner.

TLR3 ligation affects differentiation and stemness properties of gingival mesenchymal stem/progenitor cells.

AIM: Toll-like receptors are key players in mesenchymal stem/progenitor cells' micro-environmental crosstalk, endorsing various biological reactions. For the first time, this study investigates the effects of TLR3-ligation on gingival mesenchymal stem/progenitor cells (G-MSCs) stemness and differentiation properties. MATERIAL AND METHODS: G-MSCs (n = 5) were isolated, sorted using anti-STRO-1 antibodies,and sowed on culture dishes to generate colony-forming units (CFUs), and their stem/progenitor cells' features and TLR3 expression were characterized. Subsequently, TLR3 activation of G-MSCs via Poly (I:C) was done, followed by an analysis of the expression of pluripotency-related factors, mesenchymal stemness-associated surface markers, and the ability to form CFUs and multilineage differentiation, using qualitative and quantitative histochemistry and RT-PCR. RESULTS: G-MSCs demonstrated all predefined stem/progenitor cells' characteristics and TLR3 expression. TLR3-activated G-MSCs showed a significantly reduced ability to form CFUs and pluripotency transcriptional factors expression. Mesenchymal stem/progenitor cell-associated surface markers and multilinear differentiation potential were significantly higher following TLR3 ligation (p < .05, Wilcoxon signed rank test). CONCLUSIONS: TLR3-mediated activation maintains the mesenchymal stem/progenitor cells phenotype and drives G-MSCs' differentiation and commitment, with a shift away from an undifferentiated pluripotent cellular phenotype. This distinctive modulation could influence potential therapeutic applications of G-MSCs.

Approximate versus Exact Embedding for Chiroptical Properties: Reconsidering Failures in Potential and Response.

We investigate the suitability of subsystem time-dependent density-functional theory (sTDDFT) for describing chiroptical properties with a focus on optical rotation parameters. Our starting point is a new implementation of the recently proposed projection-based, coupled frozen-density embedding (FDEc) framework. We adapt the generalized, non-Hermitian formulation of TDDFT and derive corresponding expressions for regular and damped response properties from subsystem TDDFT. We verify that our implementation of this "exact" formulation allows to reproduce supermolecular results of electronic circular dichroism (ECD) spectra, of optical rotatory dispersion, and of polarizabilities. We present a systematic test of the main approximations typically introduced in practical frozen-density embedding (FDE) calculations of response properties: (i) the use of approximate nonadditive kinetic-energy (NAKE) functionals, which can be avoided through projection techniques, (ii) the use of monomer (subsystem) basis sets rather than supersystem basis sets, and (iii) the neglect of intersubsystem response coupling within the so-called uncoupled FDE (or FDEu) approximation. While approximation (i) is known to generally lead to large errors for covalently bound subsystems, we present cases in which either the basis set or the coupling step are similarly or even (much) more important. In particular, we explicitly demonstrate by comparison to a fully coupled calculation that missing intersubsystem response couplings are responsible for the failure of FDE reported in a previous study [ J. Chem. Theory Comput. 2015, 11, 5305-5315]. We show that good agreement with reference results can be obtained in this case even with standard NAKE approximations for the FDE potentials and efficient monomer basis sets, making calculations for larger systems well accessible.

Inter-subsystem charge-transfer excitations in exact subsystem time-dependent density-functional theory.

We investigate the ability of projection-based embedding (PbE)/subsystem density-functional theory to describe intersubsystem charge-transfer (CT) excitations. To this end, we derive the corresponding subsystem time-dependent density-functional theory (sTDDFT) working equations including the response kernel contributions for three different popular projection operators currently in use in connection with PbE. We demonstrate that supermolecular electronic excitation spectra can be fully restored with this "exact" sTDDFT. Both intra- and intersubsystem CT excitations can be described correctly, provided that suitable long-range corrected functionals and basis sets of sufficient flexibility are used. In particular, we show that outgoing CT excitations can be described in individual subsystem calculations without intersubsystem response coupling. We introduce efficient techniques to restrict the virtual-orbital space to obtain reasonable CT excitation energies with heavily reduced computational cost. Finally, we demonstrate the ability to extract electronic couplings between CT and local excitations with this new formulation of exact sTDDFT.

Exact subsystem time-dependent density-functional theory.

In this communication, we show that coupled subsystem time-dependent density functional theory (subsystem TDDFT) [J. Neugebauer, J. Chem. Phys. 126, 134116 (2007)] in combination with projection-based embedding (PbE) is an exact subsystem theory in the sense that supermolecular TDDFT excitation energies can exactly be restored. A correct handling of the kernel contribution due to the enforced orthogonality is crucial in this context, which leads to different PbE kernel contributions in the A and B matrices of the general TDDFT eigenvalue problem. Although this formalism has been proposed before [D. V. Chulhai and L. Jensen, Phys. Chem. Chem. Phys. 18, 21032 (2016)], the symmetric eigenvalue problem used in that work implicitly introduces an approximation concerning this kernel contribution. We show that our treatment numerically exactly reproduces supermolecular results for the previously investigated helium dimer and for the fluoroethane molecule as a more challenging case with a partitioning of a covalent bond. We also demonstrate that the symmetric approximation can lead to significant deviations, including a wrong ordering of electronic transitions.