Infrared photodissociation spectroscopy of (Al2O3)2-5FeO+: influence of Fe-substitution on small alumina clusters.

The infrared photodissociation spectra of He-tagged (Al2O3)nFeO+ (n = 2-5), are reported in the Al-O and Fe-O stretching and bending spectral region (430-1200 cm-1) and assigned based on calculated harmonic IR spectra from density functional theory (DFT). The substitution of Fe for an Al center occurs preferentially at 3-fold oxygen coordination sites located at the cluster rim and with the Fe atom in the +III oxidation state. The accompanying elongation of metal oxygen bonds leaves the Al-O network structure nearly unperturbed (isomorphous substitution). Contrary to the Al2FeO4+ (n = 1), valence isomerism is not observed, which is attributed to a smaller M:O ratio (M = Al, Fe) and consequently decreasing electron affinities with increasing cluster size.

Reduction of Hartree-Fock Wavefunctions to Kohn-Sham Effective Potentials Using Multiresolution Analysis.

We present a highly accurate numerical implementation for computing the Kohn-Sham effective potentials for molecules based on a Hartree-Fock wavefunction and density, following the RKS approach of Staroverov and co-workers [ J. Chem. Phys. 2014, 140, 18A535]. Potentials and orbitals are represented in a multiresolution wavelet basis, avoiding basis set incompleteness-related issues. Together with the RKS method, the often occurring problems of oscillating potentials are removed. The MRA implementation of the RKS method allows the generation of molecular Kohn-Sham potentials of benchmark quality. Numerical data for atoms up to Kr and a number of molecules are given, with a special emphasis on the role of nodal planes in the calculations, as showcased in HCN and benzene.

Valence and Structure Isomerism of Al2FeO4+: Synergy of Spectroscopy and Quantum Chemistry.

We provide spectroscopic and computational evidence for a substantial change in structure and gas phase reactivity of Al3O4+ upon Fe-substitution, which is correctly predicted by multireference (MR) wave function calculations. Al3O4+ exhibits a cone-like structure with a central trivalent O atom (C3v symmetry). The replacement of the Al- by an Fe atom leads to a planar bicyclic frame with a terminal Al-O•- radical site, accompanied by a change from the Fe+III/O-II to the Fe+II/O-I valence state. The gas phase vibrational spectrum of Al2FeO4+ is exclusively reproduced by the latter structure, which MR wave function calculations correctly identify as the most stable isomer. This isomer of Al2FeO4+ is predicted to be highly reactive with respect to C-H bond activation, very similar to Al8O12+ which also features the terminal Al-O•- radical site. Density functional theory, in contrast, predicts a less reactive Al3O4+-like "isomorphous substitution" structure of Al2FeO4+ to be the most stable one, except for functionals with very high admixture of Fock exchange (50%, BHLYP).

Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-mediated Regulation of PDGFRß.

Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.Objectives: To elucidate the role of TYKRIL (tyrosine kinase receptor-inducing lncRNA) as a regulator of p53/ PDGFRß (platelet-derived growth factor receptor ß) signaling pathway and to investigate its role in PAH.Methods: Pericytes and pulmonary arterial smooth muscle cells exposed to hypoxia and derived from patients with idiopathic PAH were analyzed with RNA sequencing. TYKRIL knockdown was performed in above-mentioned human primary cells and in precision-cut lung slices derived from patients with PAH.Measurements and Main Results: Using RNA sequencing data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells exposed to hypoxia and derived from patients with idiopathic PAH. TYKRIL knockdown reversed the proproliferative (n = 3) and antiapoptotic (n = 3) phenotype induced under hypoxic and idiopathic PAH conditions. Owing to the poor species conservation of TYKRIL, ex vivo studies were performed in precision-cut lung slices from patients with PAH. Knockdown of TYKRIL in precision-cut lung slices decreased the vascular remodeling (n = 5). The number of proliferating cell nuclear antigen-positive cells in the vessels was decreased and the number of terminal deoxynucleotide transferase-mediated dUTP nick end label-positive cells in the vessels was increased in the LNA (locked nucleic acid)-treated group compared with control. Expression of PDGFRß, a key player in PAH, was found to strongly correlate with TYKRIL expression in the patient samples (n = 12), and TYKRIL knockdown decreased PDGFRß expression (n = 3). From the transcription factor-screening array, it was observed that TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRß. RNA immunoprecipitation using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay revealed that TYKRIL interferes with the p53-p300 interaction (n = 3) and regulates p53 nuclear translocation.Conclusions: TYKRIL plays an important role in PAH by regulating the p53/PDGFRß axis.

Thermochemistry of FeOmHnz Species: Assessment of Some DFT Functionals.

Thermochemical data for 20 anionic, cationic, and neutral gas-phase species, including Fe0/+, FeO-/0/+/2+, FeOH0/+/2+, FeO2-/0/+, OFeOH0/+, Fe(OH)20/+, Fe(H2O)+/2+, and Fe(H2O)2+/2+ with oxidation states between +I and +IV for Fe and -I and -II for O, compiled by Schröder [ J. Phys. Chem. A 2008, 112, 13215], are used to assess the performance of the "Jacob's ladder" functionals PBE, TPSS, PBE0, and TPSSh for the SVP, TZVP, and QZVP basis sets. In addition, the BP86 and B3LYP functionals are considered. The TPSSh functional performs best. With the TZVP basis set (recommended), the mean absolute and the maximum errors are 24 and 63 kJ/mol, respectively. With 32 and 78 kJ/mol, respectively, BP86 is second best, better than PBE.

Direct determination of optimal pair-natural orbitals in a real-space representation: The second-order Moller-Plesset energy.

An efficient representation of molecular correlated wave functions is proposed, which features regularization of the Coulomb electron-electron singularities via the F12-style explicit correlation and a pair-natural orbital factorization of the correlation components of the wave function expressed in the real space. The pair-natural orbitals are expressed in an adaptive multiresolution basis and computed directly by iterative variational optimization. The approach is demonstrated by computing the second-order Moller-Plesset energies of small- and medium-sized molecules. The resulting MRA-PNO-MP2-F12 method allows for the first time to compute correlated wave functions in a real-space representation for systems with dozens of atoms (as demonstrated here by computations on alkanes as large as C10H22), with precision exceeding what is achievable with the conventional explicitly correlated MP2 approaches based on the atomic orbital representations.

Temperature- and Structure-Dependent Optical Properties and Photophysics of BODIPY Dyes.

We report on the temperature- and structural-dependent optical properties and photophysics of a set of boron dipyrromethene (BODIPY) dyes with different substitution patterns of their meso-aryl subunit. Single-crystal X-ray diffraction analysis of the compounds enabled a classification of the dyes into a sterically hindered and a unhindered group. The steric hindrance refers to a blocked rotational motion of the aryl subunit around the bond connecting this moiety to the meso-position of the BODIPY core. The energy barriers related to this rotation were simulated by DFT calculations. As follows from the relatively low rotational barrier calculated to about 17 kcal/mol, a free rotation is only possible for sterically unhindered compounds. Rotational barriers of more than 40 kcal/mol determined for the sterically hindered compounds suggest an effective freezing of the rotational motion in these molecules. With the aid of temperature-dependent spectroscopic measurements, we could show that the ability to rotate directly affects the optical properties of our set of BODIPY dyes. This accounts for the strong temperature dependence of the fluorescence of the sterically unhindered compounds which show a drastic decrease in fluorescence quantum yield and a significant shortening in fluorescence lifetime upon heating. The optical properties of the sterically hindered compounds, however, are barely affected by temperature. Our results suggest a nonradiative deactivation of the first excited singlet state of the sterically unhindered compounds caused by a conical intersection of the potential energy surfaces of the ground and first excited state which is accessible by rotation of the meso-subunit. This is in good agreement with previously reported deactivation mechanisms. In addition, our results suggest the presence of a second nonradiative depopulation pathway of the first excited singlet state which is particularly relevant for the sterically hindered compounds.

Evaluating the Solvent Stark Effect from Temperature-Dependent Solvatochromic Shifts of Anthracene.

The solvent Stark effect on the spectral shifts of anthracene is studied with temperature-dependent solvatochromic measurements. The Stark contribution ΔvStark to the absorption shift Δvp in polar solvents is measured to be ΔvStark =(53±35) cm-1 , in reasonable agreement with dielectric continuum theory estimate of 28 cm-1 , whereas the major shift Δvp ∼300 cm-1 presumably originates from the solute quadrupole. We pay attention to the accurate correction of Δvp for the nonpolar contribution that is crucial when the shifts are modest in magnitude.

Chemically accurate adsorption energies for methane and ethane monolayers on the MgO(001) surface.

A hybrid QM:QM method that combines MP2 as high-level method on cluster models with density functional theory (PBE+D2) as low-level method on periodic models is applied to adsorption of methane and ethane on the MgO(001) surface for which reliable experimental desorption enthalpies are available. Two coverages are considered, monolayer (every second Mg2+ ion occupied) and one quarter coverage (one of eight Mg2+ ions occupied). Structure optimizations are performed at the hybrid MP2:(PBE+D2) level, with the MP2 energies and forces counterpoise corrected for basis set superposition error and extrapolated to the complete basis set limit. For the MP2 calculations on the adsorbate monolayer a two-body expansion of the lateral molecule-molecule interactions is applied. Higher order correlation effects are evaluated at the hybrid MP2:(PBE+D2) equilibrium structures as coupled cluster [CCSD(T)] - MP2 differences adopting smaller basis sets. The final adsorption energies obtained for monolayer coverage are -14.0 ± 1.0 and -23.3 ± 0.6 kJ mol-1 for CH4·MgO(001) and C2H6·MgO(001), respectively. They agree within 1 kJ mol-1 - well within chemical accuracy limits - with reference energies of -15.0 ± 0.6 and -24.4 ± 0.6 kJ mol-1, respectively. The latter have been derived from measured desorption enthalpy barriers, taking zero-point vibrational energy (ZPVE) and thermal enthalpy contributions into account.

Coupled-Cluster in Real Space. 2. CC2 Excited States Using Multiresolution Analysis.

We report a first quantized approach to calculate approximate coupled-cluster singles and doubles CC2 excitation energies in real space. The cluster functions are directly represented on an adaptive grid using multiresolution analysis. Virtual orbitals are neither calculated nor needed in this approach. The nuclear and electronic cusps are taken into account explicitly regularizing the corresponding equations exactly. First calculations on small molecules are in excellent agreement with the best available LCAO results.

Coupled-Cluster in Real Space. 1. CC2 Ground State Energies Using Multiresolution Analysis.

A framework to calculate CC2 approximated coupled-cluster ground state correlation energies in a multiresolution basis is derived and implemented into the MADNESS library. The CC2 working equations are formulated in first quantization which makes them suitable for real-space methods. The first quantized equations can be interpreted diagrammatically using the usual diagrams from second quantization with adjusted interpretation rules. Singularities arising from the nuclear and electronic potentials are regularized by explicitly taking the nuclear and electronic cusps into account. The regularized three- and six-dimensional cluster functions are represented directly on an adaptive grid. The resulting equations are free of singularities and virtual orbitals, which results in a low intrinsic scaling. Correlation energies close to the basis set limit are computed for small molecules. This work is the first step toward CC2 excitation energies in a multiresolution basis.

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes.

RATIONALE: Pericytes are essential for vessel maturation and endothelial barrier function. Long noncoding RNAs regulate many cellular functions, but their role in pericyte biology remains unexplored. OBJECTIVE: Here, we investigate the effect of hypoxia-induced endoplasmic reticulum stress regulating long noncoding RNAs (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: RNA sequencing in human primary pericytes identified hypoxia-regulated long noncoding RNAs, including HypERlnc. Silencing of HypERlnc decreased cell viability and proliferation and resulted in pericyte dedifferentiation, which went along with increased endothelial permeability in cocultures consisting of human primary pericyte and human coronary microvascular endothelial cells. Consistently, Cas9-based transcriptional activation of HypERlnc was associated with increased expression of pericyte marker genes. Moreover, HypERlnc knockdown reduced endothelial-pericyte recruitment in Matrigel assays (P<0.05). Mechanistically, transcription factor reporter arrays demonstrated that endoplasmic reticulum stress-related transcription factors were prominently activated by HypERlnc knockdown, which was confirmed via immunoblotting for the endoplasmic reticulum stress markers IRE1α (P<0.001), ATF6 (P<0.01), and soluble BiP (P<0.001). Kyoto encyclopedia of genes and gene ontology pathway analyses of RNA sequencing experiments after HypERlnc knockdown indicate a role in cardiovascular disease states. Indeed, HypERlnc expression was significantly reduced in human cardiac tissue from patients with heart failure (P<0.05; n=19) compared with controls. In addition, HypERlnc expression significantly correlated with pericyte markers in human lungs derived from patients diagnosed with idiopathic pulmonary arterial hypertension and from donor lungs (n=14). CONCLUSIONS: Here, we show that HypERlnc regulates human pericyte function and the endoplasmic reticulum stress response. In addition, RNA sequencing analyses in conjunction with reduced expression of HypERlnc in heart failure and correlation with pericyte markers in idiopathic pulmonary arterial hypertension indicate a role of HypERlnc in human cardiopulmonary disease.

Analytic second nuclear derivatives of Hartree-Fock and DFT using multi-resolution analysis.

We present the formalism, implementation, and numerical results for the computation of second derivatives with respect to nuclear displacements of molecules in the formalism of multi-resolution analysis. The highly singular nuclear potentials are partially regularized to improve the numerical stability. Vibrational frequencies are well reproduced to within an RMS of a few cm-1 compared to large basis set LCAO (linear combination of atomic orbitals) calculations. Intermolecular modes, hindered rotations, and heavy atoms may lead to loss of precision. Tight precision thresholds are therefore necessary to converge to numerically stable results.

Dissociative Water Adsorption by Al3O4+ in the Gas Phase.

We use cryogenic ion trap vibrational spectroscopy in combination with density functional theory (DFT) to study the adsorption of up to four water molecules on Al3O4+. The infrared photodissociation spectra of [Al3O4(D2O)1-4]+ are measured in the O-D stretching (3000-2000 cm-1) as well as the fingerprint spectral region (1300-400 cm-1) and are assigned based on a comparison with simulated harmonic infrared spectra for global minimum-energy structures obtained with DFT. We find that dissociative water adsorption is favored in all cases. The unambiguous assignment of the vibrational spectra of these gas phase model systems allows identifying characteristic spectral regions for O-D and O-H stretching modes of terminal (µ1) and bridging (µ2) hydroxyl groups in aluminum oxide/water systems, which sheds new light on controversial assignments for solid Al2O3 phases.

Gas-Phase Vibrational Spectroscopy of the Aluminum Oxide Anions (Al2 O3 )1-6 AlO2.

We use cryogenic ion trap vibrational spectroscopy in combination with density functional theory to probe how the structural variability of alumina manifests itself in the structures of the gas-phase clusters (Al2 O3 )n AlO2- with n=1-6. The infrared photodissociation spectra of the D2 -tagged complexes, measured in the fingerprint spectral range (400-1200 cm-1 ), are rich in spectral features and start approaching the vibrational spectrum of amorphous alumina particles for n>4. Aided by a genetic algorithm, we find a trend towards the formation of irregular structures for larger n, with the exception of n=4, which exhibits a C3v ground-state structure. Locating the global minima of the larger systems proves challenging.

[Al2O4](-), a Benchmark Gas-Phase Class II Mixed-Valence Radical Anion for the Evaluation of Quantum-Chemical Methods.

The radical anion [Al2O4](-) has been identified as a rare example of a small gas-phase mixed-valence system with partially localized, weakly coupled class II character in the Robin/Day classification. It exhibits a low-lying C2v minimum with one terminal oxyl radical ligand and a high-lying D2h minimum at about 70 kJ/mol relative energy with predominantly bridge-localized-hole character. Two identical C2v minima and the D2h minimum are connected by two C2v-symmetrical transition states, which are only ca. 6-10 kJ/mol above the D2h local minimum. The small size of the system and the absence of environmental effects has for the first time enabled the computation of accurate ab initio benchmark energies, at the CCSDT(Q)/CBS level using W3-F12 theory, for a class-II mixed-valence system. These energies have been used to evaluate wave function-based methods [CCSD(T), CCSD, SCS-MP2, MP2, UHF] and density functionals ranging from semilocal (e.g., BLYP, PBE, M06L, M11L, N12) via global hybrids (B3LYP, PBE0, BLYP35, BMK, M06, M062X, M06HF, PW6B95) and range-separated hybrids (CAM-B3LYP, ωB97, ωB97X-D, LC-BLYP, LC-ωPBE, M11, N12SX), the B2PLYP double hybrid, and some local hybrid functionals. Global hybrids with about 35-43% exact-exchange (EXX) admixture (e.g., BLYP35, BMK), several range hybrids (CAM-B3LYP, ωB97X-D, ω-B97), and a local hybrid provide good to excellent agreement with benchmark energetics. In contrast, too low EXX admixture leads to an incorrect delocalized class III picture, while too large EXX overlocalizes and gives too large energy differences. These results provide support for previous method choices for mixed-valence systems in solution and for the treatment of oxyl defect sites in alumosilicates and SiO2. Vibrational gas-phase spectra at various computational levels have been compared directly to experiment and to CCSD(T)/aug-cc-pV(T+d)Z data.

Gas phase structures and charge localization in small aluminum oxide anions: Infrared photodissociation spectroscopy and electronic structure calculations.

We use cryogenic ion trap vibrational spectroscopy in combination with quantum chemical calculations to study the structure of mono- and dialuminum oxide anions. The infrared photodissociation spectra of D2-tagged AlO1-4 (-) and Al2O3-6 (-) are measured in the region from 400 to 1200 cm(-1). Structures are assigned based on a comparison to simulated harmonic and anharmonic IR spectra derived from electronic structure calculations. The monoaluminum anions contain an even number of electrons and exhibit an electronic closed-shell ground state. The Al2O3-6 (-) anions are oxygen-centered radicals. As a result of a delicate balance between localization and delocalization of the unpaired electron, only the BHLYP functional is able to qualitatively describe the observed IR spectra of all species with the exception of AlO3 (-). Terminal Al-O stretching modes are found between 1140 and 960 cm(-1). Superoxo and peroxo stretching modes are found at higher (1120-1010 cm(-1)) and lower energies (850-570 cm(-1)), respectively. Four modes in-between 910 and 530 cm(-1) represent the IR fingerprint of the common structural motif of dialuminum oxide anions, an asymmetric four-member Al-(O)2-Al ring.

Traumatic brain injury results in rapid pericyte loss followed by reactive pericytosis in the cerebral cortex.

Accumulating evidence suggests a pivotal role of PDGFRß positive cells, a specific marker for central nervous system (CNS) pericytes, in tissue scarring. Identification of cells that contribute to tissue reorganization in the CNS upon injury is a crucial step to develop novel treatment strategies in regenerative medicine. It has been shown that pericytes contribute to scar formation in the spinal cord. It is further known that ischemia initially triggers pericyte loss in vivo, whilst brain trauma is capable of inducing pericyte detachment from cerebral vessels. These data point towards a significant role of pericytes in CNS injury. The temporal and spatial dynamics of PDGFRß cells and their responses in traumatic brain injury are poorly understood. Here we show that PDGFRß positive cells initially decline in the acute phase following experimental traumatic brain injury. However, PDGFRß positive cells increase significantly in the trauma zone days after brain injury. Using various pericyte markers we identify these cells to be pericytes that are demarcated by reactive gliosis. Our data indicate that brain trauma causes a biphasic response of pericytes in the early phase of brain trauma that may be of relevance for the understanding of pathological cellular responses in traumatic brain injury.

Numerically accurate linear response-properties in the configuration-interaction singles (CIS) approximation.

In the present work, we report an efficient implementation of configuration interaction singles (CIS) excitation energies and oscillator strengths using the multi-resolution analysis (MRA) framework to address the basis-set convergence of excited state computations. In MRA (ground-state) orbitals, excited states are constructed adaptively guaranteeing an overall precision. Thus not only valence but also, in particular, low-lying Rydberg states can be computed with consistent quality at the basis set limit a priori, or without special treatments, which is demonstrated using a small test set of organic molecules, basis sets, and states. We find that the new implementation of MRA-CIS excitation energy calculations is competitive with conventional LCAO calculations when the basis-set limit of medium-sized molecules is sought, which requires large, diffuse basis sets. This becomes particularly important if accurate calculations of molecular electronic absorption spectra with respect to basis-set incompleteness are required, in which both valence as well as Rydberg excitations can contribute to the molecule's UV/VIS fingerprint.

Regularizing the molecular potential in electronic structure calculations. I. SCF methods.

We present a method to remove the singular nuclear potential in a molecule and replace it with a regularized potential that is more amenable to be represented numerically. The singular nuclear potential is canceled by the similarity-transformed kinetic energy operator giving rise to an effective nuclear potential that contains derivative operators acting on the wave function. The method is fully equivalent to the non-similarity-transformed version. We give numerical examples within the framework of multi-resolution analysis for medium-sized molecules.