Pharmacogenetics in Child and Adolescent Psychiatry: Background and Evidence-Based Clinical Applications.

The efficacy and tolerability of psychotropic medications can vary significantly among children and adolescents, and some of this variability relates to pharmacogenetic factors. Pharmacogenetics (PGx) in child and adolescent psychiatry can potentially improve treatment outcomes and minimize adverse drug reactions. This article reviews key pharmacokinetic and pharmacodynamic genes and principles of pharmacogenetic testing and discusses the evidence base for clinical decision-making concerning PGx testing. This article reviews current guidelines from the United States Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Dutch Pharmacogenetics Working Group (DPWG) and explores potential future directions. This review discusses key clinical considerations for clinicians prescribing psychotropic medications in children and adolescents, focusing on antidepressants, antipsychotics, stimulants, norepinephrine reuptake inhibitors, and alpha-2 agonists. Finally, this review synthesizes the practical use of pharmacogenetic testing and clinical decision support systems.

Photoinduced Electron Transfer between Dipolar Reactants: Solvent and Excitation Wavelength Effects.

Electron transfer (ET) quenching in nonpolar media is not as well understood as in polar environments. Here, we investigate the effect of dipole-dipole interactions between the reactants using ultrafast broadband electronic spectroscopy combined with molecular dynamics simulations. We find that the quenching of the S1 state of two polar dyes, coumarin 152a and Nile red, by the polar N,N-dimethylaniline (DMA) in cyclohexane is faster by a factor up to 3 when exciting on the red edge rather than at the maximum of their S1 ← S0 absorption band. This originates from the inhomogeneous broadening of the band due to a distribution of the number of quencher molecules around the dyes. As a consequence, red-edge excitation photoselects dyes in a DMA-rich environment. Such broadening is not present in acetonitrile, and no excitation wavelength dependence of the ET dynamics is observed. The quenching of both dyes is markedly faster in nonpolar than polar solvents, independently of the excitation wavelength. According to molecular dynamics simulations, this is due to the preferential solvation of the dyes by DMA in cyclohexane. The opposite preferential solvation is predicted in acetonitrile. Consequently, close contact between the reactants in acetonitrile requires partial desolvation. By contrast, the recombination of the quenching product is slower in nonpolar than in polar solvents and exhibits much smaller dependence, if any, on the excitation wavelength.

M11pz: A Nonlocal Meta Functional with Zero Hartree-Fock Exchange and with Broad Accuracy for Chemical Energies and Structures.

The accuracy of Kohn-Sham density functional theory depends strongly on the approximation to the exchange-correlation functional. In this work, we present a new exchange-correlation functional called M11pz (M11 plus rung-3.5 terms with zero Hartree-Fock exchange) that is built on the M11plus functional with the goal of using its rung-3.5 terms without a Hartree-Fock exchange term, especially to improve the accuracy for strongly correlated systems. The M11pz functional is optimized with the same local and rung-3.5 ingredients that are used in M11plus but without any percentage of Hartree-Fock exchange. The performance of M11pz is compared with eight local functionals, and M11pz is found to be in top three when the errors or ranks are averaged over eight grouped and partially overlapping databases: AME418/22, atomic and molecular energies; MGBE172, main-group bond energies; TMBE40, transition-metal bond energies; SR309, single-reference systems; MR54, multireference systems; BH192, barrier heights; NC579, noncovalent interaction energies; and MS20, molecular structures. For calculations of band gaps of solids, M11pz is the second best of the nine tested functionals that have zero Hartree-Fock exchange.

Comparing Density Functional Theory Metal-Ligand Bond Dissociation Enthalpies with Experimental Solution-Phase Enthalpies of Activation for Bond Dissociation.

The predictive ability of density functional theory is fundamental to its usefulness in chemical applications. Recent work has compared solution-phase enthalpies of activation for metal-ligand bond dissociation to enthalpies of reaction for bond dissociation, and the present work continues those comparisons for 43 density functional methods. The results for ligand dissociation enthalpies of 30 metal-ligand complexes tested in this work reveal significant inadequacies of some functionals as well as challenges from the dispersion corrections to some functionals. The analysis presented here demonstrates the excellent performance of a recent density functional, M11plus, which contains nonlocal rung-3.5 correlation. We also find a good agreement between theory and experiment for some functionals without empirical dispersion corrections such as M06, r2SCAN, M06-L, and revM11, as well as good performance for some functionals with added dispersion corrections such as ωB97X-D (which always has a correction) and BLYP, B3LYP, CAM-B3LYP, and PBE0 when the optional dispersion corrections are added.

Excited-state symmetry breaking in quadrupolar pull-push-pull molecules: dicyanovinyl vs. cyanophenyl acceptors.

A significant number of quadrupolar dyes behave as their dipolar analogues when photoexcited in polar environments. This is due to the occurrence of excited-state symmetry breaking (ES-SB), upon which the electronic excitation, initially distributed over the whole molecule, localises preferentially on one side. Here, we investigate the ES-SB properties of two A-D-A dyes, consisting of a pyrrolo-pyrrole donor (D) and either cyanophenyl or dicyanovinyl acceptors (A). For this, we use time-resolved vibrational spectroscopy, comparing IR absorption and femtosecond stimulated Raman spectroscopies. Although dicyanovinyl is a stronger electron-withdrawing group, ES-SB is not observed with the dicyanovinyl-based dye even in highly polar media, whereas it already takes place in weakly polar solvents with dyes containing cyanophenyl accepting groups. This difference is attributed to the large electronic coupling between the D-A branches in the former dye, whose loss upon symmetry breaking cannot be counterbalanced by a gain in solvation energy. Comparison with analogues of the cyanophenyl-based dye containing different spacers reveals that interbranch coupling does not so much depend on the distance between the D-A subunits than on the nature of the spacer. We show that transient Raman spectra probe different modes of these centrosymmetric molecules but are consistent with the transient IR data. However, lifetime broadening of the Raman bands, probably due to the resonance enhancement, may limit the application of this technique for monitoring ES-SB.

A Pilot, Open-Label, Proof-of-Concept Study To Evaluate the Efficacy and Safety of Asthiposhak® Tablets in Participants Suffering From Asthikshaya or Osteopenia.

Introduction Both osteoporosis and osteopenia are prevalent public health concerns worldwide and can lead to debilitating bone fractures. This study aimed to assess the efficacy of Asthiposhak® Tablets in individuals with Asthikshaya (osteopenia) by measuring changes in the bone mineral density (BMD) score before and after the intervention, specifically between visit 1 (baseline) and visit 8 (after 180 days of treatment). Methods The single-arm study involved the screening of participants for Asthikshaya (osteopenia) using baseline investigations, which included a bone mineral density (BMD) assessment through a dual-energy X-ray absorptiometry (DEXA) scan. A total of 36 participants were enrolled in the study, who took two Asthiposhak Tablets three times a day with lukewarm water, for a period of 180 days. Safety assessments, along with evaluations of BMD (DEXA Scan), Ayurvedic Symptom Score, and serum biochemical markers, were conducted through blood investigations. Efficacy and safety data were analyzed using 'intention-to-treat' analysis. Descriptive statistics were used to express data in percentages, mean ± SD, or median (IQR). Data at different intervals were compared using paired t-tests or Wilcoxon signed-rank tests. One-way analysis of variance (ANOVA) with Bonferroni correction tested the significance between visits for the Ayurvedic Symptom Score, and Friedman's two-way analysis of variance by ranks measured differences in vital parameters. The significance level used was p<0.05. Results Out of the initially recruited 36 participants, 30 successfully completed the study, consisting of 12 males and 18 females, with an age range of 40 to 70 years and a mean age of 51.33 years. After 180 days of treatment with Asthiposhak Tablets, a statistically significant (p<0.05) improvement in hip and spine BMD (T-score) was observed. Additionally, significant reductions in the mean Total Ayurvedic Symptom Score were noted at both 90 and 180 days of treatment compared to day 0. Moreover, the levels of bone-specific alkaline phosphatase and osteocalcin, serum bone markers, showed statistically significant (p<0.05) reduction after 180 days of treatment compared to day 0. Importantly, all safety variables, including laboratory investigations, remained within the normal range following the 180-day treatment with Asthiposhak Tablets. Conclusion Asthiposhak Tablets exhibited significant efficacy in enhancing both BMD (T-score) and Ayurvedic Symptom Score, thereby substantiating their osteoprotective potential in individuals with Asthikshaya (osteopenia). Furthermore, the tablets were found to reduce the levels of biochemical markers, such as serum bone-specific alkaline phosphatase and osteocalcin, suggesting their anti-resorptive action.

HER2/ERBB2 overexpression in advanced gallbladder carcinoma: comprehensive evaluation by immunocytochemistry and fluorescence in situ hybridisation on fine-needle aspiration cytology samples.

AIMS: Advanced gallbladder carcinoma (AGBC) carries a poor prognosis with dismal survival. There are no data regarding HER2/ERBB2 expression in AGBC. This study evaluated the overexpression of HER2/ERBB2 in cytological aspirates from AGBCs to identify potential patients for whom anti-HER2 targeted therapies can benefit. METHODS: This prospective, case-control study was performed on 50 primary AGBC cases. A detailed cytomorphological assessment, followed by immunocytochemistry (ICC) for HER2/ERBB2, was performed on AGBC cell blocks. A similar number of age-matched and gender-matched resected chronic cholecystitis specimens were included as controls. Fluorescence in situ hybridisation (FISH) was performed in equivocal cases. RESULTS: A total of 10 (20%) cases showed positive (3+), 19 (38%) equivocal (2+) expression and 21 (42%) were negative on HER2/ERBB2 ICC. None of the equivocal cases demonstrated HER2 amplification by FISH. Among the controls, none showed positive (3+) immunoexpression, 23 (46%) demonstrated equivocal expression and 27 (54%) were negative. On statistical analysis, HER2/ERBB2 overexpression was significantly associated with AGBC compared with the controls. Of all the clinical, radiological and cytomorphological parameters, the predominant papillary or acinar arrangements of the tumour cells were significantly associated with HER2/ERBB2 overexpression. CONCLUSIONS: This is the first study to evaluate the expression of HER2/ERBB2 on cytological aspirates in AGBC using ICC and FISH. HER2/ERBB2 overexpression(20%) was significantly associated with AGBC. Furthermore, predominant papillary or acinar arrangements of tumour cells in the cytological smears were significantly associated with HER2/ERBB2 overexpression. They can serve as potential predictors of HER2/ERBB2 overexpression to select AGBC patients for anti-HER2 targeted therapies.

Looking for chiral recognition in photoinduced bimolecular electron transfer using ultrafast spectroscopy.

Occurrence of chiral recognition in bimolecular photoinduced electron transfer (ET) is difficult to identify because of the predominant role of diffusion. To circumvent this problem, we apply a combination of ultrafast time-resolved fluorescence and transient electronic absorption to look for stereoselectivity in the initial, static stage of ET quenching, where diffusion is not relevant. The fluorophore and electron acceptor is a cationic hexahelicene, whereas the quencher has either stereocentered (tryptophan) or axial (binaphthol) chirality. We found that, in all cases, the quenching dynamics are the same, within the limit of error, for different diastereomeric pairs in polar and medium-polar solvents. The same absence of chiral effect is observed for the recombination of the radical pair, which results from the quenching. Molecular dynamics simulations suggest that the distribution of inter-reactant distance is independent of the chirality of the acceptor and the donor. Close contact resulting in large electronic coupling is predicted to be possible with all diastereomeric pairs. In this case, ET is an adiabatic process, whose dynamics do no longer depend on the coupling, but are rather controlled by high-frequency intramolecular modes.

Performance of Screened-Exchange Functionals for Band Gaps and Lattice Constants of Crystals.

Kohn-Sham density functional theory is the most widely used method for electronic structure calculations of solid-state systems. The screened-exchange functionals developed following the influential work of Scuseria and co-workers in 2003-2006 have significantly improved the accuracy of the predictions of solid-state properties. This work assesses six screened-exchange density functionals for the prediction of 60 band gaps (database BG60) and 68 lattice constants (database LC68). The band gaps are calculated with both consistently calculated lattice constants and experimental lattice constants. Results for the nonlocal screened-exchange functionals are compared with those for six widely used or recently developed local functionals. The results show that all the screened-exchange functionals have smaller mean absolute errors (MAEs) than any of the local functionals. All the functionals except HLE17 overestimate (on average) the lattice constants, and M06-SX gives the best performance among the compared functionals, with a MAE of 0.051 Å. All the functionals underestimate (on average) the band gaps, and M06-SX outperforms all other functionals, with a MAE of 0.47 eV. M06-SX also has the lowest root-mean-squared error for both LC68 and BG60. For the subdatabases of BG60, M06-SX shows better performance for ionic crystals and systems with large band gaps, while HSE12s gives better results for semiconductors and systems with small band gaps. Overall, M06-SX shows the best performance for solid-state systems, followed by N12-SX and HSE12s. The best-performing local functionals are M06-L, revM06-L, and HLE17 for band gaps and M06-L and revM06-L for lattice constants. We found that M06-SX, revM06-L, and N12-SX not only are well optimized for a broad array of chemical properties but also have very good performance for the databases in this paper, making them well-suited for applications involving heterogeneous chemistry.

Machine learning model for predicting Major Depressive Disorder using RNA-Seq data: optimization of classification approach.

Considering human brain disorders, Major Depressive Disorder (MDD) is seen as a lethal disease in which a person goes to the extent of suicidal behavior. Physical detection of MDD patients is less precise but machine learning can aid in improved classification of disease. The present research included three RNA-seq data classes to classify DEGs and then train key gene data using a random forest machine learning method. The three classes in the sample are 29 CON (sudden death healthy control), 21 MDD-S (a Major Depressive Disorder Suicide) being included in the second group, and 9 MDD (non-suicides MDD) which are included in the third group. With PCA analysis, 99 key genes were obtained. 47.1% data variability is given by these 99 genes. The model training of 99 genes indicated improved classification. The RF classification model has an accuracy of 61.11% over test data and 97.56% over train data. It was also noticed that the RF method offered greater accuracy than the KNN method. 99 genes were annotated using DAVID and ClueGo packages. Some of the important pathways and function observed in the study were glutamatergic synapse, GABA receptor activation, long-term synaptic depression, and morphine addiction. Out Of 99 genes, four genes, namely DLGAP1, GNG2, GRIA1, and GRIA4, were found to be predominantly involved in the glutamatergic synapse pathway. Another substantial link was observed in the GABA receptor activation involving the following two genes, GABBR2 and GNG2. Also, the genes found responsible for long-term synaptic depression were GRIA1, MAPT, and PTEN. There was another finding of morphine addiction which comprises three genes, namely GABBR2, GNG2, and PDE4D. For massive datasets, this approach will act as the gold standard. The cases of CON, MDD, and MDD-S are physically distinct. There was dysregulation in the expression level of 12 genes. The 12 genes act as a possible biomarker for Major Depressive Disorder and open up a new path for depressed subjects to explore further.

Reversible dehydrogenation and rehydrogenation of cyclohexane and methylcyclohexane by single-site platinum catalyst.

Developing highly efficient and reversible hydrogenation-dehydrogenation catalysts shows great promise for hydrogen storage technologies with highly desirable economic and ecological benefits. Herein, we show that reaction sites consisting of single Pt atoms and neighboring oxygen vacancies (VO) can be prepared on CeO2 (Pt1/CeO2) with unique catalytic properties for the reversible dehydrogenation and rehydrogenation of large molecules such as cyclohexane and methylcyclohexane. Specifically, we find that the dehydrogenation rate of cyclohexane and methylcyclohexane on such sites can reach values above 32,000 molH2 molPt-1 h-1, which is 309 times higher than that of conventional supported Pt nanoparticles. Combining of DRIFTS, AP-XPS, EXAFS, and DFT calculations, we show that the Pt1/CeO2 catalyst exhibits a super-synergistic effect between the catalytic Pt atom and its support, involving redox coupling between Pt and Ce ions, enabling adsorption, activation and reaction of large molecules with sufficient versatility to drive abstraction/addition of hydrogen without requiring multiple reaction sites.

Cr (III) genotoxicity and oxidative stress: An occupational health risk for leather tannery workers of South Asian developing countries.

In the leather industry, Cr (III) is used as a basic tanning agent. The wastewater discharged from the tannery industry contains a high concentration of chromium. Recent studies indicate the genotoxic effects especially DNA damage and oxidative stress of Cr (III) in tannery workers. Cr (III) interacts with DNA to form DNA cross-links and DNA strand breaks. It also modifies the oxidative DNA base through the Haber-Weiss reaction. The present study is based on an overview of scientific literature and previous observations regarding the effects of tannery chromium effluents on exposed workers and the population in the vicinity. This study strongly suggests for use of a non-toxic substitute of chromium to be used for the tanning process and placement of tannery industries on the outskirts of the city. In South Asian developing countries like India, Pakistan and Bangladesh where the economy is strongly dependent on leather manufacturing industries, there is a need to spread proper information regarding the harmful effects of chromium toxicity to the workforce employed in the tannery and also to the people living in the surrounding area. Workers should be provided with the required safety protections like gloves, aprons, foot/shoe covers, masks, etc. Last but most important on an immediate basis is the installation of the proper efficient waste treatment plant, so that, waste should be treated before moving out of the industry.

Cerebrospinal fluid cytology in a toddler with a posterior fossa space-occupying lesion.

An atypical teratoid rhabdoid tumour (AT/RT) is an extremely rare malignant neoplasm. Cerebrospinal fluid (CSF) involvement at presentation indicates intracranial dissemination and is associated with an aggressive course and worse outcomes. We present the characteristic cytomorphological features of AT/RT in the cerebrospinal fluid from a toddler presenting with a posterior fossa space-occupying lesion.

Transcriptomics and sequencing analysis of gene expression profiling for major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common psychiatric disorder characterized by constant sadness and a lack of interest in work and social interactions. Maintaining the transcriptome levels via the controlled regulation of mRNA processing and transport is essential to alleviating MDD. Various molecular phenotypes such as aberrant RNA splicing and stability are identified as critical determinants of MDD. AIM: This study aims to compare the mRNA expression profiles between major depressive disorder non-suicide (MDD), major depressive disorder suicide (MDD-S), and control groups using RNA-Seq. MATERIALS AND METHODS: A transcriptomics and sequencing analysis of gene expression profiling was conducted in 9 patients with MDD, 10 patients with MDD-S, and 10 control patients. RESULTS: A comparison of the sample groups revealed that the PRKACB gene was upregulated in patients with MDD. At the same time, GRM3, DLGAP1, and GRIA2 were downregulated in these patients-these genes are majorly involved in the glutamatergic pathway. Five genes (GRIA1, CAMK2D, PPP3CA, MAPK10, and PPP2R2A) of the dopaminergic pathway were downregulated in patients with the MDD-S condition when compared with the MDD and control groups. Cholinergic synapses were altered in patients with MDD when compared to the control group due to the presence of dysregulated genes (KCNQ5, PLCB4, ADCY9, CAMK2D, PIK3CA, and GNG2). CONCLUSION: The results provide a new understanding of the etiology of depression in humans and identify probable depression-associated biomarkers.

M11plus, a Range-Separated Hybrid Meta Functional Incorporating Nonlocal Rung-3.5 Correlation, Exhibits Broad Accuracy on Diverse Databases.

We present tests of the recent M11plus Minnesota density functional for a broad range of main-group and transition-metal chemistry databases, most of which were not used in in the construction of any of the Minnesota functionals. M11plus is a range-separated hybrid meta functional combining long-range nonlocal Hartree-Fock exchange with nonlocal rung-3.5 correlation. M11plus performs well for main-group thermochemistry, kinetics, and noncovalent interactions and especially well for radical species. It is numerically well behaved, it has a computational cost that is ∼1.2 to 1.5 times that of M11 in realistic calculations, and it is particularly accurate for triplet excited states, which is a difficult challenge for density functional approximations. The results show that nonlocal rung-3.5 correlation is a broadly useful ingredient for improving the performance of density functional approximations.

Prospective evaluation of the setup errors and its impact on safety margin for cervical cancer pelvic conformal radiotherapy.

AIM: The primary objective was to assess set-up errors (SE) and secondary objective was to determine optimal safety margin (SM). BACKGROUND: To evaluate the SE and its impact on the SM utilizing electronic portal imaging (EPI) for pelvic conformal radiotherapy. MATERIAL AND METHODS: 20 cervical cancer patients were enrolled in this prospective study. Supine position with ankle and knee rest was used during CT simulation. The contouring was done using consensus guideline for intact uterus. 50 Gy in 25 fractions were delivered at the isocenter with ≥95% PTV coverage. Two orthogonal (Anterior and Lateral) digitally reconstructed radiograph (DRR) was constructed as a reference image. The pair of orthogonal [Anterior-Posterior and Right Lateral] single exposure EPIs during radiation was taken. The reference DRR and EPIs were compared for shifts, and SE was calculated in the X-axis, Y-axis, and Z-axis directions. RESULTS: 320 images (40 DRRs and 280 EPIs) were assessed. The systematic error in the Z-axis (AP EPI), X-axis (AP EPI), and Y-axis (Lat EPI) ranged from -12.0 to 11.8 mm, -10.3 to 7.5 mm, and -8.50 to 9.70 mm, while the random error ranged from 1.60 to 6.15 mm, 0.59 to 4.93 mm, and 1.02 to -4.35 mm. The SM computed were 7.07, 6.36, and 7.79 mm in the Y-axis, X-axis, and Z-axis by Van Herk's equation, and 6.0, 5.51, and 6.74 mm by Stroom's equation. CONCLUSION: The computed SE helps defining SM, and it may differ between institutions. In our study, the calculated SM was approximately 8 mm in the Z-axis, 7 mm in X and Y axis for pelvic conformal radiotherapy.

M06-SX screened-exchange density functional for chemistry and solid-state physics.

Screened-exchange hybrid density functionals are especially recommended for solid-state systems because they combine the advantages of hybrid functionals with the correct physics and lower computational cost associated with the attenuation of Hartree-Fock exchange at long range. We present a screened-exchange hybrid functional, M06-SX, that combines the functional form of the local revM06-L functional with a percentage of short-range nonlocal Hartree-Fock exchange. The M06-SX functional gives good results not only for a large set of training data but also for several databases quite different from the training data. The mean unsigned error (MUE) of the M06-SX functional is 2.85 kcal/mol for 418 atomic and molecular energies (AME418) in Minnesota Database 2019, which is better than all five other screened-exchange hybrid functionals tested in this work. The M06-SX functional also gives especially good results for semiconductor band gaps, molecular dissociation energies, noncovalent interactions, barrier heights, and electronic excitation energies excluding long-range charge transfer excitations. For the LC18 lattice constants database, the M06-SX functional gives an MUE of only 0.034 Å. Therefore, the M06-SX functional is well suited for studying molecular chemistry as well as solid-state physics.

Broadband fluorescence reveals mechanistic differences in excited-state proton transfer to protic and aprotic solvents.

Excited-state proton transfer (ESPT) to solvent is often explained according to the two-step Eigen-Weller model including a contact ion pair (CIP*) as an intermediate, but general applicability of the model has not been thoroughly examined. Furthermore, examples of the spectral identification of CIP* are scarce. Here, we report on a detailed investigation of ESPT to protic (H2O, D2O, MeOH and EtOH) and aprotic (DMSO) solvents utilizing a broadband fluorescence technique with sub-200 fs time resolution. The time-resolved spectra are decomposed into contributions from the protonated and deprotonated species and a clear signature of CIP* is identified in DMSO and MeOH. Interestingly, the CIP* intermediate is not observable in aqueous environment although the dynamics in all solvents are multi-exponential. Global analysis based on the Eigen-Weller model is satisfactory in all solvents, but the marked mechanistic differences between aqueous and organic solvents cast doubt on the physical validity of the rate constants obtained.

Propyl acetate/butyronitrile mixture is ideally suited for investigating the effect of dielectric stabilization on (photo)chemical reactions.

Characterization of propyl acetate/butyronitrile (PA/BuCN) mixtures by various spectroscopic techniques is described. The neat solvents have identical viscosities and refractive indices but their dielectric constants differ significantly. Detailed solvatochromic and titration data show that the mixtures do not exhibit specific solute-solvent interactions or significant dielectric enrichment effects. Therefore, the mixtures are ideally suited for investigating the effect of dielectric stabilization on (photo)chemical reactions. Dynamic Stokes shift experiments performed on two push-pull probes demonstrate that the solvation dynamics are significantly decelerated in the mixtures as compared to the neat solvents. Therefore, the mixtures allow for varying both the extent and time scale of the dielectric stabilization in a predictable manner.

M11plus: A Range-Separated Hybrid Meta Functional with Both Local and Rung-3.5 Correlation Terms and High Across-the-Board Accuracy for Chemical Applications.

The way to improve Kohn-Sham density functional theory is to improve the exchange-correlation functionals, and functionals have been successively improved by adding new ingredients, especially local spin density gradients, nonlocal Hartree-Fock exchange, and local meta terms based on kinetic energy density. Here, we present a new kind of functional obtained by adding rung-3.5 terms to a functional including local gradients, local meta terms, and range-separated Hartree-Fock exchange. A rung-3.5 term has short-range nonlocality designed to account for nondynamic correlation; we add two kinds of rung-3.5 terms, one kind modeled on position-dependent Hartree-Fock exchange and another modeled on the spin density at a point interacting with the opposite-spin exchange hole at the same point. Optimization of the functional yields broad accuracy for both ground states and excited states with especially significant improvement for systems with strong correlation.