Development of Frozen-Density Embedded Algebraic Diagrammatic Construction Schemes for Excited States and Quantum-Chemical Investigation of Photophysical Properties of Tetrathiaheterohelicenes

Theoretical chemistry has become an important branch of modern chemistry. Theoretical investigations improve our understanding of chemical problems and can predict properties or reaction pathways. Especially in photochemistry, quantum chemical calculations are used along with spectroscopy to analyze the interactions of molecules with light. In recent years, new methods like time-dependent density functional theory (TD-DFT) and the algebraic diagrammatic construction scheme for the polarization propagator (ADC) have been developed allowing calculations of excited states of molecules of chemical relevant size with an accuracy directly comparable with experimental results. These methods allow not only for the calculation of excitation energies, but also of excited state properties, electron densities, absorption strengths and even photoreaction pathways can be calculated. This paves the way for the theoretical investigation of all photochemical processes. Typically, however, chemical reactions and spectroscopic measurements are performed in solution. Unlike in gas phase, molecules in solution are comparatively close together, leading to an interaction between the solvent and solute molecules. In biochemistry, reactions often take place in the active center of a protein and in technical photochemical applications such as organic light emitting diodes (OLEDs) the chromophore is packed in a matrix. Hence, for comparable quantum mechanical calculations, the influence of the environment has to be considered as well. Since a direct treatment of the full environment is generally not feasible due to the computational demand of quantum chemical methods, an approximative treatment of the interaction using specific environment models is made. In my dissertation, I focused on two main topics involving both the application of existing theoretical methods, and the development of new theoretical methods. In the first part, I investigated the photochemical and electrochemical properties of various phosphorus-tetrathia-[7]heterohelicenes. The ground and several excited states of tetrathia-[7]heterohelicene-dialkylphosphane-borane (TTH-DAPB) and tetrathia-[7]heterohelicene-diphenylphosphane-gold(I)-chloride (TTH-DPP-Au(I)) have been analyzed using DFT, TD-DFT and RI-CC2. These molecules belong to the the class of helicenes, which are characterized by multiple annelated aromatic rings forming a helical structure which induces chirality. The optimized ground state equilibrium structures were compared with experimental structures determined by X-ray crystallography and showed generally good agreement. The eight energetically lowest excited singlet states have been calculated. Employing a constant shift accounting for environment effects and intrinsic errors of the applied method, the calculated spectra almost perfectly resemble the experimental absorption and circular dichroism spectra. In both molecules, both the S1 and S2 state contribute to the first absorption band. Therefore, vibrationally resolved absorption spectra have been calculated for these two states for both molecules. It could be shown that only the first excited state determines the absorption band. The second excited state exhibits a very broad band due to many normal modes contributing to the vibronic excitation. In general, the TTH backbone dominates the photochemical properties and the phosphorus and gold atoms exhibit only minor influences. In addition, electrochemical properties of the phosphine-oxide TTH derivatives TTH-(PO(n-Bu)2)2, TTH-(PO(Ph)2)2 and TTH-PO(Ph)2 as well as of the two phosphine-selenide TTH derivatives TTH-(PSe(Ph)2)2 and TTH-PSe(Ph)2 have been calculated. Ionization energies and electron affinities have been computed both in gas phase and solution. In solution, all first electron detachments and attachments are localized on the TTH moiety with only minor influence of the substituents. Each process is qualitatively determined in all molecules by a single frontier orbital, which has been verified by difference density analysis. For the phosphine-oxide TTH derivatives the gas phase results resemble the results in solution. The phosphine-selenides, however, show a different picture. The lone-pairs are shifted higher in energy without stabilization of the environment, leading to an ionization localized at the selenium atom in the gas phase. The second focus of my dissertation was the development, implementation, and testing of a new method for including environment interaction in the excited state of a central molecule. To this end, I combined frozen density embedding thoery (FDET) with the ADC method to develop the new FDE-ADC method. This method is implemented in the quantum chemical program package Q-Chem as the module fdeman, which manages the FDE-ADC calculation. In FDET, the supersystem is divided in two subsystems: the embedded system (A) and the environment (B). The name „embedded system“ comes from the fact that it is embedded in the electron density of the environment. The inuence of the environment is expressed in an embedding potential, which depends on both electron densities of A and B. In fdeman, the whole FDE-ADC calculation is performed in a four step process: a) generation of the electron density of the embedded system _A(~r), b) generation of the electron density of the environment _B(~r), c) calculation of the embedding potential vlin emb(~r) and _nally d) applying vlin emb(~r) in an FDE-ADC calculation by adding it to the Fock matrix during the SCF The second focus of my dissertation was the development, implementation, and testing of a new method for including environment interaction in the excited state of a central molecule. To this end, I combined frozen density embedding theory (FDET) with the ADC method to develop the new FDE-ADC method. This method is implemented in the quantum chemical program package Q-Chem as the module FDEman, which manages the FDE-ADC calculation. In FDET, the supersystem is divided in two subsystems: the embedded system (A) and the environment (B). The name „embedded system“ comes from the fact that it is embedded in the electron density of the environment. The influence of the environment is expressed in an embedding potential, which depends on both electron densities of A and B. In FDEman, the whole FDE-ADC calculation is performed in a four step process: a) generation of the electron density of the embedded system rho_A, b) generation of the electron density of the environment rho_B, c) calculation of the embedding potential v_emb and finally d) applying v_emb in an FDE-ADC calculation by adding it to the Fock matrix during the SCF followed by an ADC calculation using the orbitals influenced by the environment. While the straight-forward implementation of FDE-ADC uses a supermolecular basis to express both density matrices and the embedding potential, an approximate variant named re-assembling of density matrix (RADM) has been introduced in which the density matrix of A is built together from MP(2) and HF based density matrices like a patchwork. The created embedding potential is subsequently cut to the monomer basis which features an FDE-ADC calculation using only the basis functions of the embedded system. This can be done since in the contraction of the density of A with the embedding potential, only the values of the block in the density matrix representing the embedded system contribute. FDE-ADC has been benchmarked up to third order perturbation theory employing three test systems, designed to exhibit an increasing strength of environment interaction. The test systems are 1) benzene with a hydrogen fluoride molecule in plane with the benzene ring, 2) benzaldehyde with a hydrogen-bonded water dimer and 3) uracil surrounded by five hydrogen-bonded water molecules. In the benchmark, the FDE-ADC results have been compared with supermolecular ADC calculations. The deviation from the reference calculation in excitation energies and oscillator strengths determines the accuracy of FDE-ADC. For SE-FDE-ADC(2) and RADM-FDE-ADC(2), mean absolute errors (MAEs) of 0.025 eV and 0.040 eV in excitation energies have been determined, respectively. For RADM-FDE-ADC(3), an MAE of 0.029 eV has been calculated. These errors are well below the intrinsic error of the underlying ADC methods, thus demonstrating the performance of FDE-ADC. This is furthermore demonstrated in three representative applications. First, the excited states of benzoquinone in 42 methanol molecules have been investigated. Next, the vertical photochemical properties of the photoswitch spiropyran in 100 water molecules have been investigated. In the last application, the core-valence excited states of carbon monoxide inside a C60-cage have been calculated. Using a frozen environment neglects the influence of the embedded system on the environment. This is called environment polarization and can be added following two different approaches. In the first variant referred to as pre-polarization, the ground state influence of the embedded system on the environment is treated by an electrostatic potential which is applied during the calculation of the environment density. This way, rho_B is not calculated in the gas phase but instead in the presence of A. In the second variant, referred to as excitation-induced environment polarization, the influence of an electronic excitation of A on the environment is considered. Therefore, the subsystems are interchanged and alternatingly embedded in each other until self-consistency (freeze and thaw). Here, two approximate variants to include excitation-induced environment polarization are introduced. In the first variant, named state-specific iteration (SSI), the alternate embedding is performed once, which prevents changes in the order of the excited states. In the second variant called difference density polarization potential (DDPP), the environment is embedded consecutively in the ground and excited state density of system A. The electron difference density describing the polarization of the environment is used to create a potential which is employed to calculate an energy correction for the excitation energy of the excited state of A. Both SSI and DDPP as well as the pre-polarization are implemented in the module FDEman in Q-Chem. In tests, both the pre-polarization and SSI could increase the accuracy of FDE-ADC. In the case of SSI, up to 35 % increased accuracy is observed. DDPP currently does not improve the results. In total, the FDE-ADC method is a promising approach for considering environmental effects on electronically excited states. The error of this method is lower than the intrinsic error of the employed ADC method. Using the RADM approximation, explicit treatment of extended environments is directly feasible, making FDE-ADC a „black box“ method for the calculation of excited states in complex environments

Radiation-Induced Graft Immobilization (RIGI): Covalent Binding of Non-Vinyl Compounds on Polymer Membranes

Radiation-induced graft immobilization (RIGI) is a novel method for the covalent binding of substances on polymeric materials without the use of additional chemicals. In contrast to the well-known radiation-induced graft polymerization (RIGP), RIGI can use non-vinyl compounds such as small and large functional molecules, hydrophilic polymers, or even enzymes. In a one-step electron-beam-based process, immobilization can be performed in a clean, fast, and continuous operation mode, as required for industrial applications. This study proposes a reaction mechanism using polyvinylidene fluoride (PVDF) and two small model molecules, glycine and taurine, in aqueous solution. Covalent coupling of single molecules is achieved by radical recombination and alkene addition reactions, with water radiolysis playing a crucial role in the formation of reactive solute species. Hydroxyl radicals contribute mainly to the immobilization, while solvated electrons and hydrogen radicals play a minor role. Release of fluoride is mainly induced by direct ionization of the polymer and supported by water. Hydrophobic chains attached to cations appear to enhance the covalent attachment of solutes to the polymer surface. Computational work is complemented by experimental studies, including X-ray photoelectron spectroscopy (XPS) and fluoride high-performance ion chromatography (HPIC)

SoDa: a Web service on solar radiation

ISBN 3-9809656-4-3International audienceA Web service has been developed for answering the needs of industry and research for information on solar radiation parameters with a satisfactory quality. It intends to solve the three major problems identified by customers: i) improving access to information, ii) improving knowledge on space and time structure and iii) improving matching of delivered information to actual needs of customers. This service (http://www.soda-is.com) is also innovative with respect to the Internet technologies: it is performing a smart networking of information sources of different natures: databases (radiation, meteorology, elevation, geography...) and algorithms (computation of radiation on slopes, sizing of systems...). These sources were available separately and are geographically dispersed. The service SoDa makes them cooperating and combines them in order to answer to requests, ranging from a series of irradiation values to the sizing of a system

Dacron® vs. PTFE as bypass materials in peripheral vascular surgery – systematic review and meta-analysis

Roll S, Müller-Nordhorn J, Keil T, et al. Dacron® vs. PTFE as bypass materials in peripheral vascular surgery – systematic review and meta-analysis. BMC Surgery. 2008;8(1): 22.Background: In peripheral vascular bypass surgery different synthetic materials are available for bypass grafting. It is unclear which of the two commonly used materials, polytetrafluoroethylene (PTFE) or polyester (Dacron®) grafts, is to be preferred. Thus, the aim of this meta-analysis and systematic review was to compare the effectiveness of these two prosthetic bypass materials (Dacron® and PTFE). Methods: We performed a systematic literature search in MEDLINE, Cochrane-Library – CENTRAL, EMBASE and other databases for relevant publications in English and German published between 1999 and 2008. Only randomized controlled trials were considered for inclusion. We assessed the methodological quality by means of standardized checklists. Primary patency was used as the main endpoint. Random-effect meta-analysis as well as pooling data in life table format was performed to combine study results. Results: Nine randomized controlled trials (RCT) were included. Two trials showed statistically significant differences in primary patency, one favouring Dacron® and one favouring PTFE grafts, while 7 trials did not show statistically significant differences between the two materials. Meta-analysis on the comparison of PTFE vs. Dacron® grafts yielded no differences with regard to primary patency rates (hazard ratio 1.04 (95% confidence interval [0.85;1.28]), no significant heterogeneity (p = 0.32, I2 = 14%)). Similarly, there were no significant differences with regard to secondary patency rates. Conclusion: Systematic evaluation and meta-analysis of randomized controlled trials comparing Dacron® and PTFE as bypass materials for peripheral vascular surgery showed no evidence of an advantage of one synthetic material over the other

Corticosteroids and regional variations in thickness of the human cerebral cortex across the lifespan

International audienceExposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4–97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Two-sided a posteriori error estimates for mixed formulations of elliptic problems

The present work is devoted to the a posteriori error estimation for mixed approximations of linear self-adjoint elliptic problems. New guaranteed upper and lower bounds for the error measured in the natural product norm are derived, and individual sharp upper bounds are obtained for approximation errors in each of the physical variables. All estimates are reliable and valid for any approximate solution from the class of admissible functions. The estimates contain only global constants depending solely on the domain geometry and the given operators. Moreover, it is shown that, after an appropriate scaling of the coordinates and the equation, the ratio of the upper and lower bounds for the error in the product norm never exceeds 3. The possible methods of finding the approximate mixed solution in the class of admissible functions are discussed. The estimates are computationally very cheap and can also be used for the indication of the local error distribution. As applications, the diffusion problem as well as the problem of linear elasticity are considered