Mechanism of Spin-Exchange Internal Conversion: Practical Proxies for Diabatic and Nonadiabatic Couplings

International audienceSpin-exchange internal conversion (SEIC) is a general class of reactions having singlet fission and triplet fusion as particular cases. Based on a charge-transfer (CT)-mediated mechanism and analytical derivation with a model Hamiltonian, we propose proxies for estimating the coupling strength in both diabatic and adiabatic pictures for general SEIC reactions. In the diabatic picture, we demonstrated the existence of a bilinear relationship between the coupling strength and molecular orbital overlap , which provides a practical way to predict diabatic couplings. In the adiabatic picture, we showed that nonadiabatic couplings can be approximated by simple functions of the wave function CT coefficients. These approaches were verified through the investigation of singlet oxygen photosensitization, where both 1 Δg and 1 g oxygen states can be competitively generated by a triplet fusion reaction. The interplay between the CT-mediated mechanism, the spatial factors of the bimolecular complex, and the electronic structure of the oxygen molecule during the reaction explains the curiously small coupling to the 1 g state along specific incidence directions. The results from both the diabatic and adiabatic pictures provide a comprehensive understanding of the reaction mechanism, which applies to general SEIC problems

Miniscalpel-Needle Treatment Is Effective for Work-Related Neck and Shoulder Musculoskeletal Disorders

Background. Work-related musculoskeletal disorders (MSDs) are a group of painful disorders of muscles, tendons, and nerves, such as neck and shoulder MSD. This study was designed to use miniscalpel-needle (MSN) technique as an intervention for work-related MSDs. Methods. Thirty-one patients with work-related MSDs and 28 healthy subjects were enrolled as controls in this study. The MSD symptoms of each patient were assessed by visual analog scale (VAS) and neck disability index (NDI). Blood samples were collected from control subjects and MSD patients before and after treatment. Serum levels of C-reactive protein (CRP) and tumor necrosis factor (TNF) were measured using ELISA. Results. Prior to MSN treatment, serum levels of CRP and TNF were significantly higher in the MSD patients than the healthy controls. Serum CRP levels correlated with VAS and NDI scores, and serum TNF levels correlated with NDI scores. Compared to pretreatment, VAS and NDI scores were significantly lower in MSD patients after MSN treatment, while serum CRP and TNF levels were significantly lower compared with the healthy control levels. Conclusions. Our results indicate that MSN may be an effective intervention for work-related MSDs and be associated with lower serum levels of inflammatory biomarkers

New Insights into the State Trapping of UV-Excited Thymine

Ljiljana Stojanović, Shuming Bai, and Mario Barbatti thank the support of the Aix-Marseille Initiative d’Excellence (A*MIDEX) grant (No. ANR-11-IDEX-0001-02) funded by the French Government “Investissements d’Avenir” program supervised by the Agence Nationale de la Recherche. This work was granted access to the HPC resources of Aix-Marseille Université financed by the project Equip@Meso (ANR-10-EQPX-29-01) also within the “Investissements d’Avenir” program. Artur F. Izmaylov acknowledges funding from a Sloan Research Fellowship and the Natural Sciences and Engineering Research Council of Canada (NSERC) through the Discovery Grants Program

Investigation of Testosterone, Androstenone, and Estradiol Metabolism in HepG2 Cells and Primary Culture Pig Hepatocytes and Their Effects on 17βHSD7 Gene Expression

Steroid metabolism is important in various species. The accumulation of androgen metabolite, androstenone, in pig adipose tissue is negatively associated with pork flavor, odour and makes the meat unfit for human consumption. The 17β-hydroxysteroid dehydrogenase type 7 (17βHSD7) expressed abundantly in porcine liver, and it was previously suggested to be associated with androstenone levels. Understanding the enzymes and metabolic pathways responsible for androstenone as well as other steroids metabolism is important for improving the meat quality. At the same time, metabolism of steroids is known to be species- and tissue-specific. Therefore it is important to investigate between-species variations in the hepatic steroid metabolism and to elucidate the role of 17βHSD7 in this process. Here we used an effective methodological approach, liquid chromatography coupled with mass spectrometry, to investigate species-specific metabolism of androstenone, testosterone and beta-estradiol in HepG2 cell line, and pig cultured hepatocytes. Species- and concentration-depended effect of steroids on 17βHSD7 gene expression was also investigated. It was demonstrated that the investigated steroids can regulate the 17βHSD7 gene expression in HepG2 and primary cultured porcine hepatocytes in a concentration-dependent and species-dependent pattern. Investigation of steroid metabolites demonstrated that androstenone formed a 3′-hydroxy compound 3β-hydroxy-5α-androst-16-ene. Testosterone was metabolized to 4-androstene-3,17-dione. Estrone was found as the metabolite for β-estradiol. Inhibition study with 17βHSD inhibitor apigenin showed that apigenin didn't affect androstenone metabolism. Apigenin at high concentration (50 μM) tends to inhibit testosterone metabolism but this inhibition effect was negligible. Beta-estradiol metabolism was notably inhibited with apigenin at high concentration. The study also established that the level of testosterone and β-estradiol metabolites was markedly increased after co-incubation with high concentration of apigenin. This study established that 17βHSD7 is not the key enzyme responsible for androstenone and testosterone metabolism in porcine liver cells. © 2012 Chen et al

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

On the decay of the triplet state of thionucleobases

International audienceSinglet oxygen production upon photosensitization plays a critical role in drugs based on thionucleobases. While for immunosuppressants its yield must be near zero, for phototherapeutic drugs it should be near the unity. In this work, we apply high-level quantum chemical modelling to investigate the decay of the triplet state of thionucleobases, a main determinant of the singlet oxygen yield. Working on CASPT2 optimizations of two prototypical thiothymines (2-thiothymine and 6-aza-2-thiothymine), we showed that the T-1 state is characterized by two pi pi* minima and by the intersection of T-1 with the singlet ground state. On the basis of this topography, we propose a two-step mechanistic model, which, depending on the energetic balance between the two minima, may have as a determining step either a slow transition between minima or a faster intersystem crossing to S-0. Chemical kinetics modelling, as well as simulations of the transient absorption spectra, confirmed that the two-step model can explain the experimental results available for both molecules. Moreover, through additional investigations of 2-thiocytosine and 6-thioguanine, we show that such a T-1 topography is a common theme for nucleobases. We also discuss how the triplet-state topography may be used to control the singlet oxygen yield, aiming at different medical applications

Think in this way, then think in that way : imposing a switch between intuition and rationalization thinking approach for creative ideation

This study investigated the impacts of different problem-solving approaches on creative ideation. In particular, the effects of intuition and rationalization on creativity, novelty and response utility were examined. Three hundred and twelve undergraduates (M age = 20.85 years, SD = 1.61) were randomly assigned to one of six experimental conditions: (1) Intuitive problem-solving approach only, (2) Rational problem-solving approach only, (3) Simultaneous intuitive and rational problem-solving approach, (4) Intuitive problem-solving approach then rational problem-solving approach, (5) Rational problem-solving approach then intuitive problem-solving approach and (6) Control (no experimental instructions), such that there were 52 participants exactly in each condition. All participants engaged in the same creative ideation task, where mood, motivation and typical thinking style were also measured. The results, under contrast analysis, demonstrated that the participants who were instructed to switch between intuition and rationalization scored significantly higher on the creative ideation task as compared to the counterparts who were instructed to think intuitively and rationally simultaneously. Results suggest that imposing a switch between intuition and rationalization thinking approach, via experimental instructions, improves creative ideation. Theoretical and practical implications are discussed.Bachelor of Art

Why Replacing Different Oxygens of Thymine with Sulfur Causes Distinct Absorption and Intersystem Crossing

WOS:000381778400004International audienceRecent experiments replacing oxygen atoms by sulfur in thymine have revealed that absorption and intersystem crossing properties of these derivatives are strongly dependent on the position and number of the substitutions, affecting their potential performance for photodynamical therapy. Using multireference quantum chemical methods (CASPT2 and DFT/MRCI), we calculated absorption spectra and spin orbit coupling matrix elements for thymine (Thy), 2-thiothymine (2tThy), 4-thiothymine (4tThy), and 2,4-dithiothymine (2,4dtThy), to investigate this relation between structure and photophysics. The simulations showed that a simple 4-electrons/4-orbital minimum model can explain the main experimentally observed spectral features. Moreover, the computational estimate of intersystem crossing lifetimes in this sequence of molecules revealed that the experimental value attributed to thymine in water might be underestimated by a factor 20, most probably due to an overlap of singlet/triplet absorption signals in the transient absorption spectrum. The difference between the absorptivity of 2tThy and 2tThd was also investigated, but no conclusive explanation could be found

Mechanism of Enhanced Triplet Decay of Thionucleobase by Glycosylation and Rate-Modulating Strategies

International audienceThe decay of the triplet state of photosensitizers is essential to their performance in singlet-oxygen generation. Experiments have shown that in thionucleosides this decay is enhanced compared to that in the corresponding thionucleobases. In this work, we applied quantum-chemical methods and chemical-kinetic modeling to investigate the effects of sugar substituent on the triplet decay of thionucleosides. The computed rates for the energetically favored conformers of thiothymidine, thiouridine, and thioguanosine (and the respective thionucleobases) show a remarkable quantitative agreement with the experimental results. We additionally show that the triplet decay enhancement is caused by the repulsion interaction between the sugar group and the sulfur atom, which reduces the activation energy for intersystem crossing, by destabilizing the T1 minimum. In some instances, an intramolecular hydrogen bond stabilizes the energy of the T1/S0 crossing point, also reducing the activation energy. This molecular understanding of the mechanism of enhanced triplet decay provides a guideline to control the triplet decay rate, which was tested in new thiothymidine derivatives.

Learning Intermolecular Electronic Coupling from a Molecular-Orbital-Pair-based Descriptor

In this work, we proposed a graphic molecular-orbital-pair-based descriptor to predict intermolecular electronic couplings (ECs). We transform the numeric grid points data of the molecular orbitals (MOs) involved in the charge or energy transfer process by reducing the thousands of grid points to a few points based on the lobes of MO. The simplified representation consists of two parts, the integral value over the space and the coordinates of centroid of each lobe. To express the intermolecular interaction for a donor-acceptor pair, each simplified MO representation from the donor is paired to the one from the acceptor. Then, the obtained MO-pair representation is the descriptor for learning the intermolecular ECs, including hole transfer (HT), electron transfer (ET) and Dexter energy transfer (DET) coupling, with a multi-layer perceptron (MLP) model. The accuracy of our model reached at a promising level of 0.1~5 meV comparing with the quantum chemistry calculations. The data size dependence tests shows that our model has exhibited good ability on low-shot learning. Therefore, the graphic MO-pair-based descriptor has been proved to be capable to characterize MO interaction features