Vibronic coupling and ultrafast electron transfer studied by picosecond time-resolved resonance Raman and CARS spectroscopy

Diese Arbeit befasst sich mit der vibronischen Kopplung zweier angeregter Elektronenniveaus in Diphenylhexatrien (DPH) und mit der Rolle von Schwingungsmoden beim ultraschnellen photoinduzierten intramolekularen Elektronentransfer in Betain-30. Mit Hilfe von Pikosekunden-zeitaufgelöster Kohärenter Antistokes Ramanspektroskopie im angeregten Zustand des DPH haben wir zum ersten Mal das Auftreten zweier extrem frequenzverbreiterter Ramanlinien beobachtet, die gegenüber dem C=C Streckschwingungsbereich zu höheren Wellenzahlen verschoben sind. Beide Ramanlinien lassen sich mit Erhöhung der Lösungsmittelpolarisierbarkeit um mehr als 50 cm-1 in Richtung niedrigerer Frequenzen verschieben. Zur Erklärung des Sachverhalts werden zwei Modelle diskutiert: (i) die Existenz zweier Isomere im ersten angeregten Elektronenniveau des DPH und (ii) vibronische Kopplung der beiden Elektronenniveaus durch eine niederfrequente asymmetrische bu Schwingungsbewegung (pseudo-Jahn-Teller Effekt). Mit Hilfe von stationärer Ramanspektroskopie und insbesondere Messungen der Stokes- und anti-Stokes-Ramanspektren mit Pikosekunden-Zeitauflösung, die Beteiligung von Molekülschwingungen beim Elektronentransfer in Betain-30 wurde untersucht. Zum ersten Mal wurde eine modenspezifische Kinetik der Ramanaktiven Schwingungen nach Elektronen Rücktransfer in Betain-30 beobachtet. Die hochfrequenten Ramanaktiven Moden werden beim Elektronen Rücktransfer bevorzugt, was zu einer nicht-thermischen Besetzung der Schwingungen führt. Das ist zumindest qualitativ in Übereinstimmung mit Rechnungen die auf Fermi's Goldener Regel basieren. Eine Thermalisierung zwischen den beobachteten Ramanaktiven Moden stellt sich frühestens 10 ps nach Anregung ein. Die Thermalisierung in dem gesamten Molekül ist aber noch nicht beendet.This thesis deals with vibronic coupling effects between two excited electronic singlet states in Diphenylhexatriene (DPH), and with the role of vibrational modes in photoinduced ultrafast electron transfer in Betaine-30. By using the picosecond time-resolved Coherent Antistokes Raman Spectroscopy method, it was possible to observe for the first time two very broad and unusual up-shifted vibrational frequencies in the excited singlet state of DPH, which have frequencies higher than frequency region of the C=C stretching mode. These two frequencies shift towards lower frequencies with increasing solvent polarizability. Two explanations have been discussed: (i) the simultaneous existence of two rotamers, where the two frequencies originate from "different molecules" and (ii) a model of vibronic coupling by an asymmetric low frequency bu-mode (pseudo-Jahn-Teller effect). By using the picosecond time-resolved anti-Stokes Raman spectroscopy method, we observed for the first time mode-specific excitation of vibrational modes after back-electron transfer in Betaine-30. In the primary event, high frequency Raman active modes are most effective in accepting energy, which leads to a non-thermal distribution of the relative populations of Raman active modes. This is qualitatively in accordance with predictions derived from Fermi's Golden Rule. Although energy transfer between the Raman active modes has been finished after about 10 to 15 ps, thermalization is not yet complete in the whole molecule

Collaboration Patterns as a Function of Research Experience Among Mixed Researchers: A Mixed Methods Bibliometric Study

Onwuegbuzie et al. (2018) documented that the degree of collaboration is higher for mixed researchers than for qualitative and quantitative researchers. The present investigation examined the (a) link between the research experience of lead authors and their propensity to collaborate (Quantitative Phase), and (b) role of research experience in collaborative mixed research studies (Qualitative Phase). Analyses of articles published in the Journal of Mixed Methods Research from 2007 (its inception) to the third issue in 2018 (time of data collection) revealed that the average research experience of lead authors decreased from 20.29 in 2007 to 14.24 in 2017 (last complete year), representing a significant reduction of 29.8%. No statistically significant relationship emerged between degree of collaboration and research experience. The qualitative phase yielded 3 themes and 9 subthemes that identified several differences and similarities between the desire for collaboration and research experience. In particular, for the least-experienced mixed methods researchers, collaboration might be associated with negative emotions (e.g., frustration, stress, anxiety) and this coupled with the lack of perceived weaknesses reported by the most-experienced sub-participants, suggest that years of experience have an impact on their affective state during the conduct of collaborative mixed methods research studies. Implications of these findings are discussed

Surface action spectroscopy with rare gas messenger atoms

Action spectroscopy with inert gas messengers is commonly used for the characterization of aggregates in the gas phase. The messengers, often rare gas atoms or D2 molecules, are attached to the gas phase aggregates at low temperature. Vibrational spectra of the aggregates are measured via detection of inert gas desorption following a vibrational excitation by variable-energy infrared light. We have constructed an apparatus for the application of action spectroscopy to surfaces of solids with the aim of establishing a new method for the vibrational spectroscopy of surfaces and deposited clusters. Experiments performed for neon covered V2O3(0001) show that this method can provide information about surface vibrations. Besides the surface sensitive channel, there is also a bulk sensitive one as demonstrated with the example of CeO2(111) thin film data. Unlike infrared reflection absorption spectroscopy, normalization to a reference spectrum is not required for action spectroscopy data, and unlike high resolution electron energy loss spectroscopy, the action spectroscopy method does not suffer from moderate resolution nor from multiple excitations. Selective decoration of specific surface features with messenger atoms may be utilized to focus the spectroscopic information onto these features

Targeting epigenetic regulation and post-translational modification with 5-Aza-2' deoxycytidine and SUMO E1 inhibition augments T-cell receptor therapy

Background Cellular immunotherapy using modified T cells offers new avenues for cancer treatment. T-cell receptor (TCR) engineering of CD8 T cells enables these cells to recognize tumor-associated antigens and tumor-specific neoantigens. Improving TCR T-cell therapy through increased potency and in vivo persistence will be critical for clinical success.Methods We evaluated a novel drug combination to enhance TCR therapy in mouse models for acute myeloid leukemia (AML) and multiple myeloma (MM).Results Combining TCR therapy with the SUMO E1 inhibitor TAK981 and the DNA methylation inhibitor 5-Aza-2’ deoxycytidine resulted in strong antitumor activity in a persistent manner against two in vivo tumor models of established AML and MM. We uncovered that the drug combination caused strong T-cell proliferation, increased cytokine signaling in T cells, improved persistence of T cells, and reduced differentiation towards exhausted phenotype. Simultaneously the drug combination enhanced immunogenicity of the tumor by increasing HLA and co-stimulation and surprisingly reducing inhibitory ligand expression.Conclusion Combining T-cell therapy with TAK981 and 5-Aza-2’ deoxycytidine may be an important step towards improved clinical outcome.MTG

MiR-30a-3p Negatively Regulates BAFF Synthesis in Systemic Sclerosis and Rheumatoid Arthritis Fibroblasts.

We evaluated micro (mi) RNA-mediated regulation of BAFF expression in fibroblasts using two concomitant models: (i) synovial fibroblasts (FLS) isolated from healthy controls (N) or Rheumatoid Arthritis (RA) patients; (ii) human dermal fibroblasts (HDF) isolated from healthy controls (N) or Systemic Sclerosis (SSc) patients. Using RT-qPCR and ELISA, we first showed that SScHDF synthesized and released BAFF in response to Poly(I:C) or IFN-γ treatment, as previously observed in RAFLS, whereas NHDF released BAFF preferentially in response to IFN-γ. Next, we demonstrated that miR-30a-3p expression was down regulated in RAFLS and SScHDF stimulated with Poly(I:C) or IFN-γ. Moreover, we demonstrated that transfecting miR-30a-3p mimic in Poly(I:C)- and IFN-γ-activated RAFLS and SScHDF showed a strong decrease on BAFF synthesis and release and thus B cells survival in our model. Interestingly, FLS and HDF isolated from healthy subjects express higher levels of miR-30a-3p and lower levels of BAFF than RAFLS and SScHDF. Transfection of miR-30a-3p antisense in Poly(I:C)- and IFN-γ-activated NFLS and NHDF upregulated BAFF secretion, confirming that this microRNA is a basal repressors of BAFF expression in cells from healthy donors. Our data suggest a critical role of miR-30a-3p in the regulation of BAFF expression, which could have a major impact in the regulation of the autoimmune responses occurring in RA and SSc.Prof. Jean Sibilia's work was supported by grants from Bristol Myers Squibb, Roche, Pfizer, Courtin Foundation and CAMPLP. Sébastien Pfeffer's work was supported by the European Research Council (ERC-StG-260767) and Agence Nationale pour la Recherche (labex netRNA, ANR-10-LABX-36). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization

TNF-alpha is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-alpha response in macrophages. LPS-activated FLS isolated from RA patients express TNF-alpha mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-alpha mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-alpha expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-alpha mRNA. Blocking miR-346 reestablished TNF-alpha expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-alpha secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-alpha synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-alpha release. These results indicate that miR-346 controls TNF-alpha synthesis by regulating TTP expression

The ICON Earth System Model Version 1.0

This work documents ICON-ESM 1.0, the first version of a coupled model based 19 on the ICON framework 20 • Performance of ICON-ESM is assessed by means of CMIP6 DECK experiments 21 at standard CMIP-type resolution 22 • ICON-ESM reproduces the observed temperature evolution. Biases in clouds, winds, 23 sea-ice, and ocean properties are larger than in MPI-ESM. Abstract 25 This work documents the ICON-Earth System Model (ICON-ESM V1.0), the first cou-26 pled model based on the ICON (ICOsahedral Non-hydrostatic) framework with its un-27 structured, icosahedral grid concept. The ICON-A atmosphere uses a nonhydrostatic dy-28 namical core and the ocean model ICON-O builds on the same ICON infrastructure, but 29 applies the Boussinesq and hydrostatic approximation and includes a sea-ice model. The 30 ICON-Land module provides a new framework for the modelling of land processes and 31 the terrestrial carbon cycle. The oceanic carbon cycle and biogeochemistry are repre-32 sented by the Hamburg Ocean Carbon Cycle module. We describe the tuning and spin-33 up of a base-line version at a resolution typical for models participating in the Coupled 34 Model Intercomparison Project (CMIP). The performance of ICON-ESM is assessed by 35 means of a set of standard CMIP6 simulations. Achievements are well-balanced top-of-36 atmosphere radiation, stable key climate quantities in the control simulation, and a good 37 representation of the historical surface temperature evolution. The model has overall bi-38 ases, which are comparable to those of other CMIP models, but ICON-ESM performs 39 less well than its predecessor, the Max Planck Institute Earth System Model. Problem-40 atic biases are diagnosed in ICON-ESM in the vertical cloud distribution and the mean 41 zonal wind field. In the ocean, sub-surface temperature and salinity biases are of con-42 cern as is a too strong seasonal cycle of the sea-ice cover in both hemispheres. ICON-43 ESM V1.0 serves as a basis for further developments that will take advantage of ICON-44 specific properties such as spatially varying resolution, and configurations at very high 45 resolution. 46 Plain Language Summary 47 ICON-ESM is a completely new coupled climate and earth system model that ap-48 plies novel design principles and numerical techniques. The atmosphere model applies 49 a non-hydrostatic dynamical core, both atmosphere and ocean models apply unstruc-50 tured meshes, and the model is adapted for high-performance computing systems. This 51 article describes how the component models for atmosphere, land, and ocean are cou-52 pled together and how we achieve a stable climate by setting certain tuning parameters 53 and performing sensitivity experiments. We evaluate the performance of our new model 54 by running a set of experiments under pre-industrial and historical climate conditions 55 as well as a set of idealized greenhouse-gas-increase experiments. These experiments were 56 designed by the Coupled Model Intercomparison Project (CMIP) and allow us to com-57 pare the results to those from other CMIP models and the predecessor of our model, the 58 Max Planck Institute for Meteorology Earth System Model. While we diagnose overall 59 satisfactory performance, we find that ICON-ESM features somewhat larger biases in 60 several quantities compared to its predecessor at comparable grid resolution. We empha-61 size that the present configuration serves as a basis from where future development steps 62 will open up new perspectives in earth system modellin