Topology and excited state multiplicity as controlling factors in the carbazole-photosensitized CPD formation and repair

Photosensitized thyminethymine (ThyThy) formation and repair can be mediated by carbazole (Cbz). The former occurs from the Cbz triplet excited state via energy transfer, while the latter takes place from the singlet excited state via electron transfer. Here, fundamental insight is provided into the role of the topology and excited state multiplicity, as factors governing the balance between both processes. This has been achieved upon designing and synthesizing different isomers of trifunctional systems containing one Cbz and two Thy units covalently linked to the rigid skeleton of the natural deoxycholic acid. The results shown here prove that the Cbz photosensitized dimerization is not counterbalanced by repair when the latter, instead of operating through-space, has to proceed through-bond. © 2022 The Authors. Published by American Chemical Society

Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts

The aim of the present work is to develop two-channel emitters to probe local hydrophobicity by means of fluorescence quenching within different biomimetic supramolecular environments. To achieve this goal, the dansyl (Dns) and tryptophan (Trp) fluorophores have been covalently attached to cholic acid (CA) in order to ensure simultaneous incorporation of the two emitting units into the same compartment. In principle, the two fluorophores of the synthesized Dns-CA-Trp probes could either exhibit an orthogonal behavior or display excited state interactions. The fluorescence spectra of 3 beta-Dns-CA-Trp showed a residual Trp emission band at ca. 350 nm and an enhanced Dns maximum in the 500-550 nm region. This reveals a partial intramolecular energy transfer, which is consistent with the Dns and Trp singlet energies. Thus, the two photoactive units are not orthogonal; nevertheless, 3 beta-Dns-CA-Trp seems appropriate as a two-channel reporter for the supramolecular systems of interest. Fluorescence quenching of 3 beta-Dns-CA-Trp by iodide (which remains essentially in bulk water) was examined within sodium cholate, sodium taurocholate, sodium deoxycholate and mixed micelles. Interestingly, a decrease in the emission intensity of the two bands was observed with increasing iodide concentrations. The most remarkable effect was observed for mixed micelles, where the quenching rate constants were one order of magnitude lower than in solution. As anticipated, the quenching efficiency by iodide decreased with increasing hydrophobicity of the microenvironment, a trend that can be correlated with the relative accessibility of the probe to the ionic quencher.Financial support from the Spanish Government (CTQ2012-38754-C03-03), Predoctoral FPU fellowship (AP2008-03295), and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Gómez Mendoza, M.; Marín García, ML.; Miranda Alonso, MÁ. (2014). Two-channel dansyl/tryptophan emitters with a cholic acid bridge as reporters for local hydrophobicity within supramolecular systems based on bile salts. Organic and Biomolecular Chemistry. 12(42):8499-8504. https://doi.org/10.1039/c4ob01394hS849985041242Vayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2011). Dansyl Derivatives of Cholic Acid as Tools to Build Speciation Diagrams for Sodium Cholate Aggregation. The Journal of Physical Chemistry Letters, 2(7), 782-785. doi:10.1021/jz200178rGomez-Mendoza, M., Marin, M. L., & Miranda, M. A. (2012). Dansyl-Labeled Cholic Acid as a Tool To Build Speciation Diagrams for the Aggregation of Bile Acids. The Journal of Physical Chemistry B, 116(51), 14776-14780. doi:10.1021/jp308624hWaissbluth, O. L., Morales, M. C., & Bohne, C. (2006). Influence of Planarity and Size on Guest Binding with Sodium Cholate Aggregates. Photochemistry and Photobiology, 82(4), 1030. doi:10.1562/2006-02-14-ra-803Rinco, O., Kleinman, M. H., & Bohne, C. (2001). Reactivity of Benzophones in the Different Binding Sites of Sodium Cholate Aggregates. Langmuir, 17(19), 5781-5790. doi:10.1021/la010526cHofmann, A. F. (1999). The Continuing Importance of Bile Acids in Liver and Intestinal Disease. Archives of Internal Medicine, 159(22), 2647. doi:10.1001/archinte.159.22.2647Nuin, E., Gómez-Mendoza, M., Andreu, I., Marin, M. L., & Miranda, M. A. (2012). New Photoactive Compounds To Probe Cholic Acid and Cholesterol inside Mixed Micelles. Organic Letters, 15(2), 298-301. doi:10.1021/ol303201yHammad, M. ., & Müller, B. . (1998). Increasing drug solubility by means of bile salt–phosphatidylcholine-based mixed micelles. European Journal of Pharmaceutics and Biopharmaceutics, 46(3), 361-367. doi:10.1016/s0939-6411(98)00037-xHammad, M. ., & Müller, B. . (1998). Solubility and stability of tetrazepam in mixed micelles. European Journal of Pharmaceutical Sciences, 7(1), 49-55. doi:10.1016/s0928-0987(98)00006-2Hammad, M. (1998). Solubility and stability of clonazepam in mixed micelles. International Journal of Pharmaceutics, 169(1), 55-64. doi:10.1016/s0378-5173(98)00117-3Hendradi, E., Obata, Y., Isowa, K., Nagai, T., & Takayama, K. (2003). Effect of Mixed Micelle Formulations Including Terpenes on the Transdermal Delivery of Diclofenac. Biological & Pharmaceutical Bulletin, 26(12), 1739-1743. doi:10.1248/bpb.26.1739Parsaee, S., Sarbolouki, M. N., & Parnianpour, M. (2002). In-vitro release of diclofenac diethylammonium from lipid-based formulations. International Journal of Pharmaceutics, 241(1), 185-190. doi:10.1016/s0378-5173(02)00238-7Yu, J., Zhu, Y., Wang, L., Peng, M., Tong, S., Cao, X., … Xu, X. (2010). Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles. Acta Pharmacologica Sinica, 31(6), 759-764. doi:10.1038/aps.2010.55Sznitowska, M., Klunder, M., & Placzek, M. (2008). Paclitaxel Solubility in Aqueous Dispersions and Mixed Micellar Solutions of Lecithin. CHEMICAL & PHARMACEUTICAL BULLETIN, 56(1), 70-74. doi:10.1248/cpb.56.70Nuin, E., Gomez-Mendoza, M., Marin, M. L., Andreu, I., & Miranda, M. A. (2013). Influence of Drug Encapsulation within Mixed Micelles on the Excited State Dynamics and Accessibility to Ionic Quenchers. The Journal of Physical Chemistry B, 117(32), 9327-9332. doi:10.1021/jp404353uCuquerella, M. C., Rohacova, J., Marin, M. L., & Miranda, M. A. (2010). Stereodifferentiation in fluorescence quenching within cholic acid aggregates. Chemical Communications, 46(27), 4965. doi:10.1039/c0cc00176gWu, J., Liu, W., Ge, J., Zhang, H., & Wang, P. (2011). New sensing mechanisms for design of fluorescent chemosensors emerging in recent years. Chemical Society Reviews, 40(7), 3483. doi:10.1039/c0cs00224kBronshtein, I., Afri, M., Weitman, H., Frimer, A. A., Smith, K. M., & Ehrenberg, B. (2004). Porphyrin Depth in Lipid Bilayers as Determined by Iodide and Parallax Fluorescence Quenching Methods and Its Effect on Photosensitizing Efficiency. Biophysical Journal, 87(2), 1155-1164. doi:10.1529/biophysj.104.041434Rohacova, J., Marin, M. L., Martínez-Romero, A., O’Connor, J.-E., Gomez-Lechon, M. J., Donato, M. T., … Miranda, M. A. (2009). Synthesis of new, UV-photoactive dansyl derivatives for flow cytometric studies on bile acid uptake. Organic & Biomolecular Chemistry, 7(23), 4973. doi:10.1039/b912134jFőrster, T. (1959). 10th Spiers Memorial Lecture. Transfer mechanisms of electronic excitation. Discuss. Faraday Soc., 27(0), 7-17. doi:10.1039/df9592700007Eaton, D. F. (1988). Reference materials for fluorescence measurement. Pure and Applied Chemistry, 60(7), 1107-1114. doi:10.1351/pac198860071107T. Förster , Modern Quantum Chemistry , Academic Press , New York , 196

Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls

The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (lambda(max) = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 < C-12 < C-7. The steady-state kinetics of the overall process, monitored through the disappearance of the typical BP absorption band at 260 nm, was much faster under N-2 than under O-2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O], 7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process.Financial support from the Spanish Government (Grants SEV-2012-0267 and CTQ2012-38754-C03-03), Generalitat Valenciana (Prometeo Program) and the Technical University of Valencia (Predoctoral FPI fellowship for P. Miro) is gratefully acknowledged.Miró Richart, P.; Marín García, ML.; Miranda Alonso, MÁ. (2016). Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls. Organic and Biomolecular Chemistry. 14(9):2679-2683. https://doi.org/10.1039/c5ob02561cS2679268314

Photoactive bile salts with critical micellar concentration in the micromolar range

The aggregation behavior of bile salts is strongly dependent on the number of hydroxyl groups. Thus, cholic acid (CA), with three hydroxyls, starts forming aggregates at 15 mM, while deoxycholic, chenodeoxycholic or ursodeoxycholic acids, with two hydroxyls, start aggregating at 5-10 mM; for lithocholic acid, with only one hydroxyl group, aggregation is observed at lower concentration (2-3 mM). Here, the singular self-assembling properties of dansyl and naproxen derivatives of CA (3 beta-Dns-CA and 3 beta-NPX-CA, respectively) have been demonstrated on the basis of their photoactive properties. Thus, the emission spectra of 3 beta-Dns-CA registered at increasing concentrations (25-140 mu M) showed a remarkable non-linear enhancement in the emission intensity accompanied by a hypsochromic shift of the maximum and up to a three-fold increase in the singlet lifetime. The inflection point at around 50-70 mu M pointed to the formation of unprecedented assemblies at such low concentrations. In the case of 3 beta-NPX-CA, when the NPX relative triplet lifetime was plotted against concentration, a marked increase (up to two-fold) was observed at 40-70 mu M, indicating the formation of new 3 beta-NPX-CA assemblies at ca. 50 mu M. Additional evidence supporting the formation of new 3 beta-Dns-CA or 3 beta-NPX-CA assemblies at 40-70 mu M was obtained from singlet excited state quenching experiments using iodide. Moreover, to address the potential formation of hybrid assemblies, 1 : 1 mixtures of 3 beta-Dns-CA and 3 beta-NPX-CA (2-60 mu M, total concentration) were subjected to steady-state fluorescence experiments, and their behavior was compared to that of the pure photoactive derivatives. A lower increase in the emission was observed for 3 beta-NPX-CA in the mixture, while a huge increase was experienced by 3 beta-Dns-CA in the same concentration range (up to 60 mu M total). A partial intermolecular energy transfer from NPX to Dns, consistent with their reported singlet energies, was revealed, pointing to the formation of extremely fluorescent hybrid assemblies at 5-10 mu M (total concentration). The morphology of the entities was investigated by means of confocal microscopy. At 90 mu M, 3 beta-Dns-CA showed disperse assemblies in the mu m range.Financial support from the Spanish Government (Grants SEV-2012-0267 and CTQ2012-38754-C03-03) and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Gómez Mendoza, M.; Marín García, ML.; Miranda Alonso, MÁ. (2016). Photoactive bile salts with critical micellar concentration in the micromolar range. Physical Chemistry Chemical Physics. 18(18):12976-12982. https://doi.org/10.1039/c6cp00813eS1297612982181

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of √s=7 TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV