| 61. |
- Abdallah, J, et al.
(författare)
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Study of inclusive J/psi production in two-photon collisions at LEP II with the DELPHI detector
- 2003
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - 0370-2693. ; 565:1-4, s. 76-86
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Tidskriftsartikel (refereegranskat)abstract
- Inclusive J/psi production in photon-photon collisions has been observed at LEP II beam energies. A clear signal from the reaction gammagamma --> J/psi + X is seen. The number of observed N(J/psi --> mu(+)mu(-)) events is 36+/-7 for an integrated luminosity of 617 pb(-1), yielding a cross-section of sigma(J/psi + X) = 45+/-9(stat) +/- 17(syst) pb. Based on a study of the event shapes of different types of gammagamma processes in the PYTHIA program, we conclude that (74+/-22) % of the observed J/psi events are due to 'resolved' photons, the dominant contribution of which is most probably due to the gluon content of the photon. (C) 2003 Published by Elsevier B.V.
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| 62. |
- Abdallah, J, et al.
(författare)
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Study of tau-pair production in photon-photon collisions at LEP and limits on the anomalous electromagnetic moments of the tau lepton
- 2004
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 35:2, s. 159-170
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Tidskriftsartikel (refereegranskat)abstract
- Tau-pair production in the process e(+)e(-) --> e(+)e(-) tau(+)tau(-) was studied using data collected by the DELPHI experiment at LEP2 during the years 1997 - 2000. The corresponding integrated luminosity is 650 pb(-1). The values of the cross-section obtained are found to be in agreement with QED predictions. Limits on the anomalous magnetic and electric dipole moments of the tau lepton are deduced.
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| 63. |
- Abdallah, J, et al.
(författare)
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The measurement of alpha(8) from event shapes with the DELPHI detector at the highest LEP energies
- 2004
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 37:1, s. 1-23
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Tidskriftsartikel (refereegranskat)abstract
- Hadronic event shape distributions are determined from data in e(+)e(-) collisions between 183 and 207 GeV. From these the strong coupling alpha(s) is extracted in O(alpha(s)(2)), NLLA and matched O(alpha(s)(2))+ NLLA theory. Hadronisation corrections evaluated with fragmentation model generators as well as an analytical power ansatz are applied. Comparing these measurements to those obtained at and around M-Z allows a combined measurement of alpha(s) from all DELPHI data and a test of the energy dependence of the strong coupling.
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| 64. |
- Abreu, P, et al.
(författare)
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b-tagging in DELPHI at LEP
- 2004
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 32:2, s. 185-208
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Tidskriftsartikel (refereegranskat)abstract
- The standard method used for tagging b-hadrons in the DELPHI experiment at the CERN LEP Collider is discussed in detail. The main ingredient of b-tagging is the impact parameters of tracks, which relies mostly on the vertex detector. Additional information, such as the mass of particles associated to a secondary vertex, significantly improves the selection efficiency and the background suppression. The paper describes various discriminating variables used for the tagging and the procedure of their combination. In addition, applications of b-tagging to some physics analyses, which depend crucially on the performance and reliability of b-tagging, are described briefly.
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| 65. |
- Ameur, Adam, et al.
(författare)
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Genetic Adaptation of Fatty-Acid Metabolism : A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids
- 2012
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 90:5, s. 809-820
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Tidskriftsartikel (refereegranskat)abstract
- Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.
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| 66. |
- Andersson-Engels, Stefan, et al.
(författare)
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Integrated system for interstitial photodynamic therapy
- 2003
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 0277-786X .- 1996-756X. ; 5142, s. 42-49
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Konferensbidrag (refereegranskat)abstract
- A novel photodynamic therapy system based on interstitial illumination using multiple fibres is under development. The aim with this system is to enable treatment of large tumour volumes and also to utilise real-time measurements to allow on-line dosimetry. Important dosimetric parameters to measure are light fluence rate, sensitizer fluorescence intensity and local blood oxygenation. A construction which allows all functions to be readily performed with a single system is presented. We believe that interstitial PDT utilising this technique may be attractive in many clinical situations.
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| 67. |
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| 68. |
- Begnini, Fabio, et al.
(författare)
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Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:4, s. 3473-3517
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Tidskriftsartikel (refereegranskat)abstract
- Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.
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| 69. |
- Begnini, Fabio, et al.
(författare)
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Mining Natural Products for Macrocycles to Drug Difficult Targets
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:2, s. 1054-1072
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Tidskriftsartikel (refereegranskat)abstract
- Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein- protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keapl and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections.
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| 70. |
- Begnini, Fabio, et al.
(författare)
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Structure-based optimization of a macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Activation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes a potential opportunity for the treatment of oxidative stress related disease. Although highly potent inhibitors of the Keap1–Nrf2 protein-protein interaction (PPI) have been reported, these compounds are based on a few reoccurring scaffolds. Here, we report a novel, structurally unique series of double-digit nM Keap1 inhibitors obtained by optimization of a natural product-derived macrocyclic lead. Exploration of the structure-activity relationship, followed by structure-based design led to a 100-fold improvement in inhibitory potency compared to the starting point. The macrocyclic core positions the pharmacophores of the inhibitors suitably for productive interactions with key residues of Keap1, including R415 and R483; both of which contribute to the highly polar nature of the binding site for Nrf2. In addition, we discovered that minor, ligand-induced reorganizations of these two arginine residues are accompanied by major differences in binding affinity between compounds in the series.
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