148 results on '"Gabel, F"'
Search Results
2. Dynamical Coupling of Intrinsically Disordered Proteins and Their Hydration Water: Comparison with Folded Soluble and Membrane Proteins
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Gallat, F.-X., Laganowsky, A., Wood, K., Gabel, F., van Eijck, L., Wuttke, J., Moulin, M., Härtlein, M., Eisenberg, D., Colletier, J.-P., Zaccai, G., and Weik, M.
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- 2012
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Catalog
3. Coupling of Protein and Hydration-Water Dynamics in Biological Membranes
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Wood, K., Plazanet, M., Gabel, F., Kessler, B., Oesterhelt, D., Tobias, D. J., Zaccai, G., and Weik, M.
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- 2007
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4. Structure of Protease1 from Pyrococcus horikoshii in space group 19 with a hexamer in the asymmetric unit
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Engilberge, S., primary, Gabel, F., additional, and Girard, E., additional
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- 2022
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5. Direct Correlation between Molecular Dynamics and Enzymatic Stability: A Comparative Neutron Scattering Study of Native Human Butyrylcholinesterase and its “Aged” Soman Conjugate
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Gabel, F., Masson, P., Froment, M.-T., Doctor, B.P., Saxena, A., Silman, I., Zaccai, G., and Weik, M.
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- 2009
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6. Dynamics of hydration water in deuterated purple membranes explored by neutron scattering
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Wood, K., Plazanet, M., Gabel, F., Kessler, B., Oesterhelt, D., Zaccai, G., and Weik, M.
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- 2008
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7. Effects of Soman Inhibition and of Structural Differences on Cholinesterase Molecular Dynamics: A Neutron Scattering Study
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Gabel, F., Weik, M., Masson, P., Renault, F., Fournier, D., Brochier, L., Doctor, B.P., Saxena, A., Silman, I., and Zaccai, G.
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- 2005
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8. A structure refinement protocol combining NMR residual dipolar couplings and small angle scattering restraints
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Gabel, F., Simon, B., Nilges, M., Petoukhov, M., Svergun, D., and Sattler, M.
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- 2008
9. New insights into microbial adaptation to extreme saline environments
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Vauclare P., Madern D., Girard E., Gabel F., Zaccai G., and Franzetti B.
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Microbiology ,QR1-502 ,Physiology ,QP1-981 ,Zoology ,QL1-991 - Abstract
Extreme halophiles are microorganisms adapted to low water activity living at the upper salt concentration that life can tolerate. We review here recent data that specify the main factors, which determine their peculiar salt-dependent biochemistry. The data suggested that evolution proceeds by stage to modify the molecular dynamics properties of the entire proteome. Extreme halophiles therefore represent tractable models to understand how fast and to what extent microorganisms adapt to environmental changes. Halophiles are also robust organisms, capable to resist multiple stressors. Preliminary studies indicated that they have developed a cellular response specifically aimed to survive when the salt condition fluctuates. Because of these properties halophilic organisms deserve special attention in the search for traces of life on other planets. more...
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- 2014
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10. The Influence of Solvent Composition on Global Dynamics of Human Butyrylcholinesterase Powders: A Neutron-Scattering Study
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Gabel, F., Weik, M., Doctor, B.P., Saxena, A., Fournier, D., Brochier, L., Renault, F., Masson, P., Silman, I., and Zaccai, G.
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- 2004
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11. Structure of deubiquitinating enzyme homolog (Pyrococcus furiosus JAMM1) in complex with ubiquitin-like SAMP2.
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Cao, S., primary, Engilberge, S., additional, Girard, E., additional, Gabel, F., additional, Franzetti, B., additional, and Maupin-Furlow, J.A., additional
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- 2017
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12. Structure of deubiquitinating enzyme homolog, Pyrococcus furiosus JAMM1.
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Maupin-Furlow, J.A., primary, Franzetti, B., additional, Cao, S., additional, Girard, E., additional, Gabel, F., additional, and Engilberge, S., additional
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- 2017
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13. Structural Characterization of HBXIP: The Protein That Interacts with the Anti-Apoptotic Protein Survivin and the Oncogenic Viral Protein HBx
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Garcia-Saez, I., Lacroix, F.B., Blot, D., Gabel, F., and Skoufias, D.A.
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- 2011
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14. A Consensus-Based Set of Measures for Oral Health Care.
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Baâdoudi, F., Trescher, A., Duijster, D., Maskrey, N., Gabel, F., van der Heijden, G. J. M. G., Listl, S., and The ADVOCATE Consortium
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ORAL hygiene ,CONSENSUS (Social sciences) ,MEDICAL care accountability ,PATIENT-centered care ,ORGANIZATIONAL transparency ,PREVENTIVE dentistry ,JOB performance ,DENTISTS' attitudes - Abstract
Increasingly more responsive and accountable health care systems are demanded, which is characterized by transparency and explicit demonstration of competence by health care providers and the systems in which they work. This study aimed to establish measures of oral health for transparent and explicit reporting of routine data to facilitate more patient-centered and prevention-oriented oral health care. To accomplish this, an intermediate objective was to develop a comprehensive list of topics that a range of stakeholders would perceive as valid, important, and relevant for describing oral health and oral health care. A 4-stage approach was used to develop the list of topics: 1) scoping of literature and its appraisal, 2) a meeting of experts, 3) a 2-stage Delphi process (online), and 4) a World Café discussion. The aim was to create consensus through structured conversations via a range of stakeholders (general dental practitioners, patients, insurers, and policy makers) from the Netherlands, Germany, the United Kingdom, Ireland, Hungary, and Denmark. The study was part of the ADVOCATE project, and it resulted in a list of 48 topics grouped into 6 clusters: 1) access to dental care, 2) symptoms and diagnosis, 3) health behaviors, 4) oral treatments, 5) oral prevention, and 6) patient perception. All topics can be measured, as they all have a data source with defined numerators and denominators. This study is the first to establish a comprehensive and multiple-stakeholder consented topic list designed for guiding the implementation of transparent and explicit measurement of routine data of oral health and oral health care. Successful measurement within oral health care systems is essential to facilitate learning from variation in practice and outcomes within and among systems, and it potentiates improvement toward more patient-centered and prevention-oriented oral health care. [ABSTRACT FROM AUTHOR] more...
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- 2017
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15. N-terminal domain of pneumococcal PhtD protein with bound Zn(II)
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Bersch, B., primary, Bougault, C., additional, Favier, A., additional, Gabel, F., additional, Roux, L., additional, Vernet, T., additional, and Durmort, C., additional
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- 2013
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16. The structure of the Box CD enzyme reveals regulation of rRNA methylation
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Lapinaite, A., primary, Simon, B., additional, Skjaerven, L., additional, Rakwalska-Bange, M., additional, Gabel, F., additional, and Carlomagno, T., additional
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- 2013
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17. NMR STRUCTURE OF THE PROTEIN-UNBOUND SPLICEOSOMAL U4 SNRNA 5' STEM LOOP
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Falb, M., primary, Amata, I., additional, Gabel, F., additional, Simon, B., additional, and Carlomagno, T., additional
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- 2010
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18. Amphipols From A to Z**.
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Popot, J.-L., Althoff, T., Bagnard, D., Baèeres, J.-L., Bazzacco, P., Billon-Denis, E., Catoire, L. J., Champeil, P., Charvolin, D., Cocco, M. J., Crémel, G., Dahmane, T., de la Maza, L. M., Ebel, C., Gabel, F., Giusti, F., Gohon, Y., Goormaghtigh, E., Guittet, E., and Kleinschmidt, J. H. more...
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MEMBRANE proteins ,POLYMERS ,BIOPHYSICS ,BIOCHEMISTRY ,WATER-soluble polymers ,VACCINES - Abstract
Amphipols (APols) are short amphipathic polymers that can substitute for detergents to keep integral membrane proteins (MPs) water soluble. In this review, we discuss their structure and solution behavior; the way they associate with MPs; and the structure, dynamics, and solution properties of the resulting complexes. All MPs tested to date form water-soluble complexes with APols, and their biochemical stability is in general greatly improved compared with MPs in detergent solutions. The functionality and ligand-binding properties of APol-trapped MPs are reviewed, and the mechanisms by which APols stabilize MPs are discussed. Applications of APols include MP folding and cell-free synthesis, structural studies by NMR, electron microscopy and X-ray diffraction, APol-mediated immobilization of MPs onto solid supports, proteomics, delivery of MPs to preexisting membranes, and vaccine formulation. [ABSTRACT FROM AUTHOR] more...
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- 2011
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19. Resistance to ship-induced waves of benthic invertebrates in various littoral habitats.
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GABEL, F., GARCIA, X. -F., BRAUNS, M., SUKHODOLOV, A., LESZINSKI, M., and PUSCH, M. T.
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COARSE woody debris , *INVERTEBRATES , *HABITATS , *RADIOACTIVE pollution of water , *RADIOACTIVE substances in rivers, lakes, etc. , *FOREST litter , *MINERAL aggregates , *CTENOPHORA , *SLASH (Logging) - Abstract
1. Ship-induced waves disturb benthic invertebrate assemblages colonizing littoral zones of lakes and rivers. However, the impact of ship-induced waves on invertebrates has rarely been quantified, and the influencing factors have not been addressed. 2. In an experimental wave tank, five benthic invertebrate species, Bithynia tentaculata, Calopteryx splendens, Dikerogammarus villosus, Gammarus roeseli and Laccophilus hyalinus, were exposed to waves of increasing shear stress (0.43–2.19 N m−2). Mean number of detached individuals was recorded for five littoral habitats [coarse woody debris (CWD), reeds, sand, stones and tree roots], representing different levels of structural complexity as quantified by their fractal dimensions (FD). 3. Results showed that detachment of invertebrates was significantly related to shear stress in all habitats except tree roots. Detachments averaged for the five species were significantly lower in habitats with a high degree of structural complexity, decreasing in the habitat sequence: sand, CWD, stones, reeds and tree roots. 4. Consistent with their different morphologies and methods of attachment to substrates, the five species displayed differences in their response to hydraulic stress that were dependent on habitat. 5. The increasing sheltering effect of structural habitat complexity was mirrored by increasing dissipation of the kinetic energy of waves; i.e. the FD of the habitat was positively correlated with shear stress reduction due to the flow resistance of the habitat. 6. Network habitats such as tree roots provided the best sheltering conditions against hydraulic disturbance, because they combined good refuge availability for all studied invertebrate species and maximal dissipation of kinetic wave energy. Consequently, persistent anthropogenic impacts, such as lakeshore modification or long-term exposure to ship-induced waves, which cause disappearance of complex littoral habitats such as tree roots or dense reed belts, will drastically increase the adverse effects of boating and ship traffic on littoral invertebrate assemblages. [ABSTRACT FROM AUTHOR] more...
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- 2008
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20. Sex differences in the antinociceptive effect of codeine and its peripheral but not central metabolism in adult mice.
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Hovhannisyan V, Berkati AK, Simonneaux M, Gabel F, Andry V, and Goumon Y
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- Animals, Male, Female, Mice, Analgesics, Opioid pharmacology, Morphine Derivatives pharmacology, Brain drug effects, Brain metabolism, Dose-Response Relationship, Drug, Analgesics pharmacology, Pain Measurement drug effects, Pain Measurement methods, Estrous Cycle drug effects, Codeine pharmacology, Codeine analogs & derivatives, Sex Characteristics
- Abstract
Codeine is a natural opiate extracted from opium poppy (Papaver somniferum) and used to alleviate mild to moderate pain. The analgesic effect of this molecule results from its metabolism into morphine which is an agonist of the mu opioid receptor. Morphine's major metabolite morphine-3-glucuronide induces both thermal and mechanical hypersensitivies while codeine-6-glucuronide has been proposed to be antinociceptive. However, sex differences in codeine antinociceptive effect and pharmacokinetics were barely studied. To this purpose, we injected male and female mice with codeine (2.5, 5, 10, 20 and 40 mg/kg) and thermal hypersensitivity was assessed 30 min after injection using the Tail Immersion Test. Moreover, both peripheral and central metabolism of codeine were evaluated respectively in the blood or pain-related brain structures in the central nervous system. The amounts of codeine and its metabolites were quantified using the isotopic dilution method by liquid chromatography coupled to a mass spectrometer. Our results show that codeine induces a greater antinociceptive effect in males than females mice independently of the estrous cycle. Moreover, major sex differences were found in the peripheral metabolism of this molecule, with higher amounts of pronociceptive morphine-3-glucuronide and less antinociceptive codeine-6-glucuronide in females than in males. Concerning the central metabolism of codeine, we did not find significant sex differences in pain-related brain structures. Collectively, these findings support a greater codeine antinociceptive effect in males than females in mice. These sex differences could be influenced by a higher peripheral metabolism of this molecule in female mice rather than central metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...
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- 2025
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21. Non-native amphipods reach higher maximum swimming velocities than natives.
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Gabel F, Vosshage ATL, and Meyer EI
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- Animals, Ecosystem, Amphipoda physiology, Introduced Species, Swimming
- Abstract
The invasion of non-native amphipods often leads to severe changes in the composition of aquatic communities and may also result in the local replacement of native species. Particularly, a lower risk of being preyed upon resulting from high swimming velocities can be an advantage in interspecific competition. Furthermore, as swimming velocities are ecologically important, they are often used in ecotoxicological studies to estimate effects of different stressors. However, knowledge on swimming velocities of native and non-native amphipods is still rather limited. We experimentally investigated the maximum swimming velocities of three native and three non-native amphipods via video analyses in the laboratory. Results showed that non-native species reach higher maximum swimming velocities compared to natives probably leading to a higher predation success and reduced risk of being preyed upon. Additionally, body length correlates positively with swimming velocities, except for the invader Dikerogammarus villosus. As D. villosus can be cannibalistic, the high swimming velocities of the small individuals may reduce the intraspecific predation and may increase the survival rates of smaller specimen. Hence, knowledge about the swimming velocities of species contribute to the understanding of interspecific competition among species and might support explanation approaches for the success of invasive species. Furthermore, it provides baselines for ecotoxicological studies of stressor impacts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) more...
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- 2024
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22. The molecular dissection of TRIM25's RNA-binding mechanism provides key insights into its antiviral activity.
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Álvarez L, Haubrich K, Iselin L, Gillioz L, Ruscica V, Lapouge K, Augsten S, Huppertz I, Choudhury NR, Simon B, Masiewicz P, Lethier M, Cusack S, Rittinger K, Gabel F, Leitner A, Michlewski G, Hentze MW, Allain FHT, Castello A, and Hennig J more...
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- Humans, Transcription Factors metabolism, Transcription Factors genetics, HEK293 Cells, Immunity, Innate, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Antiviral Agents metabolism, Antiviral Agents pharmacology, RNA Viruses genetics, Binding Sites, Tripartite Motif Proteins metabolism, Tripartite Motif Proteins genetics, RNA, Viral metabolism, RNA, Viral genetics, Ubiquitin-Protein Ligases metabolism, Ubiquitin-Protein Ligases genetics, Protein Binding
- Abstract
TRIM25 is an RNA-binding ubiquitin E3 ligase with central but poorly understood roles in the innate immune response to RNA viruses. The link between TRIM25's RNA binding and its role in innate immunity has not been established. Thus, we utilized a multitude of biophysical techniques to identify key RNA-binding residues of TRIM25 and developed an RNA-binding deficient mutant (TRIM25-m9). Using iCLIP2 in virus-infected and uninfected cells, we identified TRIM25's RNA sequence and structure specificity, that it binds specifically to viral RNA, and that the interaction with RNA is critical for its antiviral activity., (© 2024. The Author(s).) more...
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- 2024
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23. Unveiling the crystal structure of thermostable dienelactone hydrolase exhibiting activity on terephthalate esters.
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Almeida DV, Ciancaglini I, Sandano ALH, Roman EKB, Andrade VB, Nunes AB, Tramontina R, da Silva VM, Gabel F, Corrêa TLR, Damasio A, Muniz JRC, Squina FM, and Garcia W
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- Substrate Specificity, Crystallography, X-Ray, Phthalic Acids metabolism, Phthalic Acids chemistry, Esters metabolism, Esters chemistry, Models, Molecular, Bacterial Proteins metabolism, Bacterial Proteins chemistry, Bacterial Proteins genetics, Protein Conformation, Hydrogen-Ion Concentration, Kinetics, Hydrolysis, Catalytic Domain, Temperature, Enzyme Stability, Carboxylic Ester Hydrolases metabolism, Carboxylic Ester Hydrolases chemistry, Carboxylic Ester Hydrolases genetics
- Abstract
Dienelactone hydrolase (DLH) is one of numerous hydrolytic enzymes with an α/β-hydrolase fold, which catalyze the hydrolysis of dienelactone to maleylacetate. The DLHs share remarkably similar tertiary structures and a conserved arrangement of catalytic residues. This study presents the crystal structure and comprehensive functional characterization of a novel thermostable DLH from the bacterium Hydrogenobacter thermophilus (HtDLH). The crystal structure of the HtDLH, solved at a resolution of about 1.67 Å, exhibits a canonical α/β-hydrolase fold formed by eight β-sheet strands in the core, with one buried α-helix and six others exposed to the solvent. The structure also confirmed the conserved catalytic triad of DHLs formed by Cys121, Asp170, and His202 residues. The HtDLH forms stable homodimers in solution. Functional studies showed that HtDLH has the expected esterase activity over esters with short carbon chains, such as p-nitrophenyl acetate, reaching optimal activity at pH 7.5 and 70 °C. Furthermore, HtDLH maintains more than 50 % of its activity even after incubation at 90 °C for 16 h. Interestingly, HtDLH exhibits catalytic activity towards polyethylene terephthalate (PET) monomers, including bis-1,2-hydroxyethyl terephthalate (BHET) and 1-(2-hydroxyethyl) 4-methyl terephthalate, as well as other aliphatic and aromatic esters. These findings associated with the lack of activity on amorphous PET indicate that HtDLH has characteristic of a BHET-degrading enzyme. This work expands our understanding of enzyme families involved in PET degradation, providing novel insights for plastic biorecycling through protein engineering, which could lead to eco-friendly solutions to reduce the accumulation of plastic in landfills and natural environments., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...
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- 2024
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24. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.
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Mannion J, Gifford V, Bellenie B, Fernando W, Ramos Garcia L, Wilson R, John SW, Udainiya S, Patin EC, Tiu C, Smith A, Goicoechea M, Craxton A, Moraes de Vasconcelos N, Guppy N, Cheung KJ, Cundy NJ, Pierrat O, Brennan A, Roumeliotis TI, Benstead-Hume G, Alexander J, Muirhead G, Layzell S, Lyu W, Roulstone V, Allen M, Baldock H, Legrand A, Gabel F, Serrano-Aparicio N, Starling C, Guo H, Upton J, Gyrd-Hansen M, MacFarlane M, Seddon B, Raynaud F, Roxanis I, Harrington K, Haider S, Choudhary JS, Hoelder S, Tenev T, and Meier P more...
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- Humans, Animals, Mice, Cell Line, Tumor, Necroptosis drug effects, Necroptosis immunology, Neoplasms immunology, Neoplasms drug therapy, Mice, Inbred C57BL, Antineoplastic Agents pharmacology, Immunotherapy methods, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, Proteolysis drug effects, Signal Transduction drug effects, Immunogenic Cell Death drug effects
- Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2024
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25. Structured feedback and operative video debriefing with critical view of safety annotation in training of laparoscopic cholecystectomy: a randomized controlled study.
- Author
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Cizmic A, Häberle F, Wise PA, Müller F, Gabel F, Mascagni P, Namazi B, Wagner M, Hashimoto DA, Madani A, Alseidi A, Hackert T, Müller-Stich BP, and Nickel F
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- Humans, Swine, Animals, Female, Male, Learning Curve, Curriculum, Adult, Students, Medical, Formative Feedback, Young Adult, Feedback, Cholecystectomy, Laparoscopic education, Clinical Competence, Video Recording
- Abstract
Background: The learning curve in minimally invasive surgery (MIS) is lengthened compared to open surgery. It has been reported that structured feedback and training in teams of two trainees improves MIS training and MIS performance. Annotation of surgical images and videos may prove beneficial for surgical training. This study investigated whether structured feedback and video debriefing, including annotation of critical view of safety (CVS), have beneficial learning effects in a predefined, multi-modal MIS training curriculum in teams of two trainees., Methods: This randomized-controlled single-center study included medical students without MIS experience (n = 80). The participants first completed a standardized and structured multi-modal MIS training curriculum. They were then randomly divided into two groups (n = 40 each), and four laparoscopic cholecystectomies (LCs) were performed on ex-vivo porcine livers each. Students in the intervention group received structured feedback after each LC, consisting of LC performance evaluations through tutor-trainee joint video debriefing and CVS video annotation. Performance was evaluated using global and LC-specific Objective Structured Assessments of Technical Skills (OSATS) and Global Operative Assessment of Laparoscopic Skills (GOALS) scores., Results: The participants in the intervention group had higher global and LC-specific OSATS as well as global and LC-specific GOALS scores than the participants in the control group (25.5 ± 7.3 vs. 23.4 ± 5.1, p = 0.003; 47.6 ± 12.9 vs. 36 ± 12.8, p < 0.001; 17.5 ± 4.4 vs. 16 ± 3.8, p < 0.001; 6.6 ± 2.3 vs. 5.9 ± 2.1, p = 0.005). The intervention group achieved CVS more often than the control group (1. LC: 20 vs. 10 participants, p = 0.037, 2. LC: 24 vs. 8, p = 0.001, 3. LC: 31 vs. 8, p < 0.001, 4. LC: 31 vs. 10, p < 0.001)., Conclusions: Structured feedback and video debriefing with CVS annotation improves CVS achievement and ex-vivo porcine LC training performance based on OSATS and GOALS scores., (© 2024. The Author(s).) more...
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- 2024
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26. A domesticated photoautotrophic microbial community as a biofilm model system for analyzing the influence of plastic surfaces on invertebrate grazers in limnic environments.
- Author
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Bakenhus I, Jongsma R, Michler-Kozma D, Hölscher L, Gabel F, Holert J, and Philipp B
- Abstract
The environmental fate of plastic particles in water bodies is influenced by microbial biofilm formation. Invertebrate grazers may be affected when foraging biofilms on plastics compared to biofilms on natural substrata but the mechanistic basis for these effects is unknown. For analyzing these effects in ecotoxicological assays stable and reproducible biofilm communities are required that are related to the environmental site of interest. Here, a defined biofilm community was established and used to perform grazing experiments with a freshwater snail. For this, snippets of different plastic materials were incubated in the photic zone of three different freshwater sites. Amplicon sequencing of biofilms formed on these snippets showed that the site of incubation and not the plastic material dominated the microbial community composition. From these biofilms, individual microbial strains as well as photoautotrophic consortia were isolated; these consortia consisted of heterotrophic bacteria that were apparently nourished by microalga. While biofilms formed by defined dual cultures of a microalga and an Alphaproteobacterium were not accepted by the snail P. fontinalis , a photoautotrophic consortium (Co_3) sustained growth and metabolism of this grazer. Amplicon sequencing revealed that consortium Co_3, which could be stably maintained on solid medium under photoautotrophic conditions, reproducibly formed biofilms of a defined composition on three different plastic materials and on glass surfaces. In conclusion, our study shows that the generation of domesticated photoautotrophic microbial communities is a valid novel approach for establishing laboratory ecotoxicological assays with higher environmental relevance than those based on defined microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bakenhus, Jongsma, Michler-Kozma, Hölscher, Gabel, Holert and Philipp.) more...
- Published
- 2023
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27. Telestration with augmented reality improves the performance of the first ten ex vivo porcine laparoscopic cholecystectomies: a randomized controlled study.
- Author
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Cizmic A, Müller F, Wise PA, Häberle F, Gabel F, Kowalewski KF, Bintintan V, Müller-Stich BP, and Nickel F
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- Humans, Swine, Animals, Clinical Competence, Curriculum, Cholecystectomy, Laparoscopic education, Augmented Reality, Laparoscopy education
- Abstract
Introduction: The learning curve in minimally invasive surgery (MIS) is steep compared to open surgery. One of the reasons is that training in the operating room in MIS is mainly limited to verbal instructions. The iSurgeon telestration device with augmented reality (AR) enables visual instructions, guidance, and feedback during MIS. This study aims to compare the effects of the iSurgeon on the training of novices performing repeated laparoscopic cholecystectomy (LC) on a porcine liver compared to traditional verbal instruction methods., Methods: Forty medical students were randomized into the iSurgeon and the control group. The iSurgeon group performed 10 LCs receiving interactive visual guidance. The control group performed 10 LCs receiving conventional verbal guidance. The performance assessment using Objective Structured Assessments of Technical Skills (OSATS) and Global Operative Assessment of Laparoscopic Skills (GOALS) scores, the total operating time, and complications were compared between the two groups., Results: The iSurgeon group performed LCs significantly better (global GOALS 17.3 ± 2.6 vs. 16 ± 2.6, p ≤ 0.001, LC specific GOALS 7 ± 2 vs. 5.9 ± 2.1, p ≤ 0.001, global OSATS 25.3 ± 4.3 vs. 23.5 ± 3.9, p ≤ 0.001, LC specific OSATS scores 50.8 ± 11.1 vs. 41.2 ± 9.4, p ≤ 0.001) compared to the control group. The iSurgeon group had significantly fewer intraoperative complications in total (2.7 ± 2.0 vs. 3.6 ± 2.0, p ≤ 0.001) than the control group. There was no difference in operating time (79.6 ± 25.7 vs. 84.5 ± 33.2 min, p = 0.087)., Conclusion: Visual guidance using the telestration device with AR, iSurgeon, improves performance and lowers the complication rates in LCs in novices compared to conventional verbal expert guidance., (© 2023. The Author(s).) more...
- Published
- 2023
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28. Characterization of the REC114-MEI4-IHO1 complex regulating meiotic DNA double-strand break formation.
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Laroussi H, Juarez-Martinez AB, Le Roy A, Boeri Erba E, Gabel F, de Massy B, and Kadlec J
- Subjects
- Animals, Mice, DNA, Meiosis, Cell Cycle Proteins, Homologous Recombination
- Abstract
Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs), essential for fertility and genetic diversity. In the mouse, DSBs are formed by the catalytic TOPOVIL complex consisting of SPO11 and TOPOVIBL. To preserve genome integrity, the activity of the TOPOVIL complex is finely controlled by several meiotic factors including REC114, MEI4, and IHO1, but the underlying mechanism is poorly understood. Here, we report that mouse REC114 forms homodimers, that it associates with MEI4 as a 2:1 heterotrimer that further dimerizes, and that IHO1 forms coiled-coil-based tetramers. Using AlphaFold2 modeling combined with biochemical characterization, we uncovered the molecular details of these assemblies. Finally, we show that IHO1 directly interacts with the PH domain of REC114 by recognizing the same surface as TOPOVIBL and another meiotic factor ANKRD31. These results provide strong evidence for the existence of a ternary IHO1-REC114-MEI4 complex and suggest that REC114 could act as a potential regulatory platform mediating mutually exclusive interactions with several partners., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.) more...
- Published
- 2023
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29. An NMR Study of a 300-kDa AAA+ Unfoldase.
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Krüger G, Kirkpatrick J, Mahieu E, Franzetti B, Gabel F, and Carlomagno T
- Subjects
- Protein Domains, Nuclear Magnetic Resonance, Biomolecular, Proteasome Endopeptidase Complex chemistry, Proteolysis, Endopeptidase Clp chemistry, Methanocaldococcus enzymology, Saccharomyces cerevisiae enzymology
- Abstract
AAA+ ATPases are ubiquitous hexameric unfoldases acting in cellular protein quality control. In complex with proteases, they form protein degradation machinery (the proteasome) in both archaea and eukaryotes. Here, we use solution-state NMR spectroscopy to determine the symmetry properties of the archaeal PAN AAA+ unfoldase and gain insights into its functional mechanism. PAN consists of three folded domains: the coiled-coil (CC), OB and ATPase domains. We find that full-length PAN assembles into a hexamer with C
2 symmetry, and that this symmetry extends over the CC, OB and ATPase domains. The NMR data, collected in the absence of substrate, are incompatible with the spiral staircase structure observed in electron-microscopy studies of archaeal PAN in the presence of substrate and in electron-microscopy studies of eukaryotic unfoldases both in the presence and in the absence of substrate. Based on the C2 symmetry revealed by NMR spectroscopy in solution, we propose that archaeal ATPases are flexible enzymes, which can adopt distinct conformations in different conditions. This study reaffirms the importance of studying dynamic systems in solution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...- Published
- 2023
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30. A real-time analysis of GFP unfolding by the AAA+ unfoldase PAN.
- Author
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Krüger G, Kirkpatrick J, Mahieu E, Franzetti B, Gabel F, and Carlomagno T
- Subjects
- Molecular Chaperones
- Abstract
Protein quality control systems are essential to maintain a healthy proteome. They often consist of an unfoldase unit, typically an AAA+ ATPase, coupled with a protease unit. In all kingdoms of life, they function to eliminate misfolded proteins, and thus prevent that their aggregates do harm to the cell, and to rapidly regulate protein levels in the presence of environmental changes. Despite the huge progress made in the past two decades in understanding the mechanism of function of protein degradation systems, the fate of the substrate during the unfolding and proteolytic processes remains poorly understood. Here we exploit an NMR-based approach to monitor GFP processing by the archaeal PAN unfoldase and the PAN-20S degradation system in real time. We find that PAN-dependent unfolding of GFP does not involve the release of partially-folded GFP molecules resulting from futile unfolding attempts. In contrast, once stably engaged with PAN, GFP molecules are efficiently transferred to the proteolytic chamber of the 20S subunit, despite the only weak affinity of PAN for the 20S subunit in the absence of substrate. This is essential to guarantee that unfolded but not proteolyzed proteins are not released into solution, where they would form toxic aggregates. The results of our studies are in good agreement with previous results derived from real-time small-angle-neutron-scattering experiments and have the advantage of allowing the investigation of substrates and products at amino-acid resolution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...
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- 2023
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31. Central metabolism as a potential origin of sex differences in morphine antinociception but not induction of antinociceptive tolerance in mice.
- Author
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Gabel F, Hovhannisyan V, Andry V, and Goumon Y
- Subjects
- Mice, Male, Female, Animals, Chromatography, Liquid, Morphine Derivatives pharmacology, Morphine Derivatives therapeutic use, Analgesics, Opioid pharmacology, Pain drug therapy, Morphine, Tandem Mass Spectrometry
- Abstract
Background and Purpose: In rodents, morphine antinociception is influenced by sex. However, conflicting results have been reported regarding the interaction between sex and morphine antinociceptive tolerance. Morphine is metabolised in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might contribute to behavioural discrepancies. This article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice., Experimental Approach: Sex differences in morphine antinociception and tolerance were assessed using the tail-immersion test. After acute and chronic morphine treatment, morphine and M3G metabolic kinetics in the blood were evaluated using LC-MS/MS. They were also quantified in several CNS regions. Finally, the blood-brain barrier (BBB) permeability of M3G was assessed in male and female mice., Key Results: This study demonstrated that female mice showed weaker morphine antinociception and faster induction of tolerance than males. Additionally, female mice showed higher levels of M3G in the blood and in several pain-related CNS regions than male mice, whereas lower levels of morphine were observed in these regions. M3G brain/blood ratios after injection of M3G indicated no sex differences in M3G BBB permeability, and these ratios were lower than those obtained after injection of morphine., Conclusion: These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related CNS regions, consistent with weaker morphine antinociceptive effects in females. However, the role of morphine metabolism in antinociceptive tolerance seemed limited., Linked Articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc., (© 2022 The British Pharmacological Society.) more...
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- 2023
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32. Small-angle x-ray and neutron scattering of MexR and its complex with DNA supports a conformational selection binding model.
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Caporaletti F, Pietras Z, Morad V, Mårtensson LG, Gabel F, Wallner B, Martel A, and Sunnerhagen M
- Subjects
- X-Rays, Binding Sites, DNA, Bacterial metabolism, Pseudomonas aeruginosa, Bacterial Proteins chemistry, DNA genetics, DNA metabolism
- Abstract
In this work, we used small-angle x-ray and neutron scattering to reveal the shape of the protein-DNA complex of the Pseudomonas aeruginosa transcriptional regulator MexR, a member of the multiple antibiotics resistance regulator (MarR) family, when bound to one of its native DNA binding sites. Several MarR-like proteins, including MexR, repress the expression of efflux pump proteins by binding to DNA on regulatory sites overlapping with promoter regions. When expressed, efflux proteins self-assemble to form multiprotein complexes and actively expel highly toxic compounds out of the host organism. The mutational pressure on efflux-regulating MarR family proteins is high since deficient DNA binding leads to constitutive expression of efflux pumps and thereby supports acquired multidrug resistance. Understanding the functional outcome of such mutations and their effects on DNA binding has been hampered by the scarcity of structural and dynamic characterization of both free and DNA-bound MarR proteins. Here, we show how combined neutron and x-ray small-angle scattering of both states in solution support a conformational selection model that enhances MexR asymmetry in binding to one of its promoter-overlapping DNA binding sites., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.) more...
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- 2023
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33. Experimental-theoretical study of laccase as a detoxifier of aflatoxins.
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Zaccaria M, Dawson W, Russel Kish D, Reverberi M, Bonaccorsi di Patti MC, Domin M, Cristiglio V, Chan B, Dellafiora L, Gabel F, Nakajima T, Genovese L, and Momeni B
- Subjects
- Aflatoxin B1 chemistry, Laccase metabolism, Molecular Dynamics Simulation, Food Contamination analysis, Aflatoxins analysis
- Abstract
We investigate laccase-mediated detoxification of aflatoxins, fungal carcinogenic food contaminants. Our experimental comparison between two aflatoxins with similar structures (AFB
1script> and AFG 2 ) shows significant differences in laccase-mediated detoxification. A multi-scale modeling approach (Docking, Molecular Dynamics, and Density Functional Theory) identifies the highly substrate-specific changes required to improve laccase detoxifying performance. We employ a large-scale density functional theory-based approach, involving more than 7000 atoms, to identify the amino acid residues that determine the affinity of laccase for aflatoxins. From this study we conclude: (1) AFB1 is more challenging to degrade, to the point of complete degradation stalling; (2) AFG2 is easier to degrade by laccase due to its lack of side products and favorable binding dynamics; and (3) ample opportunities to optimize laccase for aflatoxin degradation exist, especially via mutations leading to π-π stacking. This study identifies a way to optimize laccase for aflatoxin bioremediation and, more generally, contributes to the research efforts aimed at rational enzyme optimization., (© 2023. The Author(s).) more...- Published
- 2023
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34. Observing protein degradation in solution by the PAN-20S proteasome complex: Astate-of-the-art example of bio-macromolecular TR-SANS.
- Author
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Gabel F
- Subjects
- X-Ray Diffraction, Scattering, Small Angle, Proteolysis, Macromolecular Substances chemistry, Proteasome Endopeptidase Complex, Neutron Diffraction methods
- Abstract
In the present book chapter we illustrate the state-of-the-art of time-resolved small-angle neutron scattering (TR-SANS) by a concrete example of a dynamic bio-macromolecular system, i.e., regulated protein degradation by the archaeal PAN-20S proteasome complex. We present the specific and unique structural information that can be obtained by this approach, in combination with bio-macromolecular deuteration and online spectrophotometric measurements of a fluorescent substrate (GFP). The complementarity with atomic-resolution structural biology techniques (SAXS, NMR, crystallography and cryo-EM) and with the advent of atomic structure prediction are discussed, as well as the respective limitations and future perspectives., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...
- Published
- 2023
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35. A round-robin approach provides a detailed assessment of biomolecular small-angle scattering data reproducibility and yields consensus curves for benchmarking.
- Author
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Trewhella J, Vachette P, Bierma J, Blanchet C, Brookes E, Chakravarthy S, Chatzimagas L, Cleveland TE 4th, Cowieson N, Crossett B, Duff AP, Franke D, Gabel F, Gillilan RE, Graewert M, Grishaev A, Guss JM, Hammel M, Hopkins J, Huang Q, Hub JS, Hura GL, Irving TC, Jeffries CM, Jeong C, Kirby N, Krueger S, Martel A, Matsui T, Li N, Pérez J, Porcar L, Prangé T, Rajkovic I, Rocco M, Rosenberg DJ, Ryan TM, Seifert S, Sekiguchi H, Svergun D, Teixeira S, Thureau A, Weiss TM, Whitten AE, Wood K, and Zuo X more...
- Subjects
- Scattering, Small Angle, X-Ray Diffraction, Consensus, Reproducibility of Results, Solvents, Benchmarking, Proteins chemistry
- Abstract
Through an expansive international effort that involved data collection on 12 small-angle X-ray scattering (SAXS) and four small-angle neutron scattering (SANS) instruments, 171 SAXS and 76 SANS measurements for five proteins (ribonuclease A, lysozyme, xylanase, urate oxidase and xylose isomerase) were acquired. From these data, the solvent-subtracted protein scattering profiles were shown to be reproducible, with the caveat that an additive constant adjustment was required to account for small errors in solvent subtraction. Further, the major features of the obtained consensus SAXS data over the q measurement range 0-1 Å
-1 are consistent with theoretical prediction. The inherently lower statistical precision for SANS limited the reliably measured q-range to <0.5 Å-1 , but within the limits of experimental uncertainties the major features of the consensus SANS data were also consistent with prediction for all five proteins measured in H2 O and in D2 O. Thus, a foundation set of consensus SAS profiles has been obtained for benchmarking scattering-profile prediction from atomic coordinates. Additionally, two sets of SAXS data measured at different facilities to q > 2.2 Å-1 showed good mutual agreement, affirming that this region has interpretable features for structural modelling. SAS measurements with inline size-exclusion chromatography (SEC) proved to be generally superior for eliminating sample heterogeneity, but with unavoidable sample dilution during column elution, while batch SAS data collected at higher concentrations and for longer times provided superior statistical precision. Careful merging of data measured using inline SEC and batch modes, or low- and high-concentration data from batch measurements, was successful in eliminating small amounts of aggregate or interparticle interference from the scattering while providing improved statistical precision overall for the benchmarking data set., (open access.) more...- Published
- 2022
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36. Self-imposed social isolation among clients of social care organisations in the COVID-19 pandemic.
- Author
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Nævestad TO, Orru K, Nero K, Schieffelers A, Olson A, Ludvigsen J, Airola M, Savadori L, Krüger M, Gabel F, and Hesjevoll I
- Abstract
Although self-imposed social isolation is an important way of reducing the risk of COVID-19 infection, previous research indicates that this behaviour varies substantially between different groups and individuals. Socially marginalized people are generally less involved in protective health behaviours, but there are few studies of their COVID-19 protective behaviours. The aims of the paper are therefore to: 1) compare self-imposed social isolation to avoid COVID-19 among socially marginalized groups, and to 2) examine factors influencing this, focusing especially on the role of social capital, risk awareness and sources of information about COVID-19. The study is based on survey data (N = 173) from people who are clients of social care organisations in Estonia, Norway, Hungary and Portugal. The sample involves clients living: a) in their homes, b) in facilities, and c) on the street or under temporary arrangements. Results indicate that the level of social isolation among the marginalized groups is comparable to that of the general population in previous studies. As hypothesized, we find that respondents living on the street or under temporary arrangements engage in less self-imposed social isolation than e.g. the respondents living in their homes. We also find lower levels of risk awareness, social capital and trust in authorities' information about COVID-19 among people living on the street or under temporary arrangements. Only linking social capital and trust in authorities' information was significantly related to respondents' social isolation, and not worry for COVID-19 infection. Thus, it seems that respondents largely self-isolated because of "duty" and not worry for infection., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tor-Olav Naevestad reports financial support was provided by European Union., (© 2022 The Authors.) more...
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- 2022
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37. Medical contrast agents as promising tools for biomacromolecular SAXS experiments.
- Author
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Gabel F, Engilberge S, Schmitt E, Thureau A, Mechulam Y, Pérez J, and Girard E
- Subjects
- Iohexol, Proteins chemistry, RNA chemistry, Scattering, Small Angle, Solvents, X-Ray Diffraction, Contrast Media, Lanthanoid Series Elements
- Abstract
Small-angle X-ray scattering (SAXS) has become an indispensable tool in structural biology, complementing atomic-resolution techniques. It is sensitive to the electron-density difference between solubilized biomacromolecules and the buffer, and provides information on molecular masses, particle dimensions and interactions, low-resolution conformations and pair distance-distribution functions. When SAXS data are recorded at multiple contrasts, i.e. at different solvent electron densities, it is possible to probe, in addition to their overall shape, the internal electron-density profile of biomacromolecular assemblies. Unfortunately, contrast-variation SAXS has been limited by the range of solvent electron densities attainable using conventional co-solutes (for example sugars, glycerol and salt) and by the fact that some biological systems are destabilized in their presence. Here, SAXS contrast data from an oligomeric protein and a protein-RNA complex are presented in the presence of iohexol and Gd-HPDO3A, two electron-rich molecules that are used in biomedical imaging and that belong to the families of iodinated and lanthanide-based complexes, respectively. Moderate concentrations of both molecules allowed solvent electron densities matching those of proteins to be attained. While iohexol yielded higher solvent electron densities (per mole), it interacted specifically with the oligomeric protein and precipitated the protein-RNA complex. Gd-HPDO3A, while less efficient (per mole), did not disrupt the structural integrity of either system, and atomic models could be compared with the SAXS data. Due to their elevated solubility and electron density, their chemical inertness, as well as the possibility of altering their physico-chemical properties, lanthanide-based complexes represent a class of molecules with promising potential for contrast-variation SAXS experiments on diverse biomacromolecular systems., (open access.) more...
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- 2022
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38. Binding stoichiometry and structural model of the HIV-1 Rev/importin β complex.
- Author
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Spittler D, Indorato RL, Boeri Erba E, Delaforge E, Signor L, Harris SJ, Garcia-Saez I, Palencia A, Gabel F, Blackledge M, Noirclerc-Savoye M, and Petosa C
- Subjects
- Models, Structural, Molecular Docking Simulation, RNA, Viral metabolism, HIV-1 metabolism, beta Karyopherins genetics, beta Karyopherins metabolism
- Abstract
HIV-1 Rev mediates the nuclear export of intron-containing viral RNA transcripts and is essential for viral replication. Rev is imported into the nucleus by the host protein importin β (Impβ), but how Rev associates with Impβ is poorly understood. Here, we report biochemical, mutational, and biophysical studies of the Impβ/Rev complex. We show that Impβ binds two Rev monomers through independent binding sites, in contrast to the 1:1 binding stoichiometry observed for most Impβ cargos. Peptide scanning data and charge-reversal mutations identify the N-terminal tip of Rev helix α2 within Rev's arginine-rich motif (ARM) as a primary Impβ-binding epitope. Cross-linking mass spectrometry and compensatory mutagenesis data combined with molecular docking simulations suggest a structural model in which one Rev monomer binds to the C-terminal half of Impβ with Rev helix α2 roughly parallel to the HEAT-repeat superhelical axis, whereas the other monomer binds to the N-terminal half. These findings shed light on the molecular basis of Rev recognition by Impβ and highlight an atypical binding behavior that distinguishes Rev from canonical cellular Impβ cargos., (© 2022 Spittler et al.) more...
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- 2022
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39. Approaches to 'vulnerability' in eight European disaster management systems.
- Author
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Orru K, Hansson S, Gabel F, Tammpuu P, Krüger M, Savadori L, Meyer SF, Torpan S, Jukarainen P, Schieffelers A, Lovasz G, and Rhinard M
- Subjects
- Europe, Humans, Italy, Norway, Sweden, Disaster Planning, Disasters
- Abstract
While social vulnerability in the face of disasters has received increasing academic attention, relatively little is known about the extent to which that knowledge is reflected in practice by institutions involved in disaster management. This study charts the practitioners' approaches to disaster vulnerability in eight European countries: Belgium; Estonia; Finland; Germany; Hungary; Italy; Norway; and Sweden. It draws on a comparative document analysis and 95 interviews with disaster managers and reveals significant differences across countries in terms of the ontology of vulnerability, its sources, reduction strategies, and the allocation of related duties. To advance the debate and provide conceptual clarity, we put forward a heuristic model to facilitate different understandings of vulnerability along the dimensions of human agency and technological structures as well as social support through private relations and state actors. This could guide risk analysis of and planning for major hazards and could be adapted further to particular types of disasters., (© 2021 The Authors Disasters © 2021 ODI.) more...
- Published
- 2022
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40. Characterization of a small tRNA-binding protein that interacts with the archaeal proteasome complex.
- Author
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Hogrel G, Marino-Puertas L, Laurent S, Ibrahim Z, Covès J, Girard E, Gabel F, Fenel D, Daugeron MC, Clouet-d'Orval B, Basta T, Flament D, and Franzetti B
- Subjects
- Archaea metabolism, Carrier Proteins, Crystallography, X-Ray, Proteomics, RNA, Transfer, Archaeal Proteins metabolism, Proteasome Endopeptidase Complex metabolism
- Abstract
The proteasome system allows the elimination of functional or structurally impaired proteins. This includes the degradation of nascent peptides. In Archaea, how the proteasome complex interacts with the translational machinery remains to be described. Here, we characterized a small orphan protein, Q9UZY3 (UniProt ID), conserved in Thermococcales. The protein was identified in native pull-down experiments using the proteasome regulatory complex (proteasome-activating nucleotidase [PAN]) as bait. X-ray crystallography and small-angle X-ray scattering experiments revealed that the protein is monomeric and adopts a β-barrel core structure with an oligonucleotide/oligosaccharide-binding (OB)-fold, typically found in translation elongation factors. Mobility shift experiment showed that Q9UZY3 displays transfer ribonucleic acid (tRNA)-binding properties. Pull-downs, co-immunoprecipitation and isothermal titration calorimetry (ITC) studies revealed that Q9UZY3 interacts in vitro with PAN. Native pull-downs and proteomic analysis using different versions of Q9UZY3 showed that the protein interacts with the assembled PAN-20S proteasome machinery in Pyrococcus abyssi (Pa) cellular extracts. The protein was therefore named Pbp11, for Proteasome-Binding Protein of 11 kDa. Interestingly, the interaction network of Pbp11 also includes ribosomal proteins, tRNA-processing enzymes and exosome subunits dependent on Pbp11's N-terminal domain that was found to be essential for tRNA binding. Together these data suggest that Pbp11 participates in an interface between the proteasome and the translational machinery., (© 2022 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.) more...
- Published
- 2022
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41. Morphine-3-Glucuronide, Physiology and Behavior.
- Author
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Gabel F, Hovhannisyan V, Berkati AK, and Goumon Y
- Abstract
Morphine remains the gold standard painkiller available to date to relieve severe pain. Morphine metabolism leads to the production of two predominant metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This metabolism involves uridine 5'-diphospho-glucuronosyltransferases (UGTs), which catalyze the addition of a glucuronide moiety onto the C3 or C6 position of morphine. Interestingly, M3G and M6G have been shown to be biologically active. On the one hand, M6G produces potent analgesia in rodents and humans. On the other hand, M3G provokes a state of strong excitation in rodents, characterized by thermal hyperalgesia and tactile allodynia. Its coadministration with morphine or M6G also reduces the resulting analgesia. Although these behavioral effects show quite consistency in rodents, M3G effects are much more debated in humans and the identity of the receptor(s) on which M3G acts remains unclear. Indeed, M3G has little affinity for mu opioid receptor (MOR) (on which morphine binds) and its effects are retained in the presence of naloxone or naltrexone, two non-selective MOR antagonists. Paradoxically, MOR seems to be essential to M3G effects. In contrast, several studies proposed that TLR4 could mediate M3G effects since this receptor also appears to be essential to M3G-induced hyperalgesia. This review summarizes M3G's behavioral effects and potential targets in the central nervous system, as well as the mechanisms by which it might oppose analgesia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gabel, Hovhannisyan, Berkati and Goumon.) more...
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- 2022
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42. Environmental conditions affect the food quality of plastic associated biofilms for the benthic grazer Physa fontinalis.
- Author
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Michler-Kozma DN, Neu TR, and Gabel F
- Subjects
- Animals, Biofilms, Food Quality, Snails, Ecosystem, Plastics toxicity
- Abstract
With an ever-increasing amount of plastic pollution in the various aquatic ecosystems around the world, the effects on organisms are still not fully understood. Most studies focus on direct effects posed by plastic intake or entanglement, but plastic debris can also affect primary production of biofilms and have an indirect impact on its consumers. This study investigates the primary production on three common plastic types in freshwater and its food quality for a benthic grazer. We hypothesized that different polymer types affect biofilm composition as well as the life parameters of its consumers. We incubated polyethylene (PE), polyethylene terephthalate (PET) and polystyrene (PS) as well as glass (control) in a productive freshwater creek for natural biofilm establishment. To account for changes in the environmental conditions, the experiment was conducted twice during winter and late spring, respectively. These biofilms were offered to the freshwater gastropod Physa fontinalis as sole food source. Growth and reproduction of the snails were measured to monitor sublethal effects. Additionally, biofilm composition was observed using confocal laser scanning microscopy (CLSM). In winter, snails feeding off PET and PE showed a significantly lower egg production and lower growth rates were observed on PET. No such effects occurred in spring. CLSM data revealed, that algal growth was significantly lower on PE and PET during the winter treatment compared to PS and glass. Since we could only find these effects during the colder and darker months (January-March), the microbial colonization on PE and PET was inhibited by the substrate under less favorable conditions of temperature and light. Hence, benign conditions may mask the adverse effects of microplastic on food webs. Our findings show that future studies on the plastisphere will need to consider such variations to further understand the influence of plastic pollution on primary production and higher trophic levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.) more...
- Published
- 2022
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43. Floating microplastic debris in a rural river in Germany: Distribution, types and potential sources and sinks.
- Author
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Eibes PM and Gabel F
- Subjects
- Ecosystem, Environmental Monitoring, Germany, Humans, Plastics, Microplastics, Water Pollutants, Chemical analysis
- Abstract
Microplastic debris affects marine as well as freshwater ecosystems and an increasing number of studies have documented the contamination in aquatic environments worldwide. However, while the research focuses on oceans and larger rivers, little is known about the situation in smaller rivers within rural catchments. Since microplastics pose various risks to ecosystems, wildlife and human health, it is important to identify potential sources, sinks and transport patterns, which are probably different for small rivers. In this study, we investigate the contamination with microplastic debris of the river Ems, representing a smaller river in Northwest Germany with an agricultural catchment. We hypothesised that with increasing river length the plastic concentration increases, especially downstream of towns, waste water treatment plant (WWTP) effluents and major tributaries as they may be important point sources of microplastics. We collected 36 surface water samples at 18 sampling sites within the first 70 km using manual driftnets. We sampled every 7 km and upstream and downstream of three larger towns, four major tributaries and four WWTP effluents. Overall, we found 1.54 ± 1.54 items m
-3 , which corresponds to the plastic concentrations in larger streams. However, the shape of the detected items differed as we did not find potential primary microplastic. Furthermore, the pattern contradicts our assumption, that the contamination increased with distance to the river's source. Downstream of towns, we found significantly less floating microplastic indicating possible sinks due to sedimentation at sites with slowing flow velocity caused by weirs in towns. Hence, the non-linear distribution pattern of microplastics indicates potential sinks of microplastics due to flow alterations on the river course. This should be considered in future studies modelling microplastic distribution and transport. Furthermore, studies especially in smaller rivers are urgently needed to identify and quantify sources and sinks and to find applicable solutions to reduce microplastic loads., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.) more...- Published
- 2022
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- View/download PDF
44. Time-resolved small-angle neutron scattering (TR-SANS) for structural biology of dynamic systems: Principles, recent developments, and practical guidelines.
- Author
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Martel A and Gabel F
- Subjects
- Scattering, Small Angle, Neutrons, Macromolecular Substances, Neutron Diffraction methods, Molecular Biology methods
- Abstract
We present an overview of time-resolved small-angle neutron scattering (TR-SANS) applied to biological systems, with a focus on bio-macromolecules and assemblies they form, together with practical guidelines. After a brief introduction to the theory and practice of SANS, we present the general setup and specifics of time-resolved experiments, as well as an overview of diverse experimental results and applications from the past ≈25years. Subsequently, we provide guidelines and practical instructions for the design, planning and execution for TR-SANS experiments, as a function of the time- and length-scales of the biological processes of interest, the availability of sample amount and deuterium labeling, and the structural information sought. We conclude with a discussion of the most recent instrumental and sample environment developments and perspectives for the future., (Copyright © 2022 Elsevier Inc. All rights reserved.) more...
- Published
- 2022
- Full Text
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45. Structure and dynamics of the quaternary hunchback mRNA translation repression complex.
- Author
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Macošek J, Simon B, Linse JB, Jagtap PKA, Winter SL, Foot J, Lapouge K, Perez K, Rettel M, Ivanović MT, Masiewicz P, Murciano B, Savitski MM, Loedige I, Hub JS, Gabel F, and Hennig J
- Subjects
- Animals, Body Patterning genetics, DNA-Binding Proteins ultrastructure, Drosophila Proteins ultrastructure, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Gene Expression Regulation, Developmental, Multiprotein Complexes genetics, Multiprotein Complexes ultrastructure, Nuclear Magnetic Resonance, Biomolecular, Protein Structure, Quaternary, RNA Recognition Motif Proteins genetics, RNA Recognition Motif Proteins ultrastructure, RNA-Binding Proteins ultrastructure, Scattering, Small Angle, Transcription Factors ultrastructure, X-Ray Diffraction, DNA-Binding Proteins genetics, Drosophila Proteins genetics, Embryonic Development genetics, RNA-Binding Proteins genetics, Transcription Factors genetics
- Abstract
A key regulatory process during Drosophila development is the localized suppression of the hunchback mRNA translation at the posterior, which gives rise to a hunchback gradient governing the formation of the anterior-posterior body axis. This suppression is achieved by a concerted action of Brain Tumour (Brat), Pumilio (Pum) and Nanos. Each protein is necessary for proper Drosophila development. The RNA contacts have been elucidated for the proteins individually in several atomic-resolution structures. However, the interplay of all three proteins during RNA suppression remains a long-standing open question. Here, we characterize the quaternary complex of the RNA-binding domains of Brat, Pum and Nanos with hunchback mRNA by combining NMR spectroscopy, SANS/SAXS, XL/MS with MD simulations and ITC assays. The quaternary hunchback mRNA suppression complex comprising the RNA binding domains is flexible with unoccupied nucleotides functioning as a flexible linker between the Brat and Pum-Nanos moieties of the complex. Moreover, the presence of the Pum-HD/Nanos-ZnF complex has no effect on the equilibrium RNA binding affinity of the Brat RNA binding domain. This is in accordance with previous studies, which showed that Brat can suppress mRNA independently and is distributed uniformly throughout the embryo., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.) more...
- Published
- 2021
- Full Text
- View/download PDF
46. Transfer and effects of PET microfibers in Chironomus riparius.
- Author
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Setyorini L, Michler-Kozma D, Sures B, and Gabel F
- Subjects
- Animals, Ecosystem, Geologic Sediments, Larva, Plastics, Polyethylene Terephthalates, Chironomidae, Water Pollutants, Chemical analysis, Water Pollutants, Chemical toxicity
- Abstract
Multiple studies in freshwater environments have verified that microplastic particles are present in water columns, sediment, and aquatic organisms. These studies indicated that certain freshwater ecosystems may act as temporary sinks of microplastic particles, leading to accumulation in the sediment and the ingestion by benthic organisms. Polyethylene terephthalate (PET) is one of the non-buoyant polymers that has been frequently found in aquatic sediments. This study aims to investigate a possible transfer of PET microfibers from aquatic to the terrestrial habitats and addressed selected effects (i.e. survival, general stress response, and growth) of PET microfibers using Chironomus riparius, a frequently applied model organism in ecotoxicological research. To assess the growth and development of C. riparius, a modified 28-day sediment chronic toxicity test was conducted, in which the main endpoint is time until emergence of the larvae. In this assay, C. riparius were exposed to artificial sediments spiked with PET microfibers. In addition, weight and head capsule lengths of the larvae were also measured. As a general stress response marker on the molecular level, Heat Shock Protein 70 (HSP70) levels were measured in two involved life stages, i.e. larvae and adults. Using staining method, ingestion of PET microfibers was verified in the adult sample. Our results clearly demonstrated that ingested microfibers by C. riparius larvae can be carried through subsequent life stages and end up in the adults. Accordingly, this is the first proof of aquatic-terrestrial transfer of PET microfibers for C. riparius. However, toxicity test results showed that there was no significant effect on the time until emergence, weight or head capsule lengths in the organisms exposed to PET microfibers compared to control organisms. HSP70 measurements showed no significant effects between control and exposure groups in the same life stage. The result suggests that PET microfibers in the applied concentration do not exert adverse effects both on organism and subcellular level in one generation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.) more...
- Published
- 2021
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47. Observing Protein Degradation by the PAN-20S Proteasome by Time-Resolved Neutron Scattering.
- Author
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Mahieu E, Covès J, Krüger G, Martel A, Moulin M, Carl N, Härtlein M, Carlomagno T, Franzetti B, and Gabel F
- Subjects
- Neutrons, Protein Transport, Proteolysis, Adenosine Triphosphatases metabolism, Proteasome Endopeptidase Complex metabolism
- Abstract
The proteasome is a key player of regulated protein degradation in all kingdoms of life. Although recent atomic structures have provided snapshots on a number of conformations, data on substrate states and populations during the active degradation process in solution remain scarce. Here, we use time-resolved small-angle neutron scattering of a deuterium-labeled GFPssrA substrate and an unlabeled archaeal PAN-20S system to obtain direct structural information on substrate states during ATP-driven unfolding and subsequent proteolysis in solution. We find that native GFPssrA structures are degraded in a biexponential process, which correlates strongly with ATP hydrolysis, the loss of fluorescence, and the buildup of small oligopeptide products. Our solution structural data support a model in which the substrate is directly translocated from PAN into the 20S proteolytic chamber, after a first, to our knowledge, successful unfolding process that represents a point of no return and thus prevents dissociation of the complex and the release of harmful, aggregation-prone products., (Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2020
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48. A Structurally Simple Vaccine Candidate Reduces Progression and Dissemination of Triple-Negative Breast Cancer.
- Author
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Amedei A, Asadzadeh F, Papi F, Vannucchi MG, Ferrucci V, Bermejo IA, Fragai M, De Almeida CV, Cerofolini L, Giuntini S, Bombaci M, Pesce E, Niccolai E, Natali F, Guarini E, Gabel F, Traini C, Catarinicchia S, Ricci F, Orzalesi L, Berti F, Corzana F, Zollo M, Grifantini R, and Nativi C more...
- Abstract
The Tn antigen is a well-known tumor-associated carbohydrate determinant, often incorporated in glycopeptides to develop cancer vaccines. Herein, four copies of a conformationally constrained mimetic of the antigen TnThr (GalNAc-Thr) were conjugated to the adjuvant CRM197, a protein licensed for human use. The resulting vaccine candidate, mime[4]CRM elicited a robust immune response in a triple-negative breast cancer mouse model, correlated with high frequency of CD4+ T cells and low frequency of M2-type macrophages, which reduces tumor progression and lung metastasis growth. Mime[4]CRM-mediated activation of human dendritic cells is reported, and the proliferation of mime[4]CRM-specific T cells, in cancer tissue and peripheral blood of patients with breast cancer, is demonstrated. The locked conformation of the TnThr mimetic and a proper presentation on the surface of CRM197 may explain the binding of the conjugate to the anti-Tn antibody Tn218 and its efficacy to fight cancer cells in mice., Competing Interests: Declaration of Interests F.B. is an employee of the GSK group of companies. All the other authors declare no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2020
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49. Current approaches for integrating solution NMR spectroscopy and small-angle scattering to study the structure and dynamics of biomolecular complexes.
- Author
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Delhommel F, Gabel F, and Sattler M
- Subjects
- Models, Molecular, Molecular Conformation, Nuclear Magnetic Resonance, Biomolecular, Scattering, Small Angle, X-Ray Diffraction, Computational Biology methods, Macromolecular Substances chemistry
- Abstract
The study of complex and dynamic biomolecular assemblies is a key challenge in structural biology and requires the use of multiple methodologies providing complementary spatial and temporal information. NMR spectroscopy is a powerful technique that allows high-resolution structure determination of biomolecules as well as investigating their dynamic properties in solution. However, for high-molecular-weight systems, such as biomolecular complexes or multi-domain proteins, it is often only possible to obtain sparse NMR data, posing significant challenges to structure determination. Combining NMR data with information obtained from other solution techniques is therefore an attractive approach. The combination of NMR with small-angle X-ray and/or neutron scattering has been shown to be particularly fruitful. These scattering approaches provide low-resolution information of biomolecules in solution and reflect ensemble-averaged contributions of dynamic conformations for scattering molecules up to megadalton molecular weight. Here, we review recent developments in the combination of nuclear magnetic resonance spectroscopy (NMR) and small-angle scattering (SAS) experiments. We briefly outline the different types of information that are provided by these techniques. We then discuss computational methods that have been developed to integrate NMR and SAS data, particularly considering the presence of dynamic structural ensembles and flexibility of the investigated biomolecules. Finally, recent examples of the successful combination of NMR and SAS are presented to illustrate the utility of their combination., (Copyright © 2020 Elsevier Ltd. All rights reserved.) more...
- Published
- 2020
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50. Once bitten, twice shy? Lessons learned from an experiment to liberalize price regulations for dental care.
- Author
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Trescher AL, Listl S, van der Galien O, Gabel F, and Kalmus O
- Subjects
- Costs and Cost Analysis, Databases, Factual, Dental Care methods, Health Care Reform methods, Humans, Models, Econometric, Netherlands, Patient Acceptance of Health Care, Dental Care economics, Dental Care statistics & numerical data, Health Care Reform economics, Politics
- Abstract
In 2012, The Netherlands established the so-called "free market experiment", which allowed providers of dental care to set the prices for their dental services themselves. The introduction of market mechanisms is intended to improve the quality of care and to contribute to cost containment, but increasing health expenditures for citizens have been observed in this context. Using large-volume health insurance claims data and exploiting the 2012 experiment in Dutch dental care, we identified the effects of a liberalization of service prices. Using pooled regression with individual fixed effects, we analyzed changes in utilization patterns of prevention-oriented dental services in response to the experiment as well as the elasticities in demand in response to variations in out-of-pocket (OOP) prices. We found substantial increases in prices and patients' OOP contributions for dental services following the liberalization with differences in increases between types of services. In response to the experiment, the proportion of treatment sessions containing preventive-oriented services decreased significantly by 3.4% among adults and by 5.3% for children and adolescents. Estimates of short-run price elasticities of demand for different services point towards differences in price sensitivity. One potential explanation for the observed variations in prices and utilization could be different extents of asymmetric information for first-stage and follow-on services. Price liberalization seems to have affected the composition of treatment sessions towards a decreasing use of preventive services, suggesting a shift in the reason for seeing a dental care provider from a regular-preventive perspective to a symptom-based restorative approach. more...
- Published
- 2020
- Full Text
- View/download PDF
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