38 results on '"Hognon C."'
Search Results
2. Faisabilité dosimétrique d’une radiothérapie stéréotaxique cérébrale basée sur l’IRM, à l’aide de scanographies synthétiques générées par réseau adversatif génératif
- Author
-
Bourbonne, V., primary, Jaouen, V., additional, Hognon, C., additional, Boussion, N., additional, Lucia, F., additional, Pradier, O., additional, Bert, J., additional, Visvikis, D., additional, and Schick, U., additional
- Published
- 2020
- Full Text
- View/download PDF
3. Adhesion Properties of Probiotic Lactobacillus Strains Isolated from Tunisian Sheep and Goat Milk.
- Author
-
Mahmoudi, I., Moussa, O. Ben, Khaldi, T. E., Kebouchi, M., Soligot-Hognon, C., Leroux, Y., and Hassouna, M.
- Subjects
GOAT milk ,SHEEP milk ,RAW milk ,LACTOBACILLUS plantarum ,LACTOBACILLUS ,ADHESION - Abstract
Four hundred strains isolated from Tunisian sheep and goat raw milks were initially screened for their ability to survive the GastroIntestinal Tract (GIT). Forty-three among the four hundred bacteria were resistant to pepsin, pH 2, pancreatin and bile salts at 0.3%, even after 5 hours of incubation. Identification using 16S rRNA gene sequencing was established and we obtained as a species Lactobacillus plantarum (29 isolates from sheep milk and 11 from goat milk) and Lactobacillus pentosus (2 isolates from sheep milk and 1 from goat milk). We showed the ability for auto-aggregation and/or hydrophobicity properties. Finally, both M63 and C78 strains showed an important level of adhesion to three intestinal epithelial cells Caco-2 TC7, HT29-MTX, and HT29-CL.16E. Taken together, these properties allow the lactobacilli strains to be considered promising beneficial strains for developing functional foods for consumers. [ABSTRACT FROM AUTHOR]
- Published
- 2019
4. Structure and Dynamics of RNA Guanine Quadruplexes in SARS-CoV-2 Genome. Original Strategies against Emerging Viruses
- Author
-
Alessio Terenzi, Emmanuelle Bignon, Giampaolo Barone, Antonio Monari, Tom Miclot, Cécilia Hognon, Marco Marazzi, Miclot T., Hognon C., Bignon E., Terenzi A., Marazzi M., Barone G., and Monari A.
- Subjects
Models, Molecular ,Letter ,Molecular model ,SARS-CoV-2 ,Chemistry ,Viral protein ,Guanine ,COVID-19 ,RNA ,Translation (biology) ,Genome, Viral ,Computational biology ,medicine.disease_cause ,G-quadruplex ,Genome ,G-Quadruplexes ,chemistry.chemical_compound ,Settore CHIM/03 - Chimica Generale E Inorganica ,medicine ,Humans ,Nucleic Acid Conformation ,RNA, Viral ,General Materials Science ,Physical and Theoretical Chemistry ,DNA - Abstract
Guanine quadruplex (G4) structures in the viral genome have a key role in modulating viruses' biological activity. While several DNA G4 structures have been experimentally resolved, RNA G4s are definitely less explored. We report the first calculated G4 structure of the RG-1 RNA sequence of SARS-CoV-2 genome, obtained by using a multiscale approach combining quantum and classical molecular modeling and corroborated by the excellent agreement between the corresponding calculated and experimental circular dichroism spectra. We prove the stability of the RG-1 G4 arrangement as well as its interaction with G4 ligands potentially inhibiting viral protein translation.
- Published
- 2021
5. How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency
- Author
-
Giampaolo Barone, Antonio Monari, Tao Jiang, Cécilia Hognon, Elise Dumont, Emmanuelle Bignon, Jeremy Morere, Tom Miclot, Morere J., Hognon C., Miclot T., Jiang T., Dumont E., Barone G., Monari A., Bignon E., Laboratoire de Physique et Chimie Théoriques (LPCT), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
General Chemical Engineering ,Population ,Library and Information Sciences ,Biology ,Proinflammatory cytokine ,mutation ,Immune system ,[CHIM]Chemical Sciences ,Humans ,education ,Pathogen ,wild-type ,education.field_of_study ,Wild type ,Membrane Proteins ,General Chemistry ,STING protein ,Immunity, Innate ,Computer Science Applications ,Sting ,molecular dynamics simulation ,Settore CHIM/03 - Chimica Generale E Inorganica ,Stimulator of interferon genes ,Immunology ,Interferons ,Signal transduction - Abstract
The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue…), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.
- Published
- 2022
6. Never Cared for What They Do: High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage
- Author
-
Tom Miclot, Cécilia Hognon, Emmanuelle Bignon, Alessio Terenzi, Stéphanie Grandemange, Giampaolo Barone, Antonio Monari, Miclot T., Hognon C., Bignon E., Terenzi A., Grandemange S., Barone G., and Monari A.
- Subjects
DNA Repair ,Organic Chemistry ,guanine quadruplexes ,DNA strand breaks ,molecular modeling and simulation ,Pharmaceutical Science ,DNA ,Genomic Instability ,Analytical Chemistry ,G-Quadruplexes ,Chemistry (miscellaneous) ,Settore CHIM/03 - Chimica Generale E Inorganica ,Drug Discovery ,Molecular Medicine ,Humans ,Physical and Theoretical Chemistry ,DNA Damage - Abstract
DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.
- Published
- 2022
7. Forever Young: Structural Stability of Telomeric Guanine Quadruplexes in the Presence of Oxidative DNA Lesions**
- Author
-
Camille Corbier, Stéphanie Grandemange, Tom Miclot, Cécilia Hognon, Alessio Terenzi, Antonio Monari, Giampaolo Barone, Miclot T., Corbier C., Terenzi A., Hognon C., Grandemange S., Barone G., Monari A., Laboratoire de Physico-Chimie Théorique (LPCT), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Palermo - University of Palermo, Centre de Recherche en Automatique de Nancy (CRAN), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)
- Subjects
Circular dichroism ,Telomerase ,Oxidative phosphorylation ,010402 general chemistry ,Immunofluorescence ,medicine.disease_cause ,01 natural sciences ,electronic circular dichroism ,Catalysis ,[SPI.AUTO]Engineering Sciences [physics]/Automatic ,chemistry.chemical_compound ,medicine ,Humans ,immunofluorescence ,chemistry.chemical_classification ,medicine.diagnostic_test ,010405 organic chemistry ,Circular Dichroism ,Organic Chemistry ,DNA ,General Chemistry ,Telomere ,molecular dynamics ,0104 chemical sciences ,3. Good health ,G-Quadruplexes ,Oxidative Stress ,Enzyme ,Biochemistry ,chemistry ,Settore CHIM/03 - Chimica Generale E Inorganica ,Guanine quadruplexes ,Nucleic Acid Conformation ,oxidative DNA lesions ,Guanine-Quadruplexes ,Oxidative stress - Abstract
International audience; Human telomeric DNA, in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine (8oxoG) lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress.
- Published
- 2021
8. Molecular basis of SARS-CoV-2 infection and rational design of potential antiviral agents: Modeling and simulation approaches
- Author
-
Cristina García-Iriepa, Tom Miclot, Giampaolo Barone, Antonio Francés-Monerris, Cécilia Hognon, Antonio Monari, Isabel Iriepa, Marco Marazzi, Stéphanie Grandemange, Alessio Terenzi, Laboratoire de Physico-Chimie Théorique (LPCT), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Universitat de València (UV), Universidad de Alcalá - University of Alcalá (UAH), Università degli studi di Palermo - University of Palermo, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Frances-Monerris A., Hognon C., Miclot T., Garcia-Iriepa C., Iriepa I., Terenzi A., Grandemange S., Barone G., Marazzi M., and Monari A.
- Subjects
0301 basic medicine ,Computer science ,drug design ,In silico ,Pneumonia, Viral ,membrane fusion ,coronavirus ,Reviews ,Drug design ,Computational biology ,Molecular Dynamics Simulation ,Viral Nonstructural Proteins ,medicine.disease_cause ,spike protein ,Antiviral Agents ,Molecular Docking Simulation ,Biochemistry ,[SPI.AUTO]Engineering Sciences [physics]/Automatic ,Modeling and simulation ,Betacoronavirus ,03 medical and health sciences ,Pandemic ,medicine ,Humans ,structural biophysics ,Pandemics ,Coronavirus ,030102 biochemistry & molecular biology ,SARS-CoV-2 ,free-energy methods ,molecular modeling ,Rational design ,COVID-19 ,General Chemistry ,Virus Internalization ,SARS unique domain ,molecular dynamics ,3. Good health ,030104 developmental biology ,Docking (molecular) ,Settore CHIM/03 - Chimica Generale E Inorganica ,Spike Glycoprotein, Coronavirus ,docking ,proteases ,Coronavirus Infections - Abstract
International audience; The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.
- Published
- 2020
9. Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses
- Author
-
Cécilia Hognon, Antonio Monari, Antonio Francés-Monerris, Giampaolo Barone, Tom Miclot, Alessio Terenzi, Stéphanie Grandemange, Marco Marazzi, Cristina Garcia Iriepa, Hognon C., Miclot T., Garcla-Iriepa C., Frances-Monerris A., Grandemange S., Terenzi A., Marazzi M., Barone G., Monari A., Laboratoire de Physique et Chimie Théoriques (LPCT), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Palermo - University of Palermo, Universidad de Alcalá - University of Alcalá (UAH), Chemical Research Institute 'Andrés M. del Río' (IQAR),Universidad de Alcalá, Instituto de Ciencia Molecular (ICMol), Universitat de València (UV), Centre de Recherche en Automatique de Nancy (CRAN), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)
- Subjects
Models, Molecular ,0301 basic medicine ,Letter ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Dimer ,Pneumonia, Viral ,Coronaviru ,Protein dimer ,Molecular Dynamics Simulation ,Viral infection ,01 natural sciences ,Virus ,Betacoronavirus ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,0103 physical sciences ,G-Quadruplexe ,Humans ,[CHIM]Chemical Sciences ,General Materials Science ,030212 general & internal medicine ,Physical and Theoretical Chemistry ,Pandemics ,Economic consequences ,030304 developmental biology ,0303 health sciences ,010304 chemical physics ,Betacoronaviru ,SARS-CoV-2 ,Chemistry ,Coronavirus Infection ,Rational design ,COVID-19 ,RNA ,Spike Glycoprotein ,3. Good health ,G-Quadruplexes ,030104 developmental biology ,Settore CHIM/03 - Chimica Generale E Inorganica ,Spike Glycoprotein, Coronavirus ,Biophysics ,RNA, Viral ,Coronavirus Infections ,Guanine-Quadruplexes ,Dimerization ,Protein Binding - Abstract
Coronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible of a global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting SARS viruses to bypass the host protective response. This work also constitutes a first step of the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.TOC GRAPHICS
- Published
- 2020
- Full Text
- View/download PDF
10. Thermodynamics of the Interaction between the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus-2 and the Receptor of Human Angiotensin-Converting Enzyme 2. Effects of Possible Ligands
- Author
-
García-Iriepa, Cristina, Hognon, Cécilia, Francés-Monerris, Antonio, Iriepa, Isabel, Miclot, Tom, Barone, Giampaolo, Monari, Antonio, Marazzi, Marco, 0000-0002-7577-8242, 0000-0001-8232-4989, 0000-0001-8773-2359, 0000-0001-9464-1463, 0000-0001-7158-7994, Garcia-Iriepa C., Hognon C., Frances-Monerris A., Iriepa I., Miclot T., Barone G., Monari A., and Marazzi M.
- Subjects
Letter ,Pneumonia, Viral ,Protein domain ,Thermodynamics ,Plasma protein binding ,Molecular Dynamics Simulation ,Peptidyl-Dipeptidase A ,Ligands ,medicine.disease_cause ,Protein-Protein Binding ,01 natural sciences ,Docking ,Betacoronavirus ,03 medical and health sciences ,Protein Domains ,0103 physical sciences ,medicine ,Humans ,General Materials Science ,Physical and Theoretical Chemistry ,Binding site ,Receptor ,Pandemics ,030304 developmental biology ,Coronavirus ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,010304 chemical physics ,SARS-CoV-2 ,Spike Protein ,COVID-19 ,Plicamycin ,Transmembrane protein ,Enzyme ,chemistry ,Settore CHIM/03 - Chimica Generale E Inorganica ,Molecular Dynamics Simulations ,Spike Glycoprotein, Coronavirus ,Angiotensin-converting enzyme 2 ,Diosmin ,Angiotensin-Converting Enzyme 2 ,Coronavirus Infections ,Protein Binding - Abstract
Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 1000000 deaths all over the world and still lacks a medical treatment despite the attention of the whole scientific community. Human angiotensin-converting enzyme 2 (ACE2) was recently recognized as the transmembrane protein that serves as the point of entry of SARS-CoV-2 into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the protein complex. Moreover, the free energy of binding between ACE2 and the active receptor binding domain of the SARS-CoV-2 spike protein is evaluated quantitatively, providing for the first time the thermodynamics of virus-receptor recognition. Furthermore, the action of different ACE2 ligands is also examined in particular in their capacity to disrupt SARS-CoV-2 recognition, also providing via a free energy profile the quantification of the ligand-induced decreased affinity. These results improve our knowledge on molecular grounds of the SARS-CoV-2 infection and allow us to suggest rationales that could be useful for the subsequent wise molecular design for the treatment of COVID-19 cases.
- Published
- 2020
11. Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes
- Author
-
Hognon, Cecilia, Gebus, Adrien, Barone, Giampaolo, Monari, Antonio, Laboratoire de Physique et Chimie Théoriques (LPCT), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Palermo - University of Palermo, Hognon C., Gebus A., Barone G., and Monari A.
- Subjects
lcsh:RM1-950 ,All atom molecular dynamic ,all atom molecular dynamics ,Article ,human DNA telomeres ,Guanine quadruplexe ,lcsh:Therapeutics. Pharmacology ,Settore CHIM/03 - Chimica Generale E Inorganica ,oxidative lesions ,[CHIM]Chemical Sciences ,heterocyclic compounds ,guanine quadruplexes ,ComputingMilieux_MISCELLANEOUS ,Human DNA telomere - Abstract
By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.
- Published
- 2019
12. Dynamics of Protein-RNA Interfaces Using All-Atom Molecular Dynamics Simulations.
- Author
-
Sabei A, Hognon C, Martin J, and Frezza E
- Subjects
- Protein Binding, RNA-Binding Proteins chemistry, RNA-Binding Proteins metabolism, Proteins chemistry, Nucleic Acid Conformation, Molecular Dynamics Simulation, RNA chemistry
- Abstract
Facing the current challenges posed by human health diseases requires the understanding of cell machinery at a molecular level. The interplay between proteins and RNA is key for any physiological phenomenon, as well protein-RNA interactions. To understand these interactions, many experimental techniques have been developed, spanning a very wide range of spatial and temporal resolutions. In particular, the knowledge of tridimensional structures of protein-RNA complexes provides structural, mechanical, and dynamical pieces of information essential to understand their functions. To get insights into the dynamics of protein-RNA complexes, we carried out all-atom molecular dynamics simulations in explicit solvent on nine different protein-RNA complexes with different functions and interface size by taking into account the bound and unbound forms. First, we characterized structural changes upon binding and, for the RNA part, the change in the puckering. Second, we extensively analyzed the interfaces, their dynamics and structural properties, and the structural waters involved in the binding, as well as the contacts mediated by them. Based on our analysis, the interfaces rearranged during the simulation time showing alternative and stable residue-residue contacts with respect to the experimental structure.
- Published
- 2024
- Full Text
- View/download PDF
13. Contrastive image adaptation for acquisition shift reduction in medical imaging.
- Author
-
Hognon C, Conze PH, Bourbonne V, Gallinato O, Colin T, Jaouen V, and Visvikis D
- Subjects
- Educational Status, Image Processing, Computer-Assisted, Diagnostic Imaging, Learning
- Abstract
The domain shift, or acquisition shift in medical imaging, is responsible for potentially harmful differences between development and deployment conditions of medical image analysis techniques. There is a growing need in the community for advanced methods that could mitigate this issue better than conventional approaches. In this paper, we consider configurations in which we can expose a learning-based pixel level adaptor to a large variability of unlabeled images during its training, i.e. sufficient to span the acquisition shift expected during the training or testing of a downstream task model. We leverage the ability of convolutional architectures to efficiently learn domain-agnostic features and train a many-to-one unsupervised mapping between a source collection of heterogeneous images from multiple unknown domains subjected to the acquisition shift and a homogeneous subset of this source set of lower cardinality, potentially constituted of a single image. To this end, we propose a new cycle-free image-to-image architecture based on a combination of three loss functions : a contrastive PatchNCE loss, an adversarial loss and an edge preserving loss allowing for rich domain adaptation to the target image even under strong domain imbalance and low data regimes. Experiments support the interest of the proposed contrastive image adaptation approach for the regularization of downstream deep supervised segmentation and cross-modality synthesis models., Competing Interests: Declaration of competing interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
- Full Text
- View/download PDF
14. Efficient biodegradation of the recalcitrant organochlorine pesticide chlordecone under methanogenic conditions.
- Author
-
Martin DE, Alnajjar P, Muselet D, Soligot-Hognon C, Kanso H, Pacaud S, Le Roux Y, Saaidi PL, and Feidt C
- Abstract
Anaerobic digestion (AD) has long been studied as an effective environmental and economic strategy for treating matrices contaminated with recalcitrant pollutants. In the present work, we investigated the bioremediation potential of AD on organic waste contaminated with chlordecone (CLD), an organochlorine pesticide extensively used in the French West Indies and classified among the most persistent organic pollutants. Digestates from animal and plant origins were supplemented with CLD and incubated under methanogenic conditions for over 40 days. The redox potential and pH monitoring showed that methanogenic conditions were preserved during the entire incubation period despite the presence of CLD. In addition, the comparison of the total biogas generated from digestates with and without CLD demonstrated no adverse effects of CLD on biogas production. For the first time, a QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) extraction method, followed by GC-MS and LC-HRMS analyses, was developed to quantify CLD and its main known transformation products (TPs) in AD experiments. A decrease in CLD concentrations was evident to a greater extent under thermophilic conditions (55 °C) compared to mesophilic conditions (37.5 °C) (CLD removal of 85 % and 42 %, respectively, after 40 days of incubation). CLD degradation was confirmed by the detection and quantification of several TPs: 10-monohydroCLD (A1), two dihydroCLDs different from 2,8-dihydroCLD (A3), pentachloroindene (B1), tetrachloroindenes (B2, B3/B4), tetra- and tri-chloroindenecarboxylic acids (C1/C2, C3/C4). Determining TPs concentrations using the QuEChERS method provided an overview of CLD fate in AD. Overall, these results reveal that AD processes can efficiently degrade CLD into several TPs from A, B, and C families while maintaining satisfactory biogas production. They pave the way to developing a scaled-up AD process capable of treating CLD-contaminated organic wastes produced by farming, thus stopping any further transfer of CLD., 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. Published by Elsevier B.V.)
- Published
- 2023
- Full Text
- View/download PDF
15. Revealing the Molecular Interactions between Human ACE2 and the Receptor Binding Domain of the SARS-CoV-2 Wild-Type, Alpha and Delta Variants.
- Author
-
Hognon C, Bignon E, Monari A, Marazzi M, and Garcia-Iriepa C
- Subjects
- Humans, SARS-CoV-2 genetics, Machine Learning, Molecular Dynamics Simulation, Protein Binding, Mutation, Spike Glycoprotein, Coronavirus genetics, Angiotensin-Converting Enzyme 2 genetics, COVID-19 genetics
- Abstract
After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in comparison with the wild-type. On one hand, although relevant variations are evidenced, only limited changes in the global stability indicators and in the flexibility profiles have been observed. On the other hand, key differences were obtained by tracking hydrophilic and hydrophobic molecular interactions, concerning both positioning at the ACE2/RBD interface and formation/disruption dynamic behavior.
- Published
- 2023
- Full Text
- View/download PDF
16. Structural and functional characterization of DdrC, a novel DNA damage-induced nucleoid associated protein involved in DNA compaction.
- Author
-
Banneville AS, Bouthier de la Tour C, De Bonis S, Hognon C, Colletier JP, Teulon JM, Le Roy A, Pellequer JL, Monari A, Dehez F, Confalonieri F, Servant P, and Timmins J
- Subjects
- Bacterial Proteins metabolism, DNA Damage, DNA Repair, DNA, Circular metabolism, Bacterial Proteins chemistry, Deinococcus genetics, Deinococcus metabolism
- Abstract
Deinococcus radiodurans is a spherical bacterium well-known for its outstanding resistance to DNA-damaging agents. Exposure to such agents leads to drastic changes in the transcriptome of D. radiodurans. In particular, four Deinococcus-specific genes, known as DNA Damage Response genes, are strongly up-regulated and have been shown to contribute to the resistance phenotype of D. radiodurans. One of these, DdrC, is expressed shortly after exposure to γ-radiation and is rapidly recruited to the nucleoid. In vitro, DdrC has been shown to compact circular DNA, circularize linear DNA, anneal complementary DNA strands and protect DNA from nucleases. To shed light on the possible functions of DdrC in D. radiodurans, we determined the crystal structure of the domain-swapped DdrC dimer at a resolution of 2.5 Å and further characterized its DNA binding and compaction properties. Notably, we show that DdrC bears two asymmetric DNA binding sites located on either side of the dimer and can modulate the topology and level of compaction of circular DNA. These findings suggest that DdrC may be a DNA damage-induced nucleoid-associated protein that enhances nucleoid compaction to limit the dispersion of the fragmented genome and facilitate DNA repair after exposure to severe DNA damaging conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
- Full Text
- View/download PDF
17. How Fragile We Are: Influence of Stimulator of Interferon Genes (STING) Variants on Pathogen Recognition and Immune Response Efficiency.
- Author
-
Morere J, Hognon C, Miclot T, Jiang T, Dumont E, Barone G, Monari A, and Bignon E
- Subjects
- Humans, Interferons, Immunity, Innate, Membrane Proteins genetics, Membrane Proteins metabolism
- Abstract
The stimulator of interferon genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP in the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the molecular mechanisms of these variants opens perspectives for personalized medicine treatments against diseases such as viral infections, cancers, or autoinflammatory diseases. Through microsecond-scale molecular modeling simulations, contact analyses, and machine learning techniques, we reveal the dynamic behavior of four STING variants (wild type, G230A, R293Q, and G230A/R293Q) and rationalize the variability of efficiency observed experimentally. Our results show that the decrease in STING activity is linked to a stiffening of key structural elements of the binding cavity together with changes in the interaction patterns within the protein.
- Published
- 2022
- Full Text
- View/download PDF
18. Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease.
- Author
-
Hognon C, Marazzi M, and García-Iriepa C
- Subjects
- Coronavirus Papain-Like Proteases, Humans, Ligands, Papain metabolism, Peptide Hydrolases metabolism, SARS-CoV-2, Protons, COVID-19 Drug Treatment
- Abstract
Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys
111 ), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys111 deprotonation of the thiol group by a Brønsted-Lowry base; (iii) Cys111 -S- addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys111 , that is, prior to the Cys111 deprotonation. For the second step, MD simulations revealed that His272 would deprotonate Cys111 after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys111 deprotonation, whose equilibrium is largely shifted toward the neutral Cys111 form. Although thermodynamically disfavored, if Cys111 is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys111 -S- negative charge redistribution over the bound ligand, proton transfer from the initially protonated His272 is favored, finally leading to an irreversibly modified Cys111 and a restored His272 . These results elucidate the selectivity of Cys111 to enable formation of a covalent bond, even if a weak proton acceptor is available, as His272 .- Published
- 2022
- Full Text
- View/download PDF
19. Never Cared for What They Do: High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage.
- Author
-
Miclot T, Hognon C, Bignon E, Terenzi A, Grandemange S, Barone G, and Monari A
- Subjects
- DNA radiation effects, DNA Damage, Genomic Instability, Humans, DNA Repair, G-Quadruplexes
- Abstract
DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.
- Published
- 2022
- Full Text
- View/download PDF
20. Structural and morphological changes of breast cancer cells induced by iron(II) complexes.
- Author
-
Nel J, Siniscalco D, Hognon C, Bouché M, Touche N, Brunner É, Gros PC, Monari A, Grandemange S, and Francius G
- Subjects
- Apoptosis, Cell Line, Tumor, Female, Ferrous Compounds, Humans, Iron, MCF-7 Cells, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms drug therapy
- Abstract
Metal-based complexes are well-established cancer chemotherapeutic drug candidates. Although our knowledge regarding their exact activity vs. toxicity profile is incomplete, changes in cell membrane biophysical properties and cytoskeletal structures have been implicated as part of the mechanism of action. Thus, in this work, we characterised the effects of iron(II)-based complexes on the structural and morphological properties of epithelial non-tumorigenic (MCF 10A) and tumorigenic (MDA-MB-231) breast cell lines using atomic force microscopy (AFM), flow cytometry and immunofluorescence microscopy. At 24 h of exposure, both the MCF 10A and MDA-MB-231 cells experienced a cell softening, and an increase in size followed by a re-stiffening at 96 h. In addition, the triple negative breast cancer cell line, MDA-MB-231, sustained a notable cytoskeletal and mitochondrial reorganization with increased actin stress fibers and cell-to-cell communication structures. An extensive all-atom molecular dynamic simulation suggests a possible direct and unassisted internalization of the metallodrug candidate, and confirmed that the cellular effects could not be ascribed to the simple physical interaction of the iron-based complexes with the biological membrane. These observations provide an insight into a link between the mechanisms of action of such iron-based complexes as anti-cancer treatment and cytoskeletal architecture.
- Published
- 2022
- Full Text
- View/download PDF
21. In silico drug discovery of IKK-β inhibitors from 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl) pyridine derivatives based on QSAR, docking, molecular dynamics and drug-likeness evaluation studies.
- Author
-
Hammoudi NE, Benguerba Y, Attoui A, Hognon C, Lemaoui T, Sobhi W, Benaicha M, Badawi M, and Monari A
- Subjects
- Drug Discovery, Molecular Docking Simulation, Molecular Dynamics Simulation, Pyridines pharmacology, I-kappa B Kinase, Quantitative Structure-Activity Relationship
- Abstract
The Inhibitor of IKK-β (nuclear factor kappa B kinase subunit beta), a specific modulator of NF-κB (nuclear factor-κB), is considered a valid target to discover new active compounds for various cancers and rheumatoid arthritis treatment. In this study a series of thirty 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl) pyridine derivatives was involved for a quantitative structure activity relationship model (QSAR) elaboration which allows the prediction of the pIC50 values of new designed compounds. The model can be used to predict the activity of new compounds within its applicability domain. Then a molecular docking study was carried out to identify the interactions between the compounds and the amino acids of the active site. After that, golden triangle, Veber's rule, and Lipinski's rule properties were calculated to identify the drug-likeness properties of the investigated compounds. Finally, in-silico-toxicity studies were performed to predict the toxicity of the new designed compounds. The analysis of the results of QSAR model and molecular docking succeeded to screen 21 interesting compounds with better inhibitory concentration having a good affinity to IKK-β. All compounds were within the range set by Veber's rule and Lipinski's rule. the analysis of golden triangle showed that the thirty 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl) pyridine derivatives would not have clearance and cell membrane permeability problems except comp6 comp12,comp20, comp21, and comp26.As for the new designed compounds, their properties may have these problems, except two compounds which are: A8m, A8p. The A1m, A1p, A3p and A11m compounds were predicted to be nontoxic. These findings indicate that the novel potent candidate drugs have promising potential to IKK-β enzyme inhibition and should motivate future experimental investigations.Communicated by Ramaswamy H. Sarma.
- Published
- 2022
- Full Text
- View/download PDF
22. Use of Active Salmon-Lecithin Nanoliposomes to Increase Polyunsaturated Fatty Acid Bioavailability in Cortical Neurons and Mice.
- Author
-
Passeri E, Elkhoury K, Jiménez Garavito MC, Desor F, Huguet M, Soligot-Hognon C, Linder M, Malaplate C, Yen FT, and Arab-Tehrany E
- Subjects
- Administration, Oral, Animals, Biological Availability, Cells, Cultured, Chromatography, Gas, Docosahexaenoic Acids analysis, Fatty Acids, Omega-3 pharmacokinetics, Female, Hippocampus chemistry, Lecithins pharmacokinetics, Liposomes, Liver chemistry, Male, Mice, Nanostructures, Neurons chemistry, Oleic Acid analysis, Palmitic Acid analysis, Particle Size, Primary Cell Culture, Rats, Fatty Acids, Omega-3 administration & dosage, Fatty Acids, Unsaturated blood, Lecithins administration & dosage, Neurons cytology, Salmon metabolism
- Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) play an important role in the development, maintenance, and function of the brain. Dietary supplementation of n-3 PUFAs in neurological diseases has been a subject of particular interest in preventing cognitive deficits, and particularly in age-related neurodegeneration. Developing strategies for the efficient delivery of these lipids to the brain has presented a challenge in recent years. We recently reported the preparation of n-3 PUFA-rich nanoliposomes (NLs) from salmon lecithin, and demonstrated their neurotrophic effects in rat embryo cortical neurons. The objective of this study was to assess the ability of these NLs to deliver PUFAs in cellulo and in vivo (in mice). NLs were prepared using salmon lecithin rich in n-3 PUFAs (29.13%), and characterized with an average size of 107.90 ± 0.35 nm, a polydispersity index of 0.25 ± 0.01, and a negative particle-surface electrical charge (-50.4 ± 0.2 mV). Incubation of rat embryo cortical neurons with NLs led to a significant increase in docosahexaenoic acid (DHA) (51.5%, p < 0.01), as well as palmitic acid, and a small decrease in oleic acid after 72 h (12.2%, p < 0.05). Twenty mice on a standard diet received oral administration of NLs (12 mg/mouse/day; 5 days per week) for 8 weeks. Fatty acid profiles obtained via gas chromatography revealed significant increases in cortical levels of saturated, monounsaturated, and n-3 (docosahexaenoic acid,) and n-6 (docosapentaenoic acid and arachidonic acid) PUFAs. This was not the case for the hippocampus or in the liver. There were no effects on plasma lipid levels, and daily monitoring confirmed NL biocompatibility. These results demonstrate that NLs can be used for delivery of PUFAs to the brain. This study opens new research possibilities in the development of preventive as well as therapeutic strategies for age-related neurodegeneration.
- Published
- 2021
- Full Text
- View/download PDF
23. Structure and Dynamics of RNA Guanine Quadruplexes in SARS-CoV-2 Genome. Original Strategies against Emerging Viruses.
- Author
-
Miclot T, Hognon C, Bignon E, Terenzi A, Marazzi M, Barone G, and Monari A
- Subjects
- COVID-19 virology, Humans, Models, Molecular, Nucleic Acid Conformation, COVID-19 genetics, G-Quadruplexes, Genome, Viral, RNA, Viral chemistry, RNA, Viral genetics, SARS-CoV-2 genetics
- Abstract
Guanine quadruplex (G4) structures in the viral genome have a key role in modulating viruses' biological activity. While several DNA G4 structures have been experimentally resolved, RNA G4s are definitely less explored. We report the first calculated G4 structure of the RG-1 RNA sequence of SARS-CoV-2 genome, obtained by using a multiscale approach combining quantum and classical molecular modeling and corroborated by the excellent agreement between the corresponding calculated and experimental circular dichroism spectra. We prove the stability of the RG-1 G4 arrangement as well as its interaction with G4 ligands potentially inhibiting viral protein translation.
- Published
- 2021
- Full Text
- View/download PDF
24. Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection.
- Author
-
Francés-Monerris A, García-Iriepa C, Iriepa I, Hognon C, Miclot T, Barone G, Monari A, and Marazzi M
- Subjects
- Angiotensin-Converting Enzyme 2 chemistry, Antiviral Agents chemistry, Binding Sites, Coronavirus 3C Proteases chemistry, Coronavirus Papain-Like Proteases chemistry, G-Quadruplexes, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Ivermectin chemistry, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Protein Domains, RNA genetics, RNA metabolism, SARS-CoV-2, Angiotensin-Converting Enzyme 2 metabolism, Antiviral Agents metabolism, Coronavirus 3C Proteases metabolism, Coronavirus Papain-Like Proteases metabolism, Ivermectin metabolism
- Abstract
The identification of chemical compounds able to bind specific sites of the human/viral proteins involved in the SARS-CoV-2 infection cycle is a prerequisite to design effective antiviral drugs. Here we conduct a molecular dynamics study with the aim to assess the interactions of ivermectin, an antiparasitic drug with broad-spectrum antiviral activity, with the human Angiotensin-Converting Enzyme 2 (ACE2), the viral 3CL
pro and PLpro proteases, and the viral SARS Unique Domain (SUD). The drug/target interactions have been characterized in silico by describing the nature of the non-covalent interactions found and by measuring the extent of their time duration along the MD simulation. Results reveal that the ACE2 protein and the ACE2/RBD aggregates form the most persistent interactions with ivermectin, while the binding with the remaining viral proteins is more limited and unspecific.- Published
- 2021
- Full Text
- View/download PDF
25. The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Transition in the Regulation of Ferritin Translation and Iron Hemostasis.
- Author
-
Hognon C, Bignon E, Harle G, Touche N, Grandemange S, and Monari A
- Subjects
- Aconitate Hydratase chemistry, Animals, Chickens, Humans, Iron-Regulatory Proteins chemistry, Molecular Dynamics Simulation, RNA, Messenger genetics, RNA, Messenger metabolism, Thermodynamics, Time Factors, Aconitate Hydratase metabolism, Cytosol enzymology, Ferritins metabolism, Hemostasis, Iron metabolism, Iron-Regulatory Proteins metabolism, Protein Biosynthesis
- Abstract
Maintaining iron homeostasis is fundamental for almost all living beings, and its deregulation correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free-iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn, this is regulated by the iron-sensitive conformational equilibrium between cytosolic aconitase and IRP1, mediated by the presence of an iron-sulfur cluster. In this contribution, we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA and the conformational transition. Furthermore, the role of the iron-sulfur cluster in driving the conformational transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations.
- Published
- 2021
- Full Text
- View/download PDF
26. Staring at the Naked Goddess: Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand.
- Author
-
Hognon C and Monari A
- Subjects
- Humans, DNA chemistry, DNA-Binding Proteins chemistry, Endonucleases chemistry, Models, Chemical
- Abstract
Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.
- Published
- 2021
- Full Text
- View/download PDF
27. Forever Young: Structural Stability of Telomeric Guanine Quadruplexes in the Presence of Oxidative DNA Lesions*.
- Author
-
Miclot T, Corbier C, Terenzi A, Hognon C, Grandemange S, Barone G, and Monari A
- Subjects
- Circular Dichroism, DNA metabolism, Humans, Nucleic Acid Conformation, Oxidative Stress, Telomere metabolism, G-Quadruplexes, Telomerase metabolism
- Abstract
Human telomeric DNA, in G-quadruplex (G4) conformation, is characterized by a remarkable structural stability that confers it the capacity to resist to oxidative stress producing one or even clustered 8-oxoguanine (8oxoG) lesions. We present a combined experimental/computational investigation, by using circular dichroism in aqueous solutions, cellular immunofluorescence assays and molecular dynamics simulations, that identifies the crucial role of the stability of G4s to oxidative lesions, related also to their biological role as inhibitors of telomerase, an enzyme overexpressed in most cancers associated to oxidative stress., (© 2021 Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
28. Dosimetric Validation of a GAN-Based Pseudo-CT Generation for MRI-Only Stereotactic Brain Radiotherapy.
- Author
-
Bourbonne V, Jaouen V, Hognon C, Boussion N, Lucia F, Pradier O, Bert J, Visvikis D, and Schick U
- Abstract
Purpose: Stereotactic radiotherapy (SRT) has become widely accepted as a treatment of choice for patients with a small number of brain metastases that are of an acceptable size, allowing for better target dose conformity, resulting in high local control rates and better sparing of organs at risk. An MRI-only workflow could reduce the risk of misalignment between magnetic resonance imaging (MRI) brain studies and computed tomography (CT) scanning for SRT planning, while shortening delays in planning. Given the absence of a calibrated electronic density in MRI, we aimed to assess the equivalence of synthetic CTs generated by a generative adversarial network (GAN) for planning in the brain SRT setting., Methods: All patients with available MRIs and treated with intra-cranial SRT for brain metastases from 2014 to 2018 in our institution were included. After co-registration between the diagnostic MRI and the planning CT, a synthetic CT was generated using a 2D-GAN (2D U-Net). Using the initial treatment plan (Pinnacle v9.10, Philips Healthcare), dosimetric comparison was performed using main dose-volume histogram (DVH) endpoints in respect to ICRU 91 guidelines (Dmax, Dmean, D2%, D50%, D98%) as well as local and global gamma analysis with 1%/1 mm, 2%/1 mm and 2%/2 mm criteria and a 10% threshold to the maximum dose. t -test analysis was used for comparison between the two cohorts (initial and synthetic dose maps)., Results: 184 patients were included, with 290 treated brain metastases. The mean number of treated lesions per patient was 1 (range 1-6) and the median planning target volume (PTV) was 6.44 cc (range 0.12-45.41). Local and global gamma passing rates (2%/2 mm) were 99.1 CI95% (98.1-99.4) and 99.7 CI95% (99.6-99.7) respectively (CI: confidence interval). DVHs were comparable, with no significant statistical differences regarding ICRU 91's endpoints., Conclusions: Our study is the first to compare GAN-generated CT scans from diagnostic brain MRIs with initial CT scans for the planning of brain stereotactic radiotherapy. We found high similarity between the planning CT and the synthetic CT for both the organs at risk and the target volumes. Prospective validation is under investigation at our institution.
- Published
- 2021
- Full Text
- View/download PDF
29. Photoinduced DNA Lesions in Dormant Bacteria: The Peculiar Route Leading to Spore Photoproducts Characterized by Multiscale Molecular Dynamics*.
- Author
-
Francés-Monerris A, Hognon C, Douki T, and Monari A
- Subjects
- DNA Damage, Ultraviolet Rays, DNA radiation effects, Molecular Dynamics Simulation, Pyrimidine Dimers chemistry, Spores, Bacterial chemistry
- Abstract
Some bacterial species enter a dormant state in the form of spores to resist to unfavorable external conditions. Spores are resistant to a wide series of stress agents, including UV radiation, and can last for tens to hundreds of years. Due to the suspension of biological functions, such as DNA repair, they accumulate DNA damage upon exposure to UV radiation. Differently from active organisms, the most common DNA photoproducts in spores are not cyclobutane pyrimidine dimers, but rather the so-called spore photoproducts. This noncanonical photochemistry results from the dry state of DNA and its binding to small, acid-soluble proteins that drastically modify the structure and photoreactivity of the nucleic acid. Herein, multiscale molecular dynamics simulations, including extended classical molecular dynamics and quantum mechanics/molecular mechanics based dynamics, are used to elucidate the coupling of electronic and structural factors that lead to this photochemical outcome. In particular, the well-described impact of the peculiar DNA environment found in spores on the favored formation of the spore photoproduct, given the small free energy barrier found for this path, is rationalized. Meanwhile, the specific organization of spore DNA precludes the photochemical path that leads to cyclobutane pyrimidine dimer formation., (© 2020 Wiley-VCH GmbH.)
- Published
- 2020
- Full Text
- View/download PDF
30. Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches.
- Author
-
Francés-Monerris A, Hognon C, Miclot T, García-Iriepa C, Iriepa I, Terenzi A, Grandemange S, Barone G, Marazzi M, and Monari A
- Subjects
- Betacoronavirus, COVID-19, Humans, Molecular Dynamics Simulation, SARS-CoV-2, Viral Nonstructural Proteins chemistry, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Virus Internalization, Antiviral Agents, Coronavirus Infections drug therapy, Coronavirus Infections virology, Drug Design, Molecular Docking Simulation, Pandemics, Pneumonia, Viral drug therapy, Pneumonia, Viral virology, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism
- Abstract
The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.
- Published
- 2020
- Full Text
- View/download PDF
31. Thermodynamics of the Interaction between the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus-2 and the Receptor of Human Angiotensin-Converting Enzyme 2. Effects of Possible Ligands.
- Author
-
García-Iriepa C, Hognon C, Francés-Monerris A, Iriepa I, Miclot T, Barone G, Monari A, and Marazzi M
- Subjects
- Angiotensin-Converting Enzyme 2, Binding Sites, COVID-19, Coronavirus Infections pathology, Coronavirus Infections virology, Diosmin chemistry, Diosmin metabolism, Humans, Molecular Dynamics Simulation, Pandemics, Peptidyl-Dipeptidase A chemistry, Plicamycin chemistry, Plicamycin metabolism, Pneumonia, Viral pathology, Pneumonia, Viral virology, Protein Binding, Protein Domains, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Thermodynamics, Betacoronavirus metabolism, Ligands, Peptidyl-Dipeptidase A metabolism, Spike Glycoprotein, Coronavirus metabolism
- Abstract
Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 1000000 deaths all over the world and still lacks a medical treatment despite the attention of the whole scientific community. Human angiotensin-converting enzyme 2 (ACE2) was recently recognized as the transmembrane protein that serves as the point of entry of SARS-CoV-2 into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the protein complex. Moreover, the free energy of binding between ACE2 and the active receptor binding domain of the SARS-CoV-2 spike protein is evaluated quantitatively, providing for the first time the thermodynamics of virus-receptor recognition. Furthermore, the action of different ACE2 ligands is also examined in particular in their capacity to disrupt SARS-CoV-2 recognition, also providing via a free energy profile the quantification of the ligand-induced decreased affinity. These results improve our knowledge on molecular grounds of the SARS-CoV-2 infection and allow us to suggest rationales that could be useful for the subsequent wise molecular design for the treatment of COVID-19 cases.
- Published
- 2020
- Full Text
- View/download PDF
32. Recent advances in iron-complexes as drug candidates for cancer therapy: reactivity, mechanism of action and metabolites.
- Author
-
Bouché M, Hognon C, Grandemange S, Monari A, and Gros PC
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Coordination Complexes pharmacology, Drug Screening Assays, Antitumor, Ferrous Compounds chemistry, Humans, Ligands, Molecular Targeted Therapy, Pyridines chemistry, Salicylates chemistry, Structure-Activity Relationship, Antineoplastic Agents chemistry, Coordination Complexes chemistry, Iron chemistry
- Abstract
In this perspective, we discuss iron-complexes as drug candidates that are promising alternatives to conventional platinum-based chemotherapies owing to their broad range of reactivities and to the targeting of different biological systems. Breakthroughs in the comprehension of iron complexes' structure-activity relationship contributed to the clarification of their metabolization pathways, sub-cellular localization and influence on iron homeostasis, while enlightening the primary molecular targets of theses likely multi-target metallodrugs. Both the antiproliferative activity and elevated safety index observed among the family of iron complexes showed encouraging results as per their therapeutic potential and selectivity also with the aim of reducing chemotherapy side-effects, and facilitated more pre-clinical investigations. The purpose of this perspective is to summarize the recent advances that contributed in unveiling the intricate relationships between the structural modifications on iron-complexes and their reactivity, cellular trafficking and global mechanisms of action to broaden their use as anticancer drugs and advance to clinical evaluation.
- Published
- 2020
- Full Text
- View/download PDF
33. Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses.
- Author
-
Hognon C, Miclot T, Garcı A-Iriepa C, Francés-Monerris A, Grandemange S, Terenzi A, Marazzi M, Barone G, and Monari A
- Subjects
- Betacoronavirus drug effects, COVID-19, Dimerization, Humans, Models, Molecular, Molecular Dynamics Simulation, Pandemics, Protein Binding, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Betacoronavirus chemistry, Betacoronavirus genetics, Coronavirus Infections virology, G-Quadruplexes drug effects, Pneumonia, Viral virology, RNA, Viral chemistry, RNA, Viral genetics
- Abstract
Coronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible for the global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting the SARS viruses to bypass the host protective response. This work also constitutes a first step in the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.
- Published
- 2020
- Full Text
- View/download PDF
34. Molecular Bases of DNA Packaging in Bacteria Revealed by All-Atom Molecular Dynamics Simulations: The Case of Histone-Like Proteins in Borrelia burgdorferi .
- Author
-
Hognon C, Garaude S, Timmins J, Chipot C, Dehez F, and Monari A
- Subjects
- Models, Molecular, Bacterial Proteins chemistry, Borrelia burgdorferi chemistry, DNA Packaging, DNA, Bacterial chemistry, Histones chemistry, Molecular Dynamics Simulation
- Abstract
DNA compaction is essential to ensure the packaging of the genetic material in living cells and also plays a key role in the epigenetic regulation of gene expression. In both humans and bacteria, DNA packaging is achieved by specific well-conserved proteins. Here, by means of all-atom molecular dynamics simulations, including the determination of relevant free-energy profiles, we rationalize the molecular bases for this remarkable process in bacteria, illustrating the crucial role played by positively charged amino acids of a small histone-like protein. We also present compelling evidence that this histone-like protein alone can induce strong bending of a DNA duplex around its core domain, a process that requires overcoming a major free-energy barrier.
- Published
- 2019
- Full Text
- View/download PDF
35. Cooperative Effects of Cytosine Methylation on DNA Structure and Dynamics.
- Author
-
Hognon C, Besancenot V, Gruez A, Grandemange S, and Monari A
- Subjects
- CpG Islands, Molecular Dynamics Simulation, Nucleic Acid Conformation, Cytosine chemistry, DNA chemistry, DNA Methylation
- Abstract
The behavior of the structural parameters of DNA considering different levels of methylation in CpG islands is studied by means of full-atom molecular dynamics simulations and electronic circular dichroism, both in an artificial model system and in a gene promoter sequence. It is demonstrated that methylation although intrinsically brings quite local perturbations may, if its level is high enough, induce cooperative effects that strongly modify the DNA backbone torsional parameters altering the helicity as compared to the nonmethylated case. Because methylation of the CpG island is correlated with the regulation of gene expression, understanding the structural modifications induced in DNA is crucial to characterize all the fine equilibria into play in epigenetics phenomena.
- Published
- 2019
- Full Text
- View/download PDF
36. The three Endonuclease III variants of Deinococcus radiodurans possess distinct and complementary DNA repair activities.
- Author
-
Sarre A, Stelter M, Rollo F, De Bonis S, Seck A, Hognon C, Ravanat JL, Monari A, Dehez F, Moe E, and Timmins J
- Subjects
- Biocatalysis, DNA, Complementary metabolism, Deoxyribonuclease (Pyrimidine Dimer) chemistry, Humans, Molecular Dynamics Simulation, Protein Conformation, Pyrimidines metabolism, Substrate Specificity, DNA Repair, DNA, Complementary genetics, Deinococcus enzymology, Deinococcus genetics, Deoxyribonuclease (Pyrimidine Dimer) genetics, Deoxyribonuclease (Pyrimidine Dimer) metabolism, Mutation
- Abstract
Endonuclease III (EndoIII) is a bifunctional DNA glycosylase that removes oxidized pyrimidines from DNA. The genome of Deinococcus radiodurans encodes for an unusually high number of DNA glycosylases, including three EndoIII enzymes (drEndoIII1-3). Here, we compare the properties of these enzymes to those of their well-studied homologues from E. coli and human. Our biochemical and mutational data, reinforced by MD simulations of EndoIII-DNA complexes, reveal that drEndoIII2 exhibits a broad substrate specificity and a catalytic efficiency surpassing that of its counterparts. In contrast, drEndoIII1 has much weaker and uncoupled DNA glycosylase and AP-lyase activities, a characteristic feature of eukaryotic DNA glycosylases, and was found to present a relatively robust activity on single-stranded DNA substrates. To our knowledge, this is the first report of such an activity for an EndoIII. In the case of drEndoIII3, no catalytic activity could be detected, but its ability to specifically recognize lesion-containing DNA using a largely rearranged substrate binding pocket suggests that it may play an alternative role in genome maintenance. Overall, these findings reveal that D. radiodurans possesses a unique set of DNA repair enzymes, including three non-redundant EndoIII variants with distinct properties and complementary activities, which together contribute to genome maintenance in this bacterium., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
37. Triplet photosensitization mechanism of thymine by an oxidized nucleobase: from a dimeric model to DNA environment.
- Author
-
Francés-Monerris A, Hognon C, Miranda MA, Lhiaubet-Vallet V, and Monari A
- Subjects
- DNA Damage, Oxidation-Reduction, Photosensitivity Disorders, Pyrimidine Dimers metabolism, DNA chemistry, Thymine chemistry
- Abstract
Nucleic acids are constantly exposed to external agents that can induce chemical and photochemical damage. In spite of the great advances achieved in the last years, some molecular mechanisms of DNA damage are not completely understood yet. A recent experimental report (I. Aparici-Espert et al., ACS Chem. Biol. 2018, 13, 542) proved the ability of 5-formyluracil (ForU), a common oxidatively generated product of thymine, to act as an intrinsic sensitizer of nucleic acids, causing single strand breaks and cyclobutane pyrimidine dimers in plasmid DNA. In the present contribution, we use theoretical methodologies to study the triplet photosensitization mechanism of thymine exerted by ForU in a model dimer and in DNA environment. The photochemical pathways in the former system are described combining the CASPT2 and TD-DFT methods, whereas molecular dynamics simulations and QM/MM calculations are employed for the DNA duplex. It is unambiguously shown that the 1n,π* state localised in ForU mediates the population of the triplet manifold, most likely the 3π,π* state centred in ForU, whereas the 3π,π* state localized in thymine can be populated via triplet-triplet energy transfer given the small energy barrier of <0.23 eV determined for this pathway.
- Published
- 2018
- Full Text
- View/download PDF
38. Comparison of steam gasification reactivity of algal and lignocellulosic biomass: influence of inorganic elements.
- Author
-
Hognon C, Dupont C, Grateau M, and Delrue F
- Subjects
- Chlamydomonas drug effects, Kinetics, Models, Theoretical, Spirulina drug effects, Temperature, Time Factors, Biomass, Chlamydomonas metabolism, Gases chemistry, Inorganic Chemicals pharmacology, Lignin chemistry, Spirulina metabolism, Steam
- Abstract
This study aims at comparing the steam gasification behaviour of two species of algal biomass (Chlamydomonas reinhardtii and Arthrospira platensis) and three species of lignocellulosic biomass (miscanthus, beech and wheat straw). Isothermal experiments were carried out in a thermobalance under chemical regime. Samples had very different contents in inorganic elements, which resulted in different reactivities, with about a factor of 5 between samples. For biomasses with ratio between potassium content and phosphorus and silicon content K/(Si+P) higher than one, the reaction rate was constant during most of the reaction and then slightly increased at high conversion. On the contrary, for biomasses with ratio K/(Si+P) lower than one, the reaction rate decreased along conversion. A simple kinetic model was proposed to predict these behaviours., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.