1,720,983 research outputs found
Explainable Machine Learning and Deep Learning Models for Predicting TAS2R-Bitter Molecule Interactions
Full text linkThis work aims to develop explainable models to predict the interactions between bitter molecules and TAS2Rs via traditional machine-learning and deep-learning methods starting from experimentally validated data. Bitterness is one of the five basic taste modalities that can be perceived by humans and other mammals. It is mediated by a family of G protein-coupled receptors (GPCRs), namely taste receptor type 2 (TAS2R) or bitter taste receptors. Furthermore, TAS2Rs participate in numerous functions beyond the gustatory system and have implications for various diseases due to their expression in various extra-oral tissues. For this reason, predicting the specific ligand-TAS2Rs interactions can be useful not only in the field of taste perception but also in the broader context of drug design. Considering that in-vitro screening of potential TAS2R ligands is expensive and time-consuming, machine learning (ML) and deep learning (DL) emerged as powerful tools to assist in the selection of ligands and targets for experimental studies and enhance our understanding of bitter receptor roles. In this context, ML and DL models developed in this work are both characterized by high performance and easy applicability. Furthermore, they can be synergistically integrated to enhance model explainability and facilitate the interpretation of results. Hence, the presented models promote a comprehensive understanding of the molecular characteristics of bitter compounds and the design of novel bitterants tailored to target specific TAS2Rs of interest
When stiffness matters: mechanosensing in heart development and disease
Full text linkDuring embryonic morphogenesis, the heart undergoes a complex series of cellular phenotypic maturations (e.g. transition of myocytes from proliferative to quiescent or maturation of the contractile apparatus), and this involves stiffening of the extracellular matrix acting in concert with morphogenetic signals. The maladaptive remodelling of the myocardium, one of the processes involved in determination of heart failure, also involve mechanical cues, with a progressive stiffening of the tissue that produces cellular mechanical damage, inflammation and ultimately myocardial fibrosis. The assessment of the biomechanical dependence of the molecular machinery (in myocardial and non-myocardial cells) is therefore essential to contextualize the maturation of the cardiac tissue at early stages and understand its pathologic evolution in ageing. Since systems to perform multiscale modelling of cellular and tissue mechanics have been developed, it appears particularly novel to design integrated mechano-molecular models of heart development and disease to be tested in ex vivo reconstituted cells/tissue-mimicking conditions. In the present contribution, we will discuss the latest implication of mechanosensing in heart development and pathology, describe the most recent models of cell/tissue mechanics and delineate novel strategies to target the consequences of heart failure with personalized approaches based on tissue engineering and induced pluripotent stem cells (iPSCs) technologies
Molecular Dynamics And Binding Mechanisms Of Volatile Anesthetics Targeting Human Tubulin
Full text linkAnesthesia, despite being the cornerstone of modern surgery, is to this date a biological puzzle. While scientific efforts still have not managed to frame its pharmacology in an exhaustive theoretical framework, microtubules inside neurons are thought to be essential for memory formation and consciousness. The potential ability of volatile anesthetics to alter or dampen the vibrational properties of microtubules justifies the spatiotemporal characterization of the interaction between such molecules and the tubulin dimer through the use of computational molecular modelling
Intelligenza Artificiale In Sanità: Proposta Di Una Nuova Metodologia Medico-legale In Materia Di Responsabilita Medica
No full textL'introduzione di una tecnologia medica innovativa (IMT) sul mercato segue un percorso evolutivo noto come hype cycle, caratterizzato da fasi di entusiasmo iniziale, delusioni, consolidamento e adozione routinaria. Per quanto riguarda l'applicazione di sistemi di Intelligenza Artificiale (IA) in campo medico ci troviamo attualmente nella fase di implementazione, caratterizzata da un forte entusiasmo, ma anche dall'emergere di rischi etici, operativi e per la salute. La rapida evoluzione degli algoritmi spesso supera la capacità di adattamento delle normative, evidenziando la necessità di regolamentazioni specifiche per la gestione di tali rischi. La medicina legale, abituata ad integrare due approcci distinti ma complementari - quello proattivo, volto a prevenire errori identificando e classificando i rischi, e quello reattivo, mirato alla ricostruzione degli eventi avversi per determinarne le cause - può rivelarsi di grande supporto ai ricercatori e al legislatore nell'integrazione sicura ed etica dell'IA. Il presente studio si propone di applicare la metodologia medico-legale utilizzata in ambito di responsabilità professionale medica, basata sulle Linee Guida dell'European Council of Legal Medicine (ECLM), per valutare casi di responsabilità professionali legate all'impiego dell'IA in medicina. I risultati sottolineano la necessità di un aggiornamento metodologico che permetta una valutazione rigorosa e condivisa del nesso causale in contesti di contenzioso medico-legale legati alle specificità dei sistemi di lA
Architecture-encoded mechanics and communication in microtubules: a multiscale computational study
Full text linkThe mechanical architecture of microtubules (MTs) is crucial for modulating their functions within cells; however, the effect of varying the number of protofilaments (PFs) on the propagation of mechanical signals remains largely unexplored. Nevertheless, MTs assembled in vitro exhibit diverse PF numbers depending on the specific tubulin composition, stabilizing agents and cellular context, suggesting a regulated architectural adaptation. Here, we performed a multiscale computational study integrating molecular dynamics, dynamical network analysis and elastic network modelling to investigate the influence of the MT architecture on structural communication and mechanics. Our results highlight that an increase in PF number alters tubulin–tubulin contact patterns, reshapes lateral surface hydrophobicity and modulates the dynamics of a specific unstructured region known as the M-loop. Remarkably, we identified a correlation between the PF number, vibrational path length and bending stiffness, revealing that MTs with larger architectures propagate mechanical information less efficiently, but offer increased structural support. These findings suggest that MT architecture may serve as a design parameter influencing the propagation of mechanical signals across scales. Moreover, they may contribute to the emerging field of neuromechanobiology, where MTs are considered potential integrators of mechanical and informational processes within neurons
Alteration of Consciousness by Anaesthetics: A Multiscale Modulation from the Molecular to the Systems Level
Full text linkGeneral anaesthesia has been used in medical practice since the mid-nineteenth century, but its pharmacological mechanism of action is still not entirely clear. In a top-down approach, investigations probe smaller and smaller scales to shed light on how anaesthetics disrupt or alter neural activity, ultimately resulting in loss of consciousness. In the past few decades, advances in neuroscience and molecular biology allowed for investigations on the brain structure and function from the behavioural level to the systems, cellular, and molecular level. This multiscale approach implicates the molecular domain as a fundamental link between general anaesthesia and consciousness, which also sheds light on how anaesthetic agents affect the pathogenesis of postoperative behavioural changes. This review discusses the current state of knowledge about the relationship between consciousness and general anaesthesia determined using pharmacokinetics, molecular biology, and advanced medical imaging, including EEG, fMRI, PET, MEG. It is hoped that the mechanisms of action of anaesthetic gases may help solve the mystery of consciousness. Conversely, understanding the cellular and molecular mechanisms of consciousness could lead to the design and development of new anaesthetic agents and technologies to controllably turn off and on consciousness. It could also generate new concepts in neurocognitive pathophysiology disorders
Mechanical communication within the microtubule through network‐based analysis of tubulin dynamics
Full text linkConformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies
Full text linkDespite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile-onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterizing their stability. This study's insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network
Multiscale Computational Analysis of the Effect of Taxol on Microtubule Mechanics
No full textMicrotubules (MTs) are widely recognized as targets for cancer therapies. They are directly related to unique mechanical properties, closely dependent on MT architecture and tubulin molecular features. Taxol is known to affect tubulin interactions resulting in the stabilization of the MT lattice, and thus the hierarchical organization stability, mechanics, and function. A deeper understanding of the molecular mechanisms through which taxol modulates intertubulin interactions in the MT lattice, and consequently, its stability and mechanical response is crucial to characterize how MT properties are regulated by environmental factors, such as interacting ligands. In this study, a computational analysis of the effect of taxol on the MT was performed at different scales, combining molecular dynamics simulation, dynamical network analysis, and elastic network modeling. The results show that the taxol-induced conformational differences at the M-loop region increase the stability of the lateral interactions and the amount of surface in contact between laterally coupled tubulins. Moreover, the conformational rearrangements in the taxane binding site result in a different structural communication pattern. Finally, the different conformation of the tubulin heterodimers and the stabilized lateral interactions resulted in a tendency toward higher deformation of the vibrating MT in the presence of taxol. Overall, this work provides additional insights into taxol-induced stabilization and relates the conformational changes at the tubulin level to the MT mechanics. Besides providing useful insights into taxol effect on MT mechanics, a methodological framework that could be used to characterize the effects of other MT stabilizing agents is presented
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