1,720,979 research outputs found
Structural Mechanism of ω-Currents in a Mutated Kv7.2 Voltage Sensor Domain from Molecular Dynamics Simulations
No full textActivation of voltage-gated ion channels is regulated by conformational changes of the voltage sensor domains (VSDs), four water- and ion-impermeable modules peripheral to the central, permeable pore domain. Anomalous currents, defined as ω-currents, have been recorded in response to mutations of residues on the VSD S4 helix and associated with ion fluxes through the VSDs. In humans, gene defects in the potassium channel Kv7.2 result in a broad range of epileptic disorders, from benign neonatal seizures to severe epileptic encephalopathies. Experimental evidence suggests that the R207Q mutation in S4, associated with peripheral nerve hyperexcitability, induces ω-currents at depolarized potentials, but the fine structural details are still elusive. In this work, we use atom-detailed molecular dynamics simulations and a refined model structure of the Kv7.2 VSD in the active conformation in a membrane/water environment to study the effect of R207Q and four additional mutations of proven clinical importance. Our results demonstrate that the R207Q mutant shows the most pronounced increase of hydration in the internal VSD cavity, a feature favoring the occurrence of ω-currents. Free energy and kinetics calculations of sodium permeation through the native and mutated VSD indicate as more favorable the formation of a cationic current in the latter. Overall, our simulations establish a mechanistic linkage between genetic variations and their physiological outcome, by providing a computational description that includes both thermodynamic and kinetic features of ion permeation associated with ω-currents
Molecular Dynamics Simulations of Ion Selectivity in a Claudin-15 Paracellular Channel
No full textClaudins are tissue-specific transmembrane proteins able to form junctions between two cells and regulate the flow of physiological solutes parallel to the cell walls, that is, the paracellular transport. Claudin-15 is highly expressed in the intestine where it forms efficient Na + channels and Cl - barriers. However, the molecular details of these biological complexes are still unclear. Here, the permeation process of Na + , K + , and Cl - ions inside a refined structural model of a claudin-15 paracellular channel is investigated using all-atom molecular dynamics simulations in a double-bilayer and explicit solvent. One-dimensional potential of mean force (PMF) profiles, calculated using umbrella sampling (US) simulations, show that the channel allows the passage of the two physiological cations while excluding chloride. These features are generated by the action of several acidic residues, in particular the ring of D55 residues which is located at the narrowest region of the pore, in correspondence with the energy minimum for cations and the peak for chloride. We also used the Voronoi-tessellated milestoning method to obtain additional PMF profiles and the permeation timescale of the three ions. The milestoning PMFs agree well with those obtained by US, and the rate calculation reveals that the passage of chloride is almost 30 times slower than that of sodium. Our results are consistent with the known ability of claudin-15 to regulate tight junction selectivity and with the experimentally determined role of the acidic residues. This further validates our structural model and provides insights into the atomistic details of ion transport in paracellular channels that could be shared by other claudin-based architectures
I vantaggi della rapidità d'azione di escitalopram: benessere soggettivo e funzionamento globale. Un caso clinico.
No full textInteractions Between 2D Graphene-Based Materials and the Nervous Tissue
No full textIn recent years, the scientific community has witnessed an exponential increase in the use of graphene for biomedical applications. For what concerns neuroscience, the interest raised by this material is given by the fact that graphene nanosheets can be used as carriers for biomolecule delivery to the central nervous system. In this case, an important aspect is the evaluation of their toxicity, which strongly depends on flake composition, chemical functionalization and dimensions. Furthermore, graphene can be exploited as a substrate for tissue engineering. In this application, conductivity is probably the most relevant amongst the various properties of the different graphene materials, as it may allow to instruct and interrogate neural networks, as well as to drive neural growth and differentiation.
This chapter discusses the engineering of graphene nanosheets able to cross the blood-brain-barrier to reach neural cells, and to achieve on-demand delivery of specific drugs. Moreover, the use of graphene to develop three-dimensional scaffolds, or as a component of hybrid composites/multi-layer organic electronics devices, is described. The need of an accurate theoretical modeling of the interface between graphene and biological material is also addressed, by describing the interaction of graphene with proteins and cell membranes at the nanoscale
Interactions Between 2D Graphene-Based Materials and the Nervous Tissue
No full textIn recent years, the scientific community has witnessed an exponential increase in the use of graphene for biomedical applications. For what concerns neuroscience, the interest raised by this material is given by the fact that graphene nanosheets can be used as carriers for biomolecule delivery to the central nervous system. In this case, an important aspect is the evaluation of their toxicity, which strongly depends on flake composition, chemical functionalization and dimensions. Furthermore, graphene can be exploited as a substrate for tissue engineering. In this application, conductivity is probably the most relevant amongst the various properties of the different graphene materials, as it may allow to instruct and interrogate neural networks, as well as to drive neural growth and differentiation.
This chapter discusses the engineering of graphene nanosheets able to cross the blood-brain-barrier to reach neural cells, and to achieve on-demand delivery of specific drugs. Moreover, the use of graphene to develop three-dimensional scaffolds, or as a component of hybrid composites/multi-layer organic electronics devices, is described. The need of an accurate theoretical modeling of the interface between graphene and biological material is also addressed, by describing the interaction of graphene with proteins and cell membranes at the nanoscale
A refined model of claudin-15 tight junction paracellular architecture by molecular dynamics simulations.
Full text linkTight-junctions between epithelial cells of biological barriers are specialized molecular structures that regulate the flux of solutes across the barrier, parallel to cell walls. The tight-junction backbone is made of strands of transmembrane proteins from the claudin family, but the molecular mechanism of its function is still not completely understood. Recently, the crystal structure of a mammalian claudin-15 was reported, displaying for the first time the detailed features of transmembrane and extracellular domains. Successively, a structural model of claudin-15-based paracellular channels has been proposed, suggesting a putative assembly that illustrates how claudins associate in the same cell (via cis interactions) and across adjacent cells (via trans interactions). Although very promising, the model offers only a static conformation, with residues missing in the most important extracellular regions and potential steric clashes. Here we present detailed atomic models of paracellular single and double pore architectures, obtained from the putative assembly and refined via structural modeling and all-atom molecular dynamics simulations in double membrane bilayer and water environment. Our results show an overall stable configuration of the complex with a fluctuating pore size. Extracellular residue loops in trans interaction are able to form stable contacts and regulate the size of the pore, which displays a stationary radius of 2.5-3.0 Å at the narrowest region. The side-by-side interactions of the cis configuration are preserved via stable hydrogen bonds, already predicted by cysteine crosslinking experiments. Overall, this work introduces an improved version of the claudin-15-based paracellular channel model that strengthens its validity and that can be used in further computational studies to understand the structural features of tight-junctions regulation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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