39 research outputs found
Frataxin Deficit Leads to Reduced Dynamics of Growth Cones in Dorsal Root Ganglia Neurons of Friedreich’s Ataxia YG8sR Model: A Multilinear Algebra Approach
Data Availability Statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.Supplementary Material:
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnmol.2022.912780/full#supplementary-material
Supplementary Video 1 | Phase-contrast imaging of living growth cone two months old isolated from the first Y47R mouse.
Supplementary Video 2 | Phase-contrast imaging of living growth cone two months old isolated from the second Y47R mouse.
Supplementary Video 3 | Phase-contrast imaging of living growth cone two months old isolated from the third Y47R mouse.
Supplementary Video 4 | Phase-contrast imaging of living growth cone two months old isolated from the first YG8sR mouse.
Supplementary Video 5 | Phase-contrast imaging of living growth cone two months old isolated from the second YG8sR mouse.
Supplementary Video 6 | Phase-contrast imaging of living growth cone two months old isolated from the third YG8sR mouse.© 2022 Muñoz-Lasso, Mollá, Sáenz-Gamboa, Insuasty, de la Iglesia-Vaya, Pook, Pallardó, Palau and Gonzalez-Cabo. Computational techniques for analyzing biological images offer a great potential to enhance our knowledge of the biological processes underlying disorders of the nervous system. Friedreich’s Ataxia (FRDA) is a rare progressive neurodegenerative inherited disorder caused by the low expression of frataxin, which is a small mitochondrial protein. In FRDA cells, the lack of frataxin promotes primarily mitochondrial dysfunction, an alteration of calcium (Ca2+) homeostasis and the destabilization of the actin cytoskeleton in the neurites and growth cones of sensory neurons. In this paper, a computational multilinear algebra approach was used to analyze the dynamics of the growth cone and its function in control and FRDA neurons. Computational approach, which includes principal component analysis and a multilinear algebra method, is used to quantify the dynamics of the growth cone (GC) morphology of sensory neurons from the dorsal root ganglia (DRG) of the YG8sR humanized murine model for FRDA. It was confirmed that the dynamics and patterns of turning were aberrant in the FRDA growth cones. In addition, our data suggest that other cellular processes dependent on functional GCs such as axonal regeneration might also be affected. Semiautomated computational approaches are presented to quantify differences in GC behaviors in neurodegenerative disease. In summary, the deficiency of frataxin has an adverse effect on the formation and, most importantly, the growth cones’ function in adult DRG neurons. As a result, frataxin deficient DRG neurons might lose the intrinsic capability to grow and regenerate axons properly due to the dysfunctional GCs they build.Ministerio de Economía y Competitividad de España (SAF2015-66625-R); Agencia Estatal de Investigación (PID2020-115190RB-I00) within the framework of the National R + D + I Plan and co-funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds; Generalitat Valenciana (ACOMP/2014/058 and PROMETEO/2018/135); CIBERER is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases. EMBO Short Fellowship (ASTF 562-2015)
Assessment of drug entrapment within liposomes using photophysical probes
The photophysical and photochemical behavior of (R)-cinacalcet (CIN) and (S)-naproxen (NPX) entrapped within liposomes has been studied. For this purpose, liposome encapsulated drugs have been prepared through thin layer evaporation and characterized by transmission electron microscopy, cryoscopy scanning electron microscopy and dynamic light scattering. Steady state and time-resolved fluorescence experiments showed similar spectra, emission quantum yields, singlet energies and lifetimes for the selected drugs, outside and inside liposomes. By contrast, laser flash photolysis experiments revealed an important enhancement of the triplet lifetimes for entrapped drugs inside liposomes, indicating the spatial confinement existing in the microenvironment prevailing in these biomimetic entities. Thus, this photophysical property shows potential as a non-invasive, direct and valuable tool to monitor encapsulation of photoactive drugs and to probe the intraliposome environment. In addition, it provides a new quantitative indicator of the capability of liposomes to act as drug carriers.We gratefully acknowledge financial support from the Carlos III Institute of Health (Servet Contract CP11/00154 for I.A. and Red RETICS de investigacion de Reacciones Adversas a Alergenos y Farmacos, RIRAAF) and from Ministero dell'Istruzione, dell'Universita e della Ricerca (M.I.U.R. Italy).Oliverio, F.; Nuin Plá, NE.; Andreu Ros, MI.; Ragno, G.; Miranda Alonso, MÁ. (2014). Assessment of drug entrapment within liposomes using photophysical probes. European Journal of Pharmaceutics and Biopharmaceutics. 88(2):551-555. https://doi.org/10.1016/j.ejpb.2014.06.013S55155588
Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems
[EN] The properties of singlet and triplet excited states are strongly medium-dependent.
Hence, these species constitute valuable tools as reporters to probe compartmentalised
microenvironments, including drug@protein supramolecular systems. In the present
review, the attention is focused on the photophysical properties of the probe drugs
(rather than those of the protein chromophores) using transport proteins (serum
albumins and 1-acid glycoproteins) as hosts. Specifically, fluorescence measurements
allow investigating the structural and dynamic properties of biomolecules or their
complexes. Thus, the emission quantum yields and the decay kinetics of the drug singlet
excited states provide key information to determine important parameters such as the
stoichiometry of the complex, the binding constant, the relative degrees of occupancy of
the different compartments, etc. Application of the FRET concept allows determining
donor-acceptor interchromophoric distances. In addition, anisotropy measurements can
be related to the orientation of the drug within the binding sites, where the degrees of
freedom for conformational relaxation are restricted. Transient absorption spectroscopy
is also a potentially powerful tool to investigate the binding of drugs to proteins, where
formation of encapsulated triplet excited states is favoured over other possible processes
leading to ionic species (i. e. radical ions), and their photophysical properties are
markedly sensitive to the microenvironment experienced within the protein binding
sites. Even under aerobic conditions, the triplet lifetimes of protein-complexed drugs are
remarkably long, which provides a broad dynamic range for identification of distinct
triplet populations or for chiral discrimination. Specific applications of the laser flash
photolysis technique include the determination of drug distribution among the bulk
solution and the protein binding sites, competition of two types of proteins to bind a
3
drug, occurrence of drug-drug interactions within protein binding sites, enzymatic-like
activity of the protein or determination of enantiomeric compositions.
The use of proteins as supramolecular hosts modifies the photoreactivity of
encapsulated substrates by providing protection against oxygen or other external
reagents, by imposing conformational restrictions in the binding pockets, or by
influencing the stereochemical outcome. In this review, a selected group of examples is
presented including decarboxylation, dehalogenation, nucleophilic addition,
dimerisation, oxidation, Norrish type II reaction, photo-Fries rearrangement and 6
electrocyclisationFinancial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, RyC-2007-00476), from the EU (PCIG12-GA-2012-334257), from the Universitat Politènica de València (SP20120757) and from the Consellería de Educació, Cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.Vayá Pérez, I.; Lhiaubet-Vallet, VL.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems. Chemical Society Reviews. 43:4102-4122. https://doi.org/10.1039/C3CS60413FS410241224
Phase-wise enhanced voltage support from electric vehicles in a Danish low-voltage distribution grid
High deployment of electric vehicles (EVs) imposes great challenges for the distribution grids, especially in unbalanced systems with notable voltage variations which detrimentally affect security of supply. On the other hand, with development of Vehicle-to-Grid technology, EVs may be able to provide numerous services for grid support, e.g., voltage control. Implemented electronic equipment will allow them to exchange reactive power for autonomous voltage support without communicating with the distribution system operator or influencing the available active power for primary transportation function. This paper proposes a voltage dependent EV reactive power control and quantifies its impact on a real Danish low-voltage grid. The observed network is a heavily unbalanced three-phase four-wire grid modeled in Matlab SimPowerSystems based on real hourly measurement data. Simulations are performed in order to evaluate phase-to-neutral voltage support benefits as well as to address neutral-to-ground values, active power losses and the unbalances at the same time. The analysis shows that reactive power supportboth raises minimum phase-to-neutral voltage magnitudes and improves voltage dispersion while the energy losses are not notably increased. Further on, since the control is voltage dependent, provided reactive power is unequal among the phases leading to greater support on heavily loaded phases and decreased unbalances caused by residential consumption. Hence, implementation of such a phase-wise enhanced voltage support could defer the need for grid reinforcement in case of large EV penetration rates, especially in highly unbalanced networks
On the price of being selfish in large populations of plug-in electric vehicles
We consider the problem of optimally scheduling the flexible electricity demand of a fleet of plug-in electric vehicles (PEVs). More specifically, we analyze the solutions of the following charging optimization problems: the welfare-optimal problem, where the overall system cost is minimized; the fleet-optimal problem, where the charging cost of the fleet as a whole is minimized by a central agent, that is the PEV aggregator; the selfish-optimal problem, where the noncooperative PEVs aim at minimizing their individual charging cost. For a homogenous PEV fleet and a simplified problem setup, we show that the solutions of the three different approaches correspond to different valley-filling results. A main insight is that, as the population of PEVs grows, the selfish-optimal solution converges to the welfare-optimal solution. On the other hand, we show that the centralized fleet-optimal solution of the PEV aggregation can be recovered via decentralized selfish-optimal solutions with respect to an appropriate price signal as the population size grows. Finally, we demonstrate our technical results on a realistic PEV fleet case study
Active Distribution Grids Offering Ancillary Services in Islanded and Grid-Connected Mode
Future Active Distribution Grids (ADGs) will incorporate a plethora of Distributed Generators (DGs) and other Distributed Energy Resources (DERs), allowing them to provide ancillary services in grid-connected mode and, if necessary, operate in an islanded mode to increase reliability and resilience. In this paper, we investigate the ability of an ADG to provide Frequency Control (FC) in grid-connected mode and ensure reliable islanded operation for a pre-specified time period. First, we formulate the operation of the grid participating in European-type FC markets as a centralized multi-period optimal power flow problem with a rolling horizon of 24 hours. Then, we include constraints to the grid-connected operational problem to guarantee the ability to switch to islanded operation at every time instant. Finally, we explore the technical and economic feasibility of offering these services on a balanced low-voltage distribution network. The results show that the proposed scheme is able to offer and respond to different FC products, while ensuring that there is adequate energy capacity at every time step to satisfy critical load in the islanded mode
SPONTANEOUS RETROPERITONEAL HEMATOMAS IN ELDERLY PATIENTS TREATED WITH LOW-MOLECULAR-WEIGHT HEPARINS
Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice
Friedreich’s ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration