Oxidative Stress in Tauopathies: From Cause to Therapy

Oxidative stress (OS) is the result of an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of cells. Due to its high oxygen demand, the human brain is highly susceptible to OS and, thus, it is not a surprise that OS has emerged as an essential component of the pathophysiology of several neurodegenerative diseases, including tauopathies. Tauopathies are a heterogeneous group of age-related neurodegenerative disorders characterized by the deposition of abnormal tau protein in the affected neurons. With the worldwide population aging, the prevalence of tauopathies is increasing, but effective therapies have not yet been developed. Since OS seems to play a key role in tauopathies, it has been proposed that the use of antioxidants might be beneficial for tau-related neurodegenerative diseases. Although antioxidant therapies looked promising in preclinical studies performed in cellular and animal models, the antioxidant clinical trials performed in tauopathy patients have been disappointing. To develop effective antioxidant therapies, the molecular mechanisms underlying OS in tauopathies should be completely understood. Here, we review the link between OS and tauopathies, emphasizing the causes of OS in these diseases and the role of OS in tau pathogenesis. We also summarize the antioxidant therapies proposed as a potential treatment for tauopathies and discuss why they have not been completely translated to clinical trials. This review aims to provide an integrated perspective of the role of OS and antioxidant therapies in tauopathies. In doing so, we hope to enable a more comprehensive understanding of OS in tauopathies that will positively impact future studies.This study has been funded by the “Instituto de Salud Carlos III” (ISCIII) through the projects CP21_00049, CP20_00007 and PI21_00183 and co-funded by the European Union.S

The spin-spin problem in celestial mechanics

We study the dynamics of two homogeneous rigid ellipsoids subject to their mutual gravitational influence. We assume that the spin axis of each ellipsoid coincides with its shortest physical axis and is perpendicular to the orbital plane. Due to such assumptions, the problem is planar and depends on particular parameters of the ellipsoids, most notably, the equatorial oblateness and the flattening with respect to the shortest physical axes. We consider two models for such configuration: while in the full model, there is a coupling between the orbital and rotational motions, in the Keplerian model, the centers of mass of the bodies are constrained to move on coplanar Keplerian ellipses. The Keplerian case, in the approximation that includes the coupling between the spins of the two ellipsoids, is what we call spin–spin problem, that is a generalization of the classical spin–orbit problem. In this paper we continue the investigations of Misquero (Nonlinearity 34:2191–2219, 2021) on the spin–spin problem by comparing it with the spin–orbit problem and also with the full model. Beside detailing the models associated to the spin–orbit and spin–spin problems, we introduce the notions of standard and balanced resonances, which lead us to investigate the existence of periodic and quasi-periodic solutions. We also give a qualitative description of the phase space and provide results on the linear stability of solutions for the spin–orbit and spin–spin problems. We conclude by providing a comparison between the full and the Keplerian models with particular reference to the interaction between the rotational and orbital motions

Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies

Desenvolupament d’un escenari de simulació CFD per a l’estudi de la vulnerabilitat de la interfase urbano- forestal

L’objectiu d’aquest projecte és crear i analitzar un escenari d’Interfase Urbano-Forestal (IUF) per mitjà del programa Pyrosim i així demostrar la utilitat d’aquest en l’estudi d’aquest tipus d’incendis i també pel disseny prestacional en un entorn IUF. Un incendi sempre comporta una gran dificultat al moment de predir la seva evolució degut a que cada escenari és totalment diferent. Al tipus de vegetació, relleu o condicions d’un incendi forestal, a les zones IUF cal afegir la varietat de materials, presència de construccions i altres elements urbans que encara dificulten més aquesta predicció. Aquest projecte consta d’una introducció del que representa una Interfase Urbano-Forestal, la situació a Catalunya i les principals problemàtiques que suposa. En aquesta introducció es tracten els principals punts febles de les construccions en front de les flames i es repassa la normativa vigent a Catalunya. També es fa una introducció al món dels programes que fan servir la Dinàmica de Fluids Computacional (CFD), amb els seus principis de funcionament, característiques i les diferents tècniques que fan servir per solucionar els problemes proposats. Tot seguit, es descriu l’escenari i la situació de l’incendi a Òdena del passat juliol del 2015 i s’explica quins són els elements que inspiren al cas d’estudi, com es fa la construcció de escenari a Pyrosim i la posterior simulació i tractament de les dades obtingudes. Per tal d’enriquir una mica més la investigació i extreure’n noves conclusions, es decideix provar un escenari amb una variació respecte el principal. Aquest consta amb uns barrots de ferro situats entre la finestra i la flama amb l’objectiu de demostrar que la presència d’aquests, alleuja l’efecte de les flames en vers del vidre

Une création sur la route : Dies d’agost de Marc Recha

Dies d’agost (2006) de Marc Recha, film de fiction issu du Master en documentaire de création de l’Université Pompeu Fabra, se présente comme un road-movie laissant une place essentielle à l’exploration du territoire et à la rencontre fortuite des personnages qu’il croise sur la route. Cet article analyse le dispositif formel singulier que met en place le film et l’économie figurative qu’il adopte, fondée sur le surgissement et l’apparition, qui permet à son réalisateur de mener une réflexion sur la mémoire individuelle et collective.Dies d’agost (2006), directed by Marc Recha, a feature film originating from the Masters in creative documentary from Pompeu Fabra University, presents itself like a road movie that leaves an essential place to the exploration of the territory and to the fortuitous encounter of the characters that cross his path. This article analyses the formal singular dispositive that the film puts in place and the figurative economy that it adopts, based on upsurge and apparition, that allows its director to engage in a reflection on the individual and collective memory

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death

Medios masivos y formación de carácter: la problematización de las masas en Adorno-Horkheimer y David Riesman

La problemática de las masas ha sido un tema recurrente en la historia de la teoría sociológica. Podría decirse que de una inicial preocupación por las muchedumbres amenazantes y movilizadas se pasó, iniciado el siglo XX, a la pregunta por los efectos de los medios masivos de comunicación. Es en esa línea que aquí se trabajarán los aportes realizados por David Riesman y dos grandes exponentes de la escuela de Frankfurt: Theodor Adorno y Max Horkheimer. Los autores de ambas perspectivas escriben desde Estados Unidos en un momento de gran desarrollo y expansión de los medios masivos de comunicación, y no solo se limitan a observar sus consecuencias, sino que también buscan dar algunas explicaciones. David Riesman lo realiza a partir de la descripción del nuevo “carácter” de la sociedad estadounidense, mientras que Adorno y Horkheimer, en concordancia con la tradición teórica que los nutre, piensan el proceso desde una perspectiva más estructural y dan cuenta de “industria cultural”. El objetivo de la presente ponencia consiste en analizar los aportes significativos de los mencionados autores a la problemática de las masas en relación con los medios de comunicación masiva. Para trabajar con la perspectiva de los teóricos de Frankfurt se utilizará La industria cultural. Ilustración como engaño de masas (1998), y para la de David Riesman La muchedumbre solitaria. Un estudio sobre la transformación del carácter norteamericano (1964).Mesa 4: El Jardín de senderos que se bifurcan. Teoría Social, Teoría sociológica, Sociología: la pregunta por lo social y sus múltiples respuestas.Facultad de Humanidades y Ciencias de la Educación (FAHCE

Nádorový metabolismus a jeho role v citlivosti leukemických buněk k L-asparagináze

Cancer metabolism and its role in the sensitivity of leukemic cells to L- asparaginase ABSTRACT No ultimate treatment strategy exists for relapsed or non-responsive (15-20%) children with acute lymphoblastic leukemia (ALL). In this study, we aimed to elucidate the impact of metabolic rewiring in leukemic cells on poor therapy response and the emergence of resistance. This dissertation focuses on l-asparaginase (ASNase), a crucial chemotherapeutic agent and its effect on leukemia, using models of leukemic cell lines and primary cells of ALL patients. Cell metabolism was assessed by measuring metabolic pathways and nutrient influx using a Seahorse analyzer and stable isotope tracing. Main findings of the study demonstrated that the ASNase- therapy response was mitigated by the activity of the mechanistic target of rapamycin (mTOR)- regulated biosynthetic pathways. This phenomenon was induced by the bone marrow environment, which enabled the activation of the resistant mechanism in leukemic cells. We next found a correlation between the following metabolic features and lower sensitivity to ASNase: low ATP- linked respiration, high mitochondrial membrane potential and high glycolytic flux before therapy. The latter was shown to have prognostic implications. Moreover, high glycolytic flux was detected in T-ALL...Klinika dětské hematologie a onkologieDepartment of Paediatric Haematology and Oncology2. lékařská fakultaSecond Faculty of Medicin

Incomplete concerted evolution and reproductive isolation at the rDNA locus uncovers nine cryptic species within Anopheles longirostris from Papua New Guinea

Abstract. Background. Nuclear ribosomal DNA (rDNA) genes and transcribed spacers are highly utilized as taxonomic markers in metazoans despite the lack of a cohesive understanding of their evolution. Here we follow the evolution of the rDNA second internal transcribed spacer (ITS2) and the mitochondrial DNA cytochrome oxidase I subunit in the malaria mosquito Anopheles longirostris from Papua New Guinea (PNG). This morphospecies inhabits a variety of ecological environments indicating that it may comprise a complex of morphologically indistinguishable species. Using collections from over 70 sites in PNG, the mtDNA was assessed via direct DNA sequencing while the ITS2 was assessed at three levels - crude sequence variation through restriction digest, intragenomic copy variant organisation (homogenisation) through heteroduplex analysis and DNA sequencing via cloning. Results. Genetic evaluation of over 300 individuals revealed that A. longirostris comprises eight ITS2 PCR-RFLP genotypes and nine ITS2 heteroduplex genotypes showing distinct copy variant organization profiles after PCR amplification. Seven of these nine genotypes were found to be sympatric with other genotypes. Phylogenetic analysis of cloned ITS2 PCR products and mtDNA COI confirmed all nine clades with evidence of reproductive isolation at the rDNA locus. Compensatory base changes in the ITS2 secondary structure or in pseudoknots were absent when closely related species were assessed. Individuals from each ITS2 genotype showed the same copy variant heteroduplex profile suggesting that the rDNA array is fixed within each genotype. Conclusion. The centromere-proximal position of the rDNA array in Anopheles mosquitoes has probably reduced interchromosomal recombination leaving intrachromosomal events responsible for the observed pattern of concerted evolution we see in these mosquitoes. The stability of these intragenomic ITS2 copy variants within individuals and interbreeding populations suggests that rDNA is moving as a single evolutionary unit through natural populations to fixation and has provided a complementary diagnostic tool to the restriction digest for studying genetic discontinuities and species boundaries. In this, the utility of the ITS2 as a universal taxonomic marker is probably contingent on several factors pertaining to spacer dimensions and the genomic location of the rDNA array with respect to recombination and proximity to regions potentially under selection