Developmental expression of 4-repeat-Tau induces neuronal aneuploidy in Drosophila tauopathy models

Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development

Impact of the flame retardant 2,2’4,4’-tetrabromodiphenyl ether (PBDE-47) in THP-1 macrophage-like cell function via small extracellular vesicles

2,2’4,4’-tetrabromodiphenyl ether (PBDE-47) is one of the most widespread environmental brominated flame-retardant congeners which has also been detected in animal and human tissues. Several studies have reported the effects of PBDEs on different health issues, including neurobehavioral and developmental disorders, reproductive health, and alterations of thyroid function. Much less is known about its immunotoxicity. The aim of our study was to investigate the effects that treatment of THP-1 macrophage-like cells with PBDE-47 could have on the content of small extracellular vesicles’ (sEVs) microRNA (miRNA) cargo and their downstream effects on bystander macrophages. To achieve this, we purified sEVs from PBDE-47 treated M(LPS) THP-1 macrophage-like cells (sEVsPBDE+LPS) by means of ultra-centrifugation and characterized their miRNA cargo by microarray analysis detecting the modulation of 18 miRNAs. Furthermore, resting THP-1 derived M(0) macrophage-like cells were cultured with sEVsPBDE+LPS, showing that the treatment reshaped the miRNA profiles of 12 intracellular miRNAs. This dataset was studied in silico, identifying the biological pathways affected by these target genes. This analysis identified 12 pathways all involved in the maturation and polarization of macrophages. Therefore, to evaluate whether sEVsPBDE+LPS can have some immunomodulatory activity, naïve M(0) THP-1 macrophage-like cells cultured with purified sEVsPBDE+LPS were studied for IL-6, TNF-α and TGF-β mRNAs expression and immune stained with the HLA-DR, CD80, CCR7, CD38 and CD209 antigens and analyzed by flow cytometry. This analysis showed that the PBDE-47 treatment does not induce the expression of specific M1 and M2 cytokine markers of differentiation and may have impaired the ability to make immunological synapses and present antigens, down-regulating the expression of HLA-DR and CD209 antigens. Overall, our study supports the model that perturbation of miRNA cargo by PBDE-47 treatment contributes to the rewiring of cellular regulatory pathways capable of inducing perturbation of differentiation markers on naïve resting M(0) THP-1 macrophage-like cells

NURE: An ERC project to study nuclear reactions for neutrinoless double beta decay

Neutrinoless double beta decay (0νββ) is considered the best potential resource to access the absolute neutrino mass scale. Moreover, if observed, it will signal that neutrinos are their own anti-particles (Majorana particles). Presently, this physics case is one of the most important research “beyond Standard Model” and might guide the way towards a Grand Unified Theory of fundamental interactions. Since the 0νββ decay process involves nuclei, its analysis necessarily implies nuclear structure issues. In the NURE project, supported by a Starting Grant of the European Research Council (ERC), nuclear reactions of double charge-exchange (DCE) are used as a tool to extract information on the 0νββ Nuclear Matrix Elements. In DCE reactions and ββ decay indeed the initial and final nuclear states are the same and the transition operators have similar structure. Thus the measurement of the DCE absolute cross-sections can give crucial information on ββ matrix elements. In a wider view, the NUMEN international collaboration plans a major upgrade of the INFN-LNS facilities in the next years in order to increase the experimental production of nuclei of at least two orders of magnitude, thus making feasible a systematic study of all the cases of interest as candidates for 0νββ

The Structure of Social Practices and the Connection between Law and Morality

One of the best-known contributions that Jules Coleman has made to legal theory lies in his idea that the rule of recognition, if conceived of as a shared cooperative activity, should be the gateway through which to incorporate moral constraints on the content of law. This analysis, however, leaves unanswered two important questions. For one thing, we do not know when or even why morality becomes a criterion of legality. And, for another thing, we still do not know what conception of morality it is that we are dealing with. In this article, we will attempt to clarify in greater depth what relations there might be between the social practice of law and its morality. We will thus see how the cooperative nature of social practices imbues law with a moral force, and how this makes it possible to establish a “weak” connection between law and morality. But to see this, we will need to single out some basic features of cooperative social practices, thus setting out a suitable framework for the view just mentioned

Alterations of the Coxiella burnetii replicative vacuole membrane integrity and interplay with the autophagy pathway

Coxiella burnetii, the etiologic agent of Q fever, is a Gram-negative obligate intracellular bacterium. It has been previously described that both the endocytic and autophagic pathways contribute to the Coxiella replicative vacuole (CRV) generation. Galectins are β-galactoside-binding lectins that accumulate in the cytosol before being secreted via a non-conventional secretory pathway. It has been shown that Galectin-3, -8, -9 monitor bacteria vacuolar rupture and endosomal and lysosomal loss of membrane integrity through binding of host glycans exposed in the cytoplasm after membrane damage. Using microinjection of fluorescence-coupled dextrans, a FRET assay, and galectins distribution, we demonstrate that Coxiella infection actually result in transient phagosomal/CRV membrane damage in a Dot/Icm-dependent manner. We also show the association of different adaptor molecules involved in autophagy and of LC3 to the limiting membrane of the CRV. Moreover, we show that upon autophagy inhibition, the proportion of CRVs labeled with galectins and less acidified increases which is associated with bacteria replication impairment. Based on these observations, we propose that autophagy can facilitate resealing of intracellular damaged membranes.Fil: Mansilla Pareja, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Bongiovanni, Antonino. Instituto Pasteur; FranciaFil: Lafont, Frank. Instituto Pasteur; FranciaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

ESCRT ‐mediated lysosome repair precedes lysophagy and promotes cell survival

International audienc

Deep Learning-Based Classification of Pancreatic Adenocarcinoma from Fine Needle Aspiration/Biopsy Microscopic Images

International audienc