mTOR-related cell-clearing systems in epileptic seizures, an update

Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABAA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin–proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activit

Simultaneous Embeddings with Few Bends and Crossings

A simultaneous embedding with fixed edges (SEFE) of two planar graphs $R$ and $B$ is a pair of plane drawings of $R$ and $B$ that coincide when restricted to the common vertices and edges of $R$ and $B$. We show that whenever $R$ and $B$ admit a SEFE, they also admit a SEFE in which every edge is a polygonal curve with few bends and every pair of edges has few crossings. Specifically: (1) if $R$ and $B$ are trees then one bend per edge and four crossings per edge pair suffice (and one bend per edge is sometimes necessary), (2) if $R$ is a planar graph and $B$ is a tree then six bends per edge and eight crossings per edge pair suffice, and (3) if $R$ and $B$ are planar graphs then six bends per edge and sixteen crossings per edge pair suffice. Our results improve on a paper by Grilli et al. (GD'14), which proves that nine bends per edge suffice, and on a paper by Chan et al. (GD'14), which proves that twenty-four crossings per edge pair suffice.Comment: Full version of the paper "Simultaneous Embeddings with Few Bends and Crossings" accepted at GD '1

A novel signalling mechanism regulating telomere length in cardiomyocytes

Clinical management and treatment of human diseases are continuously improving, with a progressive elongation of life expectancy in Western countries. As a consequence of the elevation of the average age of the population, the incidence of ageing-related diseases will progressively in- crease in the next years. Among ageing-related diseases, cardiovascular diseases still represent the first of cause of death in the Western world

On a Tree and a Path with no Geometric Simultaneous Embedding

Two graphs $G_1=(V,E_1)$ and $G_2=(V,E_2)$ admit a geometric simultaneous embedding if there exists a set of points P and a bijection M: P -> V that induce planar straight-line embeddings both for $G_1$ and for $G_2$. While it is known that two caterpillars always admit a geometric simultaneous embedding and that two trees not always admit one, the question about a tree and a path is still open and is often regarded as the most prominent open problem in this area. We answer this question in the negative by providing a counterexample. Additionally, since the counterexample uses disjoint edge sets for the two graphs, we also negatively answer another open question, that is, whether it is possible to simultaneously embed two edge-disjoint trees. As a final result, we study the same problem when some constraints on the tree are imposed. Namely, we show that a tree of depth 2 and a path always admit a geometric simultaneous embedding. In fact, such a strong constraint is not so far from closing the gap with the instances not admitting any solution, as the tree used in our counterexample has depth 4.Comment: 42 pages, 33 figure

Mitochondrial Genome Diversity in Collembola: Phylogeny, Dating and Gene Order

Collembola (springtails) are an early diverging class of apterygotes, and mark the first substantial radiation of hexapods on land. Despite extensive work, the relationships between major collembolan lineages are still debated and, apart from the Early Devonian fossil Rhyniella praecursor, which demonstrates their antiquity, the time frame of springtail evolution is unknown. In this study, we sequence two new mitochondrial genomes and reanalyze all known Collembola mt-genomes, including selected metagenomic data, to produce an improved phylogenetic hypothesis for the group, develop a tentative time frame for their differentiation, and provide a comprehensive overview of gene order diversity. Our analyses support most taxonomically recognized entities. We find support for an Entomobryomorpha + Symphypleona clade, while the position of Neelipleona could not be assessed with confidence. A Silurian time frame for their basal diversification is recovered, with an indication that divergence times may be fairly old overall. The distribution of mitochondrial gene order indicates the pancrustacean arrangement as plesiomorphic and dominant in the group, with the exception of the family Onychiuridae. We distinguished multiple instances of different arrangements in individual genomes or small clusters. We further discuss the opportunities and drawbacks associated with the inclusion of metagenomic data in a classic study on mitochondrial genome diversity

MTOR modulates intercellular signals for enlargement and infiltration in glioblastoma multiforme

Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies

Paclitaxel in endovascular devices. Identikit of a “serial killer”?

Recent developments in the management of peripheral artery disease have been momentous, and a key advance has been the introduction of drug-coated balloons, which capitalise on the mechanical effects of angioplasty balloons, and on the pharmacologic effects of anti-restenotic drugs [1,2]. Indeed, single reports from randomized trials and pooled estimates from meta-analyses have clearly showed that paclitaxel-coated balloons reduce the risk of restenosis and repeat revascularization, while improving patency, limb salvage, and freedom from claudication

Host chemical footprints induce host sex discrimination ability in egg parasitoids

Trissolcus egg parasitoids, when perceiving the chemical footprints left on a substrate by pentatomid host bugs, adopt a motivated searching behaviour characterized by longer searching time on patches were signals are present. Once in contact with host chemical footprints, Trissolcus wasps search longer on traces left by associated hosts rather than non-associated species, and, in the former case, they search longer on traces left by females than males. Based on these evidences, we hypothesized that only associated hosts induce the ability to discriminate host sex in wasps. To test this hypothesis we investigated the ability of Trissolcus basalis, T. brochymenae, and Trissolcus sp. to distinguish female from male Nezara viridula, Murgantia histrionica, and Graphosoma semipunctatum footprints. These three pentatomid bugs were selected according to variable association levels. Bioassays were conducted on filter paper sheets, and on Brassica oleracea (broccoli) leaves. The results confirmed our hypothesis showing that wasps spent significantly more time on female rather than male traces left by associated hosts on both substrates. No differences were observed in the presence of traces left by non-associated hosts. The ecological consequences for parasitoid host location behaviour are discussed

Veneto's successful lesson for a world shocked by COVID-19: think globally and act locally

Severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) infection has wreaked havoc globally, with an ominous morbidity and mortality impact.1,2 Indeed, croronavirus disease 2019 (COVID-19) still represents a formidable challenge for pathophysiology, prognostication, management, and rehabilitation. This holds even truer given the conflicting reports accrued so far for several purportedly effective interventions.1,3,4 Although substantial steps have been accomplished in terms of diagnostic yield, even recognizing early infection is still quite challenging. Each country has addressed COVID-19 in its own way, with variable results. Perusing data on China’s experience with the virus brings forward several questions in terms of completeness and truthfulness of reporting, with substantial skepticism despite several authoritative reports.5 For instance, to date, China has reported fewer COVID-19-related deaths than many smaller countries where COVID-19 spread much later (eg, The Netherlands). Countries and healthcare systems that have acted with a global vision, but also with a firm and proactive local hand, have seen the best results in terms of deaths and system derangement. Conversely, countries with a loose policy (either initially such as the United Kingdom or throughout such as Sweden) have already paid an enormous toll of life and pain, and hypothetically will continue to do so