Volume 8 - 2020 | https://doi.org/10.3389/fcell.2020.623039 This article is part of the Research TopicExosomes in Brain Health and DiseaseView all 18 articles Extracellular vesicles (EVs) are a heterogenous group of membrane-bound particles that play a pivotal role in cell–cell communication not only participating in many physiological processes but also contributing to the pathogenesis of several diseases The term EVs defines many and different vesicles based on their biogenesis and release pathway biological function as well as protocols for isolation and detection are still under investigation Recent evidences suggest the existence of novel subpopulations of EVs increasing the degree of heterogeneity between EV types and subtypes EVs have been shown to have roles in the CNS as biomarkers and vehicles of drugs and other therapeutic molecules They are known to cross the blood brain barrier allowing CNS EVs to be detectable in peripheral fluids and their cargo may give information on parental cells and the pathological process they are involved in we summarize the knowledge on the function of EVs in the pathogenesis of multiple sclerosis (MS) and discuss recent evidences for their potential applications as diagnostic biomarkers and therapeutic targets Extracellular vesicles (EVs) are nano-sized vesicles released into different body fluids, heterogeneous in terms of origin, activities, compositions. Originally considered an in vitro artifact or useless cellular debris (Chargaff and West, 1946), they became an attractive object of research when they were shown to be an evolutionary conserved way of intercellular communication (Camussi et al., 2010; Tkach and Théry, 2016) nucleic acids provide information of the cells and microenvironment where they are originally released Despite a huge advance in the knowledge of neuroinflammatory diseases a biomarker tracking every pathogenetic step is still missing One of the most conceivable reason is the “hard-to-access” stage where neuroinflammation occurs Brain and spinal cord are protected by the blood brain barrier (BBB) rather sequestered from the rest of the body and hard to be sampled and other neural cells providing a snapshot of their original environment have become the focus of thousands of studies investigating neuroinflammation Although recent studies have brought many advances in EV knowledge different points still remain to be addressed In this review we try to bridge conflicting data concerning classification we deeply dissect EVs' role either as epiphenomenon of neuroinflammation (marker of disease) or direct culprits involved in pathogenetic mechanisms (contributory cause of disease) Isolation and detection methods of different EV subtypes A conventional EV classification is based on their biogenesis and biophysical characteristics and distinguishes EVs into three major populations: exosomes, microvesicles (MVs), and apoptotic bodies. However, this classification should be considered with caution in line with recent evidences that report the presence of other subsets of EVs and add a new layer of complexity that need to be addressed in EV field (Figure 1) Cells release heterogeneous populations of EVs different in sizes and secretion pathways Exosomes are generated intracellularly from multivesicular bodies (MVBs) Microvesicles (MVs) are larger than exosomes and arise as a result of outward budding and fission of the plasma membrane Large oncosomes (LOs) are derived from the shedding of non-apoptotic blebs unique to cancer cells Apoptotic bodies are released upon cell fragmentation during apoptotic cell death Exomeres have been recently suggested to be non-membranous nanoparticles with size smaller than 50 nm; their biological role remains unknown Apoptotic bodies are 500 nm−5 μm in diameter and are released into the extracellular environment during the cell apoptotic process (Muhsin-Sharafaldine and McLellan, 2018; Xu et al., 2019). They contain fragmented subcellular organelles for degradation, and they can be characterized by cellular organelles and DNA (Caruso and Poon, 2018) Due to the substantial size overlap among these membrane vesicles confusion on their nomenclature has spread throughout the literature limiting a consensus on understanding the specific biological functions of different categories of vesicles Along with the definition of a uniformly accepted EVs nomenclature further studies specifically addressing EVs subtypes are needed in order to better standardize results obtained in the field we will specify/discriminate exosomes and MVs exclusively in studies concerning MS allowing for this distinction and use the term EVs when both types of vesicles are investigated One notable example for the study of EVs spreading in the periphery, comes from the study of a mouse model of CNS injury. Exosomes isolated from peripheral blood of damaged brain mice where intravenously injected into naïve mice, causing an immune cell activation in the liver of recipient mice (Couch et al., 2017) This is the first study which strongly indicates an immune activation of cells in CNS disease mediated by exosomes According to the possibility for the EVs to cross both undamaged and disrupted BBB, EVs could be detected in different biological fluids and represent a new class of biomarkers (Verderio et al., 2012; Galazka et al., 2017) and be also implicated in some stage of MS development and pathogenesis (Dolcetti et al., 2020) MS is a chronic inflammatory autoimmune demyelinating disease of the CNS (Harbo et al., 2013). It affects worldwide more than 2 million people, being the most common immune mediated CNS disease. MS has a typical onset between the ages of 20–40 years, women outnumbering men 3:1, being for both sexes the leading cause of non-traumatic disability in young adults (Harbo et al., 2013) A proinflammatory environment caused by cytokines and chemokines proteolytic enzymes and neurotoxic products leads to neuroinflammation demyelination and neurodegeneration occurring through CNS white and gray matter Since a long time, neurodegeneration has been recognized as crucial pathogenetic mechanism in MS, already present in the early stages of disease. Among others, oxidative stress, iron accumulation, mitochondrial injury, ion channel dysfunction, glutamate excitossicity are widely found in MS neurodegeneration (Lassmann, 2019) how and to what extent these phenomena get into action is still elusive In 2017 (Mustapic et al., 2017) L1 cell adhesion molecule (L1CAM) was appointed as a promising marker for EVs derived from CNS region The possibility of identifying EVs of neural origin represent a precious messenger of tissue releasing them Deciphering their origin and biogenesis can provide new insight into MS pathogenetic mechanisms still partially understood Conflicting results about EVs role in MS can be ascribed to different methods of studies but also to a Janus role that EVs play in MS Studies in vitro have shown that endothelium-derived EVs are involved in the activation of CD4+ and CD8+ T lymphocytes (Wheway et al., 2014) and can cause their infiltration in the CNS One of the most accredited mechanisms postulate that EVs carrying metalloproteinases have a key role in BBB disruption (Sáenz-Cuesta et al., 2014). Again, recent studies demonstrated that EVs derived from brain microvascular endothelial cells can provide a bridge protein (claudin-5) between leukocytes and endothelial cells inducing transendothelial migration of the former (Paul et al., 2016) An indirect confirmation of detrimental role of EVs in MS pathogenesis comes from experimental autoimmune encephalomyelitis (EAE), mouse model of MS. A-SMase KO mice, genetically impaired in MVs production, are protected from EAE (Verderio et al., 2012) By contrast, several studies suggest a repairing activity of EVs. Indeed, microglia exposed to IL4 or mesenchymal stem cell (MSC) can release EVs promoting oligodendrocyte precursors cells (OPC) migration and/or differentiation. Lipids embedded in EV surface have being indicated as crucial mediators of this myelin repairing activity (Lombardi et al., 2019) Using EVs as therapeutic vector to mediate a protective and repairing activity during the disease will be further explored in the review Again, one of the first studies focusing on EVs (Scolding et al., 1989) reported that oligodendrocytes can recover from injury by “membrane-attack complex-enriched vesicles” released from the surface of viable cells authors conclude that EVs are among crucial agents responsible for the immune modulation in pregnant EAE mice Another source of EVs is represented by those released by astrocytes. In response to neuronal injury, astrocytes become activated and release EVs containing IL-1β, which exacerbates tissue deterioration, fostering a vicious circle (Prada et al., 2018) interest in EVs as a potential biomarker in neuroinflammatory diseases is constantly increasing The number of original researches dealing with EVs in MS has more than quadrupled in the last 5 years We identified 27 original researches on the PubMed Database relating to EVs as biomarker in MS (see Table 2) published from 2011 to early 2020 Sixteen of these works analyzed plasma or serum-derived EVs six from the supernatant of cell cultures or PBMC In nine papers the miRNA contained in the EVs was investigated Seven papers were focused on differences in concentration of EVs with specific surface markers while three studies investigated concentration or production of the total EVs population Five publications analyzed EVs protein content three papers were focused on functional assays addressing a dramatically open issue of this disease a further validation of what previously published about EVs and MS should be required it's conceivable that EVs are involved in EAE pathogenesis Based on the possible role of EVs in EAE and MS some groups developed treatment strategies that employed the use of EVs as therapeutic tool to treat neuroinflammation and demyelination These data provided evidence that MSCs-derived exosomes can be used as cell-free therapies for autoimmune and central nervous system diseases scientists use different cell source of EVs to hit specific target cells Exosomes produced by IFNγ stimulated dendritic cells contain high levels of miR-219 a key player in oligodendrocyte precursors cells differentiation these exosomes can increase the number of mature oligodendrocytes and help the remyelination process in vivo Compared to the crucial contribution and successful results of EVs in cancer treatment, EVs applications as therapeutic delivery vehicle in neuroinflammatory diseases are yet in their early stages (Villa et al., 2019; Hernandez-Oller et al., 2020; Li et al., 2020). Currently just one clinical trial is ongoing for the treatment of chronic postsurgical temporal bone inflammations (Clinicaltrials.gov but we are sure that in the next few years the number of clinical trials using EVs as therapeutic vector will increase supporting a pivotal role for EVs both in CNS physiology and during neuroinflammatory pathogenetic processes Most of our knowledge on the role of EVs in the CNS comes since technologies to follow EVs fate in vivo are difficult and The development of tools allowing the modulation of CNS EVs release and/or uptake in vivo in animal models would represent a ground-breaking advancement for the field This would allow to highlight EVs role in physiological and pathological processes in vivo and possibly in a cell-specific manner available genetic models lack specificity and most pathways (and therefore genes) involved in EVs release or uptake have yet to be elucidated The use of EVs as biomarkers in clinical practice seems a more realistic short-term goal EVs can mirror the biology and environment of the donor cell providing a broader information on ongoing pathologies in neurological patients may provide indication of disease stage and prognosis Access to pathologically relevant tissues is extremely difficult for neurological diseases thus the use of EVs may be key since may be easily isolated from the blood What we still miss here is a deeper knowledge of EVs subpopulations in the blood to differentiate and better characterize EVs origin and their content in physiological or pathological conditions The uncertain and evolving technological landscape for EVs examination calls for a consensus on protocols for standardization of EVs isolation and analysis ISEV) are trying to do this work but cannot avoid the publication of studies of heterogeneous quality the use of EVs as therapeutic vectors in neurological diseases is just at its beginning There are some encouraging data and publications but many more pre-clinical studies must be performed before establishing ways of administration The study of the therapeutic use of EVs in the cancer field is more advanced and raises hopes we might develop EVs as therapeutic vectors in clinical trials in the future also for neurological disorders There are still several technical challenges and even more learning needs on EVs biology but we are convinced that current difficulties in this research field may be overcome and that EVs may become in the next years not only clinically useful biomarkers but also a source of information on disease pathogenesis and possibly an alternative therapy for currently untreatable diseases and AN wrote the review and correct the text RF supervised the writing of the review and correct the final form of the article All authors contributed to the article and approved the submitted version The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest PubMed Abstract | CrossRef Full Text | Google Scholar Blood circulating microparticle species in relapsing–remitting and secondary progressive multiple sclerosis cross sectional study with conventional MRI and advanced iron content imaging outcomes Effect of fingolimod action on the release of monocyte-derived microvesicles in multiple sclerosis patients A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis Altered expression of miR-326 in T cell-derived exosomes of patients with relapsing-remitting multiple sclerosis Isolation of exosomes from blood plasma: qualitative and quantitative comparison of ultracentrifugation and size exclusion chromatography methods PLoS ONE 10:e0145686 doi: 10.1371/journal.pone.0145686 extracellular vesicles and a novel form of communication in the brain PubMed Abstract | CrossRef Full Text | Google Scholar Altered levels of toll-like receptors in circulating extracellular vesicles in multiple sclerosis Multiple sclerosis treatments affect monocyte-derived microvesicle production The use of natalizumab for multiple sclerosis PubMed Abstract | CrossRef Full Text | Google Scholar Exosomes/microvesicles as a mechanism of cell-to-cell communication Microvesicles: what is the role in multiple sclerosis Apoptotic cell-derived extracellular vesicles: more than just debris PubMed Abstract | CrossRef Full Text | Google Scholar Extracellular vesicles containing IL-4 modulate neuroinflammation in a mouse model of multiple sclerosis The biological significance of the thromboplastic protein of blood PubMed Abstract | Google Scholar Placental mesenchymal stem cell-derived extracellular vesicles promote myelin regeneration in an animal model of multiple sclerosis Ectosomes and exosomes: shedding the confusion between extracellular vesicles Mesenchymal stem cell transplantation in multiple sclerosis PubMed Abstract | CrossRef Full Text | Google Scholar and intercellular interactions of exosomes and other extracellular vesicles doi: 10.1146/annurev-cellbio-101512-122326 Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation Methodological guidelines to study extracellular vesicles Subpopulations of extracellular vesicles from human metastatic melanoma tissue identified by quantitative proteomics after optimized isolation Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies Disease-modifying treatments modulate myeloid cells in multiple sclerosis patients Emerging role of extracellular vesicles in the pathophysiology of multiple sclerosis α-Synuclein in brain-derived blood exosomes distinguishes multiple system atrophy from Parkinson's disease Google Scholar Serum exosome MicroRNAs predict multiple sclerosis disease activity after fingolimod treatment Exosomal microRNA signatures in multiple sclerosis reflect disease status Frühbeis Emerging roles of exosomes in neuron–glia communication Multiple sclerosis: serum-derived exosomes express myelin proteins García-Romero DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey Induction of pregnancy during established EAE halts progression of CNS autoimmune injury via pregnancy-specific serum factors Differences in intercellular communication during clinical relapse and gadolinium-enhanced MRI in patients with relapsing remitting multiple sclerosis: a study of the composition of extracellular vesicles in cerebrospinal fluid Detection of JCPyV microRNA in blood and urine samples of multiple sclerosis patients under natalizumab therapy Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease Altered levels of plasma neuron-derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease High complement levels in astrocyte-derived exosomes of Alzheimer disease Sex and gender issues in multiple sclerosis Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study Hernandez-Oller Extracellular vesicles as drug delivery systems in cancer CNS-derived blood exosomes as a promising source of biomarkers: opportunities and challenges Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis Proteomic analysis of microvesicles derived from human mesenchymal stem cells Usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes Lässer Subpopulations of extracellular vesicles and their therapeutic potential Pathogenic mechanisms associated with different clinical courses of multiple sclerosis PubMed Abstract | CrossRef Full Text | Google Scholar Radiologically isolated syndrome: 10-year risk estimate of a clinical event Considerations and implications in the purification of extracellular vesicles – a cautionary tale CrossRef Full Text | Google Scholar Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure Lötvall Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles Defining the clinical course of multiple sclerosis Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells – evidence of unique microRNA cargos Exosome-associated miRNA profile as a prognostic tool for therapy response monitoring in multiple sclerosis patients Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function ExoCarta: a compendium of exosomal proteins and RNA PubMed Abstract | CrossRef Full Text | Google Scholar Sulfatides in extracellular vesicles isolated from plasma of multiple sclerosis patients Muhsin-Sharafaldine Tumor-derived apoptotic vesicles: with death they do part Muralidharan-Chari ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles Muralidharan-Chari Microvesicles: mediators of extracellular communication during cancer progression Myeloid extracellular vesicles: messengers from the demented brain Evaluation of selected microRNAs expression in remission phase of multiple sclerosis and their potential link to cognition The effects of high dose interferon-β1a on plasma microparticles: correlation with MRI parameters Isolation of high-purity extracellular vesicles by the combination of iodixanol density gradient ultracentrifugation and bind-elute chromatography from blood plasma Appearance of claudin-5+ leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of multiple sclerosis patients Proteomics characterization of extracellular vesicles sorted by flow cytometry reveals a disease-specific molecular cross-talk from cerebrospinal fluid and tears in multiple sclerosis Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations What are exosomes and how can they be used in multiple sclerosis therapy CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Exosomes as intercellular signalosomes and pharmacological effectors Comparison of serum exosome isolation methods for microRNA profiling Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders Sáenz-Cuesta The first dose of fingolimod affects circulating extracellular vesicles in multiple sclerosis patients Sáenz-Cuesta Extracellular vesicles in multiple sclerosis: what are they telling us Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement The role of exosomes in CNS inflammation and their involvement in multiple sclerosis New windows into the brain: central nervous system-derived extracellular vesicles in blood PubMed Abstract | CrossRef Full Text | Google Scholar The methods of choice for extracellular vesicles (EVs) characterization Comparison of small extracellular vesicles isolated from plasma by ultracentrifugation or size-exclusion chromatography: yield Comparison of isolation methods of exosomes and exosomal RNA from cell culture medium and serum Isolation and characterization of exosomes from cell culture supernatants and biological fluids Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines Extracellular vesicles in neurodegenerative disease — pathogenesis to biomarkers Communication by extracellular vesicles: where we are and where we need to go Biology and biogenesis of shed microvesicles Standardization of extracellular vesicle measurements by flow cytometry through vesicle diameter approximation Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain Shedding light on the cell biology of extracellular vesicles Myeloid microvesicles are a marker and therapeutic target for neuroinflammation A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis Cerebrospinal fluid extracellular vesicle enrichment for protein biomarker discovery in neurological disease; multiple sclerosis Endothelial microparticles interact with and support the proliferation of T cells How apoptotic cells aid in the removal of their own cold dead bodies Serum exosomes in pregnancy-associated immune modulation and neuroprotection during CNS autoimmunity Extracellular vesicle heterogeneity: subpopulations and diverse functions in cancer progression Apoptosis and apoptotic body: disease message and therapeutic target potentials Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study Yáñez,-Mó Biological properties of extracellular vesicles and their physiological functions Exosomes with membrane-associated TGF-β1 from gene-modified dendritic cells inhibit murine EAE independently of MHC restriction Extracellular vesicles and intercellular communication within the nervous system Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation miR-23b suppresses leukocyte migration and pathogenesis of experimental autoimmune encephalomyelitis by targeting CCL7 Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain Molecular biomarkers in multiple sclerosis Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients Nigro A and Furlan R (2021) Extracellular Vesicles in Neuroinflammation Received: 29 October 2020; Accepted: 21 December 2020; Published: 21 January 2021 Copyright © 2021 Marostica, Gelibter, Gironi, Nigro and Furlan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Roberto Furlan, ZnVybGFuLnJvYmVydG9AaHNyLml0 Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish a single woman has chosen a husband from as many as 25 bachelors in the American reality TV program The Bachelorette She narrows down the pool of contenders until she picks a winner Because her decisions are usually so hard to make why not have the bachelors instead compete in a chess tournament to pick the real winner Using chess to pick a husband does have an ancient precedent Choosing a husband this way actually happened in 1454 during the Renaissance in Europe a small town in the province of Vicenza in northern Italy that then belonged to the Venetian Republic and she has to decide between two suitors who are madly in love with her He declared that the two rivals would play a chess game and human actors representing the pieces would show the moves as they were made Lionora would take the winner as her husband The loser would also join the family but marry instead the younger daughter The two contenders — Rinaldo d'Angarano and Vieri da Vallonara — faced off over a chessboard in the square in front of the castle on the day of a religious festival Watching the game was not only the father and his court but the families of the two suitors as well as the entire population the father insisted that the chess challenge had to be honored by a performance of soldiers and knights with fireworks the town has celebrated this part of its legendary history with a performance in its main square which is named for the castle that borders the square The plaza is also popularly known as Piazza degli Scacchi (meaning Chess Plaza) The performance is held every two years during the second weekend of September although the production in 2020 was canceled because of the coronavirus epidemic For the reenactment of this chess challenge about 600 actors dressed in medieval costumes perform as soldiers Enhanced by fireworks and other scenic effects the spectacular performance lasts two hours The ticket prices range from 23 euros for the silver grandstand for a performance on Sunday evening to 92 euros for the platinum grandstand on Saturday evening About 3,600 spectators sit in armchairs around the center stage which is a large marble chessboard in Piazza Castello we learn a noble truth: The gioco degli scacchi (game of chess) teaches many things about life winning or losing is not as important as essere un giocatore (being a player) and not a pawn because a player is fautore del proprio destino (champion of his own destiny) even in defeat while a pawn is a victim of events even in victory the region includes other important aspects of chess history and culture In the vicinity of Marostica is the Bertoliana Library in nearby Vicenza the library houses a rare collection of chess literature Several handwritten and printed works date between the 13th and 19th centuries and are often enriched with drawings and engravings Among the treasures are "The game of chess" (1584) by Ruy Lopez de Segura "Analyse du jeu des echecs ”(1749) by François-André Danican Philidor and chess essays that explore the history of the game in Europe Although we don’t know the rest of the story about Lionara and her winning husband take heart in knowing that the winner (Ryan Sutter) of season one in 2003 of The Bachelorette did marry the bachelorette (Trista Rehn) The wedding was broadcast on national TV later that year they are still married and have two children make plans to visit Marostica during one of its performances Imagine what it's like to experience a chess game in the dreamy setting of the castle of Marostica Are you familiar with the tradition of live chess in Marostica or other examples At Chess.com, he has been an editor (part-time) since 2019 and has edited news articles and tournament reports—including those of the Candidates and World Championship Tournaments and other major events—by titled players and noted chess writers as well as Game of the Day annotations by leading grandmasters He has also been a contributing writer of chess terms and general interest articles for ChessKid.com He enjoys “top blogger” status at Chess.com His blog has won the award for Best Chess Blog from the Chess Journalists of America for several years he has also been the recipient of first-place CJA awards for feature article and educational lesson as well as honorable mention in the categories of personal narrative and historical article This blog has won the award for Best Chess Blog from the Chess Journalists of America I have also been the recipient of first-place awards for online review In addition, my article "How Knight Promotions Win Chess Games" was selected by Chess.com as "Blog of the Month." Be sure to check out these articles as well as others that I have posted I hope you enjoy reading what I have written and will follow this blog to see my future posts Log in to your Television Academy account: If you're seeking ways to connect with working television industry professionals joining our organization offers you unparalleled access Learn more about Television Academy Membership click below to start the application process Google is working hard to listen to customer feedback and ensure travel businesses and tourism officials have the information needed to continue recovery we’ll bring these tools to the travel industry in the U.S and around the world with training materials customized specifically for destination organizations and hospitality marketing professionals There are two free tools available within Travel Insights with Google that provide rich data and actionable insights Destination Insights gives travel businesses, governments, and tourism boards a clear picture of top sources of demand per destination. This can help users understand where potential travelers may be coming from and adjust marketing campaigns accordingly. The second tool, Hotel Insights helps hoteliers analyze search trends so they can understand where interest is coming from and attract new guests by creating a stronger digital presence Since we began piloting these tools last year they’ve helped government tourism officials in places like Singapore and Indonesia answer critical questions as they make decisions about border reopenings we recently launched localized versions of Travel Insights with Google in countries across Asia and Europe “As we enter into the recovery phase after the pandemic relevant and timely data will be essential for destination organizations around the world as they will be required to respond intelligently and proactively on behalf of their communities We are thrilled to partner with Google for this type of information that will help make our members successful.”—Don Welsh President and CEO of Destinations International “Partnering with Google on this initiative reinforces that what industry professionals need are insights HSMAI members that are inspiring marketing will benefit greatly by having access to the exclusive expertise that Google provides on what today’s traveler is searching for as the recovery picks up across travel and tourism.” —Robert A Based on feedback we’ve heard from our pilot partners helpful features within the Destination Insights tool Focusing Facts will allow users who visit Destination Insights to view a set of quick insights such as “Fastest growing destination globally,” “Country with the most inbound interest” and “Top city in demand.” Focusing Facts are based on the previous 84 days of data which provides a well-rounded vantage point Focusing Facts tool within Destination Insights The Demand Sizing Tool is a new section with distinct filters to compare inbound and outbound interest between one primary country and up to ten comparison countries Demand Sizing tool within Destination Insights Responsibly reinvigorating the tourism sector will take ingenuity and effort across the industry We want to support travel and tourism professionals with the tools and insights they need to connect with people searching for travel we’ll continue to seek to find new ways to support the global travel and tourism sector by sharing data and insights that can help the industry rebound one might imagine Marostica to be one of the funniest people in Canada Rather than calling for a high-octane sword duel to win the hand of his daughter Lord Taddeo Parisio decreed her two suitors must instead play a game of chess After a few hours of rollicking entertainment the winner would take home his older daughter this 1454 match has become bigger and more ostentatious in modern day with life-sized chess pieces re-enacting the game in the piazza outside where the original took place take place over three days on a massive pink-and-white marble chessboard in the center of town From Lord Parisio’s court and two daughters to human chess pieces dressed in ornate black or white 15th-century costume--complete with matching horses for the knights--each of the tiny town’s 700 residents has a part to play The two most important characters are Linora’s two lovers who can potentially re-write history in determining where the life-size pieces should move during each unique game Like the grand festival which predicated the Lord’s match all orchestrated to fully recreate the Renaissance for the huge number of tourists who flock to Marostica for the weekend.  From Venice by car: Highway A4 towards Milan After passing the toll at Grisignano di Zocco merge onto highway A31 "Valdastico" towards Piovene Rocchette Continue through Dueville and follow SS 248 Marosticana-Schiavonesca towards Marostica Two churches shoot bottle rockets at each others' bell towers in an unusual Easter celebration Annual convention held by the largest pyrotechnic community in the world Bold contestants slide in a rice paddy behind two charging bulls Men in rubber-soled boots serve as your "brakes" on this toboggan ride Hemingway described as "exhilarating." A park in Mexico offers all the experiences of an illegal border crossing except for one: the border that has been played since prehistoric times An academy where anyone can train in the exciting acrobatic sports of parkour and freerunning KQED Live EventsPRX Podcast Garage EventsEvents Around the Bay AreaMember Benefits with KQED LiveVideos from KQED LiveWatch recordings of recent KQED Live events FeaturedThat's My WordAn ongoing exploration of Bay Area hip-hop history See Senior Director of TV Programming Meredith Speight’s recommendations from this month’s KQED 9 Watch recordings of recent KQED Live events Support KQED by using your donor-advised fund to make a charitable gift Matt Marostica is the former bishop of the Berkeley ward of the Church of Jesus Christ of Latter-day Saints (Matt Marostica)As part of our First Person series Forum invites Bay Area residents to share their lived experience leading remarkable and important lives within our community Matt Marostica lives in Berkeley but is the High Councilor in the Oakland Stake of the Church of Jesus Christ of Latter-day Saints as people within the faith prefer to be called instead of the more common term Mormon says his congregation is made up of all sorts of people Marostica says he loves his church and faith community and is working to change it from the inside Former bishop of the Berkeley Ward of The Church of Jesus Christ of Latter-day Saints BY Audrey CarletonPublished Sep 21, 2018 Be the first to get our biggest stories delivered to your inbox. Two weeks ago I attended the Chess festival at Marostica The chess festival at Marostica tells the story of the daughter of Taddeo Parisio Marostica Two noblemen contend to marry the beautiful blonde-haired daughter of the Lord of Marostica these matters were usually settled by the sword to avoid any bloodshed between the two young and talented noblemen the King decided that the two should match wits instead of swords in a game of chess The King would give his daughter in marriage to the winner of the game Both were known thoughout the kingdom as accomplished chess players The loser would be given in marriage to Oldrado Lionora with her maid while the court jester looks on: This is who Rinaldo d'Angarano must "settle" for? I don't think there were any losers at the end of this game It is the beautiful new chess documentary that every fan of the game should see—whether you can make it to a film festival or stream it live on TV—and now it's an award-winner The City Of Human Chess, Chess.com's first venture into documentary film-making, was given rapturous applause and named Best Mid-Length Documentary over the weekend as it received its U.S. debut at the prestigious DOC LA Los Angeles Documentary Film Festival The film, now on general release via the streaming service MagellanTV tells the story of how a truly unique and spectacular human chess game inspired by a 15th-century tale is put on in the small market town of Marostica in northern Italy The biennial event has been running for more than a century a beautiful woman who has two suitors madly in love with her the two rivals are made to play a game of chess insisted that the challenge be played out in real life with human chess pieces in the town's main square now popularly known as Piazza degli Scacchi The human chess game was first enacted in 1923 and has been a source of local pride ever since the show has grown to involve more than 600 actors Fireworks and special effects light up the town and everybody pitches in to make it happen the performance was shelved due to the COVID-19 pandemic The film follows locals as they battle to bring this unique tradition back to life in just 25 days The film made its world premiere at the Not Film Festival in Italy in August it is receiving plaudits from the industry Besides being selected to feature at the prestigious DOC LA the film will also feature at the International Film Festival in The Hague Chess.com is pleased to announce the documentary streaming service MagellanTV has also secured global distribution rights to show The City Of Human Chess on its platform "We're honored to showcase The City of Human Chess MagellanTV's Director of Digital Marketing "Collaborating with the Chess.com team and sharing this story of tradition and passion has been a genuine pleasure." The 22-minute film was directed by the award-winning LA-based filmmaker Cecilia Albertini and produced by Chess.com's Creative Director Chandler Toffa Albertini described it as a "labor of love" and said the entire production was filmed over just three weeks We were a very small crew (a total of four people on set plus three more people in post-production) To have it screened at an important festival in Los Angeles means a lot to us It's so much fun to have our country and its traditions represented on screen at such an important festival and we are so excited for people from all over the world to see it because all of us in the crew became friends very quickly there was a general vibe of excitement and joy in the city at the time of filming because everyone was gearing up for the event Everyone we interviewed was very kind and generous with their time We had a limited time to film this because we were staying in the town for only about three weeks we had to make the most of the time we had we had to find the story; when we first started filming we thought that the film was going to have a much more character-driven angle centering on the director of the performance we realized that it was much more about the city itself and that it would be more of an 'ensemble' piece Scheduling interviews with everyone was also challenging because everyone was so busy with prepping for the performance My hopes are that it continues to play at big festivals and that it gets seen by as many people as possible We recently secured distribution through MagellanTV so many more people will be able to stream it and watch it The City Of Human Chess is available to view now on MagellanTV and will be shown at the International Film Festival in The Hague This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page BY Audrey CarletonPublished Jul 27, 2019 Sign In Register Subaru entered the Canadian automotive market with seven dealerships Ron Marostica was one of the original owners he’s celebrating the grand opening of his brand-new located on the Harbour Expressway across from Intercity Shopping Centre at a ribbon cutting ceremony that brought seven executives from Subaru Canada “We’re twice the size of what we were before and we’re very environmentally friendly the front and the side of it is complete glass We have an in-floor heating system that makes it very comfortable for our workers and our customers when they are here.” whose vision helped inspire the building’s design said they’d simply outgrown their previous location on Central Avenue a storefront they’d called home for the past two decades “From the outside they can see all the cars on the inside because there is so much glass they can sit outside the window and watch their car being worked on by licensed technicians.” senior vice-president of operations for Subaru Canada said the new dealership is a key link for the company the nearest dealership is Winnipeg and to the east “So for anyone traveling across the Trans Canada Highway if there is an issue with a vehicle or people on holidays or traveling,” Durst said “You can see all the brands are in Thunder Bay.” A new facility is also inviting to the vehicle-buying public “We want to have things that are practical environmentally friendly and it feels welcoming when you walk in,” Durst said “To see 100 per cent of the service area covered in glass to me that opens up a huge amount of transparency that customers say Mayor Bill Mauro was also on hand for the ceremony and said seeing the private sector investing in the city is a good sign This was a big brown field for a long time As a city we’re all working together to try to build a community that people are proud of that they want to live in and stay in and that new people want to come to,” Mauro said “Seeing brown-field developments really make a difference.” who is bringing brother Jim and son Kevin aboard as partners, said he’s increased his employee count by four adding they’re still looking to add more staff The dealership opened last November.  Marostica said he's hopeful his other dealership will be open by the end of August at its new location on the former Greyhound bus station property.  Your browser is out of date and potentially vulnerable to security risks.We recommend switching to one of the following browsers: Please enable JS and disable any ad blocker By subscribing, you agree to our Terms of Use and Privacy Policy In the halls of Marostica ’s Lower Castle the exhibition The Battle of the Two Kings with Mock Array will be open from August 6 to September 18 The history of chess between the 13th and 18th centuries in the books of the Bertoliana Library curated by Laura Sbicego.While the six hundred and fifty figures who will bring to life the Living Chess Game are rehearsing costumes invites the public to delve into the history of chess drawing on the treasures of the Bertoliana Library in Vicenza which has been active since the 18th century the Bertoliana holds a rare collection of universal chess literature: manuscript and printed works dated between the 13th and 19th centuries Of particular note is a very small manuscript compiled in the nineteenth century by librarians Ignazio Savi and Andrea Capparozzo which contains the bibliographic census of books on the game of chess at the time owned by the Vicenza Library That inventory was later expanded to the level of specialized bibliography super ludo scachorum (1493) by Jacopo da Cessole and Pedro Damiano da Odemira’s Manual for “learning to play chess et de le partite” (1512) Il gioco de gli scachi (1584) by Ruy Lopez de Segura or the treatise Scacchia ludus (1527) by Girolamo Vida or Il gioco de gli scachi (1617) by Pietro Carrera or theAnalyse du jeu des echecs (1749) by François-André Danican Philidor qui representant ce fameux Automate (1783) are the images of the celebrated Automa playing chess often embellished with significant illustrative plates of the different phases of the ludus Alongside the chess treatises that marked the history of the game in Europe the miniature decorating the Bible by the copyist Cambius Vicentinus is noteworthy The small illuminated scene depicts a cleric and a layman seated and playing chess: it is one of the earliest representations of chess games known to date made in France in the third quarter of the 13th century during the years when King Louis IX banned the game of chess "The celebration of chess in its various forms is always an opportunity to remember our most famous event which originated from a theatrical libretto by the volcanic Mirco Vucetich and was scheduled in even-numbered years on the beloved chessboard placed on the pavement of the square," said Simone Bucco president of the Pro Marostica Association “The exhibition also has the merit of enhancing the extraordinary chess heritage preserved by the Pro Marostica Association which has always been committed to the organization and promotion of the famous historical re-enactment which stages with large and live pieces a unique and exciting challenge.” The exhibition is organized in collaboration with the Municipality of Marostica “Città di Marostica” Chess Club Subscribe to our newsletter for Toronto art happenings You have successfully joined our subscriber list Now in its ninth year, SiriusXM Top Comic Competition is a nationwide search for Canada’s best comedian and also the biggest comedy competition in Canada Toronto’s Ashley Moffatt, Cara Connors and Chanty Marostica are among the eighteen semi-finalists vying for your votes and a shot at the grand prize of $25,000 plus international exposure with a guaranteed spot to perform at JFL Sydney (Australia) and Just For Laughs Montreal and a JFL TV taping You’ve got until August 17 to cast your vote for your favourite comic here (Limit of one vote per day.) At the end of the voting period eight finalists will compete for the title of SiriusXM’s Top Comic live at the finale Let’s make someone’s dream come true!! We’re catching up with a few local semi-finalists CM: I was obsessed with Robin Williams as a kid but equally PURE FUN and always over the top for a laugh that kind of bright soul that they all are so that I could also make people around me feel the way they made me feel Can you share with us an event from adolescence that shaped who you are today When I was thirteen I had a lot of trouble with the law I was caught spray painting at the pier one night and avoided arrest by agreeing to clean the graffiti as part of my community service hours I eventually befriended a young orca whale who I had the opportunity to train with the guidance of a professional trainer But I knew…I KNEW he belonged in the ocean So we trained and trained and trained on this one trick jump and instead of performing it in front of a live CAPTIVE audience we performed the jump for ourselves and I helped him JUMP BACK TO THE OCEAN.  Undiagnosed ADHD and being a SUPER closeted GAY doesn’t make for a cool high school experience Maddocks made it so I could always be ME in her class She taught me that bullies grow old but never grow up but that I would and she instilled in me that when I did grow up I don’t know if I was good at drama; it was just so good FOR me I’m sure I got the best grades in that class because it was the happiest I’d ever been in those four years of my life.  When I stopped caring what my parents thought of me My parents’ validation was my everything my whole life I never did anything after coming our as gay (nineteen-onward) unless they knew about it When I came out as non-binary and started to really think about myself and my choices and WHY I put such high stakes on their approval I realized they love me no matter what and one day they’ll be gone but one day I’ll be the only person who needs to be proud of me So…best to start now so they can see that I’ll be okay…OH MY GOD What’s the best thing about your current age I feel like I’m always the oldest person on stage (with the best skin) What’s the best thing about my current age I felt a shift in my thirties–like I’d arrived Thirty-four is when I let myself be me and came out to myself as trans So it will forever be a defining year of my life.  and how has it changed your view on the world?  I got locked out of my house for three hours in the pouring rain two weeks ago and I don’t believe in myself as a survivalist or a person to survive the apocalypse anymore my dog Sprocket and I will watch Futurama until the sweet embrace of death beckons us TO Fuck walking in wet shoes and being dirty on purpose What thing do you not have any control over I’ve felt my whole life like I was impersonating a woman yet I was “misgendered” as male my entire life When I finally see the forest through the trees and come out and try to present as my most masc self I’m seen as a woman more than ever before I honestly feel like the more comfortable you are with being the gender you were not assigned at birth the more that defies how people WANT to see you They grind hard against it to let you know that you’re an imposter but they’re letting you know they SEE YOU Trans people have been here before you and your parents and your parents’ parents What has been the most awkward moment in the history of your stand-up career but a moment from last week sticks out hard in my brain A group of men started talking SO LOUD on purpose every time I stared to speak they made it this fun game where they wouldn’t even be saying words but they’d be speaking louder than me So they made it their mission to make my set a living hell I treat hecklers with kid gloves and I LOVE my audience but these guys…I finally had enough and told them I’m sharing my experience as a trans person and it’s super vulnerable and not always a safe space for me I’d appreciate if you could let me say my words so I can tell my truth and my jokes.” And this dude looked me square in the face with the meanest smile I’d ever seen and said Why don’t you try being trans AND being funny.” They were escorted out shortly after I wish they’d stayed so I could’ve looked them in the face off stage There’s something that dehumanizes you to an audience when you’re on stage but hecklers aren’t so big when you’re a real person looking THEM square in the face What other skill/talent do you possess that you don’t often share on stage I sing quite a bit in my act because it always made my grandma really happy to hear my singing voice when she came to my shows and I would and still do whatever Irene wants A talent that I don’t share on stage Art and junk…it’s def in my wheelhouse To be the first trans person to do E V E R Y T H I N G What does a perfect Saturday look like to you I’m TRIPLE booked and I’m scattering with producers to get me in and out on time so I can do as many spots Nothing makes me happier than being on stage and I’m in VALHALLA when I’m busy on a Saturday I always feel like a weird concerned dad on the weekend Best to keep me on stage where I can’t question other people’s choices.  I’m BELIEVE IT OR NOT pretty high-strung and I just take the day to Netflix and cheweenie with Sprocket and whatever terrible horror movies are added to Netflix that day of the week.  Don’t forget to cast your vote here THUNDER BAY -- Michael Marostica got an early start in the car business and Michael washed cars and mowed the lawns throughout his teens I tried to see what else was out in the business world I decided I wanted to stay in the car industry The opportunity was just too hard to give up,” Michael remembers He worked in various departments to learn all aspects of the dealership and when his father retired in 2008 Michael took on the role of dealer principal Wayne Marostica has always been on 787 Central Avenue and it went through renovations in the 80s and in 2012 as the dealership expanded “We’ve grown quite a lot in the past 12 years,” Michael says.  The COVID-19 pandemic caught Michael by surprise “It took the business world and flipped it upside down A lot of things we had to figure out,” he says Their service department was deemed essential and kept operating but the sales department had to limit themselves to online sales “We shrank to half [the number of employees] and we’re now back to about 90 per cent,” he says Wayne Toyota services a large geographical area from Fort Frances in the west to Marathon in the east the best-selling vehicles were Corolla and RAV4 The past 10 years have also seen a huge increase in pickup trucks and Tacomas and Tundras are popular in northwest Ontario Michael says his passion for superior customer service and his team of employees have contributed to the success of the dealership Many of the employees have been there since his father’s time “A couple of technicians have been here for 30 years and my office manager for 25,” Michael says “We had a technician retire recently “Employee longevity is a good thing,” he says “This is a great place to be a part of.” Carhartt and Italian bootmaker Diemme have teamed up once again this spring presenting a new Bordeaux colorway of the double branded Marostica Low This premium sneaker features a sturdy canvas upper heel tab and liner all built with premium leather A special tribal heel pull provides an extra dose of color while hiking-style eyelets pay homage to the rugged heritage of both brands The Bordeaux colorway of the Carhartt x Diemme Marostica Low is available now at End. 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