Advanced Treatments and Emerging Therapies for Dystrophin- Deficient Cardiomyopathies

Dystrophinopathies are characterized by skeletal and cardiac muscle complications because of a lack or shortened DYSTROPHIN protein. Ventilation assistance and corticosteroid treatment have positively affected life outcome but lead to an increased incidence of cardiomyopathy. Cardiomyopathy is now the leading cause of death in patients with dystrophinopathy. Thus, coherent guidelines for cardiac care have become essential and need to be communicated well. Progression of cardiac complications in patients with dystrophinopathy diverges from standard dilated cardiomyopathy development and monitoring and medical care for dystrophinopathy. This chapter summarizes current guidelines and recommendations for monitoring and clinical treatment of cardiac complications in patients with dystrophinopathy and provides a thorough survey of emerging therapies focusing on cardiac outcomes

Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-COs lack initial proliferative capacity, displayed a progressive loss of sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, cardiomyocyte deterioration, fibrosis and aberrant adipogenesis were observed in DMD-COs over time. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-COs which was associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies

Compact object coalescence rate estimation from short gamma-ray burst observations

Recent observational and theoretical results suggest that Short-duration Gamma-Ray Bursts (SGRBs) are originated by the merger of compact binary systems of two neutron stars or a neutron star and a black hole. The observation of SGRBs with known redshifts allows astronomers to infer the merger rate of these systems in the local universe. We use data from the SWIFT satellite to estimate this rate to be in the range $\sim 500$-1500 Gpc$^{-3}$yr$^{-1}$. This result is consistent with earlier published results which were obtained through alternative approaches. We estimate the number of coincident observations of gravitational-wave signals with SGRBs in the advanced gravitational-wave detector era. By assuming that all SGRBs are created by neutron star-neutron star (neutron star-black hole) mergers, we estimate the expected rate of coincident observations to be in the range $\simeq 0.2$ to 1 ($\simeq 1$ to 3) yr$^{-1}$.Comment: 23 pages, 3 figures, version accepted for publicatio

Realismo, Metafisica, Modernit\ue0: In margine al volume di Vittorio Possenti 'Il realismo e la fine della filosofia'

Contro l\u2019impostazione speculativa della storiografia idealistica, che lasciava in secondo piano lo studio dettagliato del testo, e con la grande capacit\ue0 d\u2019innovazione che dalla sua fondazione contraddistingue il Consiglio Nazionale delle Ricerche, nel 1964 Tullio Gregory apr\uec la stagione di una storia delle idee strettamente legata alla storia del lessico, nella convinzione che le idee non vivono in un mondo iperuranio, pure e immacolate, ma s\u2019incarnano nei segni linguistici, impuri, spesso ambigui; segni linguistici che sono portatori di una lunga storia, crocevia di esperienze molteplici nell\u2019intrecciarsi di correnti di pensiero e di lingue diverse, nella continua trascrizione e traduzione da una ad altra cultura . Questo volume presenta gli atti del convegno che si svolse il 22 febbraio 2017, nella sala conferenza della Biblioteca di Scienza e Tecnologia \uabGuglielmo Marconi\ubb presso la sede centrale del Consiglio Nazionale delle Ricerche, dedicato a Realismo, Metafisica e Modernit\ue0, i tre concetti declinati da Vittorio Possenti nel volume Il realismo e la fine della filosofia moderna, che si pone a complemento delle sue riflessioni su Terza navigazione: Nichilismo e metafisica . Possenti \ue8 motivato evidentemente non solo da preoccupazione di ordine morale sulle conseguenze etiche del nichilismo e del postmoderno, ma anche e soprattutto dalla confusione fondamentale propagata dal carattere antirealistico, e dunque in qualche modo nichilista di molte scuole filosofiche moderne. Detto questo, la riflessione di Possenti si \ue8 mossa con forza e rigore nella direzione di reagire all\u2019abbandono della filosofia dell\u2019essere da parte del nichilismo e del postmoderno, reagendo nel migliore dei modi possibili, ossia districando punto per punto la matassa del quadro attuale della filosofia contemporanea. Difficilmente Possenti avrebbe potuto essere pi\uf9 chiaro: Non desidero sostenere che la filosofia si rinnova soltanto con la metafisica, che non \ue8 l\u2019appestato da cui guardarsi come osservava ironicamente Hegel. Vi sono pi\uf9 cammini: rinnovare la filosofia con l\u2019antropologia, oggi paurosamente sbilanciata verso naturalismo e materialismo, che propagandano una concezione antieroica dell\u2019esistenza, lodano l\u2019io minimo e comico che tanti di noi\u2028sono, auspicano la ne della dimensione religiosa e contemplativa dell\u2019esistenza e dello spazio del trascendente a favore della civilt\ue0 tecnologica. La filosofia si rinnova anche con la religione che\u2028include a un tempo protologia ed escatologia. In merito il\u2028rischio di oggi non \ue8 l\u2019assorbimento idealistico della religione nella filosofica, ma la radicale obiezione empirista, positivista e scientista contro ogni fede\u2028e trascendenza. La filosofia si rinnova in vari\u2028modi ma in maniera pi\uf9 intensa e radicale\u2028mediante il discorso metafisico e l\u2019impegno realistico. Le scienze nel loro\u2028campo sono necessarie; allontaniamo per\uf2 l\u2019illusione che\u2028possano dare risposte sul\u2028senso del tutto: non vi\u2028sono n\ue9 mai vi saranno soluzioni\u2028scientifiche a\u2028problemi\u2028metafisici . In realt\ue0 in Italia, si \ue8 dedicata molta attenzione a nichilismo e postmoderno. Se gli anni settanta e ottanta del secolo scorso registravano una fioritura di letteratura nichilista, il bisogno di confrontarsi con il nichilismo restava chiarissimo, come si vede dalle opere lasciateci da pensatori quali Luigi Pareyson e Alberto Caracciolo, che consideravano il nichilismo partendo da una raffinata sensibilit\ue0 per la dimensione religiosa. Pensatori come Gianni Vattimo, che valutando positivamente il potenziale emancipatorio del nichilismo fu il primo in Italia ad aprire al postmoderno a met\ue0 degli anni novanta, ed Emanuele Severino, che invece tacci\uf2 di nichilismo l\u2019intera filosofia occidentale per aver accettato il tempo e il divenire delle cose, e dunque il loro \uabnon esserci ancora\ubb e il loro \uabnon esserci pi\uf9\ubb, cosa che equivale, a esser precisi, a pensare l\u2019essere come nulla. L\u2019elaborazione di questo nocciolo di critica speculativa distingue Possenti dalle diverse versione del nichilismo che conosciamo da Friedrich Nietzsche e Martin Heidegger e i loro epigoni e lo porta a un confronto serrato con Edmund Husserl, Giovanni Gentile, Jacques Maritain, Paul Ricoeur, J\ufcrgen Habermas e ovviamente Gianni Vattimo, per arrivare agli scritti pi\uf9 recenti di Peter van Inwangen e Maurizio Ferraris. Del resto, lo stesso Maurizio Ferraris intervenne al convegno del 22 febbraio per confermare l\u2019urgenza della difesa del realismo a seguito delle opposte riletture della Critica della ragion pura da parte di Peter Strawson e Martin Heidegger, quando il primo chiedeva una metafisica dell\u2019esperienza e il secondo un\u2019analisi della finitezza dell\u2019essere umano, cosa che equivale \uabto the same thing, said with more passion\ubb . Rinunciamo a riassumere le posizioni degli autori delle singole relazioni perch\ue9, come si vedr\ue0 nelle pagine che seguono, sono tutte state fatte oggetto da parte di Possenti delle risposte puntuali pubblicate alla fine del volume. Ci limitiamo a ricordare che Possenti costruisce e difende una posizione filosofica che si rivela strettamente legata alla filosofia classica dell\u2019essere inaugurata da Aristotele, proseguita da Tommaso d\u2019Aquino e ripresa da Jacques Maritain. Per questo motivo, il convegno si \ue8 articolato nelle tre sezioni che compongono il presente volume: Metafisica, Ontologia e Filosofia Moderna. Nelle sue risposte Possenti ribadisce in maniera efficace come la questione di cosa sia la metafisica corrisponda alla questione di cosa sia l\u2019essere e come il superamento del nichilismo e del postmoderno, la vittoria sull\u2019oblio dell\u2019essere, possa aver luogo solo attraverso il ritorno alla metafisica

An Ensemble Analysis of Electromyographic Activity during Whole Body Pointing with the Use of Support Vector Machines

We explored the use of support vector machines (SVM) in order to analyze the ensemble activities of 24 postural and focal muscles recorded during a whole body pointing task. Because of the large number of variables involved in motor control studies, such multivariate methods have much to offer over the standard univariate techniques that are currently employed in the field to detect modifications. The SVM was used to uncover the principle differences underlying several variations of the task. Five variants of the task were used. An unconstrained reaching, two constrained at the focal level and two at the postural level. Using the electromyographic (EMG) data, the SVM proved capable of distinguishing all the unconstrained from the constrained conditions with a success of approximately 80% or above. In all cases, including those with focal constraints, the collective postural muscle EMGs were as good as or better than those from focal muscles for discriminating between conditions. This was unexpected especially in the case with focal constraints. In trying to rank the importance of particular features of the postural EMGs we found the maximum amplitude rather than the moment at which it occurred to be more discriminative. A classification using the muscles one at a time permitted us to identify some of the postural muscles that are significantly altered between conditions. In this case, the use of a multivariate method also permitted the use of the entire muscle EMG waveform rather than the difficult process of defining and extracting any particular variable. The best accuracy was obtained from muscles of the leg rather than from the trunk. By identifying the features that are important in discrimination, the use of the SVM permitted us to identify some of the features that are adapted when constraints are placed on a complex motor task

Relations de la philosophie avec son histoire

It is a great honor to present one of the proceedings of the Institut In- ternational de Philosophie in the \uablessico Intellettuale Europeo\ubb series. Both have longstanding traditions. the Institut International de Philosophie (IIP) was founded during the momentous ann\ue9e Descartes of 1937 and its meet- ings have taken place on a yearly basis (with the exception of 1939 to 1946 because of World War two). Its first president was l\ue9on Robin. Past pres- idents during the last four decades were Georg Henrik von Wright, Max Black, Paul Ricoeur, Jerzy Pelc, David Pears, Ruth Barcan Marcus, Evan- dro agazzi, tomonobu Imamichi, Jaakko Hintikka, anne Fagot-largeault, Hans lenk, tom\ue1s Calvo Mart\uednez and Enrico Berti. Ioanna Ku\ue7uradi is currently the president and Bernard Bourgeois the secretary general. to date, its membership lists 102 philosophers from forty-four countries. Its several committees are concerned with international communication and coopera- tion in philosophy from the point of view of reason and tolerance. a con- stant focus is placed on the mutual opening of philosophical cultures, tra- ditions and approaches.1 the Istituto per il lessico Intellettuale Europeo of the National Research Council of Italy (lIE and since 2001 IlIESI) was founded in 1964 and has been hosting its own international meetings every three years. We are count- ing fifty-five Entretiens de l\u2019Institut International de Philosophie and fifteen Colloqui Internazionali del Lessico Intellettuale Europeo. the IlIESI is ded- icated to the history of cultural and scientific terminology. It focuses on the phenomenon of cultural migration, which accompanies the whole history of civilizations while involving continuous relations and reciprocal exchanges among diverse cultures, and thus translations (in their widest sense) of texts and modules from one to another context, be it linguistic, economic, politi- cal, or cultural. Its researchers investigate several epochs under the assump- tion that at the root of the history of philosophy and of the sciences and more generally of the history of ideas lie textual corpora that have been de- veloped in the context of each discipline over the centuries.2 today, the \uablessico Intellettuale Europeo\ubb series, which was started in 1967, boasts 124 volumes. and we find it extremely inspiring that volume 125 of the series hosts the sixty-third IIP meeting, which is its sixth meeting in Italy, after Venice in 1958 (in coincidence with the twelfth World Con- gress of Philosophy), l\u2019aquila in 1964, Bellagio in 1982, Palermo in 1985 and Santa Margherita/Genova in 1989. all presentations but one that were given at the Entretiens de Rome of the Institut International de Philosophie on 24-28 September 2014 have found their way to this volume. appropriate funding was provided by the Italian Ministry for Education, university and Research within the PRIN2012 \u201cuniversalism and its limits\u201d, unit coordinator Riccardo Pozzo and national coordinator loris Sturlese. the four papers contributed by Giovanni Pugli- si, Hans Poser, Evandro agazzi and Enrico Berti were read at the meeting of the Committee on the History of Philosophy of the F\ue9d\ue9ration Interna- tionale des Soci\ue9t\ue9s de Philosophie (FISP) dedicated to the textual basis of the intercultural history of philosophy \u2013 Migrating Alphabets, which took place in Rome in the aula Marconi at the main seat of the National Re- search Council of Italy on 11 January 2011

Evidence for Composite Cost Functions in Arm Movement Planning: An Inverse Optimal Control Approach

An important issue in motor control is understanding the basic principles underlying the accomplishment of natural movements. According to optimal control theory, the problem can be stated in these terms: what cost function do we optimize to coordinate the many more degrees of freedom than necessary to fulfill a specific motor goal? This question has not received a final answer yet, since what is optimized partly depends on the requirements of the task. Many cost functions were proposed in the past, and most of them were found to be in agreement with experimental data. Therefore, the actual principles on which the brain relies to achieve a certain motor behavior are still unclear. Existing results might suggest that movements are not the results of the minimization of single but rather of composite cost functions. In order to better clarify this last point, we consider an innovative experimental paradigm characterized by arm reaching with target redundancy. Within this framework, we make use of an inverse optimal control technique to automatically infer the (combination of) optimality criteria that best fit the experimental data. Results show that the subjects exhibited a consistent behavior during each experimental condition, even though the target point was not prescribed in advance. Inverse and direct optimal control together reveal that the average arm trajectories were best replicated when optimizing the combination of two cost functions, nominally a mix between the absolute work of torques and the integrated squared joint acceleration. Our results thus support the cost combination hypothesis and demonstrate that the recorded movements were closely linked to the combination of two complementary functions related to mechanical energy expenditure and joint-level smoothness

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands