Michail Michajlovič Bachtin: Exotopia ed azione responsabile

Aquest article intenta reflexionar sobre els orígens del pensament de M. Bajtin, adoptant una mirada crítica sobre la reducció postmoderna operada entorn d'aquest autor. S'hi investiguen les seves obres inèdites mostrant la importància de recórrer els seus primers escrits. Es tracta de tornar “la paraula” a Bajtin, enfocant la fecunda proposta de l'autor explicitada en els conceptes d'experiència, realitat i, el més important, “exotopia”

Radici teologiche della metafisica di Xavier Zubiri

Aquest treball planteja l'anàlisi de les possibles arrels teològiques del pensament metafísic del filòsof Xavier Zubiri. Al llarg del treball anirem investigant el sistema metafísic d'un pensador que representa la problemàtica de replantejar la filosofia i la teologia segons un marc originari, retornant a les dues disciplines el seu significat primari. I per aconseguir aquest objectiu, hem considerat necessari fer un recorregut en el pensament d'un gran autor i buscar en això les possibles arrels teològiques, a través del diàleg amb la tradició filosòfica. Després de l'estudi de l'obra Sobre l'essència, i de les preocupacions metafísiques aquí elaborades, ens proposem esbrinar les assercions teològiques, sobre la realitat divina, concebuda com extàtica efusió de l'àgape, categoria metafísica de la realitat divina i via d'accés per la deïficació de l'home, considerat essència oberta i constitutivament relligat. La tesi està dividida en tres parts. En la primera ens ocuparem del context històric en el qual s'ha desenvolupat el pensament del jove pensador, fins a la trobada amb Viktor Warnach i la superació de les doctrines modernistes. En la segona, la part més sistemàtica, centrarem la dissertació en Sobre l' essència, subratllant els passatges més significatius pel que es refereix a la presència de la teologia grega i paulina. En la tercera i última part, es tanca el cercle obert amb les primeres dues seccions, amb l'aportació dels textos teològics del filòsof, per complir un pas ulterior cap a l'aplicació directa de les qüestions teològiques a la metafísica de Zubiri. L'experiència religiosa i la intel·lectual formen un conjunt, concebut a la llum d'una nova interpretació biogràfica i a partir de la font conceptual de la Teologia paulina i de la Teologia del misteri. La metafísica de l'autor, segons la nostra recerca, no pot prescindir d'aquest fonamental context religiós. I és gràcies a aquest nou enfocament que la filosofia de Zubiri adquireix profunditat en la cerca de les qüestions últimes, en acord amb l'infatigable labor de la filosofia per aconseguir la veritat.Este trabajo plantea el análisis de las posibles raíces teológicas del pensamiento metafísico del filosofo Xavier Zubiri. A lo largo del trabajo iremos investigando el sistema metafísico de un pensador que representa la problemática de replantear la filosofía y la teología según un marco originario, devolviendo a las dos disciplinas su significado primario. Y para lograr este objetivo, hemos considerado necesario hacer un recorrido en el pensamiento de un gran autor y buscar en ello las posibles raíces teológicas, a través del dialogo con la tradición filosófica. A través del estudio de la obra Sobre la esencia, y de las preocupaciones metafísicas ahí elaboradas, nos proponemos averiguar las aserciones teológicas, sobre la realidad divina, concebida como extática efusión del ágape, categoría metafísica de la realidad divina y vía de acceso para la deificación del hombre, considerado esencia abierta y constitutivamente religada. La tesis está dividida en tres partes. En la primera nos ocuparemos del contexto histórico en el cual se han desarrollado el pensamiento del joven pensador, hasta el encuentro con Viktor Warnach y la superación de las doctrinas modernistas. En la segunda, la parte más sistemática, centraremos la disertación en Sobre la esencia, subrayando los pasajes más significativos por lo que se refiere a la presencia de la teología griega y paulina. En la tercera y última parte, se cierra el círculo abierto con las primeras dos secciones, con el aporte de los textos teológicos del filósofo, para cumplir un paso ulterior hacia la aplicación directa de las cuestiones teológicas a la metafísica de Zubiri. La experiencia religiosa y la intelectual forman un conjunto, concebido a la luz de una nueva interpretación biográfica y a partir de la fuente conceptual de la Teología paulina e de la Teología del misterio. La metafísica del autor, según nuestra investigación, no puede prescindir de este fundamental contexto religioso. Y es gracias a este nuevo enfoque que la filosofía de Zubiri adquiere profundidad en la búsqueda de las cuestiones últimas, en acuerdo con el infatigable labor de la filosofía para alcanzar la verdad.This work presents the analysis of possible theological roots of metaphysical thought of the philosopher Xavier Zubiri. Throughout the work we will be investigating the metaphysical system of a thinker who represents rethink the problem of philosophy and theology as an original framework, the two disciplines returning to its primary meaning. And to achieve this purpose, we have found it necessary to take a tour at the thought of a great philosopher and look at it possible theological roots, through dialogue with the philosophical tradition. Through the study of the work on the essence, and there elaborate metaphysical concerns, we intend to find out the theological assertions about the divine reality, conceived as ecstatic outpouring of agape, metaphysical category of divine reality and path for deification of man, considered open and constitutively religated essence. The thesis is divided into three parts. In the first we look at the historical context in which they have developed the thought of the young philosopher, to the meeting with Viktor Warnach and overcoming modernist doctrines. In the second, the systematic part, the dissertation will focus on the essence, highlighting the most significant passages so it refers to the presence of Greek and Pauline theology. In the third and final part, the circle opened with the first two sections, with the contribution of theological texts of the philosopher, to fulfill a further step towards the direct application of theological metaphysics of Zubiri issues is closed. The religious experience and intellectual form a set, designed in the light of a new biographical interpretation and from the conceptual source of Pauline theology and the theology of the mystery. The metaphysics of the author, according to our research, cannot do without this fundamental religious context. And it is thanks to this new approach to the philosophy of Zubiri acquires depth in search of the latest issues, according to the tireless work of philosophy to reach the truth

Nationwide Survey of Healthcare Services for Autism Spectrum Disorders (ASD) in Italy

n/

Targeting SARS-CoV-2 Main Protease: A Successful Story Guided by an In Silico Drug Repurposing Approach

The SARS-CoV-2 main protease (Mpro) is a crucial enzyme for viral replication and has been considered an attractive drug target for the treatment of COVID-19. In this study, virtual screening techniques and in vitro assays were combined to identify novel Mpro inhibitors starting from around 8000 FDA-approved drugs. The docking analysis highlighted 17 promising best hits, biologically characterized in terms of their Mpro inhibitory activity. Among them, 7 cephalosporins and the oral anticoagulant betrixaban were able to block the enzyme activity in the micromolar range with no cytotoxic effect at the highest concentration tested. After the evaluation of the degree of conservation of Mpro residues involved in the binding with the studied ligands, the ligands’ activity on SARS-CoV-2 replication was assessed. The ability of betrixaban to affect SARS-CoV-2 replication associated to its antithrombotic effect could pave the way for its possible use in the treatment of hospitalized COVID-19 patient

Halogenated triazinediones behave as antagonists of PKR1: in vitro and in vivo pharmacological characterization

Different prokineticin receptor antagonists, based on the triazinedione scaffold, were synthesized by a new efficient method. Here we demonstrated that 5-benzyltriazinedionessubstituted in position para of the benzyl group with halogens provide compounds endowed with interesting selectivity for the Prokineticin receptor 1 (PKR1). BRET technology indicates that such substitutionresults in increased affinity for thePKR1.The affinity for PKR2, always in M range, was never significantly affected by the para-halogen-benzyl pharmacophores. The analog bearing a para-bromobenzyl pharmacophore (PC-25) displayed the highest affinity for PKR1 (~18 times higher than the reference PC-1 that bears apara-ethyl benzyl group) and the highest selectivity (~300 times). The other halogen substitutedanalogs (PC-7, PC-18 and PC-35), showed selectivity for PKR1 more than 100 times higher than for PKR2. Using transgenic mice lacking one of the two PKRs we demonstrated that all these compounds were able to abolish the Bv8-induced hyperalgesia in mice still expressing the PKR1 at doses lower than those necessary to abolish hyperalgesia in mice expressing only the PKR2. The dose ratio reflected the in- vitro evaluated receptor selectivity

Update on SARS-CoV-2 Omicron Variant of Concern and Its Peculiar Mutational Profile

The process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversification is still ongoing and has very recently led to the emergence of a new variant of concern (VOC), defined as Omicron or B.1.1.529. Omicron VOC is the most divergent variant identified so far and has generated immediate concern for its potential capability to increase SARS-CoV-2 transmissibility and, more worryingly, to escape therapeutic and vaccine-induced antibodies. Nevertheless, a clear definition of the Omicron VOC mutational spectrum is still missing. Herein, we provide a comprehensive definition and functional characterization (in terms of infectivity and/or antigenicity) of mutations characterizing the Omicron VOC. In particular, 887,475 SARS-CoV-2 Omicron VOC whole-genome sequences were retrieved from the GISAID database and used to precisely define its specific patterns of mutations across the different viral proteins. In addition, the functional characterization of Omicron VOC spike mutations was finely discussed according to published manuscripts. Lastly, residues characterizing the Omicron VOC and the previous four VOCs (Alpha, Beta, Gamma, and Delta) were mapped on the three-dimensional structure of the SARS-CoV-2 spike protein to assess their localization in the different spike domains. Overall, our study will assist with deciphering the Omicron VOC mutational profile and will shed more light on its clinical implications. This is critical considering that Omicron VOC is currently the predominant variant worldwide. IMPORTANCE The Omicron variant of concern (VOC) has a peculiar spectrum of mutations characterized by the acquisition of mutations or deletions rarely detected in previously identified variants, particularly in the spike glycoprotein. Such mutations, mostly residing in the receptor-binding domain, could play a pivotal role in enhancing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity (by increasing binding affinity for ACE2), jeopardizing spike recognition by therapeutic and vaccine-induced antibodies and causing diagnostic assay failure. To our knowledge, this is one of the first exhaustive descriptions of newly emerged mutations underlying the Omicron VOC and its biological and clinical implications

Targeting SARS-CoV-2 nsp13 Helicase and Assessment of Druggability Pockets: Identification of Two Potent Inhibitors by a Multi-Site In Silico Drug Repurposing Approach

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5′ to 3′ direction and acts in concert with the replication–transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme’s binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range

Molecular and Structural Aspects of Clinically Relevant Mutations of SARS-CoV-2 RNA-Dependent RNA Polymerase in Remdesivir-Treated Patients

(1) Background: SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target to fight COVID-19, and many RdRp inhibitors nucleotide/nucleoside analogs, such as remdesivir, have been identified or are in clinical studies. However, the appearance of resistant mutations could reduce their efficacy. In the present work, we structurally evaluated the impact of RdRp mutations found at baseline in 39 patients treated with remdesivir and associated with a different degree of antiviral response in vivo. (2) Methods: A refined bioinformatics approach was applied to assign SARS-CoV-2 clade and lineage, and to define RdRp mutational profiles. In line with such a method, the same mutations were built and analyzed by combining docking and thermodynamics evaluations with both molecular dynamics and representative pharmacophore models. (3) Results: Clinical studies revealed that patients bearing the most prevalent triple mutant P323L+671S+M899I, which was present in 41% of patients, or the more complex mutational profile P323L+G671S+L838I+D738Y+K91E, which was found with a prevalence of 2.6%, showed a delayed reduced response to remdesivir, as confirmed by the increase in SARS-CoV-2 viral load and by a reduced theoretical binding affinity versus RdRp ( Delta Gbind(WT) = 122.70 kcal/mol; Delta Gbind(P323L+ 671S+M899I) = 84.78 kcal/mol; Delta Gbind(P323L+ G671S+L838I+D738Y+K91E) = 96.74 kcal/mol). Combined computational approaches helped to rationalize such clinical observations, offering a mechanistic understanding of the allosteric effects of mutants on the global motions of the viral RNA synthesis machine and in the changes of the interactions patterns of remdesivir during its binding

Echocardiographically defined haemodynamic categorization predicts prognosis in ambulatory heart failure patients treated with sacubitril/valsartan

Aim: Echo-derived haemodynamic classification, based on forward-flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan. Methods and results: In our multicentre, open-label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m2 ) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e': ≥ or <15): Profile-A: normal-flow, normal-pressure; Profile-B: low-flow, normal-pressure; Profile-C: normal-flow, high-pressure; Profile-D: low-flow, high-pressure. Patients were started on sacubitril/valsartan and followed-up for 12.3 months (median). Rates of the composite of death/HF-hospitalization were assessed by multivariable Cox proportional-hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile-D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile-A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event-rate (per 100 patients per year) progressively increased from Profile-A to Profile-D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate-adjusted Cox model, profiles with low forward-flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC-score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high-dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile. Conclusions: Echocardiographically-derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real-world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles