Novel 4h-chromen-4-one, 2h-chromene and chroman derivatives: design, synthesis and biological evaluation

La progettazione e sintesi di nuovi antivirali strutturalmente correlati a flavanoidi e flavonoidi sia naturali che sintetici e lo studio della relativa attività anti-picornavirus dei 4H-cromen-4-oni e 2H-cromeni ha portato ad identificare l’(E)-3-stiril-2H-cromene come un inibitore potente, selettivo e ad ampio spettro d’azione nei confronti dei rhinovirus umani (HRV). l’(E)-3-stiril-2H-cromene è stato perciò selezionato come hit compound sul quale effettuare uno studio sistematico di ottimizzazione della struttura. Sono stati quindi progettati e sintetizzati un ampio numero di arilalchil cromeni, cromanoni e cromoni che sono stati saggiati in vitro nei confronti dei sierotipi 14 e 1B di HRV, scelti come rappresentati rispettivamente dei gruppi A e B di HRV. L’estensione dello screening ad altri virus ad RNA conferma la bassa citotossicità e la selettività dell’azione anti-HRV. Sono stati così selezionati i composti più potenti, ad ampio spettro d’azione anti-HRV e con alto indice terapeutico per valutarne il meccanismo d’azione. I risultati ottenuti sia sulla particella virale che sulla moltiplicazione virale suggeriscono che tutti i composti selezionati si comportano da capsid-binder, interferendo con le prime fasi dell’infezione virale, ma mentre l’(E)-3-stiril-2H-cromene agisce sull’adsorbimento del virus al recettore cellulare gli altri composti studiati non interferiscono in questa fase ma solo sul processo di uncoating. Il risultato è di notevole interesse dal momento che l’utilizzo di combinazioni di farmaci che agiscono su fasi successive della replicazione virale potrebbe essere utile per superare il problema delle mutazioni virali che rendono rapidamente inefficace la monoterapia

Novel 4h-chromen-4-one, 2h-chromene and chroman derivatives: design, synthesis and biological evaluation

La progettazione e sintesi di nuovi antivirali strutturalmente correlati a flavanoidi e flavonoidi sia naturali che sintetici e lo studio della relativa attività anti-picornavirus dei 4H-cromen-4-oni e 2H-cromeni ha portato ad identificare l’(E)-3-stiril-2H-cromene come un inibitore potente, selettivo e ad ampio spettro d’azione nei confronti dei rhinovirus umani (HRV). l’(E)-3-stiril-2H-cromene è stato perciò selezionato come hit compound sul quale effettuare uno studio sistematico di ottimizzazione della struttura. Sono stati quindi progettati e sintetizzati un ampio numero di arilalchil cromeni, cromanoni e cromoni che sono stati saggiati in vitro nei confronti dei sierotipi 14 e 1B di HRV, scelti come rappresentati rispettivamente dei gruppi A e B di HRV. L’estensione dello screening ad altri virus ad RNA conferma la bassa citotossicità e la selettività dell’azione anti-HRV. Sono stati così selezionati i composti più potenti, ad ampio spettro d’azione anti-HRV e con alto indice terapeutico per valutarne il meccanismo d’azione. I risultati ottenuti sia sulla particella virale che sulla moltiplicazione virale suggeriscono che tutti i composti selezionati si comportano da capsid-binder, interferendo con le prime fasi dell’infezione virale, ma mentre l’(E)-3-stiril-2H-cromene agisce sull’adsorbimento del virus al recettore cellulare gli altri composti studiati non interferiscono in questa fase ma solo sul processo di uncoating. Il risultato è di notevole interesse dal momento che l’utilizzo di combinazioni di farmaci che agiscono su fasi successive della replicazione virale potrebbe essere utile per superare il problema delle mutazioni virali che rendono rapidamente inefficace la monoterapia

Do neurogenic and cancer-induced muscle atrophy follow common or divergent paths?

Skeletal muscle is a dynamic tissue capable of responding to a large variety of physiological stimuli by adjusting muscle fiber size, metabolism and function. However, in pathological conditions such as cancer and neural disorders, this finely regulated homeostasis is impaired leading to severe muscle wasting, reduced muscle fiber size (atrophy), and impaired function. These disease features develop due to enhanced protein breakdown, which relies on two major degradation systems: the ubiquitin-proteasome and the autophagy-lysosome. These systems are independently regulated by different signalling pathways, which in physiological conditions, determine protein and organelle turnover. However, alterations in one or both systems, as it happens in several disorders, leads to enhanced protein breakdown and muscle atrophy. Although this is a common feature in the different types of muscle atrophy, the relative contribution of each of these systems is still under debate. Here, we will briefly describe the regulation and the activity of the ubiquitin-proteasome and the autophagy-lysosome systems during muscle wasting. We will then discuss what we know regarding how these pathways are involved in cancer induced and in neurogenic muscle atrophy, highlighting common and divergent paths. It is now clear that there is no one unifying common mechanism that can be applied to all models of muscle loss. Detailed understanding of the pathways and proteolysis mechanisms involved in each model will hopefully help the development of drugs to counteract muscle wasting in specific conditions

Founder-involvement in R&D and SMEs performance. An expanded mediated-moderated framework

Objectives. The aim of the paper is to shed light on the pivotal role of founders’ involvement in R&D and its reflexes on SMEs performance. Methodology. A conceptual framework was outlined and operationalized in terms of a mediation/moderation model. Hypotheses were developed and tested it on a random sample of 350 SMEs locate in low research-intensive areas of Southern Italy. An augmented cross-sectional design, which measures key variables using different sources at different time points, was employed. We adopted a seemingly unrelated regression to jointly analyze variables and their interactions. Findings. We observe that founders’ involvement in R&D influence positively SMEs’ performance. We also found evidence that founders’ involvement in R&D-SMEs performance association is mediated by R&D resources, Quality of the technological knowledge, and innovation outputs. At the same time the R&D resources - Quality of the technological knowledge association is positively moderated by the share of R&D subsidies. Research limits. Our study is affected by various limitations. As an example, only revenue-based measures are used as a proxy of firm performance. In addition, for controlling heterogeneity in estimates, data refer to a well-defined time window as well as to manufacturing SMEs located in specific low-research intensity geographic areas of Italy. Practical implications. Our study reveals that founders - with their firm- and context-specific capabilities - while enmeshed with R&D activities, contribute to SMEs performance. Policy makers should create incentives for founders to be involved to some extent in inventive activities. Further implications are also envisaged for both funding and training educational services. Originality of the study. Building on the intersection between resource orchestration and competence-based perspectives, we conceived and empirically analyzed founders as key actors for inventive resource orchestration at the firm level and how and under what conditions the resource orchestration made by founders is likely to nurture the performance even of low research-intensive SMEs

Letter to editor regarding: "Vertebral bone quality score independently predicts cage subsidence following transforaminal lumbar interbody fusion."

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Fuzzy Clustering Using the Convex Hull as Geometrical Model

A new approach to fuzzy clustering is proposed in this paper. It aims to relax some constraints imposed by known algorithms using a generalized geometrical model for clusters that is based on the convex hull computation. A method is also proposed in order to determine suitable membership functions and hence to represent fuzzy clusters based on the adopted geometrical model. The convex hull is not only used at the end of clustering analysis for the geometric data interpretation but also used during the fuzzy data partitioning within an online sequential procedure in order to calculate the membership function. Consequently, a pure fuzzy clustering algorithm is obtained where clusters are fitted to the data distribution by means of the fuzzy membership of patterns to each cluster. The numerical results reported in the paper show the validity and the efficacy of the proposed approach with respect to other well-known clustering algorithms

R.I.P. 2020: Universal Spiritual Renewal Through Noise - Funeral Rebirth in Boris and Merzbow’s 2R0I2P0

In a world interrupted by the COVID-19 pandemic, our society will never be the same as before and there is a sense that change is necessary in order to overcome the crisis. This feeling is grappled with and explored by the experimental rock band Boris in collaboration with noise artist Merzbow, who invite us to erect a tombstone to the year 2020 and to be reborn through sonic spirituality. This review analyses the collaboration album 2R0I2P0 by highlighting how the Japanese artists direct the listener to explore their inner self. They suggest that rebirth from the emergency can happen only by creating a link between the natural and the industrial world to rediscover a sense of purity

From online to offline: Getting ready for in-person fieldwork through social media ethnography

Since the onset of the COVID-19 pandemic, there has been a significant emphasis on finding solutions to continue academic research in light of closed borders. The inability to travel has prompted academic researchers to reconsider their approaches to fieldwork, with a particular focus on utilizing modern technology effectively to conduct accurate ethnographic research even while working remotely. This has entailed navigating the vast expanse of the internet carefully and acquiring additional tools in the field of ethnography. The primary concerns surrounding conducting remote fieldwork and ensuring the proper selection of data can be summarized by exploring strategies to overcome the challenges imposed by restrictions, as well as leveraging modern technology to study distant cultures without compromising comprehension. Taking into consideration my research on the Japanese experimental noise music scene and the necessity to collect information about the response and activities of these artists at the brink of the pandemic, I challenged my need to collect data by practising through the internet and modern technologies new ways to undertake ethnographic research through distance. In this sense, social networks demonstrated how modern ethnographic methods can be effectively applied to conduct functional social media ethnography, mitigating the challenges brought about by physical distance constraints. Specifically for my research, Reddit’s feature of organizing communities into subtopics named “subreddits” provides me with the possibility to keep in touch with reliable users and information by selecting specific subreddits related to Japan and music topics (e.g. “r/japaneseunderground”, “r/noisemusic”). Along with the existing literature and the constant online research for news related to my project, social media ethnography played a functional role not only in collecting relevant data but also in providing me with more clarity about how to further move my fieldwork once I can travel to Japan. By emphasizing the potential of social media as a valuable avenue to enhance research strategies in times of crisis, this paper aims to consider how online fieldwork created to overcome the impossibility of fieldwork travel can result in a profitable social media ethnography not only to collect data by distance but also to gain appropriate preparation for following in-person fieldwork by relying on our primary findings. By retracing step by step my research project on Japanese noise music, I will explain how undertaking online research provided me with further ideas to achieve more findings and add clarities to my research intent once I had to switch to offline fieldwork

Noise As An Act Of Free Will In Aoyama Shinji’s Movie Eli, Eli, Lema Sabachthani?

The theme of how noise music would deal with the interruption to social life caused by a pandemic has been portrayed in Aoyama Shinji’s movie Eli Eli, Lema Sabachthani? (2005), whose plot is centred on how listening to the purity of noise is able to cure a disease. By relying on noise aesthetic theories and both historical and spiritual insights, this paper will analyse this movie through the eyes of the COVID-19 pandemic, highlighting how the movie’s visual symbolism aims to represent noise as a response to incertitude, underlining how free will is inherent in humans and should be used to improve our society

(E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino) pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 ¼ 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 ¼ 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent