Inhibition of RNA helicases of ssRNA⁺ virus belonging to <i>Flaviviridae</i>, <i>Coronaviridae</i> and <i>Picornaviridae</i> families

Many viral pathogens encode the motor proteins named RNA helicases which display various functions in genome replication. General strategies to design specific and selective drugs targeting helicase for the treatment of viral infections could act via one or more of the following mechanisms: inhibition of the NTPase activity, by interferences with ATP binding and therefore by limiting the energy required for the unwinding and translocation, or by allosteric mechanism and therefore by stabilizing the conformation of the enzyme in low helicase activity state; inhibition of nucleic acids binding to the helicase; inhibition of coupling of ATP hydrolysis to unwinding; inhibition of unwinding by sterically blocking helicase translocation. Recently, by in vitro screening studies, it has been reported that several benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and Bananin derivatives are endowed with helicase inhibition of pathogen viruses belonging to Flaviviridae, Coronaviridae, and Picornaviridae families

L'acqua come risorsa paesaggistico-ambientale

Sumario: I. I diversi profili giuridicamente rilevanti del bene acqua. La sua progressiva rarefazione alla base della presa di coscienza del suo valore.— ii. L’ulteriore profilo dato dalla rilevanza paesaggistica.— iii. Il rapporto ambiente, paesaggio, pianificazioni.— iv. La non inconciliabilità della configurazione del bene culturale come bene ambientale.— v. Il governo del territorio come principale strumento di tutela paesaggistica. L’intreccio con gli altri aspetti di tutela dell’acqua.— vi. La tutela in via preventiva attraverso l’autorizzazione paesaggistica e i rapporti tra questa e il permesso di costruire.— vii. Le incongruenze nella disciplina attuale dell’autorizzazione paesistica in sanatoria.— viii. Considerazioni conclusive

Elevated plasma ceramide levels in post-menopausal women: a cross-sectional study.

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimer's disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) (β (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) (β (SE) = 2.88 (.61); p &lt; .0001) in women, and between age and ceramide (d18:1/24:1) in men (β (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women is at least partially associated with lower estradiol levels

[1,2,3]triazolo[4,5-<i>H</i>]chinoloni: una nuova classe di promettenti chemioterapici antitubercolari

Alcuni acidi triazolo[4,5-h] e [4,5-f]chinoloncarbossilici angolari, sintetizzati in precedenza come antiinfettivi del tratto urinario, hanno mostrato interessanti valori di MIC90 nei confronti di M. tuberculosis H37Rv. Allo scopo di approfondire le nostre conoscenze sui rapporti struttura-attività di questa classe, abbiamo pertanto preparato una nuove serie di derivati

Nuovi derivati chinossalinici inibitori della Diidrofolato Reduttasi (DHFR) e della Timidilato Sintetasi (TS) della <i>Leishmania major</i>: risultati preliminari

L’incidenza delle malattie protozoarie imputate al genere Leishmania è aumentata enormemente con la diffusione dell’AIDS. In particolare la forma viscerale della Leishmaniosi sta emergendo come malattia nuova e sempre più frequente. Oltre gli antimoniali altri farmaci importanti sono le pentammidine e l’amfotericina B. Un approccio abbondantemente esplorato in passato è stato lo sviluppo di farmaci antifolici antiprotozoari che bloccano il ciclo dell’acido folico, che, previa attivazione metabolica di enzimi folato dipendenti, attraverso il trasporto di unità carboniose, è responsabile della sintesi de novo degli acidi nucleici e degli amminoacidi. In questo senso sono stati usati il trimetoprim e la pirimetamina che sono attivi contro i plasmodi e i toxoplasmi, ma non contro le Leishmanie e i tripanosomi. Questi due protozoi appartenenti alla classe dei Kinetoplastidae sono sensibili agli antifolici antitumorali come il metotrexato (MTX), ma sviluppano immediatamente una chemioresistenza in quanto riattivano l’autoproduzione di acido folico mediante una via di salvataggio che impiega l’enzima Pteridina riduttasi, recentemente scoperto, appunto, nelle Leishmanie major e nel tripanosoma cruzi. Sulla base di queste premesse ci è sembrato che le nostre molecole a struttura chinossalinica, analoghe al metotrexato, potessero essere impiegate come inibitori enzimatici di questa famiglia di folato

TAPPE DI INTEGRAZIONE. FORMAZIONE CIVICA E INFORMAZIONE SULLA VITA CIVILE

Il testo Tappe d’integrazione prodotto nell’ambito di un progetto cofinanziato dall’Unione Europea e dal Ministero dell’Interno italiano, presenta una serie di materiali semplici e operativi elaborati dal Centro Come e dai docenti impegnati nei corsi di italiano per stranieri della rete della Cooperativa “Farsi prossimo” - Caritas regionali per accompagnare i primi passi dell’integrazione in Italia attraverso la conoscenza della città e dei servizi per tutti; le informazioni sull’uso dei servizi e delle opportunità; il sostegno per l’assunzione di ruoli sociali comuni, quali quello di lavoratore, genitore, paziente, consumatore...; l’esplicitazione dei diritti e dei doveri comuni.Il testo adotta il punto di vista dell’immigrato di recente arrivo e cerca di mettersi nei suoi panni per rispondere alle domande d’informazione più immediate e alle necessità proprie della prima fase di inserimento.Può essere utilizzato in classe, nell’ambito dei percorsi di formazione linguistica, proponendo quindi l’italiano per vivere e per fare, il lessico e le strutture linguistiche legate alla prima comunicazione e al livello cosiddetto di “sopravvivenza”. Può essere utilizzato anche nelle sessioni di “formazione civica e informazione sulla vita civile”, rivolte agli immigrati di recente arrivo che sottoscrivono l’accordo di integrazione o che devono acquisire i crediti necessari per il permesso di soggiorno.I materiali informativi sono stati costruiti dai docenti – sulla base di un’idea progettuale e di un format condivisi – proprio grazie alla disponibilità dei corsisti, i quali hanno vi hanno messo la loro faccia, ma hanno anche contribuito a definire meglio la storia, a precisare le domande, le situazioni e i bisogni, a indicare le urgenze e le mosse da intraprendere.La particolarità del testo Tappe d’integrazione sta quindi anche nel processo che ha portato alla sua realizzazione e che ha visto gli immigrati coinvolti in prima persona nel loro cammino d’integrazione.Stages of integrationCivic education and information on civil lifeThe text “Stages of integration”, written as part of a project co-financed by the European Union and the Italian Ministry of the Interior, presents a number of simple easy-to-use materials designed by the CENTRO COME and by the teachers engaged in the Italian language courses for foreigners within the Cooperative network “FARSI PROSSIMO” - CARITAS REGIONALI to facilitate the first steps in integration in Italy through knowledge of the city and the services available; information on the use of these services and opportunities; support for assuming common social roles, such as that of worker, parent, patient, consumer...; the explanation of common rights and duties.The text adopts the point of view of a newly arrived immigrant and tries to respond from this viewpoint to requests for necessary information and to needs specific to the first phase of integration.It can be used in the classroom as part of language training, presenting the Italian needed in everyday life, the vocabulary and linguistic structures related to basic communication at the so-called “survival” level. It can also be used during “civic education and information on civil life” presentations, for newly arrived immigrants who sign an integration agreement or who need to acquire the credits necessary for a residence permit.The information materials were designed by teachers – who worked together on this project and created a shared format - thanks to the willingness of the participants, who helped to better define the story, clarify the questions, situations and needs, indicating what was urgent and needed to be addressed.The peculiarity of “Stages of integration” is therefore also in the process that led to its creation, featuring immigrants personally involved in their journey of integration

Monitoring dynamics in bacterial competition by Imaging Mass Spectrometry

Microbial competition is a mechanism that occurs when two or more microbial species compete for ecological niches to support their survival and growth (Hibbing et al. 2010). Different factors can contribute to the outcome of microbial competition, such as molecules exchanged between the competing organisms for the regulation of cell densities and the initial spatial configuration of the microbe–microbe interaction. Specifically, production of compounds that kill or limit the growth of competing strains or species can promote niche monopolization (Gonzalez et al. 2011). The released compounds include secondary metabolite antibiotics, bacterial peptides or low-molecular-mass organic compounds. In that sense, it is very important to develop tools that could capture metabolic interactions between two or more bacterial populations. Imaging Mass Spectrometry (IMS) enables the visualization of both spatial and temporal production of a huge number of metabolites from a single bacterial species and can observe the effects of multiple microbial signals in an interspecies interaction without using tags or labels (Yang et al. 2009). This technique has the potential to be used for identification of novel metabolites and peptides that were previously undetected by other analytical methods. In this work, a combination of IMS and LC-MS/MS was used to study the competition between Listeria monocytogenes (LM) and Lactococcus lactis (LAC) to investigate the metabolic profile of each bacterium in the interacting microbial colonies. IMS analysis revealed several interesting compounds during interaction of microbial colonies. At least six compounds are uniquely expressed during the interaction between LM and LAC. These results could be useful to setup new molecular strategies in the control of bacterial species for a better food safety

Haplotype affinities resolve a major component of goat (<i>Capra hircus</i>) MtDNA D-loop diversity and reveal specific features of the Sardinian stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity. We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.</br