Genetic susceptibility to Candida infection: A new look at an old entity

In recent years, several studies have shed light on the pathogenesis of many novel immune defects associated with narrow susceptibility to bacterial, viral and fungal infections. Genetically determined forms of susceptibility to Candida species infection, which had been elusive for a long time, have been recognized. Refractory or recurrent infections of skin, nails and the mucous membranes are clinical signs of chronic mucocutaneous candidiasis, frequently associated with immunological defects in the Th17 subset, which is crucial for host response against infections at mucosal and epithelial sites. Here we review the main clinical features and the mechanisms of diseases which share CMC as main phenotype

5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action

In the effort to identify and develop new HIV-1 inhibitors endowed with innovative mechanisms, we focused our attention on the possibility to target more than one viral encoded enzymatic function with a single molecule. In this respect, we have previously identified by virtual screening a new indolinone-based scaffold for dual allosteric inhibitors targeting both reverse transcriptase-associated functions: polymerase and RNase H. Pursuing with the structural optimization of these dual inhibitors, we synthesized a series of 35 new 3-[2-(4-aryl-1,3-thiazol-2-ylidene)hydrazin-1-ylidene]1-indol-2-one and 3-[3-methyl-4-arylthiazol-2-ylidene)hydrazine-1-ylidene)indolin-2-one derivatives, which maintain their dual inhibitory activity in the low micromolar range. Interestingly, compounds 1a, 3a, 10a, and 9b are able to block HIV-1 replication with EC50 < 20 µM. Mechanism of action studies showed that such compounds could block HIV-1 integrase. In particular, compound 10a is the most promising for further multitarget compound development

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors

New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII

In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a-m). All synthesized compounds, with the exception of compound EMAC10101k, preferentially inhibit off-target hCA II isoform. Within the series, compound EMAC10101d, bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range

Ribonuclease H/DNA polymerase HIV-1 reverse transcriptase dual inhibitor: mechanistic studies on the allosteric mode of action of isatin-based compound RMNC6

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 R

Analysis of the impact of length of stay on the quality of service experience, satisfaction and loyalty

Although length of stay is a relevant variable in destination management, little research has been produced connecting it with tourists' post-consumption behaviour. This research compares the post-consumption behaviour of same-day visitors with overnight tourists in a sample of 398 domestic vacationers at two Mediterranean heritage-and-beach destinations. Although economic research on length of stay posits that there are destination benefits in longer stays, same-day visitors score higher in most of the post-consumption variables under study. Significant differences arise in hedonic aspects of the tourist experience and destination loyalty. Thus, we propose that length of stay can be used as a segmentation variable. Furthermore, destination management organisations need to consider length of stay when designing tourism policies. The tourist product and communication strategies might be adapted to different vacation durations

LA RELAZIONE TRA PROCESSI EMOTIVI E PROCESSI DI CONTROLLO COGNITIVO: I MECCANISMI DI CONFLITTO E INTERAZIONE

Nell’ultimo decennio si è sviluppato notevolmente lo studio della relazione tra processi emotivi e processi di controllo cognitivo e, attualmente, è stata sottolineata la similarità tra questi due processi. Pensiamo, per esempio, allo sviluppo dei modelli del doppio processo nell’ambito di studio delle emozioni (Barrett et al., 2007), secondo cui i processi emotivi comprendono forme di elaborazione automatica e controllata così come i processi cognitivi. In accordo con questa prospettiva, risulta necessario chiarire alcune questioni fondamentali sulla similarità tra emozioni e processi cognitivi e sui loro meccanismi di interazione. Le ricerche sull’argomento si sono interessate a due aspetti, uno riguarda il ruolo dei processi di controllo cognitivo nella regolazione emotiva, l’altro si focalizza sull’influenza delle emozioni sui processi di controllo del pensiero e del comportamento. L’obiettivo di questa rassegna critica della letteratura è di approfondire quest’ultimo filone di ricerca considerando, in particolare, la prospettiva secondo cui gli stati emotivi sarebbero attivati automaticamente e, conseguentemente, interferirebbero sull’esecuzione di compiti che richiedono controllo esecutivo (Gray, 2004; Zelazo, 2006). A tal fine, verrà delineata una prospettiva teorico/metodologica che integra i principali modelli teorici e le ricerche appartenenti a questo ambito di studi delle scienze cognitive

Assessment of renaturation measures for improvements in ecosystem services and flood risk mitigation

The present paper offers a contribution to the research on social acceptance of interventions aimed at water ecosystem improvement and flood risk mitigation through renaturation measures. A CE study has been implemented to assess trade-offs between attributes of alternative projects, including social costs deriving from proposed actions of renaturation of river flows. The aim of our approach is to investigate the role of attitudinal factors in the valuation of costs and benefits generated by renaturation measures. A Hybrid Latent Class (HLC) model is applied to the data, revealing the existence of two distinct groups, characterised by different valuations of the attributes of the project. It is found that class membership depends on latent attitudes toward environmental protection and risk perception. Our study confirms the fruitfulness of the HLC modelling approach in stated preference studies regarding ecosystems valuation, as it provides a richer understanding of public preferences and allows more finely targeted policy indications