Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase

Quantitative value of aldosterone-renin ratio for detection of aldosterone-producing adenoma: The Aldosterone-Renin Ratio for Primary Aldosteronism (AQUARR) study

Background Current guidelines recommend use of the aldosterone\u2010renin ratio (ARR) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false\u2010positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and Results We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone\u2010producing adenoma as reference index. We also assessed whether the post\u2010captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false\u2010positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post\u2010captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between\u2010area under the curve difference, 0.005; 95% CI, 120.031 to 0.040; P=0.7 for comparison, and 0.05; 95% CI, 120.061 to 0.064; P=0.051 for comparison, respectively). Conclusions These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Il consumo senza (pi\uf9) meraviglia

Per i critici del consumismo, l\u2019aspetto deteriore della societ\ue0 dei consumi continua a situarsi nello spreco (si compra troppo e lo si scarta rapidamente, senza averlo debitamente impiegato) e nella scarsa utilit\ue0 della maggior parte delle cose che si comprano. L\u2019affermazione di un consumo senza pi\uf9 il senso del limite \u2013secondo queste critiche- rallenta o annichilisce del tutto le possibilit\ue0 di sviluppo dei 4/5 del mondo e, volatilizzando irresponsabilmente le risorse planetarie, pone una grave ipoteca sulla qualit\ue0 della vita delle generazioni future. Dal punto di vista simbolico, per\uf2, il fatto di consumare azzerando i limiti comporta un pericolo molto forte anche per quel quinto di umanit\ue0 che \u201cspreca risorse in cose inutili\u201d. I limiti, infatti, sono parte integrante di ogni ritualit\ue0; anzi, il rito \ue8 propriamente un processo codificato e condiviso \u2013perci\uf2 anche \u201ccontrollato\u201d- di superamento dei limiti. Smarrendo la propria natura rituale, il consumo senza il senso del limite diventa un consumo senza senso, tout court

La fame d'esperienza degli italiani

Si fa strada nella societ\ue0 un sentimento di disincanto, che investe tanto i media quanto la comunicazione delle aziende e della politica. Tale sfiducia non \ue8, semplicemente, la conseguenza di un attacco di panico sociale e nemmeno l\ubfapplicazione di una \ubfstrategia antagonista\ubf; piuttosto, \ue8 quel tipo di scoramento che ci prende ogni qual volta rivolgiamo a una persona, in cui riponiamo stima e speranze, una domanda per noi molto rilevante, e ci sentiamo dare una risposta del tutto fuori tema. Basandosi su una serie aggiornata di dati forniti da aziende, istituti di ricerca, e think-tank universitari, \ubfLa fine della meraviglia\ubf descrive le cause e le dinamiche di questo disagio, lanciando un allarme a chi si occupa di comunicazione e \ubfal contempo- proponendo un rimedio possibile

Le nuove frontiere del marketing

saggio sull¿evoluzione del marketing esperienzial

Alla ricerca della perduta meraviglia: la comunicazione e le angosce dell'uomo post-moderno

Uno dei maggiori scogli che i comunicatori devono oggi affrontare \ue8 dato dall\u2019atteggiamento di sottile diffidenza e dal generale disincanto che pervadono i cittadini-consumatori. I cittadini-consumatori sembrano una macchina che, per produrre consenso e consumo, necessita di sollecitazioni emotive sempre pi\uf9 intense; stimoli che vengono peraltro assunti e smaltiti in pochissimo tempo

Role of MR Spectroscopy (H1-MRS) of the Testis in Men with Semen Analysis Altered

Purpose: Proton magnetic resonance spectroscopy (1 H-MRS) has been proposed as a tool to assess male infertility providing metabolic signatures related to the spermatogenesis in the testis. This study sought to identify the role of 1 H-MRS in the diagnosis of infertility in patients with semen analysis altered. Materials and Methods: 14 patients (27 testicles) with fertility problems and with an altered semen analysis (5 oligospermia, 3 asthenospermia, 6 oligoasthenospermia) and 9 controls (18 testicles) with normal spermatogenesis assessed (men with prior paternity and normal semen analysis) and normal testicles at magnetic resonance (MR) and ultrasonography (US) with colour Doppler (CD) examination were included. All patients underwent testis US and CD investigation, conventional MR examination at 1.5T including T1 and T2 weighted images in three orthogonal planes and proton magnetic resonance spectroscopy (1 H-MRS) with single-voxel PRESS (TR 2000 ms / TE 31 ms). Major metabolites peaks (choline, creatine, lipids, lactate) were calculated and compared between the patients and controls. Results: Mean choline peak in the semen analysis altered group was statistically significantly lower than the normal group (0.69 vs 1.34, 95% CI: 0.52 - 0.85; p < 0.001). 18 testicles within semen analysis altered group (66,7%) had both MR and US examination negative but mean choline peak lower then controls (1.09 vs 1.34, p < 0.001). 7 testicles of those presented also varicocele at CD investigation. Conclusion: 1 H-MRS revealed a significant shift towards lower choline peak in patients with semen analysis altered compared to controls with normal spermatogenesis. Moreover 1 HMRS provided to find out spermatogenesis disorder in patients with normal testis at MR and US examination