Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

Identification of enzyme-producing thermophilic bacilli isolated from marine vents of Aeolian Islands (Italy)

Enzyme-producing thermophilic bacilli were isolated from different thermal sites located in and around Aeolian Islands (Italy) and characterised by both molecular and culture-based methods. Spore-forming bacteria with optimal growth from 45 to 70 °C were isolated from submarine vents and a geothermal well of Aeolian Islands (Italy). Eighteen selected strains were screened for extracellular enzyme presence by using nine substrates: Tween 20, Tween 80, tributyrin, soluble starch, xylan, dextran, carragenan, gelatine and casein. Sixteen isolates were able to grow at pH 9. The isolates were differentiated on the basis of restriction pattern of their amplified 16S rDNA (ARDRA) prior to 16S rRNA gene sequence analysis. On the basis of the most complete sequencing results strain V3 was identified asGeobacillus thermodenitrificans, most of isolates (10/14) was similar at high level (≥95%) to different reference strains of the speciesBacillus licheniformis. The remaining isolates, exhibiting sequence similarity below 95%, may represent novel species of the genusBacillus

Wild food plants of popular use in Sicily

In the present work the authors report the result of their food ethnobotanical researches, which have been carried out in Sicily during the last thirty years. Data concerning 188 wild species used in the traditional Sicilian cuisine are reported. The authors underline those species that are partially or completely unknown for their culinary use and they illustrate other species that local inhabitants suggested in the prevention or treatment of symptomatologies caused by a refined diet, poor in vegetables. These data want to contribute to avoid the loss of traditional knowledge on uses and recipes concerning wild food botanicals, and to encourage further studies for those species that have not yet been sufficiently researched in their food chemical and nutritional profile. These studies may also suggest new applications for a few botanicals in medico-nutritional fields. The work includes also a short review of the seaweeds and mushrooms traditionally gathered and consumed in Sicily

Air Pad Controlled by Means of a Diaphragm-Valve: Static and Dynamic Behaviour

This paper presents the analysis of the static and dynamic performance of a passively compensated air pad. The proposed method consists in the integration of a custom-built diaphragm valve and a commercial aerostatic pad. A lumped model is used to simulate the static and dynamic performance of the pad. Results demonstrate that the proposed method is very effective when the system works with excitation frequencies below 10 Hz

A simplified semi-quantitative procedure based on the SLIP model for landslide risk assessment: the case study of Gioiosa Marea (Sicily, Italy)

Landslide risk assessment is fundamental in identifying risk areas, where mitigation measures must be introduced. Most of the existing methods are based on susceptibility assessment strongly site-specific and require information often unavailable for damage quantification. This study proposes a simplified methodology, specific for rainfall-induced shallow landslides, that tries to overcome both these limitations. Susceptibility assessed from a physically-based model SLIP (shallow landslides instability prediction) is combined with distance derived indices representing the interference probability with elements at risk in the anthropized environment. The methodology is applied to Gioiosa Marea municipality (Sicily, south Italy), where shallow landslides are often triggered by rainfall causing relevant social and economic damage because of their interference with roads. SLIP parameters are first calibrated to predict the spatial and temporal occurrence of past surveyed phenomena. Susceptibility is then assessed in the whole municipality and validated by comparison with areas affected by slide movements according to the regional databases of historical landslides. It is shown that all the detected areas are covered by points where the SLIP safety factor ranges between 0 and 2. Risk is finally assessed after computation of distances from elements at risk, selected from the land use map. In this case, results are not well validated because of lack of details in the available regional hydrogeological plan, both in terms of extension and information. Further validation of the proposed interference indices is required, e.g., with studies of landslide propagation, which can also allow considerations on the provoked damage

On the Design of a Diaphragm Valve for Aerostatic Bearings

Because of their almost zero friction, cleanness and long life, aerostatic bearings are commonly used in many applications where high precision of positioning is required, e.g. machine tools, measuring machines, semiconductor manufacturing and power board testing. However, air bearings suffer from low relative stiffness and poor damping. Active and passive compensation are two effective methods to enhance the static and dynamic performance of these kinds of bearings. Despite their higher performance, active compensation solutions are too expensive to be used in industrial applications, as a consequence of the costs related to their controllers, actuators and sensors. This paper presents the design and performance of a passive compensation method that exploits a diaphragm valve. Thanks to its ease of integration, satisfactory performance and relatively low cost, this method could be a valuable solution to increasing the stiffness of aerostatic bearings. This work provides a procedure to design diaphragm valves depending on the type of the integrated pad and the desired nominal air gap height. Results demonstrate that, once correctly designed, the diaphragm valve makes it possible to obtain bearings with quasi-static infinite stiffness at the selected air gap height

Adenosine negatively regulates duodenal motility in mice: role of A1 and A2a receptors .

BACKGROUND AND PURPOSE: Adenosine is considered to be an important modulator of intestinal motility. This study was undertaken to investigate the role of adenosine in the modulation of contractility in the mouse duodenum and to characterize the adenosine receptor subtypes involved. EXPERIMENTAL APPROACH: RT-PCR was used to investigate the expression of mRNA encoding for A(1), A(2A), A(2B) and A(3) receptors. Contractile activity was examined in vitro as changes in isometric tension. KEY RESULTS: In mouse duodenum, all four classes of adenosine receptors were expressed, with the A(2B) receptor subtype being confined to the mucosal layer. Adenosine caused relaxation of mouse longitudinal duodenal muscle; this was antagonized by the A(1) receptor antagonist and mimicked by N(6)-cyclopentyladenosine (CPA), selective A(1) agonist. The relaxation induced by A(1) receptor activation was insensitive to tetrodotoxin (TTX) or N(ω)-nitro-l-arginine methyl ester (l-NAME). Adenosine also inhibited cholinergic contractions evoked by neural stimulation, effect reversed by the A(1) receptor antagonist, but not myogenic contractions induced by carbachol. CPA and 2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680), A(2A) receptor agonist, both inhibited the nerve-evoked cholinergic contractions. l-NAME prevented only the CGS-21680-induced effects. S-(4-Nitrobenzyl)-6-thioinosine, a nucleoside uptake inhibitor, reduced the amplitude of nerve-evoked cholinergic contractions, an effect reversed by an A(2A) receptor antagonist or l-NAME. CONCLUSIONS AND IMPLICATIONS: Adenosine can negatively regulate mouse duodenal motility either by activating A(1) inhibitory receptors located post-junctionally or controlling neurotransmitter release via A(1) or A(2A) receptors. Both receptors are available for pharmacological recruitment, even if only A(2A) receptors appear to be preferentially stimulated by endogenous adenosine. LINKED ARTICLE: This article is commented on by Antonioli et al., pp. 1577–1579 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01529.

Unbalance Response Analysis of a Spindle Supported on Gas Bearings: A Comparison between Different Approaches

Gas journal bearings are widely employed in high-speed spindles for the micromachining industry. Compared to their oil and rolling counterparts, gas bearings have a longer life span, lower friction and a lower level of noise. In order to design accurate high-speed spindles supported by externally pressurized gas bearings, it is vital to analyze the characteristics of rotor bearing systems. In this paper, we present an analysis of the unbalance response of a high-speed spindle supported by gas journal bearings. A number of aspects to enhance the accuracy of the system are discussed. We performed the analysis by considering a nonlinear and a linearized numerical model validated through experimental measurements

An aerostatic pad with an internal pressure control

Because of their almost zero friction and wear, aerostatic pads are widely used in applications where very precise positioning is required. However, this kind of bearing suffers from poor damping and low specific stiffness. This paper presents a new compensation strategy to increase air pad stiffness. This method exploits a custom-built pneumatic valve which can be easily integrated with any commercial pad. The design and the working principle of the proposed system are described and studied with the aid of a lumped parameter model. The effectiveness of the proposed compensation is numerically and experimentally evaluated. The results demonstrate that the solution represents a good and cost-effective method to enhance the static stiffness of aerostatic pads