Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors

PANIC DISORDER, ANXIETY, AND CARDIOVASCULAR DISEASES

Different data indicate that psychological and/or emotional disorders may play an important role in the natural history of heart diseases. Although the major evidence is that related to depression, epidemiological data would indicate that anxiety and panic disorders are highly represented in cardiac patient, thus influencing mortality and morbidity. The diagnosis of panic disorder in patients with chest pain is crucial to a correct therapeutic approach, as well as to reduce the risks and costs of inappropriate treatments. Anxiety and panic may accelerate different direct and indirect processes involved in the pathogenesis of cardiovascular diseases: lifestyle risk factors, arterial hypertension, myocardial perfusion, autonomic nervous system or hypothalamus-pituitary-adrenal axis, platelet activation, and inflammation processes. Panic disorder seems to correlate particularly with sudden death: this suggests that it may be considered one of the main inducers of life-threatening arrhythmias, rather than to be linked to the development and progression of coronary atherosclerosis. Beyond hard outcomes, panic disorders produce negative effects on both global adjustment and life quality that may impair the course of the cardiac diseases. Interestingly, specific antipanic and anxiolytic agents seem to be particularly effective upon life quality. In any case, adequate controlled clinical trials are necessary in order to confirm the possibility of cardiovascular risk reduction by means of anxiety and panic disorder treatment

Tracing Galaxy Formation with Stellar Halos II: Relating Substructure in Phase- and Abundance-Space to Accretion Histories

This paper explores the mapping between the observable properties of a stellar halo in phase- and abundance-space and the parent galaxy's accretion history in terms of the characteristic epoch of accretion and mass and orbits of progenitor objects. The study utilizes a suite of eleven stellar halo models constructed within the context of a standard LCDM cosmology. The results demonstrate that coordinate-space studies are sensitive to the recent (0-8 Gyears ago) merger histories of galaxies (this timescale corresponds to the last few to tens of percent of mass accretion for a Milky-Way-type galaxy). Specifically, the {\it frequency, sky coverage} and {\it fraction of stars} in substructures in the stellar halo as a function of surface brightness are indicators of the importance of recent merging and of the luminosity function of infalling dwarfs. The {\it morphology} of features serves as a guide to the orbital distribution of those dwarfs. Constraints on the earlier merger history (> 8 Gyears ago) can be gleaned from the abundance patterns in halo stars: within our models, dramatic differences in the dominant epoch of accretion or luminosity function of progenitor objects leave clear signatures in the [alpha/Fe] and [Fe/H] distributions of the stellar halo - halos dominated by very early accretion have higher average [alpha/Fe], while those dominated by high luminosity satellites have higher [Fe/H]. This intuition can be applied to reconstruct much about the merger histories of nearby galaxies from current and future data sets.Comment: 21 pages, 20 figures. To appear in the Astrophysical Journa

Functionalization of a layered oxide with organic moieties: towards hybrid proton conductors

The design of innovative proton conductors for intermediate-temperature fuel cells, closing the gap between PEMFC and SOFC, is a forefront research theme in materials chemistry. [1] Layered perovskites with the Dion-Jacobson structure (ALaNb2O7) have bidimensional lanthanum niobate sheets, separated by a layer of A+ cations. These can be substituted by a variety of molecules with soft chemistry, to yield inorganic-organic hybrids. In particular, the intercalation of amines, alcohols, carboxylic or phosphonic acids, and their covalent binding to the sheets has been demonstrated recently. [2-4]We present preliminary results on the intercalation and covalent bonding of different organic molecules, in order to develop hybrid proton conductors for use in intermediate temperature fuel cells. Smaller molecules (such as alcohols) are intercalated to expand the interlayer space, to form intermediates for the further binding of proton carriers such as imidazoles or sulfonates.The intercalation process is investigated by XRD (to measure the interlayer distance) and TGA (to determine the weight loss upon thermal decomposition). NMR is applied to confirm the covalent bonding between the organic and oxide parts. The intercalation behavior of different functional groups is explained in terms of van der Waals and/or hydrogen bonding between organic chains. The interplay of theory (ab initio and periodic DFT) and experiment allowed us to elucidate the 1H and 13C-NMR spectra, and to investigate the nature of interaction (i.e. ionic or covalent bond) of the organic chains with the interlayer surface

Toward a new hybrid proton conductor: lanthanum niobate layered perovskites as a source of tailorable surfaces

The modification of metal oxide surfaces with organic moieties has been widely studied as a method of preparing organic-inorganic hybrid materials for various applications. Among inorganic oxides, the ion-exchangeable layered perovskites [1], materials composed by perovskite-like slabs and intercalated cations, stimulated authors\u2019 interest in reason of some encouraging electronic and reactive properties. In particular it is well known that the interlayer surface of such materials in their protonated form can be easily functionalized with organic groups (such as alcohols [2-3] or organophosphonic acids [4]) thus allowing the production of stable hybrid materials with new electronic and reactive features. As a first step to design a new inorganic-organic hybrid proton conductor, a comprehensive theoretical investigation of the MLaNb2O7 (M=H, Li, Na, K, Rb and Cs) series of ion-exchangeable layered perovskite is presented. In particular, their structural and electronic properties have been investigated by periodic calculations in the framework of DFT. A general very good agreement with the available experimental data has been found. The protonated compound (HLaNb2O7) has been then functionalized with imidazole trying two different settings: in the first arrangement the molecule is adsorbed on the layered oxide exposing the interlayer surface, in the second the organic moiety is just put between two perovskites slabs. This latter model, including the effect of the confinement, allowed to better reproduce the experimental structural XRD data and 13C-NMR measurements of the hybrid system. [1] Schaak, R. E. and Mallouk T. E., Chem. Mat. 2002, 14, 1455-1471. [2] Takahashi S. et al., Inorg. Chem. 1995, 34, 5065-5069. [3] Suzuki H. et al., Chem. Mater. 2003, 15, 636-641. [4] Shimada, A. et al., Chem. Mat. 2009, 21, 4155-4162

Effects of endurance, resistance and neuro-muscular electrical stimulation trainings to the anthropometric and functional mobility domains in elderly

Background and aims There\u2019s the need to increase physical activity engagement to promote healthy ageing. Different training protocols elicit different morpho-functional effects: the comprehension of the related assessment tests is a key to improve the specific proposals and to monitor adequately the adaptations. We aimed to identify the functional adaptation processes basing on different training protocols. Methods 40 healthy elderly (28 males and 12 females, 70.7 \ub1 4.39 y) were randomly divided into 4 groups: endurance, resistance, Neuro-Muscular Electrical Stimulation and control, trained for 12 weeks andex-post evaluated on anthropometric and functional domains. Results We found: significant effect for gender, time and time 7 protocols for Five Times Sit-to-Stand Test and Timed Up-and-Go test. Post-hoc analyses revealed effect for resistance and Neuro-Muscular Electrical Stimulation on Five Times Sit-to-Stand Test, and for endurance and Neuro-Muscular Electrical Stimulation on Timed Up-and-Go test. Correlations and factorial analysis linked Five Times Sit-to-Stand Test and Timed Up-and-Go test on the functional domain. Conclusions Medium-term physical interventions significantly modified functional characteristics of elderly. We found no ex-post effect on anthropometric parameters. The two functional tests are based on different underlying domains, our data therefore suggest to use both of them to specifically evaluate the training-induced functional adaptations in elderly. Our results promote the usefulness of evidence-based trainin

Farmed Gilthead Sea Bream (Sparus aurata) by-Products Valorization: Viscera Oil ω-3 Enrichment by Short-Path Distillation and In Vitro Bioactivity Evaluation

This study shows a pilot scale protocol aimed to obtain an omega 3-enriched oil after the processing of farmed gilthead sea bream viscera (SBV); this was oil was tested in vitro for bioactivity, attesting to the possibility to turn waste into profit The quality of the oil, in terms of requirements for animal and human consumption, was assessed by determining some chemical parameters, such as peroxide value (PV), thiobarbituric acid reactive substances (TBARS), ρ-anisidine (ρ-AV) content, total oxidation value (TOTOX), and phospholipids and free fatty acid (%), both in crude viscera oil (CVO) and refined viscera oil (RVO). Among the extraction conditions, the higher CVO yields were obtained at 60 °C for 10 min (57.89%) and at 80 °C for 10 min (67.5%), and the resulting oxidation levels were low when utilizing both extraction conditions. RVO, obtained from CVO extracted at 60 °C, showed the highest quality on the basis of the assessed parameters. The ethyl esters of the total fatty acid (TFA) contents extracted from RVO were enriched in the ω-3 polyunsaturated fatty acid fraction (PUFAE) up to almost 56% via short path distillation (SPD). Antioxidant activities and adipogenic properties were tested in vitro. PUFAE protected 3T3 L1 cells from oxidative stress and exerted an anti-adipogenic effect in Dicentrarchus labrax pre-adipocytes, attesting to the beneficial properties for both farmed fish and human health. These results could stimulate the adoption of solutions aimed to recover and utilize aquaculture by-products at a higher scale, turning "waste into profit" and indicating a strategy to reach more sustainable business models in aquaculture resource utilization according to the principles of the circular economy

Transplantation and young surgeons in italy

The relation between young surgeons and transplantation has always been a "love and hate" one. Until a few years ago this branch of surgery was seen as pioneering, with extreme and and extensive training, and was reserved to few elected members. Nowadays things are different. In this article we try to understand the true reasons that young Italian surgeons avoid transplantation surgery