1,183 research outputs found
Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold
A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives
26 Risk factors for poor outcomes in cystic fibrosis newborns diagnosed by neonatal screening in Italy: years 2009–2011
Evolution of Early Equus in Italy, Georgia, the Indian Subcontinent, East Africa and the Origins of African Zebras
2,12-diaza[6]helicene: An efficient non-conventional stereogenic scaffold for enantioselective electrochemical interphases
The new configurationally stable, unsymmetrical 2,12-diaza[6]helicene was synthesized as a racemate and the enantiomers were separated in an enantiopure state by semi-preparative HPLC on chiral stationary phase. Under selected alkylation conditions it was possible to obtain both the enantiopure 2-N-mono- and di-N-ethyl quaternary iodides. Metathesis with bis(trifluoromethanesulfonyl)imide anion gave low-melting salts which were tested as inherently chiral additives to achiral ionic liquids for the electrochemical enantiodiscrimination of chiral organic probes in voltammetric experiments. Remarkable differences in the oxidation potentials of the enantiomers of two probes, a chiral ferrocenyl amine and an aminoacid, were achieved; the differences increase with increasing additive concentration and number of alkylated nitrogen atoms
Pseudomonas aeruginosa (PA) resistant to colistin (CL) in Italian cystic fibrosis (CF) patients
Helicity: a non-conventional stereogenic element for designing inherently chiral ionic liquids for electrochemical enantiodifferentiation
Configurationally stable 5-aza[6]helicene (1) was envisaged as a promising scaffold for non-conventional ionic liquids (IL)s. It was prepared, purified, and separated into enantiomers by preparative HPLC on a chiral stationary phase. Enantiomerically pure quaternary salts of 1 with appropriate counterions were prepared and fully characterized. N-octyl-5-aza[6]helicenium bis triflimidate (2) was tested in very small quantities as a selector in achiral IL media to perform preliminary electrochemical enantiodifferentiation experiments on the antipodes of two different chiral probes. The new organic salt exhibited outstanding enantioselection performance with respect to these probes, thus opening the way to applications in the enantioselective electroanalysis of relevant bioactive molecules
Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study.
BACKGROUND: Although the diagnostic criteria and pathogenesis of gastrointestinal stromal tumors (GIST) have recently been elucidated, knowledge of the epidemiology of this malignancy is still limited. This study examined the incidence of GIST in the province of Modena, including pathologic features and clinical outcome. METHODS: Gastrointestinal mesenchymal tumors identified by the Modena Cancer Registry between 1991 and 2004 were analyzed with an immunohistochemical panel that included staining for CD-117 and PDGFRalpha. Size, mitotic rate, and other pathologic parameters were recorded. Each tumor was categorized into National Institutes of Health risk categories (very low, low, intermediate, and high risk). RESULTS: One hundred twenty-four cases were classified as GIST. The age-adjusted incidence rate was 6.6 per million. Seventy-five percent of patients were symptomatic; 34% had a previous or concomitant history of cancer. High-risk features were present in 47% of cases. Seventy-eight percent were submitted to radical surgery. After complete resection, the 5-year disease-free survival rates were 94%, 92%, 100%, and 40% for patients at very low, low, intermediate, and high risk, respectively. In multivariate analysis, high risk was the main predictor of recurrence. CONCLUSION: This population-based study shows that the incidence of GIST in Northern Italy is comparable to that reported in other European countries. Survival was favorable in lower risk categories and in most of the resected cases. In our study, resected patients at very low, low, and intermediate risk had a similar outcome. Our data support the need to consider high-risk patients after complete surgical resection for treatment with the best available approach
EpiHRMAssay, in tube and in silico combined approach for the scanning and epityping of heterogeneous DNA methylation
Reliable and cost-effective assays with adequate sensitivity are required to detect the DNA methylation profile in plants for scientific and industrial purposes. The proposed novel assay, named EpiHRMAssay, allows to quantify the overall methylation status at target loci and to enable high-throughput analyses. It combines in tube High Resolution Melting Analysis on bisulphite-treated templates with the in silico prediction of the melting profile of virtual epialleles using uMELTSM software. The predicted melting temperatures (Tm-s) of a set of epialleles characterized by different numbers of methylated cytosines (#mC) or different mC configurations were obtained and used to build calibration models, enabling the quantification of methylation in unknown samples using only the in tube observed melting temperature (Tm-o). EpiHRMAssay was validated by analysing the promoter region of CMT3, DDM1, and ROS1 genes involved in the regulation of methylation/demethylation processes and chromatin remodelling within a population of peach plants. Results demonstrate that EpiHRMAssay is a sensitive and reliable tool for locus-specific large-scale research and diagnostic contexts of the regulative regions of genes, in a broad range of organisms, including mammals. EpiHRMAssay also provides complementary information for the assessment of heterogeneous methylation and can address an array of biological questions on epigenetic regulation for diversity studies and for large-scale functional genomics
40Ar/39Ar ages of CAMP in North America: implications for the Triassic-Jurassic boundary and the 40K decay constant bias
The Central Atlantic magmatic province (CAMP) is one of the largest igneous provinces on Earth (>107 km²) and spanning four continents. Recent high-precision 40Ar/39Ar dating of mineral separates has provided important constraints on the age, duration, and geodynamic history of CAMP. Yet, the North American CAMP is strikingly under-represented in this dating effort. Here we present 13 new statistically robust plateau, mini-plateau and isochron ages obtained on plagioclase and sericite separates from lava flows from the Fundy (n = 10; Nova Scotia, Canada) and Hartford and Deerfield (n = 3; U.S.A.) basins. Ages mostly range from 198.6 ± 1.1 to 200.1 ± 1.4 Ma (2σ), with 1 date substantially younger at 190.6 ± 1.0 Ma. Careful statistical regression shows that ages from the upper (199.7.0 ± 1.5 Ma) and bottom (200.1 ± 0.9 Ma) units of the lava pile in the Fundy basin are statistically indistinguishable, confirming a short duration emplacement (<< 1.8 Ma; ≤1 Ma). Three ages obtained on the Hartford (198.6 ± 2.0 Ma and 199.8 ± 1.1 Ma) and Deerfield (199.3 ± 1.2 Ma) basins were measured on sericite from the upper lava flow units. We interpret these dates as reflecting synemplacement hydrothermal activity within these units. Collectively, CAMP ages gathered so far suggest a short duration of the main magmatic activity (2-3 Ma), but also suggest the possibility of a temporal migration of the active magmatic centers from north to south. Such a migration challenges a plume model that would postulate a radial outward migration of the magmatism and is more compatible with other models such as the supercontinent global warming hypothesis. When compared to the age of the Triassic-Jurassic boundary, the filtered CAMP age database suggests that the onset of the magmatic activity precedes the limit by at least few hundred thousand years, therefore suggesting a causal relationship between CAMP and the end of Triassic mass extinction. An age at 191 Ma possibly suggests a minor CAMP late tailing activity (190-194 Ma) which has already observed for dykes and sills in Africa and Brazil. We speculate that, if real, this late activity can be due to a major extensional event, possibly heralding the oceanisation process at ~190 Ma. Comparison between high quality U/Pb and 40Ar/39Ar ages of pegmatite lenses from the North Mountain basalts confirms a ~1% bias between the two chronometers. This discrepancy is likely attributed to the miscalibration of the 40K decay constants, in particular the electron capture branch
Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism
Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients' derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients' monocytes killing of A. fumigatus. CF patients' monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes
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