New Avoparcin-like Molecules from the Avoparcin Producer Amycolatopsis coloradensis ATCC 53629

Amycolatopsis coloradensis ATCC 53629 is the producer of the glycopeptide antibiotic avoparcin. While setting up the production of the avoparcin complex, in view of its use as analytical standard, we uncovered the production of a to-date not described ristosamynil-avoparcin. Ristosamynil-avoparcin is produced together with α-and β-avoparcin (overall indicated as the avoparcin complex). Selection of one high producer morphological variant within the A. coloradensis population, together with the use of a new fermentation medium, allowed to increase productivity of the avoparcin complex up to 9 g/L in flask fermentations. The selected high producer displayed a non-spore forming phenotype. All the selected phenotypes, as well as the original unselected population, displayed invariably the ability to produce a complex rich in ristosamynil-avoparcin. This suggested that the original strain deposited was not conforming to the description or that long term storage of the lyovials has selected mutants from the original population

Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity

5noopenThe design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.openPinzi L.; Foschi F.; Christodoulou M.S.; Passarella D.; Rastelli G.Pinzi, L.; Foschi, F.; Christodoulou, M. S.; Passarella, D.; Rastelli, G

Ruthenium-Catalyzed Decarboxylative Rearrangement of 4-Alkenyl-isoxazol-5-ones to Pyrrole Derivatives

Easily accessible isoxazol-5(4H)-ones are useful precursors of heterocycles. In this context, we report the ruthenium-catalyzed transformation of 4-alkenyl-substituted isoxazol-5-ones to afford 1H-pyrrole derivatives. The operative conditions were proven to be effective also on cyclohexane-fused isoxazolones giving 4,5,6,7-tetrahydroindoles. The reactions, which allow for access to tri-and tetra-substituted pyrroles in moderate to high yields, occur through decarboxylative ring-opening/ring-closure involving C-H functionalization of the alkenyl moiety

1H-NMR based serum metabolomics highlights different specific biomarkers between early and advanced hepatocellular carcinoma stages

The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (1H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that1H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan\u2013Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology

Prevalence of and risk factors for fatty liver in the general population of Northern Italy: The Bagnacavallo Study

Background: The estimation of the burden of disease attributable to fatty liver requires studies performed in the general population. Methods: The Bagnacavallo Study was performed between October 2005 and March 2009. All the citizens of Bagnacavallo (Ravenna, Italy) aged 30 to 60 years as of January 2005 were eligible. Altered liver enzymes were defined as alanine transaminase > 40 U/l and/or aspartate transaminase > 37 U/l. Results: Four thousand and thirty-three (58%) out of 6920 eligible citizens agreed to participate and 3933 (98%) had complete data. 393 (10%) of the latter had altered liver enzymes and 3540 had not. After exclusion of subjects with HBV or HCV infection, liver ultrasonography was available for 93% of subjects with altered liber enzymes and 52% of those with normal liver enzymes. The prevalence of fatty liver, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) was 0.74 (95%CI 0.70 to 0.79) vs. 0.35 (0.33 to 0.37), 0.46 (0.41 to 0.51) vs. 0.22 (0.21 to 0.24) and 0.28 (0.24 to 0.33) vs. 0.13 (0.11 to 0.14) in citizens with than in those without altered liver enzymes. Ethanol intake was not associated and all the components of the metabolic syndrome (MS) were associated with fatty liver. All potential risk factors were associated with a lower odds of normal liver vs. NAFLD while they were unable to discriminate AFLD from NAFLD. Conclusions: Fatty liver as a whole was highly prevalent in Bagnacavallo in 2005/9 and was more common among citizens with altered liver enzymes

Distorted Copulas: Constructions and Tail Dependence

Given a copula C, we examine under which conditions on an order isomorphism ψ of [0, 1] the distortion C ψ: [0, 1]2 → [0, 1], C ψ(x, y) = ψ{C[ψ−1(x), ψ−1(y)]} is again a copula. In particular, when the copula C is totally positive of order 2, we give a sufficient condition on ψ that ensures that any distortion of C by means of ψ is again a copula. The presented results allow us to introduce in a more flexible way families of copulas exhibiting different behavior in the tails

A New Methodology to Determine the Orifice for Root Canal Configurations in First Permanent Molar Root and Canal Morphologies Using Micro-Computed Tomography

Background: The distinction between where the pulp chamber ends and the root canal system begins is poorly defined within the existing literature. Methods: This paper aimed to describe a range of accurate methods to define the transition from pulp chamber to root canal in different first molar root morphologies using micro-focus computed tomography (micro-CT). Methods: The sample consisted of 86 mandibular and 101 maxillary first molars from the skeletal collections housed in the Department of Anatomy and Histology of the Sefako Makgatho Health Sciences University and the Pretoria Bone Collection. A stepwise approach using the cemento–enamel junction (CEJ) and dedicated landmarks was followed to create an automated cross-sectional slice. Results: Transition from pulp chamber to root canal could be accurately determined on maxillary and mandibular teeth. The occurrence of two separate roots in mandibular molars was 97.7%, with the remaining 2.3% having an additional disto-lingual root, with no mandibular molars displaying fused roots. In the maxillary molars, 92.1% had three separate roots and 7.9% displayed root fusion. Within this group, one tooth displayed a C-shaped root canal configuration and one a mesotaurodont-type morphology. Conclusion: The suggested methodology to determine orifice location was found to be appropriate in all morphological types.</jats:p