On the Sampling Size for Inverse Sampling

In the Big Data era, sampling remains a central theme. This paper investigates the characteristics of inverse sampling on two different datasets (real and simulated) to determine when big data become too small for inverse sampling to be used and to examine the impact of the sampling rate of the subsamples. We find that the method, using the appropriate subsample size for both the mean and proportion parameters, performs well with a smaller dataset than big data through the simulation study and real-data application. Different settings related to the selection bias severity are considered during the simulation study and real application

Bail-In Regulation and Stock Market Reaction

In response to the global financial turmoil and sovereign debt crisis, the European Union has introduced a new bail-in resolution mechanism based on the shared burden of losses between shareholders, debt-holders, and depositors. By focusing on the abnormal stock price reactions to bail-in policy announcements, this paper shows that investors perceive the new bail-in regime as a credible tool to decrease government interventions, reduce the too-big-to-fail problem, and increase market discipline in the European banking industry

Aortic stenting in the growing sheep causes aortic endothelial dysfunction but not hypertension: Clinical implications for coarctation repair

Stent implantation is the treatment of choice for adolescents and adults with aortic coarctation (CoAo). Despite excellent short-term results, 20%-40% of the patients develop arterial hypertension later in life, which was attributed to inappropriate response of the aortic baroreceptors to increased stiffness of the ascending aorta (ASAO), either congenital or induced by CoAo repair. In particular, it has been hypothesized that stent itself may cause or sustain hypertension. Therefore, we aimed to study the hemodynamic and structural impact following stent implantation in the normal aorta of a growing animal

Reference Genes for Real-Time PCR Quantification of MicroRNAs and Messenger RNAs in Rat Models of Hepatotoxicity

Hepatotoxicity is associated with major changes in liver gene expression induced by xenobiotic exposure. Understanding the underlying mechanisms is critical for its clinical diagnosis and treatment. MicroRNAs are key regulators of gene expression that control mRNA stability and translation, during normal development and pathology. The canonical technique to measure gene transcript levels is Real-Time qPCR, which has been successfully modified to determine the levels of microRNAs as well. However, in order to obtain accurate data in a multi-step method like RT-qPCR, the normalization with endogenous, stably expressed reference genes is mandatory. Since the expression stability of candidate reference genes varies greatly depending on experimental factors, the aim of our study was to identify a combination of genes for optimal normalization of microRNA and mRNA qPCR expression data in experimental models of acute hepatotoxicity. Rats were treated with four traditional hepatotoxins: acetaminophen, carbon tetrachloride, D-galactosamine and thioacetamide, and the liver expression levels of two groups of candidate reference genes, one for microRNA and the other for mRNA normalization, were determined by RT-qPCR in compliance with the MIQE guidelines. In the present study, we report that traditional reference genes such as U6 spliceosomal RNA, Beta Actin and Glyceraldehyde-3P-dehydrogenase altered their expression in response to classic hepatotoxins and therefore cannot be used as reference genes in hepatotoxicity studies. Stability rankings of candidate reference genes, considering only those that did not alter their expression, were determined using geNorm, NormFinder and BestKeeper software packages. The potential candidates whose measurements were stable were further tested in different combinations to find the optimal set of reference genes that accurately determine mRNA and miRNA levels. Finally, the combination of MicroRNA-16/5S Ribosomal RNA and Beta 2 Microglobulin/18S Ribosomal RNA were validated as optimal reference genes for microRNA and mRNA quantification, respectively, in rat models of acute hepatotoxicity

Halophenol bioremediation catalyzed by an artificial peroxidase

Halophenols (HPs) have been widely used as pesticides, herbicides and wood-preserving agents. Once released into the environment, they exert toxic effects onto living systems such as plants, animals and humans.[1] Among bioremediation strategies targeting HPs, oxidative degradation is efficiently catalyzed by natural heme-enzymes, such as Horseradish Peroxidase (HRP),[2,3] in the presence of hydrogen peroxide as an oxidant. Peroxidases activate the phenol ring, by generating both phenoxy radical and carbocationic species, which further react to give coupling and/or oxidative dehalogenation products, such as chlorinated benzo-p-dioxins and quinones. The ability of these enzymes to cause phenolic coupling may allow the immobilization of toxic phenolic substances, such as HPs, limiting their bioavailability and suppressing their toxic effects. Humic acids (HA) are ubiquitous organic materials in terrestrial and aquatic ecosystems to which HPs can covalenty bind upon activation. In order to improve the chemical stability of natural peroxidases along with their catalytic efficiency, in recent years a variety of artificial biomimetic systems has been developed and evaluated to this purpose. [4] In this area, our ongoing project, focused on the design and synthesis of artificial enzymes led us to explore the activity of an artificial peroxidase, FeIII-Mimochrome VI*a (FeMC6*a), towards HPs.[5] Herein, the oxidative degradation of HPs catalyzed by FeMC6*a and its use in bioremediation strategies are reported. FeMC6*a is able to convert a variety of HPs, including 2,4,6-trichlorophenol (TCP) with 840-fold higher catalytic efficiency than natural HRP. 1. J. Huff, Chemosphere 2012, 89, 521. 2. S. Sumithran, M. Sono, G. M. Raner, J. H. Dawson, J. Inorg. Biochem. 2012, 117, 316. 3. K. Morimoto, K.Tatsumi, K-I Kuroda, Soil Biology & Biochemistry 2000, 32, 1071. 4. M. Chino, L. Leone, G. Zambrano, F. Pirro, D. D’Alonzo, V. Firpo, D. Aref, L. Lista, O. Maglio, F. Nastri, A. Lombardi, Biopolymers, 2018, e23107. 5. G. Caserta, M. Chino, V. Firpo, G. Zambrano, L. Leone, D. D’Alonzo, F. Nastri, O. Maglio, V. Pavone, A. Lombardi, ChemBioChem 2018, cbic.201800200

Whole-brain histogram and voxel-based analyses of apparent diffusion coefficient and magnetization transfer ratio in celiac disease, epilepsy, and cerebral calcifications syndrome

BACKGROUND AND PURPOSE: Diffusion and magnetization transfer (MT) techniques have been applied to the investigation with MR of epilepsy and have revealed changes in patients with or without abnormalities on MR imaging. We hypothesized that also in the coeliac disease (CD), epilepsy and cerebral calcifications (CEC) syndrome diffusion and MT techniques could reveal brain abnormalities undetected by MR imaging and tentatively correlated to epilepsy. MATERIALS AND METHODS: Diffusion and MT weighted images were obtained in 10 patients with CEC, 8 patients with CD without epilepsy and 17 healthy volunteers. The whole brain apparent diffusion coefficient (ADC) and MT ratio (MTR) maps were analyzed with histograms and the Statistical Parametric Mapping 2 (SPM2) software. We employed the non-parametric Mann-Whitney U test to assess differences for ADC and MTR histogram metrics. Voxel by voxel comparison of the ADC and MTR maps was performed with 2 tails t-test corrected for multiple comparison. RESULTS: A significantly higher whole brain ADC value as compared to healthy controls was observed in CEC (P = 0.006) and CD (P = 0.01) patients. SPM2 showed bilateral areas of significantly decreased MTR in the parietal and temporal subcortical white matter (WM) in the CEC patients. CONCLUSION: Our study indicates that diffusion and MT techniques are also capable of revealing abnormalities undetected by MR imaging. In particular patients with CEC syndrome show an increase of the whole brain ADC histogram which is more pronounced than in patients with gluten intolerance. IN CEC patients, voxel-based analysis demonstrates a localized decrease of the MTR in the parieto-temporal subcortical WM

A biomimetic metalloporphyrin catalyzes indole oxidation with high selectivity

Indole is one of the most common heterocyclic scaffolds available in nature. It occurs in several natural compounds, including alkaloids, plant hormones, flower scents and dyes.1 Despite the structural simplicity of this molecule, indole oxidation commonly results in the formation of a large number of products, including the 2- or 3-oxygenated compounds, di-oxygenated and more complex molecules. For this reason, indole oxidation has become a widespread model reaction to test the efficacy of both biological catalysts2,3 and their synthetic analogues.4,5 Most of the catalysts examined so far gave poor selectivity toward any of the oxidation products.2-5 Here we present the results concerning oxidation of indole and its derivatives catalyzed by Mn-Mimochrome VI*a (Mn-MC6*a). Mn-MC6*a is a synthetic peptide-porphyrin conjugate conceived to act as a miniaturized heme-protein model.6 Mn-MC6*a is able to oxidize indole under unprecedented site-selective conditions, yielding to 3-oxindolenine as single product. Additionally, the reaction selectivity is dramatically altered when 1- or 3-methyl-substituted indoles are used as substrates. The formation and isolation of the reactive 3-oxindolenine is highly important, since it is believed to represent a useful synthon in organic synthesis. Accordingly, the exploitation of its reactivity with nucleophiles, in order to provide one pot transformations, is currently ongoing, with the aim to further increase the synthetic potential of our catalyst. 1. Burton, T.C. in Heterocyclic scaffolds II: Reactions and applications of indoles; Gribble, G.W., Ed.; Springer-Verlag Berlin Heidelberg, 2011. 2. Kuo, H. H. and Mauk, A. G.; Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 13966–13971. 3. Barrios, D. A. et al. J. Am. Chem. Soc. 2014, 136, 7914-7925. 4. Linhares, M. et al. Appl. Catal. A. 2014, 470, 427–433. 5. Poon L. C.-H. et al. J. Am. Chem. Soc. 2011, 133, 1877–1884. 6. Caserta, G. et al. ChemBioChem 2018 (doi: 10.1002/cbic.201800200

Aromatase inhibitors: the journey from the state of the art to clinical open questions

Breast cancer is a major cause of death among females. Great advances have been made in treating this disease, and aromatase inhibitors (AIs) have been recognized as the cornerstone. They are characterized by high efficacy and low toxicity. The authors reviewed the available literature and defined state-of-the-art AI management. This study was designed to assist clinicians in addressing the need to equally weigh patients’ needs and disease control rates in their everyday clinical practice. Today, AIs play a central role in the treatment of hormone receptor-positive breast cancer. In this study, an expert panel reviewed the literature on the use of AIs, discussing the evolution of their use in various aspects of breast cancer, from pre- and postmenopausal early breast cancer to metastatic breast cancer, along with their management regarding efficacy and toxicity. Given the brilliant results that have been achieved in improving survival in everyday clinical practice, clinicians need to address their concerns about therapy duration and the adverse effects they exert on bone health, the cardiovascular system, and metabolism. Currently, in addition to cancer treatment, patient engagement is crucial for improving adherence to therapy and supporting patients’ quality of life, especially in a selected subset of patients, such as those receiving an extended adjuvant or combination with targeted therapies. A description of modern technologies that contribute to this important goal is provided

Site-selective indole oxidation catalyzed by a Mn-containing artificial metalloenzyme

Metalloenzymes have become attractive tools for application in oxidation catalysis, since a complex protein environment exerts a highly specific control on the reactivity of the metal center.1 Compared to synthetic catalysts, enzymes cover only a limited repertoire of reactions and substrates. The development of hybrid catalysts, obtained by anchoring catalytic metal complexes to native or artificial biomolecular scaffolds, is aimed at merging the advantages of both systems while overcoming the drawbacks.2,3 In this area, our research is devoted to the development of peptide-porphyrin conjugates resembling natural heme-proteins, called “Mimochromes”.3,4 Among them, Mimochrome VIa (MC6a) is the most promising catalyst, thanks to its robust but flexible scaffold. MC6a, in its MnIII complex, (Mn-MC6a) is an efficient catalyst with enzyme-like properties, because fast and chemoselective reactions with a peroxygenase-like mechanism were found in the oxidation of thioethers. Even more remarkably, Mn-MC6a selectively exhibits either peroxygenase- or catalase-like activity depending on the reaction conditions. Here we present the oxidation of indole and its derivatives catalyzed by Mn-MC6a, with the aim of exploiting the catalytic properties of this artificial enzyme in reactions with potential synthetic applications. Indole is one of the most common heterocyclic scaffolds available in nature. It occurs in several natural compounds (such as alkaloids and plant hormones) and is part of many pharmaceuticals.5-8 Despite the structural simplicity of this molecule, indole oxidation leads to a large number of products, including mono- and di-oxygenated compounds. Indole oxidation has been studied with both biological5,6 and synthetic7,8 catalysts. In all the approaches described so far, no or weak selectivity toward any of the oxidation products has been reported.5-8 Conversely, Mn-MC6a is able to oxidize indole under unprecedented site-selective conditions, yielding to 3-oxindolenine as single product. Additionally, the reaction selectivity is dramatically altered when 1- or 3-methyl-substituted indoles are used as substrates. A detailed mechanistic analysis will help to rationalize the outstanding selectivity of the catalyst. References: 1. Sheldon, R. A. and Woodley, J. M. Chem. Rev. 2018, 118, 801–838. 2. Schwizer, F. et al. Chem. Rev. 2018, 118, 142-231. 3. Chino, M. et al. Biopolymers 2018 (doi: 10.1002/bip.23107). 4. Nastri, F. et al. Chem. Soc. Rev., 2016, 45, 5020-5054. 5. Kuo, H. H. and Mauk, A. G.; Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 13966–13971. 6. Barrios, D. A. et al. J. Am. Chem. Soc. 2014, 136, 7914-7925. 7. Linhares, M. et al. Appl. Catal. A. 2014, 470, 427–433. 8. Poon L. C.-H. et al. J. Am. Chem. Soc. 2011, 133, 1877–1884