Reversible linear differential equations

Let ? be a meromorphic connection on a vector bundle over a compact Riemann surface Γ. An automorphism $\sigma :\Gamma \to \Gamma$ is called a symmetry of ? if the pullback bundle and the pullback connection can be identified with ?. We study the symmetries by means of what we call the Fano group; and, under the hypothesis that ? has a unimodular reductive Galois group, we relate the differential Galois group, the Fano group and the symmetries by means of an exact sequence.     

Two new ternary complexes of copper(II) with tetracycline or doxycycline and 1,10-phenanthroline and their potential as antitumoral: cytotoxicity and DNA cleavage

This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: [Cu(doxycycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (1) and [Cu(tetracycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double-strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, [Cu(phen)(2)](2+) is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC(50) values of 1.93 and 2.59 μmol L(-1) for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells.     

Photoinduced DNA cleavage promoted by two copper(II) complexes of tetracyclines and 1,10-phenanthroline

In this report, we demonstrate how UV-light exposure can enhance DNA cleavage promoted by two copper(II) complexes of tetracyclines and 1,10-phenanthroline about 40 times in comparison to nonirradiated conditions. In addition, new aspects regarding their DNA binding properties, as well as the mechanism of the cleavage reaction, were also investigated.     

Optimization of <Emphasis Type="Italic">α</Emphasis>-Terpineol Production by the Biotransformation of <Emphasis Type="Italic">R</Emphasis>-(+)-Limonene and (−)-β-Pinene

The main objective of this work is to present the optimization of the biotransformation of R-(+)-limonene and (−)-β-pinene aiming at the production of α-terpineol by strains of fungal and yeasts previously isolated by our research group using the methodology of experimental design. New optimized experimental data on α-terpineol production by the biotransformation of R-(+)-limonene and (−)-β-pinene using newly isolated microorganisms are reported in this work. Conversion of about 1,700 mg/L was achieved when R-(+)-limonene was used as substrate and the newly isolated strain 05.01.35 as microorganism at the central point of the experimental design, corresponding to a substrate concentration of 1.75%, mass of inoculum of 2 g, and substrate to ethanol volume ratio of 1:1. The same experimental condition led to higher conversions when (−)-β-pinene was used as substrates and the strains coded as 04.05.08 and 01.04.03 as microorganism. Here, conversions of about 770 mg/L were achieved.     

Assessment of the in vivo genotoxicity of new lead compounds to treat sickle cell disease

The compounds 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (C1), (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (C2), 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C3), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (C4), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C5), and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (C6) were evaluated with a micronucleus test using mouse peripheral blood to identify new candidate drugs for the treatment of sickle cell disease (SCD) that are safer than hydroxyurea. The compounds induced an average frequency of micronucleated reticulocytes (MNRET) of less than six per 1,000 cells at 12.5, 25, 50, and 100 mg/kg, whereas hydroxyurea induced an average MNRET frequency of 7.8, 9.8, 15, and 33.7 per 1000 cells respectively, at the same concentrations. Compounds C1-C6 are new non-genotoxic in vivo candidate drugs for the treatment of SCD symptoms.     

Quantum gravity at the LHC

We study the production of massless gravitons at the LHC and compare our results to those obtained in extra-dimensional models. The signature in both cases is missing energy plus jets. In case of non-observation, the LHC could be used to put the tightest limit to date on the value of the Planck mass.     

Characterization of lidocaine:hydroxypropyl-β-cyclodextrin inclusion complex

An inclusion complex was prepared between the local anesthetic lidocaine (LDC) and hydroxypropyl-β-CD (HP-β-CD). The complex was characterized by thermal analysis (differential scanning calorimetry, DSC), UV absorption and high-pressure liquid chromatography (HPLC). DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of LDC (77 °C). Phase-solubility diagrams allowed the determination of the association constant between LDC and HP-β-CD (35.7 ± 4.7 M⁻¹). The rate of LDC release decreased after complexation and thermodynamic parameters from the HPLC studies (ΔG° = −2.65 kJ/mol) revealed that a stable complex was formed.     

Proteomics Approach of Rapamycin Anti-Tumoral Effect on Primary and Metastatic Canine Mammary Tumor Cells In Vitro

Rapamycin is an antifungal drug with antitumor activity and acts inhibiting the mTOR complex. Due to drug antitumor potential, the aim of this study was to evaluate its effect on a preclinical model of primary mammary gland tumors and their metastases from female dogs. Four cell lines from our cell bank, two from primary canine mammary tumors (UNESP-CM1, UNESP-CM60) and two metastases (UNESP-MM1, and UNESP-MM4) were cultured in vitro and investigated for rapamycin IC₅₀. Then, cell lines were treated with rapamycin IC₅₀ dose and mRNA and protein were extracted in treated and non-treated cells to perform AKT, mTOR, PTEN and 4EBP1 gene expression and global proteomics by mass spectrometry. MTT assay demonstrated rapamycin IC₅₀ dose for all different tumor cells between 2 and 10 μM. RT-qPCR from cultured cells, control versus treated group and primary tumor cells versus metastatic tumor cells, did not shown statistical differences. In proteomics were found 273 proteins in all groups, and after data normalization 49 and 92 proteins were used for statistical analysis for comparisons between control versus rapamycin treatment groups, and metastasis versus primary tumor versus metastasis rapamycin versus primary tumor rapamycin, respectively. Considering the two statistical analysis, four proteins, phosphoglycerate mutase, malate dehydrogenase, l-lactate dehydrogenase and nucleolin were found in decreased abundance in the rapamycin group and they are related with cellular metabolic processes and enhanced tumor malignant behavior. Two proteins, dihydrolipoamide dehydrogenase and superoxide dismutase, also related with metabolic processes, were found in higher abundance in rapamycin group and are associated with apoptosis. The results suggested that rapamycin was able to inhibit cell growth of mammary gland tumor and metastatic tumors cells in vitro, however, concentrations needed to reach the IC₅₀ were higher when compared to other studies.     

LC Evaluation of Intestinal Transport of Praziquantel

Praziquantel (PZQ) is a highly lipophilic drug with low aqueous solubility. Despite this, it is well absorbed from the gastrointestinal tract. In this study, a simple LC method was developed and validated, in order to monitor the concentration of PZQ in TC-199 buffer in vitro, in the rat everted gut sac absorption model. PZQ was analyzed by a reversed-phase LC method with an isocratic mobile phase containing acetonitrile and water in the proportions 45:55. The flow-rate was 1 mL min⁻¹ and PZQ was determined by measuring absorbance at 215 nm, at 25 °C. The method was found to be specific, as none of the components of TC-199 or intestinal sac artefacts interfered with the drug peak. Recovery was within acceptable statistical limits. The limit of detection was 0.54 μg mL⁻¹ and the limit of quantitation was 1.63 μg mL⁻¹. The calibration curve was found to be linear in the concentration range of 10–90 μg mL⁻¹ PZQ. The proposed method was found to be rapid and selective and hence can be applied in the monitoring of the absorption of PZQ in in vitro everted gut sac absorption studies.