Filipe Teixeira

Calibration sets and the accuracy of vibrational scaling factors: A case study with the X3LYP hybrid functional

A linear least-squares methodology was used to determine the vibrational scaling factors for the X3LYP density functional. Uncertainties for these scaling factors were calculated according to the method devised by Irikura et al. [J. Phys. Chem. A 109, 8430 (2005)]. The calibration set was systematically partitioned according to several of its descriptors and the scaling factors for X3LYP were recalculated for each subset. The results show that the scaling factors are only significant up to the second digit, irrespective of the calibration set used. Furthermore, multivariate statistical analysis allowed us to conclude that the scaling factors and the associated uncertainties are independent of the size of the calibration set and strongly suggest the practical impossibility of obtaining vibrational scaling factors with more than two significant digits.

Towards the Discovery of a Novel Class of Monoamine Oxidase Inhibitors: Structure–Property–Activity and Docking Studies on Chromone Amides

Monoamine oxidase (MAO) is a mammalian enzyme present in two isoforms (MAO-A and MAO-B) that is localized on the outer mitochondrial membrane and is involved in the oxidative deamination of exogenous and endogenous amines. Due to their central role in neurotransmitter metabolism, these isoforms represent attractive drug targets. In fact, MAO-A inhibitors are frequently used as antidepressants and antianxiety agents, while MAO-B inhibitors are relevant tools in the therapy of Alzheimer’s and Parkinson’s diseases. The chromone scaffold (4H)-1-benzopyran-4-one has been recognized as a putative pharmacophore for several targets. It has been recently studied as a valid scaffold for the design of selective MAO-B inhibitors. Furthermore, the simplicity of its synthesis make chromone carboxamide derivatives attractive to medicinal chemists. Recent data obtained by our group has shown that the presence of the same type of substituents on the 2or 3-position of the pyrone ring discloses different pharmacological profiles—a circumstance that can be illustrated with the following chromone isomers: N-phenyl-4oxo-4H-chromone-2-carboxamide (1) and N-phenyl-4-oxo-4Hchromone-3-carboxamide (2) ; the former is inactive, while the latter is a selective and potent MAO-B inhibitor : IC50 (hMAOB) = 0.40 0.022 mm, selectivity index (SI) >250. To gain insight into the physicochemical properties that determine the activity of these types of benzopyran derivatives (1 and 2), it was decided to further explore the regiospecificity of the carboxamide function by acquiring relevant theoretical and spectroscopic data. From the conformational analysis of chromones 1 and 2, it can be concluded that the diagram of the relative potential energy of the two isomers shows that they have different profiles (Figure 1). The energetic difference between the minima detected suggests the presence of an added stabilizing driving force, for example, an intramolecular hydrogen bond in chromone 2 (Figure 2). Conformational analysis also shows that, because of the presumed hydrogen bond, the structure of chromone 2 is much more rigid than that of 1 (Figure 2). Therefore, a subsequent study evaluating the thermodynamic stability of the most relevant prototropic tautomers/rotomers of compound 2 in the gas phase, while taking solvent effects into account, was performed. Accordingly, the presumed existence of the two species stabilized by intramolecular hydrogen bonds (amide 2 a/iminol 2 c tautomers) was included. The data clearly indicates that, in the gas phase, tautomers 2 b and 2 c are thermodynamically unstable when compared to tautomer 2 a. The significance of the hydrogen bond as a stabilizing force on the structure of 2 can be explained by the relatively large enthalpies (see Table 1). Since preliminary calculations showed that the iminol tautomer (2 c) was approximately 15 kcal mol 1 higher in energy, it was deemed energetically unfavorable and consequently omitted from subsequent studies. In order to provide experimental evidence for the presence of the hydrogen bond, NMR spectra (acquired in CDCl3 and DMSO) were collected and analyzed. The data obtained so far corroborates the presence, in solution, of a strong intramolecular hydrogen bond in compound 2 (Table 2). 6] The strong hy[a] A. Gaspar, Prof. N. Milhazes, Prof. F. Borges CIQUP, Departamento de Qu mica e Bioqu mica Faculdade de CiÞncias, Universidade do Porto Rua Campo Alegre 687, 4169-007 Porto (Portugal) Fax: (+ 351) 220 402 009 E-mail : fborges@fc.up.pt [b] Dr. F. Ortuso, Prof. S. Alcaro Dipartimento di Scienze Farmacobiologiche Universit “Magna Græcia” di Catanzaro Complesso “Nin Barbieri”, 88021, Roccelletta di Borgia, Catanzaro (Italy) Fax: (+ 39) 0961391490 E-mail : alcaro@unicz.it [c] F. Teixeira, Prof. A. Melo, Prof. M. N. D. S. Cordeiro REQUIMTE, Departamento de Qu mica e Bioqu mica Faculdade de CiÞncias, Universidade do Porto, Porto (Portugal) [d] Prof. E. Uriarte Departamento de Quimica Organica, Faculdad de Farmacia Universidad de Santiago de Compostela Avda. das Ciencias, 15782 Santiago de Compostela (Spain) [e] Prof. N. Milhazes Instituto Superior de CiÞncias de Safflde-Norte R. Central de Gandra, 1317 Gandra PRD (Portugal) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201000452. 1 Note : the polar aprotic solvent characteristics of DMSO are excellent for hydrogen bond acceptance that to some extent can disrupt the hydrogen bond that is being sought out via NMR by forming intermolecular hydrogen bonds between itself and the system under study.

Escala de sonolência de Epworth na síndroma de apneia obstrutiva do sono: uma subjetividade subestimada

Excessive daytime sleepiness is a major symptom in obstructive sleep apnea syndrome (OSAS) and can be evaluated using both subjective and objective methods. The Epworth Sleepiness Scale (ESS) is a simple and validated questionnaire for assessing subjective daytime sleepiness in the context of sleep disorders. Although its subjective character may limit the accurate expression of daytime sleepiness, the clinical benefit of sequential ESS is clear and demonstrates how ESS scores evolve in individual patients and how these scores may relate to various parameters. In this context we compared the severity of daytime sleepiness reported at baseline visit with severity of baseline sleepiness assessed, retrospectively, after treatment with automatic positive airway pressure (APAP). We conducted a prospective study that included 66 patients evaluated in a sleep clinic diagnosed with OSAS. The diagnosis was confirmed by in-laboratory or portable sleep studies. Their mean age was 53.3 years and the majority were men (88%, n=58). The ESS was answered during the first interview (baseline daytime sleepiness). During follow-up visits, after APAP treatment, the patient was asked to assess baseline sleepiness, retrospectively, as well as post-treatment sleepiness. The mean baseline ESS score was 11.8, mean retrospective baseline ESS 15.4, with a mean difference of 3.55 (p<0.001 t-Test) and post-treatment ESS 7.3. There was no significant correlation between the difference in ESS score (baseline - retrospective baseline) with the average daily (hours) use of APAP, the apnea-hypopnea index (AHI), the minimal recorded SatO(2), disease duration, body mass index (BMI) and age. Our findings confirm that the severity of subjective sleepiness reported before treatment with positive airway pressure is often underestimated by patients with OSAS.

Challenging the limits of detection of sialylated Thomsen-Friedenreich antigens by in-gel deglycosylation and nano-LC-MALDI-TOF-MS.

The identification of sialylated Thomsen–Friedenreich antigens in proteins poses much interest in the context of cancer research. MALDI‐TOF‐MS is a powerful technique for this purpose; still it shows considerable low sensitivity for sialylated molecules due to in‐source and metastable decomposition. Herein, we report a target‐driven strategy to identify these antigens in minute amounts of glycoproteins isolated in polyacrylamide gels. The glycans were recovered from gel spots by reductive β‐elimination, permethylated and analyzed by nano‐LC‐MALDI‐TOF‐MS. A computational algorithm was developed to filter spectral noise and enhance/isolate the signals of interest. Sialylated antigens were identified in minute amounts of fetuin (0.1 μg) and plasminogen (1.0 μg) by this approach.MS assignments were further validated by enzymatic methods. This methodology allowed a fivefold decrease in the current LOD of fetuin sialylated O‐glycans by MALDI‐TOF‐MS.

Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O -glycosylation extension

Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may offer potential to treat tumour hypoxic niches harbouring more malignant cells.

Evaluation of IEEE 802.11 Underwater Networks Operating at 700 MHz, 2.4 GHz and 5 GHz

The usage of Autonomous Underwater Vehicles (AUVs), Remotely Operated Vehicles (ROVs), and sensors in surveillance, maintenance and inspection of underwater facilities is increasing the need for broadband, cost-effective communications solutions. Current solutions, mainly based on acoustic communications, enable long ranges but provide low bitrates and have high communication delays. Despite its strong attenuation underwater, RF is envisioned as a technology to enable broadband, short-range communications. We present an ns-3 and an experimental evaluation of IEEE 802.11 networks in freshwater at 700 MHz, 2.4 GHz and 5 GHz frequency bands. Evaluation results confirm the accuracy of the new developed ns-3 underwater RF propagation model and show that IEEE 802.11 networks are feasible for broadband, short range underwater communications, with range and throughput exceeding 2 m and 100 Mbit/s, respectively.

Antenna design for underwater radio communications

In this paper we assess the influence of the conductivity of the medium on the radiation characteristics and input impedance of a loop antenna designed for underwater communications. The initial study is based on simulation of the antenna characteristics using FEKO electromagnetic (EM) software. Additionally, an equivalent circuit model of the antenna is also obtained and simulation of the input impedance on ADS software shows good agreement with the EM simulator. It is found that the radiation pattern, of the loop antenna changes significantly with the conductivity of the medium, from freshwater to seawater. The loop antennas were built with baluns and tested in freshwater, where the insertion loss between two identical antennas and the radiation pattern of one of them were also measured. The results show good agreement with the simulations.

Roots of Acetate-Vanadium Linkage Isomerism: A QTAIM Study

The possibility of linkage isomerism in a number of vanadium(IV) and vanadium(V) complexes with acetate was surveyed using Density Functional Theory (DFT) and Baders Quantum Theory of Atoms in Molecules (QTAIM). The results show that vanadium-acetate linkages may be classified as bidentate symmetrical, bidentate asymmetrical, or monodentate, the latter being observed in about 40% of the cases. These latter ones correspond to situations where the two oxygen atoms of the acetate moiety are not equivalent. They are associated with an energy penalty of about 263 kJ·mol(-1), as determined by the distribution of the scaled kinetic energy of the atomic basins forming the acetate ligand. In the presence of bidentate symmetrical vanadium-acetate linkages, the inner valence-shell charge concentrations on the vanadium atom deviate from the traditional VSEPR-derived arrangement, with an energy penalty of about 780 kJ·mol(-1). A compromise situation is partially accomplished in the case of bidentate asymmetrical linkages, which allow a Gillespiean-like arrangement of the inner valence-shell charge concentrations. In this case, one of these local charge concentrations lies close to a V-OAcO bond, which slightly disrupts the equivalence between the two oxygen atoms in the acetate ligand.

Evaluation of Underwater IEEE 802.11 Networks at VHF and UHF Frequency Bands using Software Defined Radios

Radio Frequency (RF) communications suffer high attenuation underwater, limiting the range of standard IEEE 802.11 networks to a few centimeters underwater. The usage of custom RF solutions at lower frequencies to increase range entails high development costs, and proprietary hardware. This paper evaluates the performance of cost-effective, mass-market IEEE 802.11 networks underwater at different frequencies in the sub-GHz bands using Software Defined Radio platforms. Optimizations to the gr-ieee802.11 implementation, together with custom designed antennas, allowed the testing of frequencies in the 70-700 MHz range, in a large-scale freshwater tank, and in real-world, seawater conditions in Tagus river estuary. Results show a frequency-dependent communications range up to 5 m in freshwater and 1.8 m in seawater, with bitrates up to 550 kbit/s and delay under 45 ms. This proves the feasibility of IEEE 802.11 networks in the sub-GHz bands for applications such as video streaming from an autonomous underwater vehicle and underwater sensors.

Simple descriptors for assessing the outcome of aza-Diels–Alder reactions

The iminium aza-Diels–Alder (iADA) reaction of cyclopentadiene with 16 protonated alkyl alkylimineglyoxilates was studied using density functional theory (DFT) in order to elucidate how different substitution patterns in the dienophile may affect the reaction’s outcome. Additionally, the application of the polarisable continuum model (PCM) together with the evaluation of the thermodynamic properties at different temperatures further allowed the surveying of the importance of such factors. These effects were combined into linear models which use the temperature, Taft’s constants and characteristics of the solvent as descriptors for modelling and predicting the activation enthalpy and enthalpic balance of the iADA reactions under study. This model performs in a satisfactory manner, providing a cross-validation of the DFT framework traditionally used for predicting the outcome of these reactions and also uncovering novel insights into how the substitution patterns in the dienophile, the solvent and the temperature interact in order to give the characteristic regio- and stereoselectivity of the iADA reaction. Moreover, the results show that Taft’s polar and steric substituent constants are important descriptors for assessing the outcome of iADA reactions.