Theoretical calculations of an osmium molecular switch

Indexación: Web of Science; Scielo.ABSTRACT We have investigated the molecular, electronic and optical properties of the [Os(tpy-py)2]2+ complex (tpy-py = 4'-(4-pyridyl)-2,2':6',2"-terpyridine) and its protonated derivative [Os(tpy-pyH)2]4+ through Density Functional Relativistic calculations including Scalar and Spin Orbit corrections. The molecular geometry of the parent complex is not strongly modified by the protonation at the basic nitrogen atoms of the pyridine moieties of the terpyridine ligands in the complex. On the other hand, the optical properties of these complexes can be controlled by a change in the chemical acid-base environment, converting them into suitable materials to act as molecular switches or pH sensor devices.http://ref.scielo.org/54hzc

Changes in Nerve Conduction Studies Predate Clinical Symptoms Onset in Early Onset Val30Met Hereditary ATTR Amyloidosis

Background and purpose: Hereditary amyloidosis related to transthyretin (ATTR) is a rare and progressive disease that, despite the phenotypic heterogeneity, a length-dependent sensorimotor axonal neuropathy (ATTR-PN) is the classic hallmark. Timely diagnosis is paramount for early treatment implementation. Methods: Sixty-nine asymptomatic gene carriers (Val30Met) were assessed during a 4-year period to identify those remaining asymptomatic versus those converting to ATTRV30M-PN. Conversion to symptomatic was defined as presenting with two definite symptoms of ATTRV30M-PN. Composite neurophysiological scores of sensory (SNS), motor (MNS), and sympathetic skin response (SSRS) amplitudes were used to assess neuropathy progression. We used mixed-effects modeling and ordinal logistic regression to assess neurophysiological evolution over time. Results: Of all asymptomatic gene carriers, 55.1% (n = 38/69) converted over the period of this analysis. The progression of the SNS relative to baseline was different between groups (asymptomatic gene carriers vs. converters), the decline being greater in the converter group (time × group interaction p = 0.040), starting about 2 years before symptom onset. No significant change occurred regarding MNS or SSRS. Moreover, the percentage of cases with an annual decline on the SNS of at least 25%, gradually and significantly increased in the converter group, representing a 1.92 increase in risk of developing symptoms for those with such reduction on the last evaluation. Conclusions: A simple composite neurophysiological sum score can predict the onset of ATTRV30M-PN symptoms by as much as 2 years, highlighting the importance of a systematic follow-up of asymptomatic gene carriers, allowing a timely diagnosis, and management of symptomatic disease.info:eu-repo/semantics/publishedVersio

A theoretical study of the cluster glass-Kondo-magnetic disordered alloys

The physics of disordered alloys, such as typically the well known case of CeNi1-xCux alloys, showing an interplay among the Kondo effect, the spin glass state and a magnetic order, has been studied firstly within an average description like in the Sherrington-Kirkpatrick model. Recently, a theoretical model (PRB 74, 014427 (2006)) involving a more local description of the intersite interaction has been proposed to describe the phase diagram of CeNi1-xCux. This alloy is an example of the complex interplay between Kondo effect and frustration in which there is in particular the onset of a cluster-glass state. Although the model given in Ref. PRB 74, 014427 (2006) has reproduced the different phases relatively well, it is not able to describe the cluster-glass state. We study here the competition between the Kondo effect and a cluster glass phase within a Kondo Lattice model with an inter-cluster random Gaussian interaction. The inter-cluster term is treated within the cluster mean-field theory for spin glasses, while, inside the cluster, an exact diagonalisation is performed including inter-site ferromagnetic and intra-site Kondo interactions. The cluster glass order parameters and the Kondo correlation function are obtained for different values of the cluster size, the intra-cluster ferromagnetic coupling and the Kondo intra-site coupling. We obtain, for instance, that the increase of the Kondo coupling tends to destroy the cluster glass phase.Comment: 6 pages, 2 figures, Accepted for publication in Physica

Association of micro and nanocarriers with thin films for buccal delivery of bioactive molecules

Visando o aumento da biodisponibilidade dos compostos bioactivos administrados por via oral (com especial ênfase para a absorção bucal), o plano de trabalhos deste programa doutoral visou a optimização de formulações de filmes orais e de micro- e nanopartículas que, conjugados constituam sistemas inovadores com atividade sinérgica. As moléculas bioactivas seleccionadas para estudar o comportamento e eficácia das formulações optimizadas foram a cafeína e dois péptidos presentes na proteína do soro do leite com actividades antihipertensora (sequência: KGYGGVSLPEW) e relaxante (sequência: YLGYLEQLLR). O processo de optimização das formulações foi iniciado pela seriação e comparação preliminar dos excipientes para a produção de filmes e micro/nanopartículas. No primeiro estudo realizado, foram optimizadas e comparadas duas formulações de filmes (usando-se os polímeros carboximetilcelulose sódica e gelatina tipo A) como veículos para libertação oral de cafeína. Verificou-se, através da análise por espectroscopia no infravermelho por transformada de Fourier com reflectância total atenuada (FTIR-ATR), que a estrutura química da cafeína não fora alterada durante o processo de produção dos filmes. Concluiu-se também, através do ensaio de dissolução estabelecido pela Farmacopeia Americana (USP), que os filmes produzidos com gelatina tipo A permitiram uma libertação mais lenta da cafeína ao passo que os filmes de carboximetilcelulose apresentaram um perfil de libertação imediata. Em concordância, o valor de permeabilidade aparente da cafeína, determinada através do ensaio de permeabilidade ex vivo, através de excisões de intestino delgado de origem porcina, verificou-se superior quando esta foi veiculada pelos filmes de carboximetilcelulose, comparativamente com os filmes de gelatina tipo A. O tempo de desintegração de ambas as formulações mostrou-se, contudo, demasiado alto para formulações orodispersíveis, não ocorrendo desintegração completa após 30 segundos. Ainda na sequência da escolha do polímero com melhores características para integrar a composição de filmes orais, uma nova formulação contendo goma-guar foi optimizada por desenho factorial. Os filmes de goma-guar apresentaram características mecânicas e físico-químicas superiores às verificadas para os filmes de carboximetilcelulose e gelatina, tomando-se como factores de decisão a capacidade de absorção de água, a erosão em saliva artificial e o tempo de desintegração apresentados pelos filmes de goma-guar. Procedeu-se também à optimização (por desenho fatorial) de uma formulação de micropartículas de alginato que garantissem, em conjunto com os filmes de goma-guar, uma libertação controlada de cafeína, assim como uma maior biodisponibilidade da mesma. A associação de micropartículas de alginato aos filmes de gomaguar – GfB - não induziu alterações das características químicas da cafeína, de acordo com o verificado por FTIR-ATR, nem toxicidade para as linhas celulares usadas para mimetizar as mucosas bucal (TR146) e intestinal (Caco-2/HT29-MTX), de acordo com os resultados obtidos pelo ensaio de viabilidade celular MTT (Brometo de 3-(4,5-Dimethylthiazol-2-yl)-2,5- Diphenyltetrazólio). Adicionalmente, os perfis de libertação e permeabilidade in vitro (através das linhas celulares TR146 e Caco-2/HT29-MTX cultivadas em camada) e ex vivo (através de epitélio intestinal de origem porcina) mostraram-se mais lentos que os observados para as micropartículas de alginato, filmes de goma-guar ou com a solução controlo de cafeína. A formulação GfB promoveu o aumento do contacto efectivo entre a cafeína e o epitélio bucal, oferecendo uma permeação mais completa ao longo do tempo. De forma a incrementar também a biodisponibilidade do péptido KGYGGVSLPEW com actividade anti-hipertensora, as micropartículas de alginato foram substituídas por nanopartículas de ácido poli(láctico-co-glicólico) – PLGA - por estas oferecerem uma eficácia de associação superior, assim como um maior potencial de permeação das membranas biológicas, dado o tamanho de partícula ser significativamente inferior. A formulação de nanopartículas de PLGA foi optimizada por desenho factorial. O sistema compreendido pelas nanopartículas de PLGA associadas aos filmes de goma-guar (GfNp) não comprometeu a viabilidade das linhas celulares TR146 e Caco-2/HT29-MTX às concentrações testadas. O sistema desenvolvido promoveu a libertação e permeabilidade controladas do péptido, através das células TR146 e Caco-2/HT29- MTX cultivadas em camada, comparativamente com os filmes e nanopartículas isoladamente, assim como com a solução de péptido livre (controlo). Contudo, a permeabilidade aparente verificou-se superior para a formulação GfNp, comparativamente com as restantes formulações. Estes resultados deveram-se ao contacto íntimo entre o péptido e o epitélio absorptivo, promovido pela formulação GfNp. Verificou-se ainda, através da realização do ensaio in vitro da capacidade de inibição da enzima conversora da angiotensina I, que o péptido transportado por GfNp apresentava a maior actividade anti-hipertensora após ser sujeito à simulação do tracto gastrointestinal, comparativamente com o péptido transportado pelas nanopartículas ou filme, isoladamente, ou com a solução de péptido livre. O sistema previamente optimizado para a libertação do péptido antihipertensor foi também usado de forma a incrementar a biodisponibilidade do péptido relaxante alfa-casozepina (sequência: YLGYLEQLLR). Através do ensaio MTT, foi possível concluir que nenhuma das formulações comprometeu a viabilidade da linha celular TR146 e da co-cultura Caco-2 /HT29- MTX. Por isso, a permeabilidade do péptido, sujeito às condições do tracto gastrointestinal simulado, através dos modelos in vitro bucal e intestinal foi estudada. Verificou-se que a associação de nanopartículas de PLGA com filmes de goma-guar promoveu um aumento da permeabilidade face às nanopartículas e filmes não conjugados, assim como com o péptido em solução (controlo). Estes resultados estão correlacionados com o incremento da mucoadesão conferida pela associação das nanopartículas de PLGA com os filmes de goma-guar, verificada através da análise da adesividade e trabalho de adesão à língua de vaca. Validada a efectividade das formulações para a libertação e permeabilidade de cafeína e péptidos bioactivos, foram realizados estudos preliminares de modo a verificar a estabilidade da formulação GfB e a compreender a opinião de potenciais futuros consumidores face aos produtos desenvolvidos. As formulações foram sujeitas a condições de degradação acelerada (i.e. 40 ºC e 75% de humidade relativa) de acordo com a International Conference of Harmonization (ICH), não se verificando alterações químicas da cafeína em nenhum dos tempos de amostragem (imediatamente após a preparação da formulação e após 3, 6 e 9 meses) através da análise do espectro obtido por ATR-FTIR, assim como dos tempos de retenção em HPLC-UV. Verificou-se ainda um aumento significativo do conteúdo em água de GfB ao longo dos tempos de amostragem. Por fim, um estudo por focus group e um estudo de análise sensorial com um painel naive permitiram compreender a adequabilidade dos sabores propostos, assim como a tolerância à acidez e amargor por parte do consumidor. Observou-se uma ligeira tendência para a aceitação do sabor a menta e alguma tolerância ao amargor e acidez quando a menta foi usada na formulação. Os sistemas para libertação oral de compostos bioactivos, desenvolvidos e optimizados no âmbito desta tese, induziram melhorias significativas no comportamento farmacocinético in vitro dos compostos veiculados. De facto, a associação de filmes orais com micro- ou nanopartículas pode representar um novo sistema de libertação que ofereça maior efectividade e adesão por parte do consumidor/utente.Aiming for the protection and absorption enhancement of bioactive compounds administered by oral route (with special focus on buccal absorption), this thesis had as goals, the optimization of oral films and micro/nanoparticles which, through conjugation of both, worked as innovative oral delivery systems with synergic activity. The bioactive molecules selected to study the behaviour and efficacy of the optimized formulations were caffeine and two whey-derived peptides with antihypertensive and relaxing activities (sequences: KGYGGVSLPEW and YLGYLEQLLR, respectively). The optimization process began with the selection and preliminary comparison of the characteristics of the excipients to be used to prepare films. Indeed, the first study included the optimization and comparison of two film formulations as carriers for the oral release of caffeine, prepared using sodium carobymethylcellullose and type A gelatine as polymers. It was observed by the analysis of the spectra obtained by Fourier-transformed infrared spectroscopy with attenuated total reflectance (FTIR-ATR) that caffeine chemical structure was not altered during the film production process. It was also observed, through the dissolution assay established by the United States Pharmacopoeia (USP), that type A gelatine films offered a slow caffeine release, whereas caroboxymethylcellulose films offered a burst release profile. Accordingly, the apparent permeability of caffeine observed from the ex vivo permeability assay, across small intestine tissues from porcine origin, was higher for carboxymethylcellullose films than for type A gelatine films. Nonetheless, disintegration time of both formulations was too high to meet the criteria of orodispersible formulations, taking longer than 30 s to achieve total disintegration. Still in the process of choosing the best polymer to integrate the composition of oral films, a new formulation containing guar gum as polymer was optimized by factorial design. Guar gum films presented superior mechanical and physico-chemical characteristics than carobxymethylcellullose or type A gelatine films, mainly regarding water-uptake capacity, erosion in artificial saliva and disintegration time. Furthermore, a formulation of alginate microparticles was also optimized by factorial design to associate with guar gum films and guarantee the controlled release of caffeine, as well as an increased bioavailability. The association of alginate beads to guar gum films – GfB – did not induce alterations in the chemical characteristics of caffeine, as outlined in the data obtained by FTIR-ATR, nor cytotoxicity to the cell lines used to mimic the buccal (TR146) or intestinal (Caco-2/HT29-MTX) mucosa, as determined by MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). Additionally, the release and in vitro (through TR146 and Caco-2/HT29-MTX cell lines) and ex vivo (through porcine intestinal mucosa) permeability profiles of caffeine from GfB was slower when compared with alginate microparticles, guar gum films or caffeine control solution. GfB also increased the effective contact between caffeine and buccal epithelia, offering a more complete permeation along time. Further, aiming to increment the bioavailability of the peptide KGYGGVSLPEW with antihypertensive activity, alginate beads were replaced with poly(lactic-co-glycolic) acid (PLGA) nanoparticles, since the last offer a higher association efficiency and a higher permeability of biologic membranes, due to the significantly lower particle size. The formulation of PLGA nanoparticles was optimized by factorial design. The delivery system comprising PLGA nanoparticles into guar gum films (GfNp) did not compromise the viability of the cell lines TR146 and Caco-2/HT29-MTX at tested concentrations. Moreover, GfNp promoted a slower peptide release and in vitro permeability across TR146 and Caco-2/HT29-MTX cell layers when compared with the films and nanoparticles alone or with a free peptide solution (control). However, apparent permeability was higher for GfNp when compared with remaining formulations. Results may be due to the intimate contact between the peptide and the epithelia, promoted by GfNp. It was also possible to observe that the peptide carried by GfNp presented a higher in vitro capacity to inhibit the angiotensin-converting enzyme after being subjected to the simulation of gastrointestinal tract, therefore presenting higher antihypertensive potential, when compared with the peptide carried by the nanoparticles or films alone or with the control solution (free peptide). The previously optimized system as carrier and delivery system for the antihypertensive peptide was also used to enhance the bioavailability of the relaxing peptide alpha-casozepine (sequence: YLGYLEQLLR). It was possible to conclude, through MTT assay, that none of the formulations compromised cell viability of TR146 cell line or Caco-2/HT29-MTX co-culture. Moreover, peptide permeability across in vitro buccal and intestinal epithelial models, while being subjected to simulated gastrointestinal tract, was higher and faster (higher apparent permeability) for the association of guar gum films with PLGA nanoparticles, when compared with PLGA nanoparticles or guar gum films alone or with the free peptide solution (control). Obtained results are related with the increased mucoadhesion conferred by the association of PLGA nanoparticles with guar gum films, verified through the analysis of adhesivity and work of adhesion to cow tongue. After validation of the effectivity of the formulations regarding release and permeability of caffeine and bioactive peptides, preliminary studies were performed to understand the stability of GfB and the opinion of potential future consumers of the developed products. Formulations were subjected to accelerated degradation conditions according to the International Conference of Harmonization (ICH) and it was verified, through analysis of spectra (by FTIR-ATR spectroscopy) and retention times (by HPLC-UV), that no chemical alterations of caffeine molecule carried by GfB were observed in any of the set time points (i.e. immediately after preparation of GfB and 3, 6 and 9 months after preparation, under accelerated degradation conditions – 40 ºC and 75% of relative humidity). Moreover, an increased water content was observed along the three time points. Further, a focus group and a sensory analysis study with a naïve panel allowed to understand the suitability of the flavours but also the tolerability to acidity and bitterness by the consumer. A slight tendency to the acceptance of mint flavour and some tolerance to bitterness and acidity was verified when mint was used in the formulation. Developed and optimized oral delivery systems in the scope of the present thesis induced significant improvements on the in vitro pharmacokinetic behaviour of carried bioactive molecules. Indeed, the association of oral films with micro- and nanoparticles may represent conceptually new delivery systems that offer higher effectivity and consumer/patient compliance

Griffiths phase of the Kondo insulator fixed point

Heavy fermion compounds have long been identified as systems which are extremely sensitive to the presence of impurities and other imperfections. In recent years, both experimental and theoretical work has demonstrated that such disorder can lead to unusual, non-Fermi liquid behavior for most physical quantities. In this paper, we show that this anomalous sensitivity to disorder, as well as the resulting Griffiths phase behavior, directly follow from the proximity of metallic heavy fermion systems to the Kondo insulator fixed point.Comment: 5 pages, 4 figures; Proceedings of the SCES, August 2000, to appear in the Journal of Magnetism and Magnetic Material

Susceptibility inhomogeneity and non-Fermi liquid behavior in UCu_{5-x}Pt_x

Transverse-field muSR shifts and relaxation rates have been measured in the non-Fermi liquid (NFL) alloy system UCu_{5-x}Pt_x, x = 1.0, 1.5, and 2.5. At low temperatures the fractional spread in Knight shifts delta K/K approx deltachi/chi is gtrsim 2 for x = 1, but is only half this value for x = 1.5 and 2.5. In a disorder-driven scenario where the NFL behavior is due to a broadly distributed (Kondo or Griffiths-phase cluster) characteristic energy E, our results indicate that delta E/E_{rm av} approx (delta K/K)_{T=0} is similar for UCu_{5-x}Pd_x (x = 1 and 1.5) and UCu_4Pt, but is reduced for UCu_{5-x}Pt_x, x = 1.5 and 2.5. This reduction is due to a marked increase of E with increasing x; the spread delta E is found to be roughly independent of x. Our results correlate with the observed suppression of other NFL anomalies for x > 1 in UCu_{5-x}Pt_x but not in UCu_{5-x}Pd_x, and are further evidence for the importance of disorder in the NFL behavior of both these alloy systems.Comment: 4 pages, 2 figures, submitted to 10th International Conference on Muon Spin Rotation, Relaxation, and Resonance, Oxford, UK, August 200

Propuesta de mejoramiento de la cadena de abastecimiento enfocada en la gestión de inventarios, proceso de almacenamiento y preparación de pedidos en el CEDI de COLNOTEX S.A.

Ingeniero (a) IndustrialPregrad

Buybacks: short-term effect and future implications for the United States stock market

The main purpose of this work was to analyze the impact of stock buybacks on the American stock market. Firstly, the abnormal returns on the days following a repurchase transaction were calculated, and evidence was found that there are positive cumulative average abnormal returns on the days following it. Additionally, the Earnings-per-Share’s impact was analyzed indicating that there is some inflation of this metric due to buybacks. Finally, the evolution of the firms’ financial strength was analyzed, allowing to conclude that this buyback trend is harming the companies’ balance sheets and might endanger them in the future