Dual-Drug Delivery System Based on In Situ Gel-Forming Nanosuspension of Forskolin to Enhance Antiglaucoma Efficacy

The present study was designed to improve the bioavailability of forskolin by the influence of precorneal residence time and dissolution characteristics. Nanosizing is an advanced approach to overcome the issue of poor aqueous solubility of active pharmaceutical ingredients. Forskolin nanocrystals have been successfully manufactured and stabilized by poloxamer 407. These nanocrystals have been characterized in terms of particle size by scanning electron microscopy and dynamic light scattering. By formulating Noveon AA-1 polycarbophil/poloxamer 407 platforms, at specific concentrations, it was possible to obtain a pH and thermoreversible gel with a pH(gel)/T-gel close to eye pH/temperature. The addition of forskolin nanocrystals did not alter the gelation properties of Noveon AA-1 polycarbophil/poloxamer 407 and nanocrystal properties of forskolin. The formulation was stable over a period of 6 months at room temperature. In vitro release experiments indicated that the optimized platform was able to prolong and control forskolin release for more than 5 h. The in vivo studies on dexamethasone-induced glaucomatous rabbits indicated that the intraocular pressure lowering efficacy for nanosuspension/hydrogel systems was 31% and lasted for 12 h, which is significantly better than the effect of traditional eye suspension (18%, 4-6 h). Hence, our investigations successfully prove that the pH and thermoreversible polymeric in situ gel-forming nanosuspension with ability of controlled drug release exhibits a greater potential for glaucoma therapy.

Assessment of In-House Natural Product and Synthetic Compound Libraries Based on In vitro Inhibition of Cholinesterases

The first line medication for mild to moderate Alzheimer s disease (AD) is based on cholinesterase inhibitors which prolong the effect of the neurotransmitter acetylcholine in cholinergic nerve synapses which relieves the symptoms of the disease. Implications of cholinesterases involvement in disease modifying processes has increased interest in this research area. The drug discovery and development process is a long and expensive process that takes on average 13.5 years and costs approximately 0.9 billion US dollars. Drug attritions in the clinical phases are common due to several reasons, e.g., poor bioavailability of compounds leading to low efficacy or toxic effects. Thus, improvements in the early drug discovery process are needed to create highly potent non-toxic compounds with predicted drug-like properties. Nature has been a good source for the discovery of new medicines accounting for around half of the new drugs approved to market during the last three decades. These compounds are direct isolates from the nature, their synthetic derivatives or natural mimics. Synthetic chemistry is an alternative way to produce compounds for drug discovery purposes. Both sources have pros and cons. The screening of new bioactive compounds in vitro is based on assaying compound libraries against targets. Assay set-up has to be adapted and validated for each screen to produce high quality data. Depending on the size of the library, miniaturization and automation are often requirements to reduce solvent and compound amounts and fasten the process. In this contribution, natural extract, natural pure compound and synthetic compound libraries were assessed as sources for new bioactive compounds. The libraries were screened primarily for acetylcholinesterase inhibitory effect and secondarily for butyrylcholinesterase inhibitory effect. To be able to screen the libraries, two assays were evaluated as screening tools and adapted to be compatible with special features of each library. The assays were validated to create high quality data. Cholinesterase inhibitors with various potencies and selectivity were found in natural product and synthetic compound libraries which indicates that the two sources complement each other. It is acknowledged that natural compounds differ structurally from compounds in synthetic compound libraries which further support the view of complementation especially if a high diversity of structures is the criterion for selection of compounds in a library.

Role of CIP2A in carcinogenesis

Worldwide and notably in the developed countries, cancer is an increasing cause of morbidity and mortality, being the second most common cause of death after ischemic heart disease. Now and in the future new cancer cases need to be diagnosed earlier. Prognostic factors may be helpful in recognizing and handling those patients who need more aggressive therapy, and it is also desirable to predict treatment response accurately. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein predominantly expressed in malignant tissues and inhibiting protein phosphatase 2A (PP2A) activity; it is a promising target for cancer therapy. The aim of this thesis was to evaluate the prognostic role of CIP2A in solid cancers, and for this purpose to explore expression of CIP2A, and investigating regulation of CIP2A in order to gain insight into signalling pathways leading to alteration in prognosis. Patients diagnosed with gastric, serous ovarian, tongue, or colorectal cancer at Helsinki University Central Hospital were included. Tumour tissue microarrays assembled from specimens from these patients were prepared and stained immunohistochemically for CIP2A protein expression. Associations with clinicopathologic parameters and other biomarkers were explored, and survival analyses were done according to the Kaplan-Meier method. Study of the role of CIP2A in intracellular signalling in vitro involved gastric, ovarian, and tongue cancer cell lines. We found CIP2A to be highly expressed in gastric, ovarian, tongue, and colorectal cancer specimens. CIP2A was associated with clinicopathologic parameters characterizing an aggressive disease, namely advanced stage, high grade, p53 immunopositivity, and high proliferation index. CIP2A led to recognition of gastric, ovarian, and tongue cancer patients with poor prognosis, however, with a cancer type-specific cut-off level for prognostic significance. In tongue cancer, it served as an independent prognostic marker. In contrast, in colorectal cancer, CIP2A provided no prognostic value. In cancer cell lines, CIP2A was highly expressed at both protein and mRNA levels, and promoted cell proliferation and anchorage-independent growth. In gastric cancer, we demonstrated with a MYCER construct in mouse embryo fibroblasts that activation of MYC led to increased CIP2A mRNA expression, and hence we suggested that a positive feedback mechanism between CIP2A and MYC may potentiate and prolong the oncogenic activity of these proteins. We demonstrated in ovarian cancer an association between CIP2A and EGFR protein overexpression and EGFR gene amplification. In ovarian and tongue cancer cells we showed that depletion of EGFR downregulates CIP2A expression. In conclusion, high CIP2A expression occurred frequently among patients with aggressive disease. CIP2A may serve as a prognostic marker in gastric, ovarian, and tongue cancer and thus may help in tailoring therapy for cancer patients. The positive feedback mechanism between CIP2A and MYC, as well as the positive regulation of CIP2A by EGFR, are a few signalling pathways regulating and regulated by CIP2A. These and other mechanisms need to be studied further, however. CIP2A is a potential target for therapy, and its potential role as predictive marker and as a tumour marker in serum requires exploration.

Curcumin-Arteether Combination Therapy of Plasmodium berghei-Infected Mice Prevents Recrudescence Through Immunomodulation

Earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria. In a parasite recrudescence model in mice infected with Plasmodium berghei (ANKA), a single dose of alpha, beta-arteether (ART) with three oral doses of curcumin prevented recrudescence, providing almost 95% protection. The parasites were completely cleared in blood with ART-alone (AE) or ART+curcumin (AC) treatments in the short-term, although the clearance was faster in the latter case involving increased ROS generation. But, parasites in liver and spleen were not cleared in AE or AC treatments, perhaps, serving as a reservoir for recrudescence. Parasitemia in blood reached up to 60% in AE-treated mice during the recrudescence phase, leading to death of animals. A transient increase of up to 2-3% parasitemia was observed in AC-treatment, leading to protection and reversal of splenomegaly. A striking increase in spleen mRNA levels for TLR2, IL-10 and IgG-subclass antibodies but a decrease in those for INF gamma and IL-12 was observed in AC-treatment. There was a striking increase in IL-10 and IgG subclass antibody levels but a decrease in INF gamma levels in sera leading to protection against recrudescence. AC-treatment failed to protect against recrudescence in TLR2(-/-) and IL-10(-/-) animals. IL-10 injection to AE-treated wild type mice and AC-treated TLR22/2 mice was able to prolong survival. Blood from the recrudescence phase in AE-treatment, but not from AC-treatment, was able to reinfect and kill naive animals. Sera from the recrudescence phase of AC-treated animals reacted with several parasite proteins compared to that from AE-treated animals. It is proposed that activation of TLR2-mediated innate immune response leading to enhanced IL-10 production and generation of anti-parasite antibodies contribute to protective immunity in AC-treated mice. These results indicate a potential for curcumin-based combination therapy to be tested for prevention of recrudescence in falciparum and relapse in vivax malaria.

Tungsten-based nanomaterials (WO3 & Bi2WO6): Modifications related to charge carrier transfer mechanisms and photocatalytic applications

Heterogeneous photocatalysis is an ideal green energy technology for the purification of wastewater. Although titania dominates as the reference photocatalyst, its wide band gap is a bottleneck for extended utility. Thus, search for non-TiO2 based nanomaterials has become an active area of research in recent years. In this regard, visible light absorbing polycrystalline WO3 (2.4-2.8 eV) and Bi2WO6 (2.8 eV) with versatile structure-electronic properties has gained considerable interest to promote the photocatalytic reactions. These materials are also explored in selective functional group transformation in organic reactions, because of low reduction and oxidation potential of WO3 CB and Bi2WO6 VB, respectively. In this focused review, various strategies such as foreign ion doping, noble metal deposition and heterostructuring with other semiconductors designed for efficient photocatalysis is discussed. These modifications not only extend the optical response to longer wavelengths, but also prolong the life-time of the charge carriers and strengthen the photocatalyst stability. The changes in the surface-bulk properties and the charge carrier transfer dynamics associated with each modification correlating to the high activity are emphasized. The presence of oxidizing agents, surface modification with Cu2+ ions and synthesis of exposed facets to promote the degradation rate is highlighted. In depth study on these nanomaterials is likely to sustain interest in wastewater remediation and envisaged to signify in various green energy applications. (C) 2015 Elsevier B.V. All rights reserved.

Extended ageing time and temperature effects on quality of sub-primal cuts of boxed beef

[EN]Most of the information indicating ageing improves tenderness has been collected on the loin and rib-eye muscles over relatively short ageing times, assuming that all muscles will react similarly. In the present study, the effect of extended ageing times on instrumental texture (56 d) and sensory characteristics (42 d) of six different beef sub-primals [striploin (SL), inside round (IR), outside round (OR), eye of round (ER), blade eye (BE) and chuck tender (CT)] was studied. The effects of two ageing temperatures (1and 58C) were also compared. In general, ageing increased tenderness (P<0.05) of SL, BE, ER and CT sub-primals, although BE shear force increased after 42 d of ageing. On the other hand, ageing had no effect on IR tenderness (P<0.05) and resulted in a decrease in tenderness of OR (P<0.05) until day 35, with a later increase after 42 d of ageing. Increasing ageing temperature (58C) had limited effect on tenderness, but ageing time and temperature increases led to lower flavour and higher off-flavour intensity (P<0.05) of the studied sub-primals. These results suggest that cutspecific maximum ageing times and rigid adherence to temperature maximums would be of benefit to optimize postslaughter processes and meat quality

Evaluation of wheat or corn dried distillers' grains with solubles on performance and carcass characteristics of feedlot steers

[EN]A study was conducted on crossbred steers (n=275; 376±924 kg) to evaluate performance and carcass quality of cattle fed wheat or corn dried distillers’ grains with solubles (DDGS). The control ration contained 86.6% rolled barley grain, 5.7% supplement and 7.7% barley silage (DM basis). The four treatments included replacement of barley grain at 20 or 40% of the diet (DM basis) with wheat or corn DDGS. Steers were slaughtered at a common end weight of 645 kg with 100 steers randomly (n=20 per treatment) selected for determination of the retail yield of sub-primal boneless boxed beef (SPBBB). Data were analyzed as a completely randomized design using pen as the experimental unit. Feeding increasing levels of wheat DDGS led to a quadratic increase in dry matter intake (DMI) (P<0.01), whereas increasing levels of corn DDGS led to a quadratic decrease in DMI (P=0.01). Average daily gain was not influenced (P=0.13) by feeding wheat or corn DDGS, but cattle fed corn DDGS exhibited a quadratic increase (P=0.01) in gain:feed. As a result, a quadratic increase (P<0.01) in calculated NEg of the diet was observed as corn DDGS levels increased. A linear decrease (P=0.04) in days on feed (169, 166 and 154 d) was noted when increasing levels of wheat DDGS (0, 20 and 40%) were fed. Dressing percentage increased in a linear fashion with wheat DDGS (P<0.01) inclusion level and in a quadratic fashion (P=0.01) as corn DDGS inclusion level increased although other carcass traits were not affected (P=0.10) by treatment. The results indicate that replacement of barley grain with corn or wheat DDGS up to 40% of the diet (DM) can lead to superior performance (improved gain:feed or reduced days on feed, respectively) with no detrimental effect on quality grade or carcass SPBBB yield.

Las casas-torre bajomedievales. Análisis sistémico de un proceso de reestructuración espacial/territorial

[ES] La torre banderiza es uno de los más relevantes elementos del patrimonio construido vasco. Diseminados por toda la geografía de la comunidad autónoma, se pueden encontrar ejemplos representativos de este tipo arquitectónico, característico de una convulsa etapa que se prolongó algo más allá del período de crisis bajomedieval (siglos XIV-XVI). Este trabajo pretende por un lado formular una propuesta interpretativa sistémica e integradora que, partiendo del análisis estratigráfico de las fábricas, muestre el peso específico de esta construcción como elemento de gestión de los recursos del territorio. Pero sobre todo, en las siguientes líneas se hace una decidida apuesta por una forma de entender la investigación histórico-arqueológica.

About the limits of metalanguage: An essay on the modelisation of Latin grammatical lexicography

[EN] Progress in methodology in specific fields is usually very closely linked to the technological progress in other areas of knowledge. This justifies the fact that lexicographical techniques have had to wait for the arrival of the IT era of the last decades of the 20th century in order to be able to create specialised electronic dictionaries which can house and systemise enormous amounts of information which can later be dealt with quickly and efficiently. This study proposes a practical-methodological model which aims to solve the grammatical treatment of adverbs in Ancient Latin. We have suggested a list of 5 types, in a decreasing order from a greater to lesser degree of specialisation; technical (T), semi-technical (S-T), instrumental-valued (I-V), instrumental- descriptive (I-D), instrumental-expository (I-E).

Ahozkotasunaren irakaskuntza bigarren hezkuntzako testuliburuetan

[EN]Traditionally writing skills have been given priority in language teaching and so, oral skills have been put aside. However, during the last years many voices have asserted the importance of oral skills. Therefore, they claim that oral language teaching must be emphasized at school. Also, the necessity of strengthening oral language is shown in the new curriculum. Nevertheless, those intentions are reflected in very different ways in textbooks. In this work we have looked into the treatment that oral language is given in teaching materials because, in our opinion, textbooks are one of the most important tools for teachers. The facts show that the importance given to oral language and the exercises and tools needed to work that skill are very different from one publishing house to another. Besides, we have confirmed that all the textbooks don’t satisfy the requirements proposed in the Basque official curriculum (e.g. didactic sequences) or that the approach to the text or the way to work with it are not always what they should be. Therefore, it is obvious that we have still a long way in the field of oral language and specially in the way of teaching oral skills

Discrepancias en el seno de la burguesía guipuzcoana en torno a la libertad de comercio y el traslado de aduanas durante los siglos XVIII y XIX

[ES] El objetivo del presente artículo es demostrar y analizar las discrepancias que hubo en el seno de la burguesía guipuzcoana durante los siglos XVIII y XIX en torno a la habilitación de los puertos guipuzcoanos para el comercio directo con América y el traslado de aduanas desde el interior a la costa. Para ello, se acude a la extensa historiografía que se ha ocupado del tema y se hace un análisis crítico de cierto número de representaciones enviadas por el grupo de comerciantes disidentes, con el fin de llevar a cabo un reco- rrido por el debate en torno a ambas cuestiones, que se prolongó desde el advenimiento de la dinastía borbónica hasta los decretos de 1841. A pesar de la visión unívoca que se ha dado del mencionado debate, según la cual parti- ciparon dos bloques perfectamente diferenciados, la documentación muestra una mayor heterogeneidad en las posturas, de manera que en el seno de la burguesía comercial se perciben ciertas divisiones y discrepancias. Si bien es cierto que en un principio los bloques parecen tener un discurso claramente beligerante, aunque también existen todavía puntos de coincidencia, a medi- da que transcurre el tiempo, las posturas se van radicalizando y diversifi- cando, creando una mayor heterogeneidad.

The Experimental and Numerical Studies on Gas Production from Hydrate Reservoir by Depressurization

A set of experimental system to study hydrate dissociation in porous media is built and some experiments on hydrate dissociation by depressurization are carried out. A mathematical model is developed to simulate the hydrate dissociation by depressurization in hydrate-bearing porous media. The model can be used to analyze the effects of the flow of multiphase fluids, the kinetic process and endothermic process of hydrate dissociation, ice-water phase equilibrium, the variation of permeability, convection and conduction on the hydrate dissociation, and gas and water productions. The numerical results agree well with the experimental results, which validate our mathematical model. For a 3-D hydrate reservoir of Class 3, the evolutions of pressure, temperature, and saturations are elucidated and the effects of some main parameters on gas and water rates are analyzed. Numerical results show that gas can be produced effectively from hydrate reservoir in the first stage of depressurization. Then, methods such as thermal stimulation or inhibitor injection should be considered due to the energy deficiency of formation energy. The numerical results for 3-D hydrate reservoir of Class 1 show that the overlying gas hydrate zone can apparently enhance gas rate and prolong life span of gas reservoir.

Meu nome não é ninguém: narrativa sobre excluídos na Literatura Brasileira Contemporânea: Cidade de Deus e Meu nome não é Johnny

O tema da exclusão social sempre esteve presente na Literatura Brasileira, porém, na virada do século XX para o XXI, ele ganha ainda mais relevo, através de narrativas realistas, chocantes, exacerbadas de violência e até anomia, que enfatizam a imagem dos excluídos. Cidade de Deus (Paulo Lins: 1997) e Meu nome não é Johnny (Guilherme Fiuza: 2004) focalizam a exclusão dos envolvidos com o narcotráfico. A despeito das diferenças entre as duas narrativas, os seus protagonistas entram em ação a partir da marginalidade; ganham autonomia, no cenário urbano, através da criminalidade, e se tornam ameaçadoramente visíveis, depois de uma histórica invisibilidade. O estudo das complexidades concernentes ao tratamento ficcional do tema se distribuiu, nessa dissertação, em três capítulos. No primeiro capítulo, as obras foram estudadas individualmente, em função da organização dos relatos no espaço narrativo. O segundo capítulo abordou a correlação entre geografia cultural e teoria da literatura, em suas considerações sobre a proeminência da categoria do espaço para o trabalho narratológico. Nessa perspectiva interdisciplinar, foram analisadas as paisagens ficcionais de ambos os romances e, em seguida, articulou-se o roteiro ficcional de cada romance com o pensamento de Foucault sobre os lugares heterotópicos. No terceiro capítulo, intertextualizando o binômio disciplinar geografia cultural e literatura com a filosofia, retroagiu-se aos filósofos idealistas alemães que teorizaram sobre o trágico e intuíram que a tragicidade não se manifesta apenas na tragédia, mas também em obras que lidam com a experiência do irrepresentável, da representação negativa e, em termos estéticos, do sublime. Conjugando as idéias de Hölderlin sobre o vislumbre do divino, de Schopenhauer sobre a metafísica da música, e de Nietzsche sobre a correlação entre o apolíneo e o dionisíaco, tragédia e música, chegou-se à conclusão de que ambas as narrativas incorporam produtivamente ao projeto ficcional duas metáforas absolutas (Hans Blumenberg) que dizem respeito à exclusão/inclusão: a cidade e o hipocorístico (Johnny), dois espaços um material, outro alegórico interativos, em ambos os romances. Em Meu nome não é Johnny, o percurso simbólico do protagonista o leva do sofrimento à redenção social e à inclusão (grandemente graças à atividade musical); em Cidade de Deus, a brutalização progressiva das relações humanas leva à erradicação de qualquer manifestação da sensibilidade, a uma cidade sem música e à permanência da exclusão

Arqueozoología analítica. Otro ejemplo práctico derivado de la obra de Georges Laplace

Homenaje a Georges Laplace, realizado en Vitoria-Gasteiz el 13,14 y 15 de noviembre de 2012. Edición a cargo de Aitor Calvo, Aitor Sánchez, Maite García-Rojas y Mónica Alonso-Eguíluz.

Mas e embora: uma descrição morfossintática e semântico-pragmática

Esta dissertação é o resultado de dois anos de estudo e de pesquisa dedicados à formação, à estrutura e ao funcionamento da língua portuguesa. A inconformidade com o tratamento um tanto superficial que os compêndios gramaticais prescritivos, sobretudo os escolares, têm dado à classificação das conjunções coordenativas adversativas e das subordinativas adverbiais concessivas e, por conseguinte, das orações em que elas se inserem, foi a motivação e é o que justifica a escolha do tema. Essa maneira de abordar a questão tem misturado descrições sintáticas com semânticas, sem, muitas vezes, levar em consideração a aplicabilidade e a pertinência de uma ou de outra oração no discurso. Dessa forma, esta dissertação se propõe a descrever os comportamentos morfossintáticos e semântico- -pragmáticos dos períodos formados com as conjunções mas e embora à luz da semântica enunciativa, e a averiguar até que ponto a vagueza de abordagem desse tema tem refletido na formação daqueles que têm a língua portuguesa como língua materna no Brasil. Para tanto, o trabalho apresenta a seguinte estrutura: num primeiro momento, serão considerados a metodologia usada para a feitura do trabalho e os pressupostos teóricos que melhor fundamentam-no. A teoria está dividida em três momentos, a saber, o enfoque dado pela tradição gramatical, o enfoque dado pela linguística à noção de coordenação e de subordinação, e o enfoque dado pela semântica enunciativa às conjunções mas e embora. Num segundo momento, serão explanadas as análises feitas dos corpora presentes no texto: um para corroborar as ideias presentes em um dos capítulos teóricos (corpus de textos de opinião); e outro para averiguar se a superficialidade da abordagem do tema ao longo do tempo tem afetado na formação de leitores e escritores proficientes em língua portuguesa (corpus de transcrição). A análise do segundo corpus o corpus de transcrição, em que pessoas de diferentes níveis de estudo foram testadas no que tange ao conhecimento acerca da transformação de períodos compostos por coordenação adversativa em subordinação adverbial concessiva e vice-versa; além de se descobrir se não iniciariam uma frase com a conjunção adversativa mas tem capítulo à parte e revelará o que não é tão difícil de pressupor: 67,4% das frases transcritas revelam o desconhecimento que as pessoas têm acerca da diferença morfossintática e semântico-pragmática de períodos formados pelas conjunções adversativa e concessiva, mas e embora, respectivamente