Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.

Albert Einstein Commemorative Medal

Obverse: A likeness of Einstein according to the sculpture seen in the entrance to the Mathematics Institute of the Hebrew University of Jerusalem. Reverse: A mathematical formula in Einstein's handwriting.

THE BERGMAN KERNEL FUNCTION

In this note, we point out that a large family of n x n matrix valued kernel functions defined on the unit disc D subset of C, which were constructed recently in [9], behave like the familiar Bergman kernel function on ID in several different ways. We show that a number of questions involving the multiplication operator on the corresponding Hilbert space of holomorphic functions on D can be answered using this likeness.

On Musical Self-Similarity : Intersemiosis as Synecdoche and Analogy

Self-similarity, a concept taken from mathematics, is gradually becoming a keyword in musicology. Although a polysemic term, self-similarity often refers to the multi-scalar feature repetition in a set of relationships, and it is commonly valued as an indication for musical coherence and consistency . This investigation provides a theory of musical meaning formation in the context of intersemiosis, that is, the translation of meaning from one cognitive domain to another cognitive domain (e.g. from mathematics to music, or to speech or graphic forms). From this perspective, the degree of coherence of a musical system relies on a synecdochic intersemiosis: a system of related signs within other comparable and correlated systems. This research analyzes the modalities of such correlations, exploring their general and particular traits, and their operational bounds. Looking forward in this direction, the notion of analogy is used as a rich concept through its two definitions quoted by the Classical literature: proportion and paradigm, enormously valuable in establishing measurement, likeness and affinity criteria. Using quantitative qualitative methods, evidence is presented to justify a parallel study of different modalities of musical self-similarity. For this purpose, original arguments by Benoît B. Mandelbrot are revised, alongside a systematic critique of the literature on the subject. Furthermore, connecting Charles S. Peirce s synechism with Mandelbrot s fractality is one of the main developments of the present study. This study provides elements for explaining Bolognesi s (1983) conjecture, that states that the most primitive, intuitive and basic musical device is self-reference, extending its functions and operations to self-similar surfaces. In this sense, this research suggests that, with various modalities of self-similarity, synecdochic intersemiosis acts as system of systems in coordination with greater or lesser development of structural consistency, and with a greater or lesser contextual dependence.

Mantenimiento en el laboratorio del pez cebra

El pez cebra (Danio rerio) se utiliza como organismo modelo en distintos campos como la biomedicina o la toxicogenómica. Las ventajas que ofrece frente a otros modelos animales, hace que se haya convertido en los últimos años en uno de los organismos modelo más utilizado en experimentación. La similitud de su desarrollo embrionario con el de otros vertebrados superiores o la semejanza de su genoma con la del ser humano lo han colocado en el punto de mira de las principales investigaciones. Pero disponer de ejemplares óptimos tanto de embriones como de adultos para su utilización en investigación, requiere de unos cuidados y de una atención adecuada. Para su mantenimiento se deberán tener en cuenta el tipo de instalaciones para su cría, la calidad del agua donde se encuentran, la alimentación que reciben o los procesos de reproducción utilizados. El objetivo de este estudio ha sido elaborar un protocolo de mantenimiento del pez cebra, que optimice los cuidados necesarios para que el número de embriones viables sea máximo y también poder mantener un número de ejemplares adultos en buenas condiciones.

Aristóteles, «Poética» 1454a 24, y la tragedia del siglo IV

[ES] La cualidad de "semejantes", el requisito que Aristóteles señala han de poseer los personajes de la tragedia en «Poét.» 1454a 24, ha recibido fundamentalmente dos interpretaciones distintas. Una, la que supone que tal semejanza lo es con el hombre ordinario, está bien asentada dentro de la argumentación general de la «Poética»; la otra, que relaciona el concepto con el prototipo mítico, requiere más aclaraciones que la anterior si se pretende que pueda ser aristotélica. De ello nos ocupamos en el presente artículo, poniendo en relación la práctica contemporánea, la tragedia del siglo IV, con las opiniones de Aristóteles en la «Poética».

Loosely packed self-assembled monolayer of N-hexadecyl-3,6-di(p-mercaptophenylacetylene)carbazole on gold and its application in biomimetic membrane research

Dithiols of N-hexadecyl-3,6-di(p-mercaptophenylacetylene)carbazole (HDMC) have been synthesized and employed to form self-assembled monolayers (SAMs) on gold. One characteristic of the HDMC molecule is its peculiar molecular structure consisting of a large and rigid headgroup and a small and flexible alkyl-chain tail. HDMC adsorbates can attach to gold substrates by a strong Au-S bond with weak van der Waals interactions between the alkyl-chain tails, leading to a loosely packed hydrophobic SAM. In this way we can couple hybrid bilayer membranes (HBMs) to gold surfaces with more likeness to a cell bilayer than the conventional HBMs based on densely packed long-chain alkanethiol SAMs. The insulating properties and stability of the HDMC monolayer as well as the HDMC/lipid bilayer on gold have been investigated by electrochemical techniques including cyclic voltammetry and impedance spectroscopy. To test whether the quality of the bilayer is sufficiently high for biomimetic research, we incorporated the pore-forming protein a-hemolysin) and the horseradish peroxidase into the bilayers, respectively.

Age and gender influences on sensory perceptions of novel low cost nutrient-rich food products developed using traditional Ghanaian food ingredients

Background: A number of factors are known to influence food preferences and acceptability of new products. These include their sensory characteristics and strong, innate neural influences. In designing foods for any target group, it is important to consider intrinsic and extrinsic characteristics which may contribute to palatability, and acceptability of foods. Objective: To assess age and gender influences on sensory perceptions of novel low cost nutrient-rich food products developed using traditional Ghanaian food ingredients. Materials and Methods: In this study, a range of food products were developed from Ghanaian traditional food sources using the Food Multimix (FMM) concept. These products were subjected to sensory evaluation to assess the role of sensory perception on their acceptability among different target age groups across the life cycle (aged 11-68 years olds) and to ascertain any possible influences of gender on preference and choice. Variables including taste, odour, texture, flavour and appearance were tested and the results captured on a Likert scale and scores of likeness and acceptability analysed. Multivariate analyses were used to develop prediction models for targeted recipe development for different target groups. Multiple factor analysis of variance (ANOVA) and logistic linear regression were employed to test the strength of acceptability and to ascertain age and gender influences on product preference. Results: The results showed a positive trend in acceptability (r = 0.602) which tended towards statistical significance (p = 0.065) with very high product favourability rating (91% acceptability; P=0.005). However, age [odds ratios=1.44 (11-15 years old) odds ratios=2.01 (18-68 years old) and gender (P=0.000)] were major influences on product preference with children and females (irrespective of age) showing clear preferences or dislike of products containing certain particular ingredients. Conclusion: These findings are potentially useful in planning recipes for feeding interventions involving different vulnerable and target groups.

Design and evaluation of tinnitus synthesis methods: From spectral to spatial matching

Purpose
This study was designed to investigate methods to help patients suffering from unilateral tinnitus synthesizing an auditory replica of their tinnitus.

Materials and methods
Two semi-automatic methods (A and B) derived from the auditory threshold of the patient and a method (C) combining a pure tone and a narrow band-pass noise centred on an adjustable frequency were devised and rated on their likeness over two test sessions. A third test evaluated the stability over time of the synthesized tinnitus replica built with method C, and its proneness to merge with the patient's tinnitus. Patients were then asked to try and control the lateralisation of this single percept through the adjustment of the tinnitus replica level.

Results
The first two tests showed that seven out of ten patients chose the tinnitus replica built with method C as their preferred one. The third test, performed on twelve patients, revealed pitch tuning was rather stable over a week interval. It showed that eight patients were able to consistently match the central frequency of the synthesized tinnitus (presented to the contralateral ear) to their own tinnitus, which leaded to a unique tinnitus percept. The lateralisation displacement was consistent across patients and revealed an average range of 29dB to obtain a full lateral shift from the ipsilateral to the contralateral side.

Conclusions
Although spectrally simpler than the semi-automatic methods, method C could replicate patients' tinnitus, to some extent. When a unique percept between synthesized tinnitus and patients' tinnitus arose, lateralisation of this percept was achieved.

Sir Isaac Brock Facial Reconstruction Project, n.d.

Christian Cardell Corbet, a descendant of Guernsey, Channel Islands, was born in 1966 at Pickering Beach on Lake Ontario. He developed his talents as a landscape artist and at the young age of 14 he began his informal education in commercial signage from his paternal grandfather. He studied at the University of Guelph and McMaster University Anatomy Laboratory. Corbet traveled to England where he began to experiment more in abstraction and non-objective work. In 1995, he presented a portrait of HM Queen Elizabeth the Queen Mother at Clarence House. This brought his career to an international level. He also creates two-dimensional works and has received acclaim for his bronze art medallions. He has gained international recognition as a Forensic Artist working as Artist in Residence for the University of Western Ontario. He does facial reconstructions for special assignments. These original drawings relate to a sculpted medallion of Brock which was authorized by Sir Geoffrey Rowland, Bailiff, Guernsey, Channel Islands and Minister of Education of the States of Guernsey. This is the first time in known recorded history that a forensic analysis and sculpture has been created to accurately depict the facial likeness of Sir Isaac Brock. This project has been established to mark the 2012 anniversary of the death of Brock.

Une méthode d'évaluation fiable pour mesurer les caractéristiques psychoacoustiques de l'acouphène.

Le diagnostic de l’acouphène repose sur le rapport verbal du patient. Cependant, les paramètres psychoacoustiques, tels que la hauteur et la sonie de l’acouphène, sont essentiels pour l’évaluation et pour discriminer les fausses plaintes. Quantifier le percept de l’acouphène reste un objectif de recherche important. Nous avons cherché à: (1) évaluer la précision d'une nouvelle méthode d'évaluation des acouphènes du type « likeness rating » avec une méthode de présentation continue de la hauteur, en considérant la formation musicale, et (2) vérifier si les mesures psychoacoustiques de l’acouphène ont la sensibilité et la spécificité pour détecter les personnes simulant un acouphène. Nous avons recruté des musiciens et des non-musiciens souffrant d'acouphènes et des simulateurs sans acouphènes. La plupart d’entre eux ont été testés une seconde fois quelques semaines plus tard. La hauteur de l’acouphène a d’abord été évaluée en utilisant la méthode « likness rating ». Des sons purs ont été présentés de manière aléatoire de 0.25 kHz à 16 kHz et les participants devaient coter la ressemblance de chaque son par rapport à leur acouphène, et en ajuster son volume de 0 à 100 dB SPL. La hauteur a ensuite été évaluée par une méthode, où les participants devaient apparier la hauteur de leur acouphène en déplaçant leur doigt sur une bande tactile générant des sons purs en continu de 0.5 kHz à 20 kHz par pas de 1 Hz. Les capacités à apparier des sons externes ont été évaluées en utilisant cet appareil. La hauteur prédominante de l’acouphène était similaire entre les deux méthodes pour les musiciens et les non-musiciens, bien que les musiciens montraient de meilleures capacités d’appariement face à des sons externes. Les simulateurs ont coté la sonie bien au-dessus que les autres groupes avec un grand degré de spécificité (94,4%), et ont été inconsistants dans l’appariement de cette sonie (pas de la hauteur) d’une session à une autre. Les données de la seconde session montrent des réponses similaires pour l’appariement de la hauteur pour les deux méthodes ainsi que pour tous nos participants. En conclusion, la hauteur et la sonie correspondent au percept de l’acouphène et doivent en plus être utilisées avec des échelles visuelles analogiques, qui sont plus corrélées avec la gêne et la détresse. Enfin, l’appariement de la sonie est sensible et spécifique à déterminer la présence de l’acouphène.

An improved lesion detection approach based on similarity measurement between fuzzy intensity segmentation and spatial probability maps

The application of automatic segmentation methods in lesion detection is desirable. However, such methods are restricted by intensity similarities between lesioned and healthy brain tissue. Using multi-spectral magnetic resonance imaging (MRI) modalities may overcome this problem but it is not always practicable. In this article, a lesion detection approach requiring a single MRI modality is presented, which is an improved method based on a recent publication. This new method assumes that a low similarity should be found in the regions of lesions when the likeness between an intensity based fuzzy segmentation and a location based tissue probabilities is measured. The usage of a normalized similarity measurement enables the current method to fine-tune the threshold for lesion detection, thus maximizing the possibility of reaching high detection accuracy. Importantly, an extra cleaning step is included in the current approach which removes enlarged ventricles from detected lesions. The performance investigation using simulated lesions demonstrated that not only the majority of lesions were well detected but also normal tissues were identified effectively. Tests on images acquired in stroke patients further confirmed the strength of the method in lesion detection. When compared with the previous version, the current approach showed a higher sensitivity in detecting small lesions and had less false positives around the ventricle and the edge of the brain

O sindicalismo e a administração publica

A dissertação aqui apresentada versa sobre uma temática nova, quer vista sob a ótica do nascimento do fato sociológico analisado - O Sindicalismo e a Administração Pública quer se considere a quase inexistência de fontes nas quais se possa abeberar, para que fosse possível estabelecer o fio condutor no desenvolvimento do tema. A temática foi analisada em dois planos: primeiro, fêz-se uma apreciação crítica da história do associativismo no Brasil, em sua simbiose com o aspecto social, com o lado econômico e com o lastro jurídico, ao ser analisado o caminho percorrido desde o primeiro clarão do Brasil até os dias presentes. Em segundo estágio, perquiriu-se a questão sindical, no que diz respeito à sua etiologia, o seu despertar mais consciente na década de 80 do nosso século, perpassando pela criação das Centrais Sindicais, ao serem detectados os desvios ideológicos, as contradições, a sua fisiologia em função de sua organização, ideário e ação na direção do que se propõem em nome de seus afiliados. Com efeito, o núcleo do trabalho se cinge à arregimentação do corpo de funcionários públicos com vistas a um eficaz - hoje, ainda muito incipiente - congraçamento, ao se deparar com uma forte resistência institucional, de vez que só a partir da Constituição de 1988, é que se abriu caminho para o direito de associação sindical a esse estamento dos agentes públicos. As disfunções são, aí, analisadas em relação ao despreparo dos Recursos Humanos no exercício de liderança e em confronto com a estrutura institucional anacrônica e de feitio autoritário, para fazer valer, de forma eficaz e efetiva, um bom desempenho da ação sindical, que se deseja genuína, autônoma e autógena, em função dos interesses de classe e a ter em vista a excelência dos serviços públicos; o fenômeno estudado, inversamente, mostra o processamento de uma luta sindical radicada em estrutura antidemocrática, em que o Estado financia os sindicatos e todo o aparelhamento sindical vertical, via contribuição sindical e a considerar que esse lastro sustentador da luta sindical é decalque de uma época de predominância de valores chauvinistas, exaltados no Brasil - e em outros países -, nas décadas de 30 e 40. Ainda foi feito um estudo comparativo com três modelos de sindicalismo, quais sejam: o francês, o alemão e o português. Os dois primeiros por razões de se constituirem em paradigmas de países centrais, tendo em vista que: (1) a França é modelo inspirador das instituições ocidentais, em sede político-jurídico-social, haja vista a sua História prenhe de fatos solapadores do statu quo ante; e (2) a Alemanha, por ter uma classe eficazmente institucionalizada de agentes públicos, tendo tradição araigada desde a burocracia prussiana, o que dá o toque de elevado profissionalismo a esses agentes públicos, os quais contam com uma agremiação sindical que guarda independência com relação ao movimento sindical do trabalhador privado, este, também consolidado em poderosa organização sindical naquele país. Portugal aparece no trabalho como o ascendente cultural do Brasil, o que implica em ser mostrado o nascedouro sindical desse país, dentro do clima cultural em que viveu e vive a península lusitana, e com isso se tenta elucidar o estágio de seu sindicalismo, as suas disfunções e auto funções , as suas semelhanças com o modelo brasileiro, as suas inclinações e natureza. As conclusões aferidas registram alguns aspectos relevantes: 1º) o Brasil nasceu de uma Administração centralizadora, marcada por uma máquina administrativa ineficaz, ineficiente, com a marca do Estato-império e sem a presença da construção concomitante de uma nação que é retardatária no assentar a viga da cidadania, o que levou a delongar a formação dos anseios e do espírito genuinamente autóctones. A repressão ao desenvolvimento das letras foi um entrave à criação de um espírito de povo, com a variante de ser uma maioria inculta, massacrantemente iletrada, em meio a uma pirâmide social em que se registrava apenas uma base desmesurada e um vértice acanhado, sem ter de permeio outras classes sociais que pudessem ser ou vir a ser estratificadas. Na esteira desses elementos, concluiu-se que: 2º) o movimento associativo é uma realidade incipiente e adormecido durante séculos, o que desbordou em uma apatia que só hoje começa a ser sacudida, através dos movimentos associativistas e sindical, este último nascido no meio das fábricas e estendido a algumas capitais de maior relevância política ou de maior peso econômico. o aspecto de maior magnitude para o trabalho foi a sinalização aberta aos servidores públicos para que se sindicalizassem, do que decorreu a conclusão de que essa ação precisa ser tangenciada e carreada a ser um movimento mais autenticamente ligado aos interesses da classe, pois por desvirtuamento contingencial em face da iniciante pouca expressão e inexperiência desse estamento, a ação sindical desses servidores sempre esteve à ilharga do movimento sindical do trabalhador privado, o qual tem outra linha de ação direcionada a interesses mais ligados ao conflito trabalho vs. capital, interesses esses que não se coadunam e nem se identificam com as aspirações e necessidades do funcionalismo público, mesmo que, muitas vezes, a questão do conflito desses agentes tenha uma interface no conjunto da pauta de reivindicação dos trabalhadores privados, ou seja, a questão salarial. O imperativo maior - e esta é a base da recomendação mais substancial - é conduzir a ação dos agentes públicos de forma heterodoxa na direção de se independentizar o movimento sindical desses agentes, a ser impulsionado pelas suas peculiaridades e por sua essencialidade ditada pela sua ontologia de servidores da coisa pública e tendo o público como sua clientela. Este é, em síntese, o caminho aqui trilhado.

Negros misturados: um estudo de caso sobre identidades negras em Mossoró-RN

With more or less 213.000 habitants, Mossoró is the second more developed city from the Rio Grande do Norte. The town is proclamated like the land of freedom. To so far, exist four moments in your history related with the defence of freedom that is point like truthful from so proclamation. Suchlike happenings are the first female vote on Brazil, the resistance against the Lampião s band, the worman s mutiny and the slave release in 1883, five year before the Áurea law sanction. These happenings are commemorate yearly on setember with one big theatrical event called by the freedom high. Inside this contexto of exaltation to freedom, there is one black movement by name black and beautiful. Is the present dissertation, talked about the building of black identities between the black militants of Mossoró and the dwellers from the Santo Antônio district. With such approach, we intend to think about possibles differences or likeness, how the militants and dwellers from the refered district self-calleds like blacks or not. We are understanding black identity like one process to self-affirmation done by specificities of the social context and the individual particularity. This way, the identity change into one dynamic and contextual reality, gone always by one business process against the interaction of the social actors. So we search to discuss the specificities that involve the process to building of black identities in the city of freedom

Habitus, representações sociais e a construção do ser professora da educação infantil da cidade de Campina Grande - PB

We present here the results of a study whose objectives were to identify the social representation of being a professor of early childhood education in Campina Grande - PB, in the public state and municipal levels, and detect structural diagrams of a possible mental habitus of professorial faculty of education child, which would form the basis for the construction of this representation. As a theoretical base, we adopted the model developed by Domingos Sobrinho (1998, 2000, 2003, 2010, 2011), which articulates the Theory of Social Representations, Serge Moscovici, and the foundations and concepts of Pierre Bourdieu praxiology. It is based also on the Central Nucleus Theory, which focuses on the structural approach of social representations. Thus, puts in evidence the relational dynamics and symbolic, through which individuals come into contact, describe, understand and reproduce the outside world in his image and likeness. 199 teachers participated in the study of child care and pre-schools of Campina Grande - PB and 109 of the state. The methods and techniques used were: a) participant observation of everyday life of teachers of kindergartens and preschools, b) semi-structured interview, c) free associations of words with inducing the expression 'being a professor of early childhood education is ...' and d) semi-structured questionnaire. The data were analyzed in the case of interviews through the categorical content analysis, as proposed by Bauer (2010); free-associations, using the software Ensemble L'Analyse des Programmes Permettant evocations (EVOC), developed by Vergès (2002), which combines frequency and average order of recall (or association) and the questionnaire data, the Statistical Package for the Social Sciences (SPSS). It was verified the existence of a unique social representation shared by the population studied, but its content is structured differently. For local teachers, the centrality of the content is given by the elements commitment, dedication, responsibility, and rewarding teachers for this state revolves around the elements of love, patience, and rewarding responsibility. However, it is constructed mainly based on the related produced by a religious habitus and maternal habitus, which are part of the genesis of the establishment of professorial habitus in focus, among other cultural references of secondary influence. We conclude that a teacher of early childhood education actually researched, is materialized in the practices of educating and caring, in a clear fusion of the role of teacher and mother