Comparative molecular field analysis of a series of inhibitors of HIV-1 protease

Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.

Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

Alzheimer`s disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.

Three-Dimensional Quantitative Structure-Activity Relationship Study of Antitumor 2-Formylpyridine Thiosemicarbazones Derivatives as Inhibitors of Ribonucleotide Reductase

In order to extend previous SAR and QSAR studies, 3D-QSAR analysis has been performed using CoMFA and CoMSIA approaches applied to a set of 39 alpha-(N)-heterocyclic carboxaldehydes thiosemicarbazones with their inhibitory activity values (IC(50)) evaluated against ribonucleotide reductase (RNR) of H.Ep.-2 cells (human epidermoid carcinoma), taken from selected literature. Both rigid and field alignment methods, taking the unsubstituted 2-formylpyridine thiosemicarbazone in its syn conformation as template, have been used to generate multiple predictive CoMFA and CoMSIA models derived from training sets and validated with the corresponding test sets. Acceptable predictive correlation coefficients (Q(cv)(2) from 0.360 to 0.609 for CoMFA and Q(cv)(2) from 0.394 to 0.580 for CoMSIA models) with high fitted correlation coefficients (r` from 0.881 to 0.981 for CoMFA and r(2) from 0.938 to 0.993 for CoMSIA models) and low standard errors (s from 0.135 to 0.383 for CoMFA and s from 0.098 to 0.240 for CoMSIA models) were obtained. More precise CoMFA and CoMSIA models have been derived considering the subset of thiosemicarbazones (TSC) substituted only at 5-position of the pyridine ring (n=22). Reasonable predictive correlation coefficients (Q(cv)(2) from 0.486 to 0.683 for CoMFA and Q(cv)(2) from 0.565 to 0.791 for CoMSIA models) with high fitted correlation coefficients (r(2) from 0.896 to 0.997 for CoMFA and r(2) from 0.991 to 0.998 for CoMSIA models) and very low standard errors (s from 0.040 to 0.179 for CoMFA and s from 0.029 to 0.068 for CoMSIA models) were obtained. The stability of each CoMFA and CoMSIA models was further assessed by performing bootstrapping analysis. For the two sets the generated CoMSIA models showed, in general, better statistics than the corresponding CoMFA models. The analysis of CoMFA and CoMSIA contour maps suggest that a hydrogen bond acceptor near the nitrogen of the pyridine ring can enhance inhibitory activity values. This observation agrees with literature data, which suggests that the nitrogen pyridine lone pairs can complex with the iron ion leading to species that inhibits RNR. The derived CoMFA and CoMSIA models contribute to understand the structural features of this class of TSC as antitumor agents in terms of steric, electrostatic, hydrophobic and hydrogen bond donor and hydrogen bond acceptor fields as well as to the rational design of this key enzyme inhibitors.

Expression, purification and kinetic characterization of His-tagged glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi

Trypanosomes are flagellated protozoa responsible for serious parasitic diseases that have been classified by the World Health Organization as tropical sicknesses of major importance. One important drug target receiving considerable attention is the enzyme glyceraldehyde-3-phosphate dehydrogenase from the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (T. cruzi Glyceraldehyde-3-phosphate dehydrogenase (TcGAPDH); EC 1.2.1.12). TcGAPDH is a key enzyme in the glycolytic pathway of T. cruzi and catalyzes the oxidative phosphorylation of D-glyceraldehyde-3-phosphate (G3P) to 1,3-bisphosphoglycerate (1,3-BPG) coupled to the reduction of oxidized nicotinamide adenine dinucleotide, (NAD(+)) to NADH, the reduced form. Herein, we describe the cloning of the T. cruzi gene for TcGAPDH into the pET-28a(+) vector, its expression as a tagged protein in Escherichia coli, purification and kinetic characterization. The His(6)-tagged TcGAPDH was purified by affinity chromatography. Enzyme activity assays for the recombinant His(6)-TcGAPDH were carried out spectrophotometrically to determine the kinetic parameters. The apparent Michaelis-Menten constant (K(M)(app)) determined for D-glyceraldehyde-3-phosphate and NAD(+) were 352 +/- 21 and 272 +/- 25 mu M, respectively, which were consistent with the values for the untagged enzyme reported in the literature. We have demonstrated by the use of Isothermal Titration Calorimetry (ITC) that this vector modification resulted in activity preserved for a higher period. We also report here the use of response surface methodology (RSM) to determine the region of optimal conditions for enzyme activity. A quadratic model was developed by RSM to describe the enzyme activity in terms of pH and temperature as independent variables. According to the RMS contour plots and variance analysis, the maximum enzyme activity was at 29.1 degrees C and pH 8.6. Above 37 degrees C, the enzyme activity starts to fall, which may be related to previous reports that the quaternary structure begins a process of disassembly. (C) 2010 Elsevier Inc. All rights reserved.

Insights into the Molecular Requirements for the Anti-obesity Activity of a Series of CB1 Ligands

Two-dimensional and 3D quantitative structure-activity relationships studies were performed on a series of diarylpyridines that acts as cannabinoid receptor ligands by means of hologram quantitative structure-activity relationships and comparative molecular field analysis methods. The quantitative structure-activity relationships models were built using a data set of 52 CB1 ligands that can be used as anti-obesity agents. Significant correlation coefficients (hologram quantitative structure-activity relationships: r 2 = 0.91, q 2 = 0.78; comparative molecular field analysis: r 2 = 0.98, q 2 = 0.77) were obtained, indicating the potential of these 2D and 3D models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted (calculated) values are in good agreement with the experimental results. The final quantitative structure-activity relationships models, along with the information obtained from 2D contribution maps and 3D contour maps, obtained in this study are useful tools for the design of novel CB1 ligands with improved anti-obesity potency.

The relative perceptual weight of two Swedish prosodic contrasts

Abstract. In addition to 9 vowel and 18 consonant phonemes, Swedish has three prosodic phonemic contrasts: word stress, quantity and tonal word accent. There are also examples of distinctive phrase or sentence stress, where a verb can be followed by either an unstressed preposition or a stressed particle. This study focuses on word level and more specifically on word stress and tonal word accent in disyllabic words. When making curriculums for second language learners, teachers are helped by knowing which phonetic or phonological features are more or less crucial for the intelligibility of speech and there are some structural and anecdotal evidence that word stress should play a more important role for intelligibility of Swedish, than the tonal word accent. The Swedish word stress is about prominence contrasts between syllables, mainly signaled by syllable duration, while the tonal word accent is signaled mainly by pitch contour. The word stress contrast, as in armen [´arːmən] ‘the arm’ - armén [ar´meːn] ‘the army’, the first word trochaic and the second iambic, is present in all regional varieties of Swedish, and realized with roughly the same acoustic cues, while the tonal word accent, as in anden [´anːdən] ‘the duck’ - anden [`anːdən] ‘the spirit’ is absent in some dialects (as well as in singing), and also signaled with a variety of tonal patterns depending on region. The present study aims at comparing the respective perceptual weight of the two mentioned contrasts. Two lexical decision tests were carried out where in total 34 native Swedish listeners should decide whether a stimulus was a real word or a non-word. Real words of all mentioned categories were mixed with nonsense words and words that were mispronounced with opposite stress pattern or opposite tonal word accent category. The results show that distorted word stress caused more non-word judgments and more loss, than distorted word accent. Our conclusion is that intelligibility of Swedish is more sensitive to distorted word stress pattern than to distorted tonal word accent pattern. This is in compliance with the structural arguments presented above, and also with our own intuition.

Library Privacy Policies in 2015: Strategies for Renewed Relevance

In recent decades, library associations have advocated for the adoption of privacy and confidentiality policies as practical support to the Library Code of Ethics with a threefold purpose to (1) define and uphold privacy practices within the library, (2) convey privacy practices to patrons and, (3) protect against potential liability and public relations problems. The adoption of such policies has been instrumental in providing libraries with effective responses to surveillance initiatives such as warrantless requests and the USA PATRIOT ACT. Nevertheless, as reflected in recent news stories, the rapid emergence of data brokerage relationships and technologies and the increasing need for libraries to utilize third party vendor services have increased opportunities for data surveillers to access patrons’ personal information and reading habits, which are funneled and made available through multiple online library service platforms. Additionally, the advice that libraries should “contract for the same level of privacy reflected in their privacy policies” is no longer realistic given that the existence of multiple vendor contracts negotiated at arms length is likely to produce varying privacy terms and even varying definitions of what constitutes personal information (PII). These conditions sharply threaten the effectiveness and relevance of library privacy policies and privacy initiatives in that such policies increasingly offer false comfort by failing to reflect privacy weaknesses in the data sharing landscape and vendor contracts when library-vendor contracts fail to keep up with vendor data sharing capabilities. While some argue that library privacy ethics are antiquated and rendered obscure in the current online sharing economy PEW studies point to pronounced public discomfort with increasing privacy erosion. At the same time, new directions in FTC enforcement raise the possibility that public institutions’ privacy policies may serve as swords to unfair or deceptive commercial trade practices – offering the potential of renewed relevance for library privacy and confidentiality policies. This dual coin of public concern and the potential for enhanced FTC enforcement suggests that when crafting privacy polices libraries must now walk the knife’s edge by offering patrons both realistic notice about the limitations of protections the library can ensure while at the same time publicly holding vendors accountable to library privacy ethics and expectations. Potential solutions for how to walk this edge are developed and offered as a subject for further discussion to assist the modification of model policies for both public and academic libraries alike.

Um olhar multicultural sobre as políticas públicas para indígenas no governo federal

Este trabalho parte da premissa de que as políticas públicas universalistas não podem ser concebidas uniformemente para uma população sem se considerarem as diferenças culturais, porque tal situação comprometeria os resultados desejados. Para elucidarmos melhor tal premissa, selecionamos a questão indígena brasileira. A referência teórica desta pesquisa, o multiculturalismo, é estrangeira, portanto não ignoramos as limitações e a necessidade de adaptação de que necessita quando transportada para a realidade brasileira. De duas análises já existentes sobre o nível de políticas multiculturais nos países Latinos, comparamos a situação do Brasil com os outros países a fim de formar uma idéia geral sobre o contexto brasileiro em relação aos demais. A pesquisa, então, parte da revisão das condições históricas dos indígenas desde os anos 1970 e é complementada com indicadores demográficos das populações autóctones cotejadas com a nacional. Nesse momento já podemos apontar as dificuldades no aspecto normativo das políticas públicas multiculturais. Uma análise detalhada das propostas de políticas públicas específicas para os indígenas, no Plano Plurianual de 2008-2011 do Governo Federal, indica possíveis contradições entre diferentes programas e ações. Também verificamos a forma como o Ministério da Educação (MEC) e a sua Secretaria específica (SECAD/MEC) abordam a questão da diversidade cultural, na defesa de programas e ações sob perspectiva diferente dos do multiculturalismo. Finalizamos com um estudo dos limites e das oportunidades desse tratamento na questão indígena no Brasil, do que se conclui que há um movimento incipiente pró-multiculturalismo no país.

A inscrição psicológica do sintoma: uma aproximação psicoanalítica a psicossomática

Os discursos familiares encerram, no seu bojo, mitos sociais, sentimentos e fantasias inconscientes a eles conectados, que permaneceram secretos e poderosos através de sua historicidade e que vão se inscrever na matéria-prima pura: o recém-nascido, que deve ser moldado mediante o processo de identificação, investimentos libidinais e registro do discurso das pulsões e seus representantes. A partir de uma abordagem psicanalítica dos sintomas psicossomáticos, estudamos os primórdios da constituição do sujeito do inconsciente, recorrendo à estruturação do narcisismo e do inconsciente, construindo-se como uma linguagem ao encadear os significantes por contiguidade ou semelhança, respectivamente, por deslocamentos e condensações, isto é, construindo-se numa cadeia como metonímias e metáforas que se organizam num discurso. O narcisismo seria a causa do corpo. Este último, suporte biológico, que se torna erógeno a partir do discurso materno cujo desejo antecipa uma gestalt à imagem, organizando e delimitando o corpo despedaçado e anárquico do bebê. Como estrutura narcísica relacionamos a articulação das pulsões, das zonas erógenas, do desejo, do recalcamento fixando os representantes que irão constituir um Ego corporal. O sintoma no real do corpo apareceria como efeito de uma desorganização na articulação dos significantes do desejo materno como legalidade de um discurso, dificultando a inscrição simbólica da significação dos limites e fronteiras do corpo erógeno do bebê, cujo representante da pulsão evidencia-se como demanda de significação.

Tipificação do crime de terrorismo no Brasil

O terrorismo contemporâneo se destaca como um dos mais discutidos tópicos da agenda política internacional. No contexto da globalização, a atuação de grupos extremistas é bem mais complexa e articulada do que jamais foi, e sua periculosidade é exacerbada pela potencial utilização de armas de destruição em massa. Se é certo que a solução para seu enfrentamento pode ser almejada pela cooperação entre as nações, é igualmente verdadeiro que o Direito pode ser um instrumento idôneo para assegurar melhor colaboração e maior efetividade das medidas. Partindo do pressuposto que o terrorismo pode ser compreendido como um instituto do Direito Criminal, apresento esta monografia, a fim de investigar como o Brasil – que notoriamente carece de normatização útil na legislação ordinária – poderia criar uma lei antiterror. A metodologia de pesquisa é primordialmente descritiva, com enfoque na compreensão do terrorismo enquanto instituto jurídico-criminal. Dedicamo-nos a um estudo crítico dos aspectos teóricos e práticos de se criar uma lei antiterror, inclusive estudando projetos de lei em tramitação, a fim de ver como o Legislativo tem abordado a matéria.

Análise de agrupamentos dos dados de DFA oriundos de perfis elétricos de indução de poços de petróleo

The main objective of this study is to apply recently developed methods of physical-statistic to time series analysis, particularly in electrical induction s profiles of oil wells data, to study the petrophysical similarity of those wells in a spatial distribution. For this, we used the DFA method in order to know if we can or not use this technique to characterize spatially the fields. After obtain the DFA values for all wells, we applied clustering analysis. To do these tests we used the non-hierarchical method called K-means. Usually based on the Euclidean distance, the K-means consists in dividing the elements of a data matrix N in k groups, so that the similarities among elements belonging to different groups are the smallest possible. In order to test if a dataset generated by the K-means method or randomly generated datasets form spatial patterns, we created the parameter Ω (index of neighborhood). High values of Ω reveals more aggregated data and low values of Ω show scattered data or data without spatial correlation. Thus we concluded that data from the DFA of 54 wells are grouped and can be used to characterize spatial fields. Applying contour level technique we confirm the results obtained by the K-means, confirming that DFA is effective to perform spatial analysis

Fases do desenvolvimento e diferenciação testicular em cutias (Dasyprocta aguti) criadas em cativeiros

A cutia (Dasyprocta aguti) é um roedor silvestre encontrado amplamente na região Nordeste do Brasil. É uma espécie muito utilizada pela população humana de baixa renda como fonte alternativa de proteína na alimentação. Foram utilizadas 31 cutias, machos, provenientes da Universidade Federal do Piauí (FUFPI), Estado do Piauí e da Escola Superior de Agricultura de Mossoró Estado do Rio Grande do Norte. Os animais foram divididos em grupos etários desde o nascimento até os 14 meses de idade. O diâmetro nuclear médio foi obtido pela medida de 10 núcleos do tipo celular estudado em cada testículo, no estágio 1 do ciclo do epitélio seminífero. Nos animais que não apresentaram o epitélio organizado em estágios bem definidos em virtude da idade, foram feitas medidas em secções transversais escolhidas somente pelo contorno circular. O início da assincronia do processo espermatogênico foi observado a partir dos seis meses de idade. A puberdade, na cutia Dasyprocta aguti, foi definitivamente estabelecida a partir dos nove meses de idade, pois estavam presentes todos os tipos celulares e espermatozóides liberados no lume tubular em grande parte do parênquima testicular.

Whistle variability in South Atlantic spinner dolphins from the Fernando de Noronha Archipelago off Brazil

A series of quali- and quantitative analyses were conducted to evaluate the variability of spinner dolphin whistles from the Fernando de Noronha Archipelago off Brazil. Nine variables were extracted from each whistle contour, and the whistle contours shapes were classified into the seven categories described in Driscoll (1995). The analysis showed mean beginning and ending frequencies values of 10.78 and 12.74 kHz, respectively. on average, whistle duration was relatively short, with mean values around 0.495 s (N=702). Comparative analyses were also conducted to investigate the relationship between the obtained results and those presented in previous studies. When comparing averages, the results of the study of Oswald et al. (2003) in the Tropical Eastern Pacific (TEP) presented less significant differences in relation to this study; only whistle duration differed significantly between both works. The results of multivariate classification tests also pointed TEP population as the closest related to the population studied here. The similarities between such disjunct populations might be attributed to a more recent isolation event (the closing of the Panama Isthmus) than the divergence that has driven North and South Atlantic populations apart. (c) 2006 Acoustical Society of America.

Antenas planares multicamadas com materiais supercondutores e fotônico para comunicações móveis

Recently, planar antennas have been studied due to their characteristics as well as the advantages that they offers when compared with another types of antennas. In the mobile communications area, the need for this kind of antennas have became each time bigger due to the intense increase of the mobile communications this sector. That needs of antennas which operate in multifrequency and wide bandwidth. The microstrip antennas presents narrow bandwidth due the loss in the dielectric generated by radiation. Another limitation is the radiation pattern degradation due the generation of surface waves in the substrate. In this work some used techniques to minimize the disadvantages (previously mentioned) of the use of microstrip antennas are presented, those are: substrates with PBG material - Photonic Bandgap, multilayer antennas and with stacked patches. The developed analysis in this work used the TTL - Transverse Transmission Line method in the domain of Fourier transform, that uses a component of propagation in the y direction (transverse to the direction real of propagation z), treating the general equations of electric and magnetic field as functions of Ey and Hy. One of the advantages of this method is the simplification of the field equations. therefore the amount of equations lesser must the fields in directions x and z be in function of components Ey and Hy. It will be presented an brief study of the main theories that explain the superconductivity phenomenon. The BCS theory. London Equations and Two Fluids model will be the theories that will give support the application of the superconductors in the microfita antennas. The inclusion of the superconductor patch is made using the resistive complex contour condition. This work has as objective the application of the TTL method to microstrip structures with single and multilayers of rectangular patches, to obtaining the resonance frequency and radiation pattern of each structure

Otimização de forma aplicando B-splines sob critério integral de tensões

This work proposes a computational methodology to solve problems of optimization in structural design. The application develops, implements and integrates methods for structural analysis, geometric modeling, design sensitivity analysis and optimization. So, the optimum design problem is particularized for plane stress case, with the objective to minimize the structural mass subject to a stress criterion. Notice that, these constraints must be evaluated at a series of discrete points, whose distribution should be dense enough in order to minimize the chance of any significant constraint violation between specified points. Therefore, the local stress constraints are transformed into a global stress measure reducing the computational cost in deriving the optimal shape design. The problem is approximated by Finite Element Method using Lagrangian triangular elements with six nodes, and use a automatic mesh generation with a mesh quality criterion of geometric element. The geometric modeling, i.e., the contour is defined by parametric curves of type B-splines, these curves hold suitable characteristics to implement the Shape Optimization Method, that uses the key points like design variables to determine the solution of minimum problem. A reliable tool for design sensitivity analysis is a prerequisite for performing interactive structural design, synthesis and optimization. General expressions for design sensitivity analysis are derived with respect to key points of B-splines. The method of design sensitivity analysis used is the adjoin approach and the analytical method. The formulation of the optimization problem applies the Augmented Lagrangian Method, which convert an optimization problem constrained problem in an unconstrained. The solution of the Augmented Lagrangian function is achieved by determining the analysis of sensitivity. Therefore, the optimization problem reduces to the solution of a sequence of problems with lateral limits constraints, which is solved by the Memoryless Quasi-Newton Method It is demonstrated by several examples that this new approach of analytical design sensitivity analysis of integrated shape design optimization with a global stress criterion purpose is computationally efficient