Oroidin Inhibits the Activity of the Multidrug Resistance Target Pdr5p from Yeast Plasma Membranes

Oroidin was isolated from the marine sponge Agelas sventres and inhibited the activity and function of Pdr5p, an enzyme responsible for the multidrug resistance phenotype in Saccharomyces cerevisiae. This compound may help in the development of new drugs that reverse this dangerous phenotype of pathogenic yeast and fungi.

Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors

A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.

CDK9 a potential target for drug development

The family of Cyclin-Dependent Kinases (CDKs) can be subdivided into two major functional groups based on their roles in cell cycle and/or transcriptional control. CDK9 is the catalytic subunit of positive transcription elongation factor b (P-TEFb). CDK9 is the kinase of the TAK complex (Tat-associated kinase complex), and binds to Tat protein of HIV, suggesting a possible role for CDK9 in AIDS progression. CDK9 complexed with its regulatory partner cyclin T1, serves as a cellular mediator of the transactivation function of the HIV Tat protein. P-TEFb is responsible for the phosphorylation of the carboxyl-terminal domain of RNA Pol II, resulting in stimulation of transcription. Furthermore, the complexes containing CDK9 induce the differentiation in distinct tissue. The CDK9/cyclin T1 complex is expressed at higher level in more differentiated primary neuroectodermal and neuroblastoma tumors, showing a correlation between the kinase expression and tumor differentiation grade. This may have clinical and therapeutical implications for these tumor types. Among the CDK inhibitors two have shown to be effective against CDK9: Roscovitine and Flavopiridol. These two inhibitors prevented the replication of human immunodeficiency virus (HIV) type 1 by blocking Tat transactivation of the HIV type 1 promoter. These compounds inhibit CDKs by binding to the catalytic domain in place of ATP, preventing transfer of a phosphate group to the substrate. More sensitive therapeutic agents of CDK9 can be designed, and structural studies can add information in the understanding of this kinase. The major features related to CDK9 inhibition will be reviewed in this article.

Oscar Wilde’s “The Happy Prince” : The Hidden Messages and the Debate on the Target Audience

Oscar Wilde’s fairytales have been read to children for more than a century. Nevertheless, since the time of their publication in 1888 and 1891, the target audience of The Happy Prince and Other Tales and A House of Pomegranates have been the concern of critics. Delving into the context behind the rich and colourful imagery, one can find implications of homosexuality, the Paterian aesthetic and religious connotations. According to Carol Tattersall, The Happy Prince and Other Tales successfully mislead the public that it is innocent of any intention to undermine established standards of living or writing. Tattersall’s argument is based on comparing the first collection to Wilde’s second, A House of Pomegranates, which was perceived as “offensive and immoral” (136). On the other hand, William Butler Yeats states in his introduction to The Complete Works of Oscar Wilde that overall the reviewers of The Happy Prince and Other Tales were hostile because of Wilde’s aesthetic views (ixxvi). But Yeats overlooks the fact that Wilde was very pleased and proud, dashing notes to friends and reviewers and signing copies to many people (Tattersall 129). In general, the reception of Wilde’s first collection was more positive than that of the second because it was milder and more subtle in its controversial themes.

English as the target language : A literature study on teachers’ and L2 learners’ language use in the upper elementary classroom

Even though English is a subject where Swedish pupils do well compared to pupils in other countries, research indicates that pupils are not always motivated to learn in the English classroom. Therefore, the aim of this study is to find research relating to the use of the target language in classrooms for pupils at the upper elementary level, particularly language learners in Sweden. The focus of this thesis is to find out what benefits and challenges accompany the use of the target language during English lessons, as well as what pupils’ opinions are on the consistent use of the target language in the classroom. This literature review of five research articles shows that it is beneficial for pupils’ language development to have lessons where mainly the target language is used. It is for example beneficial for pupils’ ability to speak, their pronunciation, vocabulary and ability to use language strategies. The results show that there are challenges as well, especially for the teachers, since use of the target language presumes that the teacher has good language skills and is capable of scaffolding each pupil at their individual level and in their zone of proximal development. Furthermore, there are challenges like differences in pupils’ skill level, creating tasks that both motivate and stimulate, and creating a safe learning environment. Even though the results in this thesis are limited, it is still obvious that it is an important area, where more research is necessary in order to assist teachers in how to teach English as effectively as possible.

What happens after the central bank of Brazil increases the target interbank rate by 1%?

I start presenting an explicit solution to Taylorís (2001) model, in order to illustrate the link between the target interest rate and the overnight interest rate prevailing in the economy. Next, I use Vector Auto Regressions to shed some light on the evolution of key macroeconomic variables after the Central Bank of Brazil increases the target interest rate by 1%. Point estimates show a four-year accumulated output loss ranging from 0:04% (whole sample, 1980 : 1-2004 : 2; quarterly data) to 0:25% (Post-Real data only) with a Örst-year peak output response between 0:04% and 1:0%; respectively. Prices decline between 2% and 4% in a 4-year horizon. The accumulated output response is found to be between 3:5 and 6 times higher after the Real Plan than when the whole sample is considered. The 95% confidence bands obtained using bias-corrected bootstrap always include the null output response when the whole sample is used, but not when the data is restricted to the Post-Real period. Innovations to interest rates explain between 4:9% (whole sample) and 9:2% (post-Real sample) of the forecast error of GDP.

What if firms adjust their debt-equity ratios toward a target range?

We estimate optimal target-ranges of capital structure controlling for a series of firmspecific characteristics and accounting for the serial correlation that arises from the dynamic component of the leverage choice. Then, we empirically examine if firms adjust their leverages toward the estimated optimal ranges. Our analysis suggests that the observed behavior of firms is consistent with the notion of range-adjustment.

What happens after the Central Bank of Brazil increases the target interbank rate by 1%?

In this paper I use Taylor's (2001) model and Vector Auto Regressions to shed some light on the evolution of some key macroeconomic variables after the Central Bank of Brazil, through the COPOM, increases the target interest rate by 1%. From a quantitative perspective, the best estimate from the empírical analysis, obtained with a 1994 : 2 - 2004 : 2 subsample of the data, is that GDP goes through an accumulated decline, over the next four years, around 0.08%. Innovations to interest rates explain around 9.2% of the forecast erro r of GDP.

Especulative (sic) attack on exchange rate target zone regime : the uncertainty case

We present a continuous time target zone model of speculative attacks. Contrary to most of the literature that considers the certainty case, i.e., agents know for sure the Central Bank behavior in the future, we build uncertainty into the madel in two different ways. First, we consider the case in whicb the leveI of reserves at which the central bank lets the regime collapse is uncertain. Alternatively, we ana1ize the case in which, with some probability, the government may cbange its policy reducing the initially positive trend in domestic credito In both cases, contrary to the case of a fixed exchange rate regime, speculators face a cost of launching a tentative attack that may not succeed. Such cost induces a delay and may even prevent its occurrence. At the time of the tentative attack, the exchange rate moves either discretely up, if the attack succeeds, or down, if it fails. The remlts are consistent with the fact that, typically, an attack involves substantial profits and losses for the speculators. In particular, if agents believed that the government will control fiscal imbalances in the future, or alternatively, if they believe the trend in domestic credit to be temporary, the attack is postponed even in the presence of a signal of an imminent collapse. Finally, we aIso show that the timing of a speculative attack increases with the width of the target zone.

Toxicity of the therapeutic potassium permanganate to tilapia Oreochromis niloticus and to non-target organisms Ceriodaphnia dubia (microcrustacean cladocera) and Pseudokirchneriella subcapitata (green microalgae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Sensitivity evaluation of a single-step PCR assay using Ehrlichia canis p28 gene as a target and its application in diagnosis of canine ehrlichiosis

O objetivo deste estudo foi aperfeiçoar um ensaio de PCR que amplificasse um fragmento de 843 pares de bases do gene p28 da Ehrlichia canis e compará-lo com outros dois métodos de PCR utilizados para amplificar partes do gene 16S rRNA e dsb do gênero Ehrlichia. Amostras sanguíneas foram colhidas de cães com diagnóstico clínico de erliquiose. A amplificação do gene p28 pela PCR produziu um fragmento de 843pb e esse ensaio permitiu a detecção do DNA de um parasita dentre 1 bilhão de células. Todas as amostras positivas detectadas pela PCR baseada no gene p28 foram também positivas pela nested PCR para detecção do gene 16S rRNA e também pela PCR dsb. Dentre as amostras negativas para a PCR p28, 55,3% foram co-negativas, mas 27,6% foram positivas pela PCR baseada nos genes 16S rRNA e dsb. A PCR p28 parece ser um teste útil para detecção molecular de E. canis, entretanto otimizações na sensibilidade nesta PCR são necessárias, para que esta técnica se torne uma importante alternativa no diagnóstico da erliquiose canina.

Cruzain inhibition by hydroxymethylnitrofurazone and nitrofurazone: investigation of a new target in Trypanosoma cruzi

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)