Synthesis of novel and potent vorapaxar analogues

Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM

Identification of an active metabolite of PAR-1 antagonist RWJ-58259 and synthesis of analogues to enhance its metabolic stability

The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259

TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells.

The major high-affinity thrombin receptor, proteinase activated receptor-1 (PAR-1) is expressed at low levels by the normal epithelium but is upregulated in many types of cancer, including lung cancer. The thrombin-PAR-1 signalling axis contributes to the activation of latent TGFβ in response to tissue injury via an αvβ6 integrin-mediated mechanism. TGFβ is a pleiotropic cytokine that acts as a tumour suppressor in normal and dysplastic cells but switches into a tumour promoter in advanced tumours. In this study we demonstrate that TGFβ is a positive regulator of PAR-1 expression in A549 lung adenocarcinoma cells, which in turn increases the sensitivity of these cells to thrombin signalling. We further demonstrate that this effect is Smad3-, ERK1/2- and Sp1-dependent. We also show that TGFβ-mediated PAR-1 upregulation is accompanied by increased expression of integrin αv and β6 subunits. Finally, TGFβ pre-stimulation promotes increased migratory potential of A549 to thrombin. These data have important implications for our understanding of the interplay between coagulation and TGFβ signalling responses in lung cancer.Medical Research Council UK (MRC) CASE studentship with Novartis awarded to RCC, MRC Centenary Award awarded to NS and RCC, and MRC Career Development Award G0800340 to CJS

On a conjecture of Goodearl: Jacobson radical non-nil algebras of Gelfand-Kirillov dimension 2

For an arbitrary countable field, we construct an associative algebra that is graded, generated by finitely many degree-1 elements, is Jacobson radical, is not nil, is prime, is not PI, and has Gelfand-Kirillov dimension two. This refutes a conjecture attributed to Goodearl

Growth, entropy and commutativity of algebras satisfying prescribed relations

In 1964, Golod and Shafarevich found that, provided that the number of relations of each degree satisfy some bounds, there exist infinitely dimensional algebras satisfying the relations. These algebras are called Golod-Shafarevich algebras. This paper provides bounds for the growth function on images of Golod-Shafarevich algebras based upon the number of defining relations. This extends results from [32], [33]. Lower bounds of growth for constructed algebras are also obtained, permitting the construction of algebras with various growth functions of various entropies. In particular, the paper answers a question by Drensky [7] by constructing algebras with subexponential growth satisfying given relations, under mild assumption on the number of generating relations of each degree. Examples of nil algebras with neither polynomial nor exponential growth over uncountable fields are also constructed, answering a question by Zelmanov [40]. Recently, several open questions concerning the commutativity of algebras satisfying a prescribed number of defining relations have arisen from the study of noncommutative singularities. Additionally, this paper solves one such question, posed by Donovan and Wemyss in [8].Comment: arXiv admin note: text overlap with arXiv:1207.650

A NOTE ON NIL AND JACOBSON RADICALS IN GRADED RINGS

It was shown by Bergman that the Jacobson radical of a Z-graded ring is homogeneous. This paper shows that the analogous result holds for nil rings, namely, that the nil radical of a Z-graded ring is homogeneous. It is obvious that a subring of a nil ring is nil, but generally a subring of a Jacobson radical ring need not be a Jacobson radical ring. In this paper it is shown that every subring which is generated by homogeneous elements in a graded Jacobson radical ring is always a Jacobson radical ring. It is also observed that a ring whose all subrings are Jacobson radical rings is nil. Some new results on graded-nil rings are also obtained

Estruturação dos objetivos de aprendizagem para ambientes de educação on-line

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Ciência da Computação.O objetivo deste trabalho é prover o processo e a avaliação funcional dos componentes que compõem um ambiente de e-aprendizagem baseado em Objetos de aprendizagem, apresentando as definições, propriedades e aplicações dos Objetos de aprendizagem, que se referem à criação e reutilização dos objetos para desenvolver ambientes de aprendizagem. Os padrões utilizados para desenvolvimento de conteúdos estruturados para ambientes de aprendizagem para Web também serão descritos. Também é abordado o potencial da Web semântica, a qual transforma a Web em um meio em que a informação é interpretada, trocada e processada. Apresentar como a linguagem XML e a orientação a objeto se relacionam com os Objetos de aprendizagem é outro tópico abordado. O trabalho inclui, ainda, um protótipo para um ambiente de aprendizagem online utilizando os objetos de aprendizagem

Examining the Theoretical Framework of Behavioral Activation for Major Depressive Disorder: Smartphone-Based Ecological Momentary Assessment Study

Background: Behavioral activation (BA), either as a stand-alone treatment or as part of cognitive behavioral therapy, has been shown to be effective for treating depression. The theoretical underpinnings of BA derive from Lewinsohn et al's theory of depression. The central premise of BA is that having patients engage in more pleasant activities leads to them experiencing more pleasure and elevates their mood, which, in turn, leads to further (behavioral) activation. However, there is a dearth of empirical evidence about the theoretical framework of BA.Objective: This study aims to examine the assumed (temporal) associations of the 3 constructs in the theoretical framework of BA.Methods: Data were collected as part of the "European Comparative Effectiveness Research on Internet-based Depression Treatment versus treatment-as-usual" trial among patients who were randomly assigned to receive blended cognitive behavioral therapy (bCBT). As part of bCBT, patients completed weekly assessments of their level of engagement in pleasant activities, the pleasure they experienced as a result of these activities, and their mood over the course of the treatment using a smartphone-based ecological momentary assessment (EMA) application. Longitudinal cross-lagged and cross-sectional associations of 240 patients were examined using random intercept cross-lagged panel models.Results: The analyses did not reveal any statistically significant cross-lagged coefficients (all P>.05). Statistically significant cross-sectional positive associations between activities, pleasure, and mood levels were identified. Moreover, the levels of engagement in activities, pleasure, and mood slightly increased over the duration of the treatment. In addition, mood seemed to carry over, over time, while both levels of engagement in activities and pleasurable experiences did not.Conclusions: The results were partially in accordance with the theoretical framework of BA, insofar as the analyses revealed cross-sectional relationships between levels of engagement in activities, pleasurable experiences deriving from these activities, and enhanced mood. However, given that no statistically significant temporal relationships were revealed, no conclusions could be drawn about potential causality. A shorter measurement interval (eg, daily rather than weekly EMA reports) might be more attuned to detecting potential underlying temporal pathways. Future research should use an EMA methodology to further investigate temporal associations, based on theory and how treatments are presented to patients.</p

Interrole conflict and self-efficacy to manage work and family demands mediate the relationships of job and family demands with stress in the job and family domains

Background and objectives: This study derives from Work–Home Resources model (ten Brummelhuis, L. L., & Bakker, A. B. (2012). A resource perspective on the work–home interface: The work–home resources model. American Psychologist, 67(7), 545–556. doi:10.1037/a0027974) and Social Cognitive Theory (Bandura, A. (1986). Social foundations of thought and action: A social cognitive theory. Englewood Cliffs, NJ, US: Prentice-Hall, Inc.) to investigate mechanisms responsible for the effect of job and family demands on work- and family-related perceived stress. We hypothesized that interrole conflict and self-efficacy to manage work and family demands operate either independently or sequentially transmitting the effects of demands on perceived stress. Design: A sample of 100 employees of various occupations participated in the study conducted online in two waves: Time 1 (T1) and Time 2 (T2) with a three-month interval. Method: Regression analysis with bootstrapping was applied. Results: Interrole conflict (T1) did not mediate the relationships between demands (T1) and perceived stress (T2), whereas self-efficacy (T1) mediated only those between family demands (T1) and stress (T2). However, data supported the sequential mediation hypotheses: Demands (T1) were associated with increased interrole conflict (T1) which in turn decreased self-efficacy (T1) and ultimately resulted in the elevated perceived stress at work and in the family (T2). Conclusions: Demands originating in one domain can impact stress both in the same and other life areas through the sequence of interrole conflict and context-specific self-efficacy. KEYWORDS: Demands, family–work conflict, work–family conflict, self-efficacy, stres