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.

Estrogen receptor: Structural differences and potential implications on selectivity examined by the GRID/CPCA approach

Selective Estrogen Receptor Modulators ( SERMs) have been developed, but the selectivity towards the subtypes ( ER or ER is not well understood. Based on three-dimensional structural properties of ligand binding domains, a model that takes into account this aspect was developed via molecular interaction fields and consensus principal component analysis (GRID/CPCA).

The Molecular Chaperone Hsp70 Family Members Function by a Bidirectional Heterotrophic Allosteric Mechanism

The Hsp70 family is one of the most important and conserved molecular chaperone families. It is well documented that Hsp70 family members assist many cellular processes involving protein quality control, as follows: protein folding, transport through membranes, protein degradation, escape from aggregation, intracellular signaling, among several others. The Hsp70 proteins act as a cellular pivot capable of receiving and distributing substrates among the other molecular chaperone families. Despite the high identity of the Hsp70 proteins, there are several homologue Hsp70 members that do not have the same role in the cell, which allow them to develop and participate in such large number of activities. The Hsp70 proteins are composed of two main domains: one that binds ATP and hydrolyses it to ADP and another which directly interacts with substrates. These domains present bidirectional heterotrophic allosteric regulation allowing a fine regulated cycle of substrate binding and release. The general mechanism of the Hsp70s cycle is under the control of ATP hydrolysis that modulates the low (ATP-bound state) and high (ADP-bound state) affinity states of Hsp70 for substrates. An important feature of the Hsp70s cycle is that they have several co-chaperones that modulate their cycle and that can also interact and select substrates. Here, we review some known details of the bidirectional heterotrophic allosteric mechanism and other important features for Hsp70s regulating cycle and function.

Development and Application of a Highly Selective Biomimetic Sensor for Detection of Captopril, an Important Ally in Hypertension Control

A biomimetic sensor is proposed as a promising new analytical method for determination of captopril in different classes of samples. The sensor was prepared by modifying a carbon paste electrode with iron (II) phthalocyanine bis(pyridine) [FePe(dipy)] complex. Amperometric measurements in a batch analytical mode were first carried out in order to optimize the sensor response. An applied potential lower than 0.2 V vs Ag vertical bar AgCl in 0.1 mol L(-1) of TRIS buffer at pH 8.0 provided the best response, with a linear range of 2.5 x 10(-5) to 1.7 x 10(-4) mol L(-1). A detailed investigation of the selectivity of the sensor, employing seventeen other drugs, was also performed. Recovery studies were carried out using biological and environment samples in order to evaluate the sensor`s potential for use with these sample classes. Finally, the performance of the biomimetic sensor was optimized in a flow injection (FIA) system using a wall jet electrochemical cell. Under optimized flow conditions, a broad linear response range, from 5.0 x 10(-4) to 2.5 x 10(-2) mol L(-1), was obtained for captopril, with a sensitivity of 210 +/- 1 mu A L mol(-1).

Understanding eParticipation : Contemporary PhD eParticipation Research in Europe

This book presents contemporary European research on eParticipation by means of a 13 chapters each describing a PhD research project as well as analyses of this research. The book both reflects the field and contributes to shaping it by discussing both long-standing and emerging issues. Contributions include three chapters on issues of DEVELOPMENT, including communities of practice, user-centred development, and safety & privacy issues, four chapters on IMPLEMENTATION, including spatial planning, participatory budgeting, and transformation processes, and five chapters on issues of USE, focusing on local government, developing countries, EU, civil society and NGO.

Levine Family Reunion Members, interviewed by Wendy Miller in September 2009: Transcript

The Levine family held an extensive reunion during the Summer of 2009 during which 29 DVDs of raw material were recorded for use in the creation of a Levine family mini-documentary. Many of these DVDs contain oral history interviews conducted by Wendy Miller, one of the organizers of the reunion. Although these interviews were not designed for historical research, they contain valuable historical information. Some of the family members interviewed include: Ben Arnon (4/5), Marjorie, Stephen, and Michael Kaplan (8), Glenyce Miller Kaplan (starts in 15, continues in 9; separate interview in 13), Burt, Phyllis, and Louis Shiro (9) [Burt Shiro also in 26/27], Myrt and Gordon Wolman (9), Ted and Billy Alfond (10), Barbara and Joan Alfond (10), Susan and Peter Alfond (10), Alice Emory [caregiver for Bibby] (11), Eric Bloom and Stu Cushner (11), Saralee Kaplan Bloom (11), Sarah Miller Arnon (12), Kayla and Jenna Cushner (12), Josh Soros and Eliana Miller-Kaplan (12), Sarah, Wendy, and Julie Miller (starts in 12, continues in 14), Bill Shutzer (13), Maschia and Glicka Kaplan, Sharon Kushner, Dan Hood (13), Gene, Alex, Kate Cohen (14), Ben, Jeremy, Joselyn Arnon (14), Wendy and Julie Miller at the store (15), and Eric Bloom (15).

Gravity: a new play by Greg Belanger

Gravity was first performed at Strider Theatre, Colby College in Waterville, Maine. It was directed by the author with the following cast: STEVEN: Harold Withee PAMELA: Sue Larsen JEREMY: Jason Reifler IXXTOR: Amanda Starr MOTHER: Catherine C. Coyne BREIT: Scott W. Cole TONI: Laura Smishkiss