Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Membrane interaction of polymyxin B and synthetic analogues studied in biomimetic systems: implications for antibacterial action

Membrane-active antimicrobial peptides, such as polymyxin B (PxB), are currently in the spotlight as potential candidates toovercome bacterial resistance. We have designed synthetic analogs ofPxB in order to determine the structural requirements for membraneaction. Since the mechanism of action of PxB involves interaction withboth the outer membrane and the cytoplasmic membrane of Gramnegative bacteria, we have used an approach based on mimicking theouter layers of these membranes using monolayers, Langmuir-Blodgettfilms and unilamelar vesicles, and applying a battery of biophysicalmethods in order to dissect the different events of membraneinteraction. Collectively, results indicate that the PxB analogues act inthe bacterial membrane by the same mechanism than PxB, and that cationic amphipathicity determines peptide activity.

Affirmative Action through Extra Prizes

Some affirmative action policies establish that a set of disadvantaged competitors has access to an extra prize. Examples are gender quotas or a prize for national competitors in an international competition. We analyse the effects of creating an extra prize by reducing the prize in the main competition. Contestants differ in ability and agents with relatively low ability belong to a disadvantaged minority. All contestants compete for the main prize, but only disadvantaged agents can win the extra prize. We show that an extra prize is a powerful tool to ensure participation of disadvantaged agents. Moreover, for intermediate levels of the disadvantage of the minority, introducing an extra prize increases total equilibrium effort compared to a standard contest. Thus, even a contest designer not interested in affirmative action might establish an extra prize in order to enhance competition. Keywords: Asymmetric contest, equality of opportunity, affirmative action, discrimination, prize structure, exclusion principle. JEL: C72, D72, I38, J78

El discurso escrito de la Odontología : análisis retórico discursivo de casos clínicos hispanos (1999-2005)

El propósito de este estudio fue identificar y analizar algunos rasgos retóricos discursivos de casos clínicos (CC) odontológicos. Se seleccionó, al azar, un corpus de 40 CC de cuatro revistas odontológicas hispanas (1999-2005). Se encontró que predomina el formato 'introducción, descripción del caso , discusión', siendo la 'descripción del caso' la sección distintiva. Prevalecen las secuencias narrativas y descriptivas en todas las secciones retóricas. Además,hay muy pocas citas, aparecen esencialmente en la 'introcucción' y en la 'discusión' . Se registró el uso de atenuantes en las distintas secciones retóricas del CC: predominó el uso de impersonales, empleados para ocultar el agente de la acción, y aproximadores, para expresar impresión, variabilidad y honestidad. En cuanto al posicionamiento, predominaron el impersonal y plural mayestático. Se concluye que pese a la variabilidad retórica discursiva, el corpus analizado podría definirse como un género discursivo, descriptivo, narrativo e impersonal. El CC es un género importante para las distintas sub-especialidades odontológicas; por lo tanto, los resultados tienen aplicaciones didácticas para la enseñanza del discurso odontológico. Incorporar el CC al currículum de odontología permitiría al estudiante desarrollar las competencias para producir, comprender y publicar este género

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif

The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.

Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

Action Research : the first steps to start up a pilot experiment in heritage education

Peer-reviewed

"In vitro" comparative experimental study of antimicrobial action of mouth washing products

Regular use of mouth rinses modifies the oral habitat, since bacterial populations are submitted to a high selective pressure during the treatment exercised by the active presence of the disinfectant. Mostly mouth rinses are based on the antibacterial effect of Chlorhexidine, Triclosan, essential oils and other antibacterials although other pharmaceutical characteristics can also affect their effectiveness. In this paper we compare"in vitro" the antibacterial effect of different oral rinsing solutions. Minimal Inhibitory Concentrations (MIC) and Minimal Bactericidal Concentrations (MBC) were determined as well as the kinetics of bacterial death in the presence of letal concentrations of the mouth rinses. MIC values expressed as Maximal Inhibitory Dilution (MID) of the mouth rinse ranged from 1 to 1/2048 depending on the microorganism and product, whereas Minimal Biocidal Concentration (MBC), expressed as Maximal Biocidal Dilution (MBD) ranged from 1 to 1/1024, being in general one dilution less than MIC. Maximal Biocidal Dilution is a good tool to measure the actual efficiency of mouth washing solutions. However, kinetics of death seems to be better in our work killing curves demonstrate that bacterial populations are mostly eliminated during the first minute after the contact of bacterial suspension and the mouth-washing solution. In all tested bacterial species mouth-washing solutions tested were able to reduce until suspension treated except 1 and 5