RNA virus error catastrophe: Direct molecular test by using ribavirin

RNA viruses evolve rapidly. One source of this ability to rapidly change is the apparently high mutation frequency in RNA virus populations. A high mutation frequency is a central tenet of the quasispecies theory. A corollary of the quasispecies theory postulates that, given their high mutation frequency, animal RNA viruses may be susceptible to error catastrophe, where they undergo a sharp drop in viability after a modest increase in mutation frequency. We recently showed that the important broad-spectrum antiviral drug ribavirin (currently used to treat hepatitis C virus infections, among others) is an RNA virus mutagen, and we proposed that ribavirin's antiviral effect is by forcing RNA viruses into error catastrophe. However, a direct demonstration of error catastrophe has not been made for ribavirin or any RNA virus mutagen. Here we describe a direct demonstration of error catastrophe by using ribavirin as the mutagen and poliovirus as a model RNA virus. We demonstrate that ribavirin's antiviral activity is exerted directly through lethal mutagenesis of the viral genetic material. A 99.3% loss in viral genome infectivity is observed after a single round of virus infection in ribavirin concentrations sufficient to cause a 9.7-fold increase in mutagenesis. Compiling data on both the mutation levels and the specific infectivities of poliovirus genomes produced in the presence of ribavirin, we have constructed a graph of error catastrophe showing that normal poliovirus indeed exists at the edge of viability. These data suggest that RNA virus mutagens may represent a promising new class of antiviral drugs.

Indole-3-Acetic Acid Controls Cambial Growth in Scots Pine by Positional Signaling1

The vascular cambium produces secondary xylem and phloem in plants and is responsible for wood formation in forest trees. In this study we used a microscale mass-spectrometry technique coupled with cryosectioning to visualize the radial concentration gradient of endogenous indole-3-acetic acid (IAA) across the cambial meristem and the differentiating derivatives in Scots pine (Pinus sylvestris L.) trees that had different rates of cambial growth. This approach allowed us to investigate the relationship between growth rate and the concentration of endogenous IAA in the dividing cells. We also tested the hypothesis that IAA is a positional signal in xylem development (C. Uggla, T. Moritz, G. Sandberg, B. Sundberg [1996] Proc Natl Acad Sci USA 93: 9282–9286). This idea postulates that the width of the radial concentration gradient of IAA regulates the radial number of dividing cells in the cambial meristem, which is an important component for determining cambial growth rate. The relationship between IAA concentration in the dividing cells and growth rate was poor, although the highest IAA concentration was observed in the fastest-growing cambia. The radial width of the IAA concentration gradient showed a strong correlation with cambial growth rate. The results indicate that IAA gives positional information in plants.

The "allosteric three-site model" of elongation cannot be confirmed in a well-defined ribosome system from Escherichia coli.

For the functional role of the ribosomal tRNA exit (E) site, two different models have been proposed. It has been suggested that transient E-site binding of the tRNA leaving the peptidyl (P) site promotes elongation factor G (EF-G)-dependent translocation by lowering the energetic barrier of tRNA release [Lill, R., Robertson, J. M. & Wintermeyer, W. (1989) EMBO J. 8, 3933-3938]. The alternative "allosteric three-site model" [Nierhaus, K.H. (1990) Biochemistry 29, 4997-5008] features stable, codon-dependent tRNA binding to the E site and postulates a coupling between E and aminoacyl (A) sites that regulates the tRNA binding affinity of the two sites in an anticooperative manner. Extending our testing of the two conflicting models, we have performed translocation experiments with fully active ribosomes programmed with heteropolymeric mRNA. The results confirm that the deacylated tRNA released from the P site is bound to the E site in a kinetically labile fashion, and that the affinity of binding, i.e., the occupancy of the E site, is increased by Mg2+ or polyamines. At conditions of high E-site occupancy in the posttranslocation complex, filling the A site with aminoacyl-tRNA had no influence on the E site, i.e., there was no detectable anticooperative coupling between the two sites, provided that second-round translocation was avoided by removing EF-G. On the basis of these results, which are entirely consistent with our previous results, we consider the allosteric three-site model of elongation untenable. Rather, as proposed earlier, the E site-bound state of the leaving tRNA is a transient intermediate and, as such, is a mechanistic feature of the classic two-state model of the elongating ribosome.

The natural killer cell receptor Ly-49A recognizes a peptide-induced conformational determinant on its major histocompatibility complex class I ligand.

Natural killer (NK) cells are inhibited from killing cellular targets by major histocompatibility complex (MHC) class I molecules. In the mouse, this can be mediated by the Ly-49A NK cell receptor that specifically binds the H-2Dd MHC class I molecule, then inhibits NK cell activity. Previous experiments have indicated that Ly-49A recognizes the alpha 1/alpha 2 domains of MHC class I and that no specific MHC-bound peptide appeared to be involved. We demonstrate here that alanine-substituted peptides, having only the minimal anchor motifs, stabilized H-2Dd expression and provided resistance to H-2Dd-transfected, transporter associated with processing (TAP)-deficient cells from lysis by Ly-49A+ NK cells. Peptide-induced resistance was blocked only by an mAb that binds a conformational determinant on H-2Dd. Moreover, stabilization of "empty" H-2Dd heavy chains by exogenous beta 2-microglobulin did not confer resistance. In contrast to data for MHC class I-restricted T cells that are specific for peptides displayed MHC molecules, these data indicate that NK cells are specific for a peptide-induced conformational determinant, independent of specific peptide. This fundamental distinction between NK cells and T cells further implies that NK cells are sensitive only to global changes in MHC class I conformation or expression, rather than to specific pathogen-encoded peptides. This is consistent with the "missing self" hypothesis, which postulates that NK cells survey tissues for normal expression of MHC class I.

A structural motif for the voltage-gated potassium channel pore.

Mutation studies have identified a region of the S5-S6 loop of voltage-gated K+ channels (P region) responsible for teraethylammonium (TEA) block and permeation/selectivity properties. We previously modeled a similar region of the Na+ channel as four beta-hairpins with the C strands from each of the domains forming the external vestibule and with charged residues at the beta-turns forming the selectivity filter. However, the K+ channel P region amino acid composition is much more hydrophobic in this area. Here we propose a structural motif for the K+ channel pore based on the following postulates (Kv2.1 numbering). (i) The external TEA binding site is formed by four Tyr-380 residues; P loop residues participating in the internal TEA binding site are four Met-371 and Thr-372 residues. (ii) P regions form extended hairpins with beta-turns in sequence ITMT. (iii) only C ends of hairpins form the inner walls of the pore. (iv) They are extended nonregular strands with backbone carbonyl oxygens of segment VGYGD facing the pore with the conformation BRLRL. (v) Juxtaposition of P loops of the four subunits forms the pore. Fitting the external and internal TEA sites to TEA molecules predicts an hourglass-like pore with the narrowest point (GYG) as wide as 5.5 A, suggesting that selectivity may be achieved by interactions of carbonyls with partially hydrated K+. Other potential cation binding sites also exist in the pore.

DNA recombination is sufficient for retroviral transduction.

Oncogenic retroviruses carry coding sequences that are transduced from cellular protooncogenes. Natural transduction involves two nonhomologous recombinations and is thus extremely rare. Since transduction has never been reproduced experimentally, its mechanism has been studied in terms of two hypotheses: (i) the DNA model, which postulates two DNA recombinations, and (ii) the RNA model, which postulates a 5' DNA recombination and a 3' RNA recombination occurring during reverse transcription of viral and protooncogene RNA. Here we use two viral DNA constructs to test the prediction of the DNA model that the 3' DNA recombination is achieved by conventional integration of a retroviral DNA 3' of the chromosomal protooncogene coding region. For the DNA model to be viable, such recombinant viruses must be infectious without the purportedly essential polypurine tract (ppt) that precedes the 3' long terminal repeat (LTR) of all retroviruses. Our constructs consist of a ras coding region from Harvey sarcoma virus which is naturally linked at the 5' end to a retroviral LTR and artificially linked at the 3' end either directly (construct NdN) or by a cellular sequence (construct SU) to the 5' LTR of a retrovirus. Both constructs lack the ppt, and the LTR of NdN even lacks 30 nucleotides at the 5' end. Both constructs proved to be infectious, producing viruses at titers of 10(5) focus-forming units per ml. Sequence analysis proved that both viruses were colinear with input DNAs and that NdN virus lacked a ppt and the 5' 30 nucleotides of the LTR. The results indicate that DNA recombination is sufficient for retroviral transduction and that neither the ppt nor the complete LTR is essential for retrovirus replication. DNA recombination explains the following observations by others that cannot be reconciled with the RNA model: (i) experimental transduction is independent of the packaging efficiency of viral RNA, and (ii) experimental transduction may invert sequences with respect to others, as expected for DNA recombination during transfection.

O SNRC e os novos instrumentos de financiamento do agronegócio: o mercado de crédito rural brasileiro entre dois modelos

Esta pesquisa mostra como o desenvolvimento do sistema jurídico institucional do mercado de crédito rural no Brasil se desenvolveu a ponto de permitir a convivência de dois modelos normalmente considerados antitéticos: o modelo de economia de mercado coordenado via bancos públicos e o modelo de economia de mercado liberal. O primeiro capítulo da dissertação reconstrói como a teoria do Law and Finance que permite identificar adequadamente esse resultado de pesquisa se desenvolve a partir da crise das postulações e premissas da teoria econômica neoclássica. O segundo capítulo narra o desenvolvimento e crise do modelo do Sistema Nacional de Crédito Rural entre as décadas de 1960 e 1980, partindo de uma análise sobre sua estrutura, regulação e institutos. Passando dos modelos de organização financeira para as modalidades de crédito rural, o capítulo narra a lógica, estrutura e evolução do modelo calcado na alocação de recursos por banco públicos, de modo que essa elucidação de contexto histórico permite que se verifique a grande ruptura que é introduzida no sistema de financiamento rural a partir dos anos 2000. O terceiro capítulo narra e descreve o surgimento da estrutura, regulação e institutos regidos pela lógica de mercado liberal, até então ausente no SNCR para, após, realizar uma apreciação do resultado alcançado. Ao final, a conclusão reúne os principais achados dessa pesquisa, destaca os principais pontos de sua narrativa e os problematiza para uma agenda de pesquisa futura.

Identifying the role of natural resources in knowledge-based strategies of development

Knowledge has adopted a preferential role in the explanation of development while the evidence about the effect of natural resources in countries’ performance is more controversial in the economic literature. This paper tries to demonstrate that natural resources may positively affect growth in countries with a strong natural resources specialization pattern although the magnitude of these effects depend on the type of resources and on other aspects related to the production and innovation systems. The positive trajectory described by a set of national economies mainly specialized in natural resources and low-tech industries invites us to analyze what is the combination of factors that serves as engine for a sustainable development process. With panel data for the period 1996-2008 we estimate an applied growth model where both traditional factors and other more related to innovation and absorptive capabilities are taken into account. Our empirical findings show that according to the postulates of a knowledge-based approach, a framework that combines physical and intangible factors is more suitable for the definition of development strategies in those prosperous economies dominated by natural resources and connected activities, while the internationalization process of activities and technologies become also a very relevant aspect.

Understanding Mastectomy from a Self Psychology Perspective: The Breast as a Self Object

For many women, if not all, breasts are an important component of bodyself-image; a woman may love them or dislike them, but she is rarely neutral" (Young, 2003, p.152). Breast cancer may be one of the oldest forms of cancer known to humans (American Cancer Society, 2010), and in 2008 in the United States over 182,000 women and almost 2,000 men were diagnosed with some form of breast cancer (American Cancer Society, 2008). In that same year 40,480 women and 450 men died from the disease. While any type of cancer diagnosis can instill a fear of mortality and incapacitation in the recipient, breast cancer holds a special meaning for women because of the significance placed on the breast both personally and societally. Removal of the breast tissue and muscle, or mastectomy, remains one of the primary forms of treatment for this disease. The breast plays an important role in a woman's identity, and the loss of one or both breasts due to breast cancer can have a monumental impact on her sense of self. A mastectomy affectsnot only a woman's relationship with herself, but with her family, friends, and society. It changes her outlook on life, her perception of her roles in the world, and her interest in interacting with others. Exploring these issues is important to understanding how doctors, nurses, mental health professionals, family members and support networks can best assist patients in coping with their illness. This paper attempts to understand the psychological issues and injuriesassociated with mastectomy through the lens of Self Psychology. It postulates that the breast itself is a selfobject for most women, and that its loss results in the fragmentation of the self. I will focus particularly on women between the ages of 25 and 40 years of age, in the marital and parental phases of developmental (Wolf, 1988), as the effect of a mastectomy on body image, sexuality, and genderbased roles such as motherhood has been shown to differ according to the age of the patient, with younger patients experiencing more distress (Ashing-Giwa et al, 2004).

Investigating evidence for different black hole accretion modes since redshift z ∼ 1

Chandra data in the COSMOS, AEGIS-XD and 4 Ms Chandra Deep Field South are combined with multiwavelength photometry available in those fields to determine the rest-frame U − V versus V − J colours of X-ray AGN hosts in the redshift intervals 0.1 < z < 0.6 (mean z¯=0.40) and 0.6 < z < 1.2 (mean z¯=0.85). This combination of colours provides an effective and least model-dependent means of separating quiescent from star-forming, including dust reddened, galaxies. Morphological information emphasizes differences between AGN populations split by their U − V versus V − J colours. AGN in quiescent galaxies consist almost exclusively of bulges, while star-forming hosts are equally split between early- and late-type hosts. The position of AGN hosts on the U − V versusV − J diagram is then used to set limits on the accretion density of the Universe associated with evolved and star-forming systems independent of dust induced biases. It is found that most of the black hole growth at z≈ 0.40 and 0.85 is associated with star-forming hosts. Nevertheless, a non-negligible fraction of the X-ray luminosity density, about 15–20 per cent, at both z¯=0.40 and 0.85, is taking place in galaxies in the quiescent region of the U − V versus V − J diagram. For the low-redshift sub-sample, 0.1 < z < 0.6, we also find tentative evidence, significant at the 2σ level, that AGN split by their U − V and V − J colours have different Eddington ratio distributions. AGN in blue star-forming hosts dominate at relatively high Eddington ratios. In contrast, AGN in red quiescent hosts become increasingly important as a fraction of the total population towards low Eddington ratios. At higher redshift, z > 0.6, such differences are significant at the 2σ level only for sources with Eddington ratios ≳ 10^− 3. These findings are consistent with scenarios in which diverse accretion modes are responsible for the build-up of supermassive black holes at the centres of galaxies. We compare these results with the predictions of theGALFORM semi-analytic model for the cosmological evolution of AGN and galaxies. This model postulates two black hole fuelling modes, the first is linked to star formation events and the second takes place in passive galaxies. GALFORM predicts that a substantial fraction of the black hole growth at z < 1 is associated with quiescent galaxies, in apparent conflict with the observations. Relaxing the strong assumption of the model that passive AGN hosts have zero star formation rate could bring those predictions in better agreement with the data.

A Study of the Martyrdom Altarpiece

"This paper will explore an unstudied fifteenth-century English alabaster altarpiece referred to as the Martyrdom Altarpiece. Based on dated and current scholarship, this analysis postulates two scenarios of the object's history. The first scenario postulates the Martyrdom Altarpiece as being commissioned by the Carthusian order. This position is based on stylistic and iconographic readings of the object that correlate with Carthusian analogs. These interpretations are strengthened by documentation sold with the Martyrdom Altarpiece during its 1978 auction sale. Scenario two argues that the Martyrdom Altarpiece's origins are not Carthusian, furthermore suggesting that the object is a composite or truncated piece"

Domesticidad y familia: ambigüedad y contradicción en los modelos de feminidad en el franquismo

La instauración de la dictadura franquista significó la consolidación de un modelo de familia que, mediante la combinación de elementos católicos y falangistas, se convirtió en la base legitimadora del nuevo régimen. Aunque en teoría se trataba de sujetos subordinados, el papel desempeñado por las mujeres en la estructura familiar fue muy destacado. El espacio de la influencia y no del poder fue el destinado para ellas. Este artículo se plantea como principal objetivo conocer la manera en que estas mujeres interiorizaron los postulados de género del régimen y cómo reaccionaron ante ellos. La utilización de la fuente oral, siempre rica en matices, nos guiará en el proceso de construcción subjetiva de cuatro mujeres pertenecientes a distintas clases sociales y que, como hijas, novias, esposas y madres, aprendieron a ser mujeres en el franquismo.

On terminological figurativeness: From theory to practice

Terminologists’ interest in studying the role of metaphor and metaphorical terms in specialized communication has proliferated since the first papers addressing this issue appeared in the 1990s. However, we believe that some facets of terminological meaning still remain overlooked or merit further analysis. This paper attempts to contribute to the study of one of these facets: the figurative meaning of some compound terms used in the domain of luxury marketing and business. In order to present a systematized view of this phenomenon we will adopt some theoretical tools from the Conventional Figurative Language Theory, in order to confirm the validity of some of its postulates for compound term analysis. Next, a contrastive approach between English, Spanish and Russian compound terms will put the theoretical ideas into practice with the aim of illustrating their applied and metalinguistic potential. Some basic conclusions will be offered at the end of the paper.

Puesta en valor de la arquitectura moderna residencial post-terremoto de 1944. San Juan – Argentina

La ciudad y su arquitectura testimonian las culturas que modelan y remodelan sus formas y espacios en el tiempo. Toda comunidad tiene derecho a un ambiente urbano apto para el desarrollo humano sustentable. Desarrollo sustentable, es aquel que asegura la satisfacción de las necesidades del presente, sin comprometer los recursos con que generaciones futuras puedan satisfacer las propias (Naciones Unidas, 1987). Significa el uso racional y responsable de toda clase de recursos, especialmente los no renovables, como el patrimonio arquitectónico. La ciudad de San Juan fue reconstruida bajo influencias de los postulados del Movimiento Moderno tras el terremoto de 1944 que destruyó casi la totalidad de sus edificios patrimoniales. La arquitectura moderna es considerada internacionalmente un patrimonio a legar a las generaciones futuras. En San Juan, las obras residenciales modernas corren el riesgo de ser transformadas o demolidas ante un posible reemplazo por nuevas obras más redituables, por la dinámica del desarrollo urbano y la ausencia de protección que preserve este patrimonio. Es objetivo de este trabajo promover el reconocimiento, valoración y protección, de obras patrimoniales residenciales, exponentes de la modernidad arquitectónica local.

An Integrative Definition of Coaching Effectiveness and Expertise

The purpose of the current paper is to present an integrative definition of coaching effectiveness and expertise that is both specific and conceptually grounded in the coaching, teaching, positive psychology, and athletes' development literature. The article is organized into six sections. The first section is used to situate the proposed definition in the predominant conceptual models of coaching. The second, third, and fourth sections provide detailed discussion about each of the three components of the proposed definition of coaching effectiveness: (a) coaches' knowledge, (b) athletes' outcomes, and (c) coaching contexts. The proposed definition is presented in the fifth section along with a clarification of common terminology and guiding postulates. The final section includes implications for practice and research.