Tethering Viral Restriction to Signal Transduction

Tetherin serves as an innate sensor of viral infection in addition to its role in inhibiting virus release from infected cells. In this issue, Galão et al. (2014) provide important insights into the mechanism of virus-induced signal transduction by tetherin

Structural Basis for the Antiviral Activity of BST-2/Tetherin and Its Viral Antagonism

The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin) blocks the release of HIV-1 and other enveloped viruses. In turn, these viruses have evolved specific antagonists to counteract this host antiviral molecule, such as the HIV-1 protein Vpu. BST-2 is a type II transmembrane protein with an unusual topology consisting of an N-terminal cytoplasmic tail (CT) followed by a single transmembrane (TM) domain, a coiled-coil extracellular (EC) domain, and a glycosylphosphatidylinositol (GPI) anchor at the C terminus. We and others showed that BST-2 restricts enveloped virus release by bridging the host and virion membranes with its two opposing membrane anchors and that deletion of either one completely abrogates antiviral activity. The EC domain also shows conserved structural properties that are required for antiviral function. It contains several destabilizing amino acids that confer the molecule with conformational flexibility to sustain the protein’s function as a virion tether, and three conserved cysteine residues that mediate homodimerization of BST-2, as well as acting as a molecular ruler that separates the membrane anchors. Conversely, the efficient release of virions is promoted by the HIV-1 Vpu protein and other viral antagonists. Our group and others provided evidence from mutational analyses indicating that Vpu antagonism of BST-2-mediated viral restriction requires a highly specific interaction of their mutual TM domains. This interpretation is further supported and expanded by the findings of the latest structural modeling studies showing that critical amino acids in a conserved helical face of these TM domains are required for Vpu–BST-2 interaction and antagonism. In this review, we summarize the current advances in our understanding of the structural basis for BST-2 antiviral function as well as BST-2-specific viral antagonism

Inference based on SVARs identified with sign and zero restrictions: Theory and applications

Are optimism shocks an important source of business cycle fluctuations? Are deficit-financed tax cuts better than deficit-financed spending to increase output? These questions have been previously studied using structural vector autoregressions (SVAR) identified with sign and zero restrictions and the answers have been positive and definite in both cases. Although the identification of SVARs with sign and zero restrictions is theoretically attractive because it allows the researcher to remain agnostic with respect to the responses of the key variables of interest, we show that current implementation of these techniques does not respect the agnosticism of the theory. These algorithms impose additional sign restrictions on variables that are seemingly unrestricted that bias the results and produce misleading confidence intervals. We provide an alternative and efficient algorithm that does not introduce any additional sign restriction, hence preserving the agnosticism of the theory. Without the additional restrictions, it is hard to support the claim that either optimism shocks are an important source of business cycle fluctuations or deficit-financed tax cuts work best at improving output. Our algorithm is not only correct but also faster than current ones

High systemic levels of interleukin-10, interleukin-22 and C-reactive protein in Indian patients are associated with low in vitro replication of HIV-1 subtype C viruses

<p>Abstract</p> <p>Background</p> <p>HIV-1 subtype C (HIV-1C) accounts for almost 50% of all HIV-1 infections worldwide and predominates in countries with the highest case-loads globally. Functional studies suggest that HIV-1C is unique in its biological properties, and there are contradicting reports about its replicative characteristics. The present study was conducted to evaluate whether the host cytokine environment modulates the <it>in vitro </it>replication capacity of HIV-1C viruses.</p> <p>Methods</p> <p>A small subset of HIV-1C isolates showing efficient replication in peripheral blood mononuclear cells (PBMC) is described, and the association of <it>in vitro </it>replication capacity with disease progression markers and the host cytokine response was evaluated. Viruses were isolated from patient samples, and the corresponding <it>in vitro </it>growth kinetics were determined by monitoring for p24 production. Genotype, phenotype and co-receptor usage were determined for all isolates, while clinical category, CD4 cell counts and viral loads were recorded for all patients. Plasmatic concentrations of cytokines and, acute-phase response, and microbial translocation markers were determined; and the effect of cytokine treatment on <it>in vitro </it>replication rates was also measured.</p> <p>Results</p> <p>We identified a small number of viral isolates showing high <it>in vitro </it>replication capacity in healthy-donor PBMC. HIV-1C usage of CXCR4 co-receptor was rare; therefore, it did not account for the differences in replication potential observed. There was also no correlation between the <it>in vitro </it>replication capacity of HIV-1C isolates and patients' disease status. Efficient virus growth was significantly associated with low interleukin-10 (IL-10), interleukin-22 (IL-22), and C-reactive protein (CRP) levels in plasma (p < .0001). <it>In vitro</it>, pretreatment of virus cultures with IL-10 and CRP resulted in a significant reduction of virus production, whereas IL-22, which lacks action on immune cells appears to mediate its anti-HIV effect through interaction with both IL-10 and CRP, and its own protective effect on mucosal membranes.</p> <p>Conclusions</p> <p>These results indicate that high systemic levels of IL-10, CRP and IL-22 in HIV-1C-infected Indian patients are associated with low viral replication <it>in vitro</it>, and that the former two have direct inhibitory effects whereas the latter acts through downstream mechanisms that remain uncertain.</p

Determinants of Rapid Transit Planning Processes in Ecuador

This research presents a novel framework for the quantitative and qualitative analysis of rapid transit planning processes based on a mixed-method approach, along with the corresponding results: the relative importance of factors that affect the projects, a ranking of the critical barriers that hinder their implementations, and the implications of private participation. The planning and implementation of rapid transit in Ecuador has proven to be a daunting endeavor. Nineteen projects have been planned, but only nine have reached implementation. This research seeks to understands how these projects’ design and implementation processes were shaped. The analysis of the design process focuses on how different factors (demand, local conditions, financial, social and political) have influenced all of the rapid transit projects in Ecuador over the past three decades by evaluating their relative significance on each system component (alignment, size, and technology). This analysis uses a multiple-case methodology including in-depth interviews with the senior members of the technical teams, as well as a survey component based on the Analytic Hierarchy Process (AHP) for quantification of the relative significance of the factors. The analysis shows five key results: 1) Each project was unique and external factors introduced a varying degree of complexity into each planning process; 2) The systems’ alignments and sizes were mostly driven by demand and local conditions (i.e., a rational planning process); 3) The main factor driving technology selection has evolved over time from system demand to political (i.e., a political bargaining approach); 4) Negative economic conditions had a large influence on the factors of all project components; and 5) There is a lack of rational alternative evaluation and an absence of corresponding tools/guidelines in Ecuador. Nonetheless, several processes included practices that contributed to a more rational planning process: lifecycle cost analysis for the various technology alternatives, explicit decision-maker guidelines, transferring the demand risk to the private sector, and the use of Multicriteria Decision Analysis (MCDA). In terms of project implementation, this research evaluates the critical barriers for project implementation along with corresponding mitigation measures. A mixed-method, based on an existing theoretical framework and Best-Worst Scaling (BWS), is proposed and applied. The analysis is grounded by in-depth interviews and surveys conducted with the technical teams of the planned projects. Results show the top tier of the critical barriers is composed of 1) Lack of political leadership, commitment or continuity; 2) Underestimation of implementation complexities; 3) Political frictions; and 4) Rushed planning processes. Seven key mitigation measures were identified and linked to each barrier: 1) Connect the social, political and technical perspectives; 2) Aim at starting construction before the end of political cycles; 3) Increase the private role in the procurement strategy; 4) Increase community input during planning; 5) Generate public opinion monitoring; 6) Adapt projects features to community input (when applicable); and 7) Focus on the implementation of one trunkline at a time. Moreover, evidence suggests critical barriers are not technology specific, but rather endemic to the planning process and that the projects’ critical political dependence promoted planning based on political cycles in detriment of long-term efforts. These findings align with previous results from developing cities, confirming the transferability of results at an aggregate level, but also show that the barriers and corresponding mitigation measures can be context specific. In both, the design and implementation stages, the private participation led to different outcomes. The two largest cities in Ecuador each implemented three BRT corridors (1995 to 2013). The projects present similar characteristics, and thus a unique opportunity to analyze how private participation influenced their performance. The analysis identifies the level of private participation and to what extent it influenced the outcomes of the projects. Two approaches were identified: 1) Including incumbent operators by delegating vehicle acquisitions and operations; and 2) Replacing them with a public company. Financial strength and interest of the incumbent operators to continue functioning along parallel routes were major issues. Quito was successful in the implementation of the first corridor through public delivery, but failed its attempts with private participation. Guayaquil surmounted the barriers for effective private participation through a Special Purpose Vehicle (SPV) that managed the risk due to the inherent nature of the consortiums. This research provides the first comprehensive analysis of the design and implementation processes in Ecuador. It is expected that the results will contribute to more efficient and sustainable investments in the future

Importancia quirúrgica de la expresión morfológica de la arteria hepática y sus colaterales

ResumenLa irrigaci&oacute;n hep&aacute;tica ha sido ampliamente estudiada en diferentes grupos poblacionales mediante t&eacute;cnicas anat&oacute;micas directas e imaginol&oacute;gica, sin embargo los estudios se han caracterizado por mostrar los resultados de una manera que hacen dif&iacute;cil su comprensi&oacute;n al predominar el componente descriptivo de las muestras evaluadas o clasificaciones que por su complejidad no han sido adecuadamente asimiladas por la comunidad acad&eacute;mica. Recientemente se clasificaron estas variantes seg&uacute;n el origen de la irrigaci&oacute;n hep&aacute;tica, agrupando en 3 grupos, cada uno con varios tipos. Se asimilaron los hallazgos de diferentes autores a esta clasificaci&oacute;n y se promediaron, siendo el Grupo 1 tipo I considerado como patr&oacute;n com&uacute;n el m&aacute;s frecuente (70.4%), adem&aacute;s en el grupo 2 los tipos I y II tuvieron una frecuencia significativa. El conocimiento de los diferentes patrones de la irrigaci&oacute;n hep&aacute;tica es indispensable para lograr abordajes exitosos durante procedimientos complejos, como el trasplante hep&aacute;tico, gastrectom&iacute;as eintervenciones en la v&iacute;a biliar, lo cual puede disminuir las complicaciones durante la realizaci&oacute;n de los mencionados intervenciones quir&uacute;rgicas; adem&aacute;s el conocimiento del amplio espectro de la irrigaci&oacute;n hep&aacute;tica se convierte en requisito que permite adecuadas interpretaciones imaginol&oacute;gicas; son estas las motivaciones que condujeron a la realizaci&oacute;n de esta revisi&oacute;n tem&aacute;tica.[Ballesteros LE, Arias JF. Importancia quir&uacute;rgica de la expresi&oacute;n morfol&oacute;gica de la arteria hep&aacute;tica y sus colaterales. Revisi&oacute;n&nbsp; documental&nbsp; de&nbsp; 1995&nbsp; a&nbsp; 2005.&nbsp; MedUNAB&nbsp; 2008; 11:162-167].Palabras clave: Arteria hep&aacute;tica, H&iacute;gado, Arteria celiaca

Variation in Thermal Sensitivity and Thermal Tolerances in an Invasive Species across a Climatic Gradient: Lessons from the Land Snail Cornu aspersum

The ability of organisms to perform at different temperatures could be described by a continuous nonlinear reaction norm (i.e., thermal performance curve, TPC), in which the phenotypic trait value varies as a function of temperature. Almost any shift in the parameters of this performance curve could highlight the direct effect of temperature on organism fitness, providing a powerful framework for testing thermal adaptation hypotheses. Inter-and intraspecific differences in this performance curve are also reflected in thermal tolerances limits (e.g., critical and lethal limits), influencing the biogeographic patterns of species' distribution. Within this context, here we investigated the intraspecific variation in thermal sensitivities and thermal tolerances in three populations of the invasive snail Cornu aspersum across a geographical gradient, characterized by different climatic conditions. Thus, we examined population differentiation in the TPCs, thermal-coma recovery times, expression of heat-shock proteins and standard metabolic rate (i.e., energetic costs of physiological differentiation). We tested two competing hypotheses regarding thermal adaptation (the "hotter is better" and the generalist-specialist trade-offs). Our results show that the differences in thermal sensitivity among populations of C. aspersum follow a latitudinal pattern, which is likely the result of a combination of thermodynamic constraints ("hotter is better") and thermal adaptations to their local environments (generalist-specialist trade-offs). This finding is also consistent with some thermal tolerance indices such as the Heat-Shock Protein Response and the recovery time from chill-coma. However, mixed responses in the evaluated traits suggest that thermal adaptation in this species is not complete, as we were not able to detect any differences in neither energetic costs of physiological differentiation among populations, nor in the heat-coma recovery. © 2013 Gaitán-Espitia et al.Link_to_subscribed_fulltex