Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

Topology analysis and visualization of Potyvirus protein-protein interaction network

Background: One of the central interests of Virology is the identification of host factors that contribute to virus infection. Despite tremendous efforts, the list of factors identified remains limited. With omics techniques, the focus has changed from identifying and thoroughly characterizing individual host factors to the simultaneous analysis of thousands of interactions, framing them on the context of protein-protein interaction networks and of transcriptional regulatory networks. This new perspective is allowing the identification of direct and indirect viral targets. Such information is available for several members of the Potyviridae family, one of the largest and more important families of plant viruses. Results: After collecting information on virus protein-protein interactions from different potyviruses, we have processed it and used it for inferring a protein-protein interaction network. All proteins are connected into a single network component. Some proteins show a high degree and are highly connected while others are much less connected, with the network showing a significant degree of dissortativeness. We have attempted to integrate this virus protein-protein interaction network into the largest protein-protein interaction network of Arabidopsis thaliana, a susceptible laboratory host. To make the interpretation of data and results easier, we have developed a new approach for visualizing and analyzing the dynamic spread on the host network of the local perturbations induced by viral proteins. We found that local perturbations can reach the entire host protein-protein interaction network, although the efficiency of this spread depends on the particular viral proteins. By comparing the spread dynamics among viral proteins, we found that some proteins spread their effects fast and efficiently by attacking hubs in the host network while other proteins exert more local effects. Conclusions: Our findings confirm that potyvirus protein-protein interaction networks are highly connected, with some proteins playing the role of hubs. Several topological parameters depend linearly on the protein degree. Some viral proteins focus their effect in only host hubs while others diversify its effect among several proteins at the first step. Future new data will help to refine our model and to improve our predictions.This work was supported by the Spanish Ministerio de Economia y Competitividad grants BFU2012-30805 (to SFE), DPI2011-28112-C04-02 (to AF) and DPI2011-28112-C04-01 (to JP). The first two authors are recipients of fellowships from the Spanish Ministerio de Economia y Competitividad: BES-2012-053772 (to GB) and BES-2012-057812 (to AF-F).Bosque, G.; Folch Fortuny, A.; Picó Marco, JA.; Ferrer, A.; Elena Fito, SF. (2014). Topology analysis and visualization of Potyvirus protein-protein interaction network. 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Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species

The immune inflammatory response is a double edged sword. During infectious diseases, regulatory T cells can prevent eradication of the pathogen but can also limit inflammation and tissue damage. We investigated the role of regulatory T cells in chronic dermal leishmaniasis caused by species of the parasite Leishmania that are endemic in South and Central America. We found that although individuals with chronic lesions have increased regulatory T cells in their blood and at skin sites where immune responses to Leishmania were taking place compared to infected individuals who do not develop disease, their capacity to control the inflammatory response to Leishmania was inferior. However, healing of chronic lesions at the end of treatment was accompanied by an increase in the number and capacity of regulatory T cells to inhibit the function of effector T cells that mediate the inflammatory response. Different subsets of regulatory T cells, defined by the expression of molecular markers, were identified during chronic disease and healing, supporting the participation of distinct regulatory T cells in the development of disease and the control of inflammation during the healing response. Immunotherapeutic strategies may allow these regulatory T cell subsets to be mobilized or mitigated to achieve healing

Nursing and fuzzy logic: an integrative review Enfermería y lógica fuzzy: una revisión de integradora Enfermagem e lógica fuzzy: uma revisão integrativa

This study conducted an integrative review investigating how fuzzy logic has been used in research with the participation of nurses. The article search was carried out in the CINAHL, EMBASE, SCOPUS, PubMed and Medline databases, with no limitation on time of publication. Articles written in Portuguese, English and Spanish with themes related to nursing and fuzzy logic with the authorship or participation of nurses were included. The final sample included 21 articles from eight countries. For the purpose of analysis, the articles were distributed into categories: theory, method and model. In nursing, fuzzy logic has significantly contributed to the understanding of subjects related to: imprecision or the need of an expert; as a research method; and in the development of models or decision support systems and hard technologies. The use of fuzzy logic in nursing has shown great potential and represents a vast field for research.<br>Este estudio tuvo como objetivo realizar una revisión integradora investigando como la lógica fuzzy ha sido utilizada en investigaciones con participación de enfermeros. La búsqueda de los artículos fue realizada en las bases de datos CINAHL, Embase, SCOPUS, Medline y PubMed, sin especificar un intervalo de años determinado. Fueron incluidos artículos en los idiomas: portugués, inglés y castellano; con una temática relacionada a la enfermería y a la lógica fuzzy; y con autoría o participación de enfermeros. La muestra final fue de 21 artículos, de ocho países. Para el análisis, los artículos fueron distribuidos en las categorías: teoría, método y modelo. En la enfermería, la lógica fuzzy ha contribuido significativamente para la comprensión de temas relativos a la imprecisión o a la necesidad del especialista, como método de investigación y en el desarrollo de modelos o sistemas de apoyo a la decisión y de tecnologías duras. El uso de la lógica fuzzy en la enfermería ha demostrado gran potencial y representa un vasto campo para investigaciones.<br>Este estudo teve como objetivo realizar revisão integrativa, investigando como a lógica fuzzy tem sido utilizada em pesquisas com participação de enfermeiros. A busca dos artigos foi realizada nas bases de dados CINAHL, Embase, Scopus, MEDLINE e PubMed, sem intervalo de anos especificado. Foram incluídos artigos na língua portuguesa, inglesa e espanhola; com temática relacionada à enfermagem e à lógica fuzzy, e autoria ou participação de enfermeiros. A amostra final foi de 21 artigos, de oito países. Para análise, os artigos foram distribuídos nas categorias: teoria, método e modelo. Na enfermagem, a lógica fuzzy tem contribuído significativamente para a compreensão de temas relativos à imprecisão ou à necessidade do especialista, como método de pesquisa e no desenvolvimento de modelos ou sistemas de apoio à decisão e de tecnologias duras. O uso da lógica fuzzy, na enfermagem, tem demonstrado grande potencial e representa vasto campo para pesquisas

Post weaning diarrhea in pigs: risk factors and non‑colistin‑based control strategies

Post-weaning diarrhea (PWD) is one of the most serious threats for the swine industry worldwide. It is commonly associated with the proliferation of enterotoxigenic Escherichia coli in the pig intestine. Colistin, a cationic antibiotic, is widely used in swine for the oral treatment of intestinal infections caused by E. coli, and particularly of PWD. However, despite the effectiveness of this antibiotic in the treatment of PWD, several studies have reported high rates of colistin resistant E. coli in swine. Furthermore, this antibiotic is considered of very high importance in humans, being used for the treatment of infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB). Moreover, the recent discovery of the mcr-1 gene encoding for colistin resistance in Enterobacteriaceae on a conjugative stable plasmid has raised great concern about the possible loss of colistin effectiveness for the treatment of MDR-GNB in humans. Consequently, it has been proposed that the use of colistin in animal production should be considered as a last resort treatment only. Thus, to overcome the economic losses, which would result from the restriction of use of colistin, especially for prophylactic purposes in PWD control, we believe that an understanding of the factors contributing to the development of this disease and the putting in place of practical alternative strategies for the control of PWD in swine is crucial. Such alternatives should improve animal gut health and reduce economic losses in pigs without promoting bacterial resistance. The present review begins with an overview of risk factors of PWD and an update of colistin use in PWD control worldwide in terms of quantities and microbiological outcomes. Subsequently, alternative strategies to the use of colistin for the control of this disease are described and discussed. Finally, a practical approach for the control of PWD in its various phases is proposed