12 research outputs found

    N2-Phenyl-9-(hydroxyalkyl)guanines and related compounds are substrates for Herpes simplex thymidine kinases

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    Herpes simplex virus (HSV) types 1 and 2 thymidine kinases (TK) are responsible for phosphorylation of antiherpes acyclonucleosides such as acyclovir (ACV) and 9-(4-hydroxybutyl)guanine (HBG). Related compounds, the N2-phenyl-9-(hydroxyalkyl)guanines, are devoid of direct antiviral activity, but potently inhibit the viral TKs and block viral reactivation from latency in vivo. The similarity in structure between the acyclonucleosides and TK inhibitors raised the question of the relevance of phosphorylation of certain of the latter analogs in their mechanisms of action. Using recombinant TKs and HPLC analysis of reaction mixtures, we report that the lead TK inhibitor N2-phenyl-9-(4-hydroxybutyl)guanine (HBPG) and its pentyl homolog (HPnPG) are excellent substrates for the enzymes, approaching the efficiency with which the natural substrate thymidine is phosphorylated, and significantly better than ACV or HBG. Other 9-hydroxyalkyl congeners are substrates for the enzymes, but with much poorer efficiency. HBPG triphosphate was a poor inhibitor of HSV DNA polymerase, the target of acyclonucleoside triphosphates, suggesting that phosphorylation of HBPG is not important in its mechanism of blocking viral reactivation in vivo. The fact that HBPG is an efficient substrate is consistent, however, with its binding mode based both on molecular modeling studies and x-ray structure of the HBPG:TK complex

    Opportunities and challenges of other effective area-based conservation measures (OECMs) for biodiversity conservation

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    In 2010, the Convention on Biological Diversity adopted the Strategic Plan for Biodiversity 2011-2020. As international attention turns to the development of the post-2020 Global Biodiversity Framework, discussions are focusing on the way in which other effective area-based conservation measures (OECMs) should be reflected in the Framework. To inform this discussion, we gathered in-depth perspectives and expert elicitation on the opportunities and challenges that OECMs offer and present to biodiversity conservation. To do so, we conducted semi-structured interviews with experts involved in OECM-related deliberations. The explicit consideration of OECMs in conservation policy represents a recognition that there are sites outside of formal protected area networks that benefit biodiversity and ecosystems in important ways. However, these benefits and the future social and ecological impacts of OECMs will depend largely on robust guidelines for their identification, effective monitoring, and whether relevant actors report the areas they govern as OECMs.This work was undertaken under the support of CNPq (Conselho Nacional de Desenvolvimento Científico e Tecológico – Brazil). We thank all the interviewees for their time and support

    Sensitivity of Monkey B Virus (Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides▿

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    Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to “activate” nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and l enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease

    Otwarta arena. Spór o corridę de toros w Hiszpanii. Perspektywa socjologiczno-antropologiczna

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    Książka ukazuje corridę de toros – hiszpańską tradycję, w szerokim kontekście społeczno-kulturowym. Autorka przybliża toczący się od lat w hiszpańskim społeczeństwie dyskurs publiczny wokół widowisk tauromachiach. W publikacji przedstawiono narrację, którą posługują się zarówno przeciwnicy, jak i zwolennicy corridy de toros, osadzoną w kontekście politycznym, społecznym i kulturowym. Dla polskiego czytelnika interesujący może być nie tylko sam opis kontrowersyjnej tradycji, ale również kierunki, w których owa tradycja ewoluuje. Praca jest efektem wieloletnich badań terenowych oraz wnikliwej analizy hiszpańskiej prasy.The book presents the Spanish tradition corrida de toros in a broad social and cultural context. On the one hand, it provides a very detailed ethnographic account of this cultural phenomenon. On the other, it presents the ongoing public debate on tauromachic shows engaging Spanish society for many years. This publication relates and also provides an interpretation of the narratives of both opponents and supporters of corrida de toros. These two narratives have been placed in the political, social, cultural and ethical context. What might be interesting for the (Polish) reader is not only the actual description of this controversial tradition, but also the various ways it has evolved. This book is based on years of longitudinal field research, as well as an in-depth analysis of the Spanish press

    Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer’s disease

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    Several studies support the relation between leptin and Alzheimer’s disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated withAb1-42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Ab accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time
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