Toxicity and pathophysiology of palytoxin congeners after intraperitoneal and aerosol administration in rats

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Toxicon 150 (2018): 235-250, doi:10.1016/j.toxicon.2018.06.067.Preparations of palytoxin (PLTX, derived from Japanese Palythoa tuberculosa) and the congeners 42-OH-PLTX (from Hawaiian P. toxica) and ovatoxin-a (isolated from a Japanese strain of Ostreopsis ovata), as well as a 50:50 mixture of PLTX and 42-OH-PLTX derived from Hawaiian P. tuberculosa were characterized as to their concentration, composition, in-vitro potency and interaction with an anti-PLTX monoclonal antibody (mAb), after which they were evaluated for lethality and pathophysiological effects by intraperitoneal (IP) and aerosol administration to rats. Once each preparation was characterized as to its toxin composition by LC-HRMS and normalized to a total PLTX/OVTX concentration using HPLC-UV, all four preparations showed similar potency towards mouse erythrocytes in the erythrocyte hemolysis assay and interactions with the anti-PLTX mAb. The IP LD50 values derived from these experiments (1-3 μg/kg for all) were consistent with published values, although some differences from the published literature were seen. The aerosol LD50 values (.03-.06 μg/kg) confirmed the exquisite potency of PLTX suggested by the literature. The pathophysiological effects of the different toxin preparations by IP and aerosol administration were similar, albeit with some differences. Most commonly affected tissues were the lungs, liver, heart, kidneys, salivary glands, and adrenal glands. Despite some differences, these results suggest commonalities in potency and mechanism of action among these PLTX congeners.This work was supported by the Defense Threat Reduction Agency, through the Joint Program Executive Office for Chemical and Biological Defense, Contract number CB10396. Additional support to DMA and DLK was provided by National Science Foundation (Grant OCE-1314642) and National Institutes of Health (NIEHS-1P50-ES021923-01) through the Woods Hole Center for Oceans and Human Health

Mechanisms of abrupt loss of virus control in a cohort of previous HIV controllers

Altres ajuts: FIPSE grant 360737-09; AELIX TherapeuticsA few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4 + T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro -determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8 + T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants. Elite and viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell tropism of circulating virus, evidence for HIV superinfection, cellular immune responses to HIV, as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in vitro viral suppression, even in the context of protective HLA alleles, predicts a loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8 T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5- to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials. IMPORTANCE A few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4 + T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro -determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8 + T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants

The Tree Biodiversity Network (BIOTREE-NET): prospects for biodiversity research and conservation in the Neotropics

Biodiversity research and conservation efforts in the tropics are hindered by the lack of knowledge of the assemblages found there, with many species undescribed or poorly known. Our initiative, the Tree Biodiversity Network (BIOTREE-NET), aims to address this problem by assembling georeferenced data from a wide range of sources, making these data easily accessible and easily queried, and promoting data sharing. The database (GIVD ID NA-00-002) currently comprises ca. 50,000 tree records of ca. 5,000 species (230 in the IUCN Red List) from \u3e2,000 forest plots in 11 countries. The focus is on trees because of their pivotal role in tropical forest ecosystems (which contain most of the world\u27s biodiversity) in terms of ecosystem function, carbon storage and effects on other species. BIOTREE-NET currently focuses on southern Mexico and Central America, but we aim to expand coverage to other parts of tropical America. The database is relational, comprising 12 linked data tables. We summarise its structure and contents. Key tables contain data on forest plots (including size, location and date(s) sampled), individual trees (including diameter, when available, and both recorded and standardised species name), species (including biological traits of each species) and the researchers who collected the data. Many types of queries are facilitated and species distribution modelling is enabled. Examining the data in BIOTREE-NET to date, we found an uneven distribution of data in space and across biomes, reflecting the general state of knowledge of the tropics. More than 90% of the data were collected since 1990 and plot size varies widely, but with most less than one hectare in size. A wide range of minimum sizes is used to define a \u27tree\u27. The database helps to identify gaps that need filling by further data collection and collation. The data can be publicly accessed through a web application at http://portal.biotreenet.com. Researchers are invited and encouraged to contribute data to BIOTREE-NET

La Red Internacional de Inventarios Forestales (BIOTREE-NET) en Mesoamérica: avances, retos y perspectivas futuras

Conservation efforts in Neotropical regions are often hindered by lack of data, since for many species there is a vacuum of information, and many species have not even been described yet. The International Network of Forest Inventory Plots (BIOTREE-NET) gathers and facilitates access to tree data from forest inventory plots in Mesoamerica, while encouraging data exchange between researchers, managers and conservationists. The information is organised and standardised into a single database that includes spatially explicit data. This article describes the scope and objectives of the network, its progress, and the challenges and future perspectives. The database includes above 50000 tree records of over 5000 species from more than 2000 plots distributed from southern Mexico through to Panama. Information is heterogeneous, both in nature and shape, as well as in the geographical coverage of inventory plots. The database has a relational structure, with 12 inter-connected tables that include information about plots, species names, dbh, and functional attributes of trees. A new system that corrects typographical errors and achieves taxonomic and nomenclatural standardization was developed using The Plant List (http://theplantlist.org/) as reference. Species distribution models have been computed for around 1700 species using different methods, and they will be publicly accessible through the web site in the future (http://portal.biotreenet.com). Although BIOTREE-NET has contributed to the development of improved species distribution models, its main potential lies, in our opinion, in studies at the community level. Finally, we emphasise the need to expand the network and encourage researchers willing to share data and to join the network and contribute to the generation of further knowledge about forest biodiversity in Neotropical regions

Assessment of impairment of the electrodes by increasing the number of pulses of the welding time on IF and HSLA steels galvanized and involvement of the mechanical properties in the nuggets welds

The objective of the following work is to analyze the deterioration of the quality of the welding buttons made in three different grades of galvanized conventional high resistance steels, caused by the wear of the copper electrodes, is the objective of the present study; which consists of performing 1000 welding points on two high resistance HSLA steels and one IF steel. 10 pairs of strip of 76.2 mm x 914 mm x two sheet thicknesses are used, in which 100 welding points are made. The characterization for evaluation was carried out in each twenty-fifth welding point until reaching 1000 points. The characterization consists of the measurement of indentation, penetration, hardness tests and stress tests.El objetivo del siguiente trabajo es analizar el deterioro de la calidad de los botones de soldadura realizado en tres diferentes grados de aceros de alta resistencia convencionales galvanizados, causado por el desgaste de los electrodos de cobre, es el objetivo del presente estudio; el cual consiste en realizar 1000 puntos de soldadura sobre dos aceros de alta resistencia HSLA y un acero IF. Se utilizan 10 pares de tira de 76.2 mm x 914 mm x dos espesores de lámina, en los cuales se realizan 100 puntos de soldadura. La caracterización para evaluación se realizó en cada veinticincoavo punto de soldadura hasta llegar a los 1000 puntos. La caracterización consiste en la medición de indentación, penetración, ensayos de dureza y ensayos de tensión