Loss of CD8 and TCR binding to Class I MHC ligands following T cell activation

The capacity of T cells to bind peptide/MHC ligands changes with T cell development and differentiation. Here we study changes in peptide/MHC multimer binding following T cell activation. Surprisingly, T cell activation caused a marked reduction in specific peptide/MHC Class I multimer binding, which was distinct from transient TCR down-regulation, and was especially dramatic for engagement with low-affinity peptide/MHC ligands. Direct CD8-Class I interactions were also profoundly and rapidly impaired following T cell stimulation, even though surface CD8α and CD8β levels were unchanged after activation, suggesting that decreased CD8 co-receptor binding contributes to this effect. Finally, we show that enzymatic desialylation restores much of the multimer binding on activated T cells, suggesting that altered glycosylation may inhibit TCR/CD8 binding to peptide/MHC ligands. These radical changes in activated T cells' ability to perceive peptide/MHC ligands may contribute to selective outgrowth of clones with high affinity for the stimulatory ligan

Toxic Effect of the Explosive Depth Charge Chemicals from the Ship SANKISAN MARU on the Coral Reef Fish Dascyllus aruanus (L) 1

Abstract The coral reef fish Dascyllus aruanus (damselfish) was subjected to various concentrations of explosive depth charge chemicals from the sunken Japanese cargo ship SANKISAN MARU to determine if the leaking of these chemicals into the waters of Truk Lagoon would pose a potential threat to marine organisms. Experiments using yellow powder (6% water, 83% ammonium picrate, 10% aluminum powder, and 1% benzene-soluble organics) resulted in a 48-hour TL 50 value of 118 mg/1 and a 96-hour TL 50 value of 95 mg/1. Experiments using black powder (34% water, 4% ammonium picrate, and 42% inert humic acid-type polymer containing an undetermined proportion of powdered aluminum and inorganic aluminum salts) resulted in a 48-hour TL 50 value of 1200 mg/l and a 96-hour TL 50 value of 1000 mg/l

Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells

AbstractPositive selection of functional CD8+ T cells expressing an MHC class I-restricted T cell receptor can be induced in fetal thymus organ culture by class I-binding peptides related to the antigenic peptide ligand. Peptides that act as antagonist or weak agonist/antagonist ligands for mature T cells work efficiently in this regard. In the present study, we have investigated whether low concentrations of the original agonist peptide, or variants that still have a strong agonist activity can also mediate positive selection. The antigenic peptide did not Induce positive selection at any concentration tested. A strong agonist variant was capable of stimulating the differentiation of TCRhl CD8+ cells, giving the appearance of phenotypic positive selection. However, these cells lacked biological function, since they could not proliferate In response to antigen. The most efficient positive selection resulted with Ilgands that did not activate mature T cells or stimulate negative selection

Detuning CD8 T cells: down-regulation of CD8 expression, tetramer binding, and response during CTL activation

CD8 is critical for T cell recognition of peptide/class I major histocompatability complex ligands, yet is down-regulated during activation of CD8 T cells. We report that loss of CD8 expression early during in vivo responses to vaccinia virus or Listeria monocytogenes (LM) correlates with decreased T cell staining with specific class I/peptide tetramers and reduced CD8 T cell sensitivity for antigen. Loss of CD8 cell surface expression occurs despite sustained mRNA expression, and CD8 levels return to normal levels during differentiation of memory cells, indicating a transient effect. We determined that during response to LM, CD8 down-regulation is regulated by T cell reactivity to type I interferon (IFN-I) because CD8 loss was averted on IFN-I receptor–deficient T cells. IFN-I alone was not sufficient to drive CD8 down-regulation, however, as antigen was also required for CD8 loss. These results suggest that CD8 effector T cell differentiation involves a transient down-regulation of antigen sensitivity (CTL “detuning”), via reduced CD8 expression, a feature that may focus the effector response on target cells expressing high levels of antigen (e.g., infected cells), while limiting collateral damage to bystander cells

Best Practices for Tourism Center Development Along the Red Sea Coast

The spectacular coastlines along Egypt\u27s Red Sea and Gulf of Aqaba are the focus for one of the fastest growing tourism economies in the world. In order to accomplish national objectives for growth in permanent, well-paying jobs and in foreign exchange earnings, the Tourism Development Authority (TDA) has launched an initiative to make land available to investors for resort development along these coastlines. As of December, 1997, 6,000 hotel rooms are under construction in the Red Sea region and the TDA has proposals for at least 240 major resorts to be built by the year 2020. While this program has begun to yield impressive results in terms of new hotel construction, tourism jobs and tourist visitations, TDA has recognized that priority must be given to guiding private development in ways that protect Egypt\u27s natural heritage and insure that tourism can be sustained far into the future. It is clear from experience to date that such rapid growth, if not carefully planned and managed, threatens the very attractions that bring visitors here. In the best practices described here, TDA defines well planned and managed -- as distinct from haphazard and destructive -- tourism development for the Red Sea coastal environment. We look to lessons gained from several case studies of tourism center sites being jointly planned by TDA and development companies and from studies of successful established tourism centers in Egypt and from other parts of the world. We also draw upon technical literature from a variety of related fields, including marine biology, landscape architecture, engineering, tourism marketing, environmental planning, and others. These lessons and research are distilled into best practices for the planning and siting of new tourism centers and for the use and protection of environmental assets adjacent to the centers including the coral reef ecosystems, the beaches and headlands, the setback areas along coastal waters, and the surrounding desert landscape. This Best Practices Handbook is designed to be practical, well-illustrated and easily understood. It covers aspects of tourism center development that will: assist the development community to achieve environmentally sound, aesthetically pleasing and market-sensitive tourism centers, and assist the TDA and other public agencies by providing benchmarks on which to set environmental policies, guide the location of tourism centers and the subdivision of public lands, judge development plans and proposals, and base environmental management regulations. In the first section, Best Practices focuses on the framework for tourism development and environmental protection: the roles and responsibilities of key groups and the development process. The subsequent section describes the unique physical and environmental context in which tourism development is occurring and the special measures needed to respect these development shaping features. The subsequent sections address the best practices to accomplish sustainable tourism development. The best practices are not presented as a rigid set of prescribed steps and procedures, but rather as guidance and assistance in designing successful tourism facilities and managing the environmental assets on which tourism depends. Furthermore, this should be seen as our first effort. We intend to build upon and refine these practices as wel gain continued experience. Your suggestions for improvement will be sincerely appreciated

Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation

<p>Abstract</p> <p>Background</p> <p>Previous reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec) effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM), an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks.</p> <p>Results</p> <p>All subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli), there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted.</p> <p>Conclusion</p> <p>The results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation.</p

Identification of a novel retroviral gene unique to human immunodeficiency virus type 2 and simian immunodeficiency virus SIVMAC

Human and simian immunodeficiency-associated retroviruses are extraordinarily complex, containing at least five genes, tat, art, sor, R, and 3' orf, in addition to the structural genes gag, pol, and env. Recently, nucleotide sequence analysis of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus SIVMAC revealed the existence of still another open reading frame, termed X, which is highly conserved between these two viruses but absent from HIV-1. In this report, we demonstrate for the first time that the X open reading frame represents a functional retroviral gene in both HIV-2 and SIVMAC and that it encodes a virion-associated protein of 14 and 12 kilodaltons, respectively. We also describe the production of recombinant TrpE/X fusion proteins in Escherichia coli and show that sera from some HIV-2-infected individuals specifically recognize these proteins

In Vivo Survival and Homeostatic Proliferation of Natural Killer Cells

While the specificity and development of natural killer (NK) cells have been intensely studied, little is known about homeostasis of the mature NK population. Here we show that mouse NK cells undergo homeostatic proliferation when transferred into NK-deficient Rag−/− γC−/− hosts. Normal NK functional activity is maintained during this process, although there are some changes in NK phenotype. Using cell sorting, we demonstrate that mature (Mac-1hi) NK cells undergo homeostatic proliferation in an NK-deficient environment, yet immature (Mac-1lo) NK cells also proliferate in such hosts. We find that mature NK cells survive but do not proliferate in hosts which possess an endogenous NK pool. However, we go on to show that mature NK survival is critically dependent on interleukin (IL)-15. Surprisingly, NK survival is also compromised after transfer of cells into IL-15Rα−/− mice, implying that IL-15 responsiveness by bystander cells is critical for NK maintenance. These data imply that, similar to T cells, homeostasis of the NK pool is much more dynamic than previously appreciated and this may be relevant to manipulation of NK cells for therapeutic purposes