180 research outputs found
The effects of dams on longitudinal variation in river food webs
We examined the effects of two dams on longitudinal variation of riverine food webs using stable isotope and gut contents analyses along four rivers in the Hunter Valley in eastern Australia. Longitudinal 15N enrichment was observed in most invertebrate taxa and food sources but significant longitudinal variation was rare for 13C, and composition of gut contents of invertebrate taxa did not vary significantly with longitudinal position. Most invertebrates and food sources were more 15N-enriched at sites immediately downstream of the dams than expected from their upstream longitudinal position, a result not mirrored by gut contents and 13C. Enrichment of 15N downstream may be attributed to altered water quality as a result of impoundment but further research is necessary to elucidate whether physico-chemical riverine processes or trophic mechanisms are responsible. Our observations regarding the influence of dams on isotope ratios are contrary to the few existing studies, suggesting the small volumes relative to annual inflows of dams in the present study limit downstream impacts by maintaining aspects of flow variability. © 2013 © 2013 Taylor & Francis
The effect of applications of gypsum and a coal combustion by-product on acid East Texas soils
Last updated: 6/9/200
Alfalfa growth on acid soils treated with gypsum and a coal combustion by-product
Last updated: 6/9/200
Alfalfa Response.to Gypsum and Calcium Sulfite Sludge Applied to Acid Soils to Reduce Phytotoxicity of Subsoil Aluminum
Last updated: 6/12/200
Involvement of metabolic and immune responses in the pathogenesis of Abacavir hypersensitivity reaction
Oral presentatio
Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire
Idiosyncratic adverse drug reactions are unpredictable, dose independent and
potentially life threatening; this makes them a major factor contributing to
the cost and uncertainty of drug development. Clinical data suggest that many
such reactions involve immune mechanisms, and genetic association studies have
identified strong linkage between drug hypersensitivity reactions to several
drugs and specific HLA alleles. One of the strongest such genetic associations
found has been for the antiviral drug abacavir, which causes severe adverse
reactions exclusively in patients expressing the HLA molecular variant B*57:01.
Abacavir adverse reactions were recently shown to be driven by drug-specific
activation of cytokine-producing, cytotoxic CD8+ T cells that required
HLA-B*57:01 molecules for their function. However, the mechanism by which
abacavir induces this pathologic T cell response remains unclear. Here we show
that abacavir can bind within the F-pocket of the peptide-binding groove of
HLA-B*57:01 thereby altering its specificity. This supports a novel explanation
for HLA-linked idiosyncratic adverse drug reactions; namely that drugs can
alter the repertoire of self-peptides presented to T cells thus causing the
equivalent of an alloreactive T cell response. Indeed, we identified specific
self-peptides that are presented only in the presence of abacavir, and that
were recognized by T cells of hypersensitive patients. The assays we have
established can be applied to test additional compounds with suspected HLA
linked hypersensitivities in vitro. Where successful, these assays could speed
up the discovery and mechanistic understanding of HLA linked hypersensitivities
as well as guide the development of safer drugs
The influence of T cell development on pathogen specificity and autoreactivity
T cells orchestrate adaptive immune responses upon activation. T cell
activation requires sufficiently strong binding of T cell receptors on their
surface to short peptides derived from foreign proteins bound to protein
products of the major histocompatibility (MHC) gene products, which are
displayed on the surface of antigen presenting cells. T cells can also interact
with peptide-MHC complexes, where the peptide is derived from host (self)
proteins. A diverse repertoire of relatively self-tolerant T cell receptors is
selected in the thymus. We study a model, computationally and analytically, to
describe how thymic selection shapes the repertoire of T cell receptors, such
that T cell receptor recognition of pathogenic peptides is both specific and
degenerate. We also discuss the escape probability of autoimmune T cells from
the thymus.Comment: 12 pages, 7 figure
Effects of thymic selection of the T cell repertoire on HLA-class I associated control of HIV infection
Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.Mark and Lisa Schwartz FoundationNational Institutes of Health (U.S.) (Director’s Pioneer award)Philip T. and Susan M. Ragon FoundationJane Coffin Childs Memorial Fund for Medical ResearchBill & Melinda Gates FoundationNational Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health (U.S.) (contract no. HHSN261200800001E)National Institutes of Health (U.S.). Intramural Research ProgramNational Cancer Institute (U.S.)Center for Cancer Research (National Cancer Institute (U.S.)
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