Selective reduction of coliforms in constructed wetlands

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Total synthesis of Mycobacterium tuberculosis dideoxymycobactin-838 and stereoisomers: diverse CD1a-restricted T cells display a common hierarchy of lipopeptide recognition

Mycobacterium tuberculosis produces dideoxymycobactin-838 (DDM-838), a lipopeptide that potently activates T cells upon binding to the MHC-like antigen-presenting molecule CD1a. M. tuberculosis produces DDM-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. We describe a high-yielding solution-phase synthesis of DDM-838 that features a Mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation conditions that prevent double-bond isomerization of the Z-C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM-838. Isomers of DDM-838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a-restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM-838 isomers, highlighting the exquisite sensitivity of lipopeptide-reactive T cells for the natural DDM stereochemistry

Effect of Nuclear Fuel Rods Deformation on Coolant Flow through Fuel Assembly

Tato práce se zabývá vlivem změny geometrie průtočných kanálů chladiva na termohydraulický výpočet aktivních zón lehkovodních reaktorů. Nejprve je podán výklad pojednávající o lehkovodních reaktorech, struktuře jejich aktivních zón a také popis paliva pro tyto reaktory. Zvláštní pozornost je věnována reaktorům VVER. Je diskutován možný vliv deformace paliva na průtok chladiva reaktorem, jak jej popisují jiné práce. V další části je popsána úloha termohydraulických výpočtů s jejími východisky a proveden jednoduchý termohydraulický výpočet metodou subkanálové analýzy na experimentálním svazku.This thesis deals with the influence of changes in the geometry of coolant flow channels on the thermohydraulic analysis of light water reactor active zones. Firstly, an explanation is provided about light water reactors, the structure of their active zones, and a description of the fuel used in these reactors. Special attention is given to VVER reactors. The possible impact of fuel deformation on the coolant flow through the reactor is discussed based on findings from other studies. In the following section, the task of thermohydraulic calculations is described, along with its fundamentals, and a simple thermohydraulic calculation is performed using the subchannel analysis method on an experimental bundle

T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex

Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iTreg) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iTreg TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition

Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers

Studies on the biology of mucosal-associated invariant T cells (MAIT cells) in mice have been hampered by a lack of specific reagents. Using MR1-antigen (Ag) tetramers that specifically bind to the MR1-restricted MAIT T cell receptors (TCRs), we demonstrate that MAIT cells are detectable in a broad range of tissues in C57BL/6 and BALB/c mice. These cells include CD4(-)CD8(-), CD4(-)CD8(+), and CD4(+)CD8(-) subsets, and their frequency varies in a tissue- and strain-specific manner. Mouse MAIT cells have a CD44(hi)CD62L(lo) memory phenotype and produce high levels of IL-17A, whereas other cytokines, including IFN-gamma, IL-4, IL-10, IL-13, and GM-CSF, are produced at low to moderate levels. Consistent with high IL-17A production, most MAIT cells express high levels of retinoic acid-related orphan receptor gamma t (ROR gamma t), whereas ROR gamma t(lo) MAIT cells predominantly express T-bet and produce IFN-gamma. Most MAIT cells express the promyelocytic leukemia zinc finger (PLZF) transcription factor, and their development is largely PLZF dependent. These observations contrast with previous reports that MAIT cells from V alpha 19 TCR transgenic mice are PLZF(-) and express a naive CD44(lo) phenotype. Accordingly, MAIT cells from normal mice more closely resemble human MAIT cells than previously appreciated, and this provides the foundation for further investigations of these cells in health and disease

Seismic tipping analysis of a spent nuclear fuel shipping cask sitting on a crush pad

A crush pad has been designed and analyzed to absorb the kinetic energy of an accidentally dropped spent nuclear fuel shipping cask into a 44 ft. deep cask unloading pool. Conventional analysis techniques available for evaluating a cask for tipping due to lateral seismic forces assume that the cask rests on a rigid surface. In this analysis, the cask (110 tons) sits on a stainless steel encased (0.25 in. top plate), polyurethane foam (4 ft. thick) crush pad. As the cask tends to rock due to horizontal seismic forces, the contact area between the cask and the crush pad is reduced, increasing the bearing stress, and causing the pivoting corner of the cask to depress into the crush pad. As the crush pad depresses under the cask corner, the pivot point shifts from the corner toward the cask center, which facilitates rocking and potential tipping of the cask. Subsequent rocking of the cask may deepen the depression, further contributing to the likelihood of cask tip over. However, as the depression is created, the crush pad is absorbing energy from the rocking cask. Potential tip over of the cask was evaluated by performing a non-linear, dynamic, finite element analysis with acceleration time history input. This time history analysis captured the effect of a deforming crush pad, and also eliminated conservatisms of the conventional approaches. For comparison purposes, this analysis was also performed with the cask sitting on a solid stainless steel crush pad. Results indicate that the conventional methods are quite conservative relative to the more exacting time history analysis. They also indicate that the rocking motion is less on the foam crush pad than on the solid stainless steel pad

Platinum-modified DNA : solution structure and protein-binding preferences of 1,2-intrastrand d(GpG) adducts

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1997.Vita.Includes bibliographical references (leaves 138-142).by Shari Uldrich Dunham.Ph.D

Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells

Mucosal-associated invariant T cells (MAIT cells) express a semi-invariant T cell receptor (TCR) alpha-chain, TRAV1-2-TRAJ33, and are activated by vitamin B metabolites bound by the major histocompatibility complex (MHC)-related class I-like molecule, MR1. Understanding MAIT cell biology has been restrained by the lack of reagents to specifically identify and characterize these cells. Furthermore, the use of surrogate markers may misrepresent the MAIT cell population. We show that modified human MR1 tetramers loaded with the potent MAIT cell ligand, reduced 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH2OH), specifically detect all human MAIT cells. Tetramer(+) MAIT subsets were predominantly CD8(+) or CD4(-)CD8(-), although a small subset of CD4(+) MAIT cells was also detected. Notably, most human CD8(+) MAIT cells were CD8 alpha(+)CD8 beta(-/lo), implying predominant expression of CD8 alpha alpha homodimers. Tetramer-sorted MAIT cells displayed a T(H)1 cytokine phenotype upon antigen-specific activation. Similarly, mouse MR1-rRL-6-CH2OH tetramers detected CD4(+), CD4(-)CD8(-) and CD8(+) MAIT cells in V. 19 transgenic mice. Both human and mouse MAIT cells expressed a broad TCR-beta repertoire, and although the majority of human MAIT cells expressed TRAV1-2-TRAJ33, some expressed TRAJ12 or TRAJ20 genes in conjunction with TRAV1-2. Accordingly, MR1 tetramers allow precise phenotypic characterization of human and mouse MAIT cells and revealed unanticipated TCR heterogeneity in this population

Tolerance has its limits: how the thymus copes with infection

The thymus is required for T cell differentiation; a process that depends on which antigens are encountered by thymocytes, the environment surrounding the differentiating cells, and the thymic architecture. These features are altered by local infection of the thymus and by the inflammatory mediators that accompany systemic infection. Although once believed to be an immune privileged site, it is now known that antimicrobial responses are recruited to the thymus. Resolving infection in the thymus is important because chronic persistence of microbes impairs the differentiation of pathogen-specific T cells and diminishes resistance to infection. Understanding how these mechanisms contribute to disease susceptibility, particularly in infants with developing T cell repertoires, requires further investigation.We thank Joana Neves and Nadine Santos for critical reading of the manuscript. This work was supported by Portuguese Foundation for Science and Technology (FCT) grant PTDC/SAU-MII/101663/2008 and individual fellowships to CN-A and CN. SMB was supported by National Institutes of Health Grant R01 R56 AI067731