Good Bye, Soldier Boy

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Thermoconditional modulation of the pleiotropic sensitivity phenotype by the Saccharomyces cerevisiae PRP19 mutant allele pso4-1

The conditionally-lethal pso4-1 mutant allele of the spliceosomal-associated PRP19 gene allowed us to study this gene’s influence on pre-mRNA processing, DNA repair and sporulation. Phenotypes related to intron-containing genes were correlated to temperature. Splicing reporter systems and RT–PCR showed splicing efficiency in pso4-1 to be inversely correlated to growth temperature. A single amino acid substitution, replacing leucine with serine, was identified within the N-terminal region of the pso4-1 allele and was shown to affect the interacting properties of Pso4-1p. Amongst 24 interacting clones isolated in a two-hybrid screening, seven could be identified as parts of the RAD2, RLF2 and DBR1 genes. RAD2 encodes an endonuclease indispensable for nucleotide excision repair (NER), RLF2 encodes the major subunit of the chromatin assembly factor I, whose deletion results in sensitivity to UVC radiation, while DBR1 encodes the lariat RNA splicing debranching enzyme, which degrades intron lariat structures during splicing. Characterization of mutagen-sensitive phenotypes of rad2{Delta}, rlf2{Delta} and pso4-1 single and double mutant strains showed enhanced sensitivity for the rad2{Delta} pso4-1 and rlf2{Delta} pso4-1 double mutants, suggesting a functional interference of these proteins in DNA repair processes in Saccharomyces cerevisiae

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 three species monomer-monomer model: A mean-field analysis and Monte Carlo study

We study the phase diagram and critical behavior of a one dimensional three species monomer-monomer surface reaction model. Static Monte Carlo simulations show a phase diagram consisting of a reactive steady state bordered by three equivalent unreactive phases where the surface is saturated with one monomer species. The transitions from the reactive to saturated phases are all continuous, while the transitions between poisoned phases are first-order, with bicritical points where the reactive phase meets two poisoned phases. A mean-field cluster analysis predicts all of the qualitative features of the phase diagram only when correlations up to triplets of adjacent sites are included. Dynamic Monte Carlo simulations show that the transition from the reactive to a saturated phase show critical behavior in the directed percolation universality class, while the bicritical point shows critical behavior in the even branching annihilating random walk class. The crossover from bicritical to critical behavior is also studied.Comment: 16 pages using RevTeX, plus 10 figures. Uses psfig.st

Research data supporting the publication "Under Pressure: Offering Fundamental Insight into Structural Changes on Ball Milling Battery Materials"

Data depository includes the following: Powder X-ray diffraction (PXRD) of the ball-milled Li2MoO4 (at 40Hz and 50Hz, with varying ball size of 7 and 10 mm). PXRD of H-Nb2O5 ball-milled at 40 Hz and 50 Hz (7 mm ball) Electrochemical data of Li2MoO4 and Li2MnO3 (ball-milled samples). TEM of Li2MoO4 and the ball-milled equivalent. Li and Mo NMR of Li2MoO4 and the ball-milled equivalent

STS in management education: connecting theory and practice

This paper explores the value of science and technology studies (STS) to management education. The work draws on an ethnographic study of second year management undergraduates studying decision making. The nature and delivery of the decision making module is outlined and the value of STS is demonstrated in terms of both teaching method and module content. Three particular STS contributions are identified and described: the social construction of technological systems; actor network theory; and ontological politics. Affordances and sensibilities are identified for each contribution and a discussion is developed that illustrates how these versions of STS are put to use in management education. It is concluded that STS has a pivotal role to play in critical management (education) and in the process offers opportunities for new forms of managin

Computing the first eigenpair of the p-Laplacian via inverse iteration of sublinear supersolutions

We introduce an iterative method for computing the first eigenpair $(\lambda_{p},e_{p})$ for the $p$-Laplacian operator with homogeneous Dirichlet data as the limit of $(\mu_{q,}u_{q})$ as $q\rightarrow p^{-}$, where $u_{q}$ is the positive solution of the sublinear Lane-Emden equation $-\Delta_{p}u_{q}=\mu_{q}u_{q}^{q-1}$ with same boundary data. The method is shown to work for any smooth, bounded domain. Solutions to the Lane-Emden problem are obtained through inverse iteration of a super-solution which is derived from the solution to the torsional creep problem. Convergence of $u_{q}$ to $e_{p}$ is in the $C^{1}$-norm and the rate of convergence of $\mu_{q}$ to $\lambda_{p}$ is at least $O(p-q)$. Numerical evidence is presented.Comment: Section 5 was rewritten. Jed Brown was added as autho