Immunogenetics of drug-induced skin blistering disorders. Part II: Synthesis

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon examining the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events including Stevens-Johnson syndrome and Toxic epidermal necrolysis). New results from an exemplar study on shared precipitating and perpetuating inner causes with other related disease phenotypes including aphtous stomatitis, Behcets, erythema multiforme, Hashimoto's thyroiditis, pemphigus, periodic fevers, Sweet's syndrome and drug-induced multisystem hypersensitivity are presented. A call for a collaborative, wider demographic profiling and deeper immunotyping in suggested future work is made.

Immunogenetics of drug-induced skin blistering disorders. Part I: Perspective

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon the examination of the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events, including Stevens-Johnson syndrome and toxic epidermal necrolysis). An overarching pharmacogenetic schema is proposed. Immune cognition and early-effector processes are focused upon and a challenging synthesis around systems evolution is explained by a variety of projective analogies. Etiology, human leukocyte antigen-B, immune stability, clysiregulation, pharmacomimicry, viruses and an aggressive ethnically differentiated 'karmic' response are discussed.

Proteornics analysis unravels the functional repertoire of coronavirus nonstructural protein 3

Severe acute respiratory syndrome (SARS) coronavirus infection and growth are dependent on initiating signaling and enzyme actions upon viral entry into the host cell. Proteins packaged during virus assembly may subsequently form the first line of attack and host manipulation upon infection. A complete characterization of virion components is therefore important to understanding the dynamics of early stages of infection. Mass spectrometry and kinase profiling techniques identified nearly 200 incorporated host and viral proteins. We used published interaction data to identify hubs of connectivity with potential significance for virion formation. Surprisingly, the hub with the most potential connections was not the viral M protein but the nonstructurall protein 3 (nsp3), which is one of the novel virion components identified by mass spectrometry. Based on new experimental data and a bioinformatics analysis across the Coronaviridae, we propose a higher-resolution functional domain architecture for nsp3 that determines the interaction capacity of this protein. Using recombinant protein domains expressed in Escherichia coli, we identified two additional RNA-binding domains of nsp3. One of these domains is located within the previously described SARS-unique domain, and there is a nucleic acid chaperone-like domain located immediately downstream of the papain-like proteinase domain. We also identified a novel cysteine-coordinated metal ion-binding domain. Analyses of interdomain interactions and provisional functional annotation of the remaining, so-far-uncharacterized domains are presented. Overall, the ensemble of data surveyed here paint a more complete picture of nsp3 as a conserved component of the viral protein processing machinery, which is intimately associated with viral RNA in its role as a virion component.

Nuclear magnetic resonance structure of the N-terminal domain of nonstructural protein 3 from the severe acute respiratory syndrome coronavirus

This paper describes the structure determination of nsp3a, the N-terminal domain of the severe acute respiratory syndrome coronavirus (SARS-CoV) nonstructural protein 3. nsp3a exhibits a ubiquitin-like globular fold of residues 1 to 112 and a flexibly extended glutamic acid-rich domain of residues 113 to 183. In addition to the four beta-strands and two alpha-helices that are common to ubiquitin-like folds, the globular domain of nsp3a contains two short helices representing a feature that has not previously been observed in these proteins. Nuclear magnetic resonance chemical shift perturbations showed that these unique structural elements are involved in interactions with single-stranded RNA. Structural similarities with proteins involved in various cell-signaling pathways indicate possible roles of nsp3a in viral infection and persistence.

A survey of primary homology assessment: different botanists perceive and define characters in different ways

Cladistic analyses begin with an assessment of variation for a group of organisms and the subsequent representation of that variation as a data matrix. The step of converting observed organismal variation into a data matrix has been considered subjective, contentious, under-investigated, imprecise, unquantifiable, intuitive, as a black-box, and at the same time as ultimately the most influential phase of any cladistic analysis (Pimentel and Riggins, 1987; Bryant, 1989; Pogue and Mickevich, 1990; de Pinna, 1991; Stevens, 1991; Bateman et al., 1992; Smith, 1994; Pleijel, 1995; Wilkinson, 1995; Patterson and Johnson, 1997). Despite the concerns of these authors, primary homology assessment is often perceived as reproducible. In a recent paper, Hawkins et al. (1997) reiterated two points made by a number of these authors: that different interpretations of characters and coding are possible and that different workers will perceive and define characters in different ways. One reviewer challenged us: did we really think that two people working on the same group would come up with different data sets? The conflicting views regarding the reproducibility of the cladistic character matrix provoke a number of questions. Do the majority of workers consistently follow the same guidelines? Has the theoretical framework informing primary homology assessment been adequately explored? The objective of this study is to classify approaches to primary homology assessment, and to quantify the extent to which different approaches are found in the literature by examining variation in the way characters are defined and coded in a data matrix.

Cosmic effects on the intimate screen: J. B. Priestley, Ralph Richardson and 'Johnson over Jordan' (1965)

This article considers ideas about the suitability of experimental, non-naturalist, narrative forms in theatre and television, through the example of a 1965 BBC2 adaptation of J. B. Priestley's 1939 play Johnson over Jordan. Using both textual analysis of the programme and research into the BBC production documentation, this essay explains how the circumstances and conditions of 1960s television adaptation and the star casting of Sir Ralph Richardson transformed Priestley's stage play. The TV adaptation achieved cosmic effects on an intimate scale, through inference and the imaginative integration of the studio space with dubbed sound.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Further clarifying the competition–performance relation: reply to D. W. Johnson et al. (2012)

In their commentary, D. W. Johnson, Johnson, and Roseth (2012) provided some laudatory statements about our article, but they also expressed a number of concerns. The concerns focus on the following issues: types and definitions of competition, our choice of control group, the nature of performance-approach and performance-avoidance goals, the comprehensiveness of the opposing processes model, and performance-approach goals and constructive competition. We respond to each of these issues in turn and conclude with a statement regarding working to build an integrative model of the competition–performance relation (and beyond).

Johnson and Juvenal in John Ashbery's 'An Additional Poem' (1962)

A note on Ashbery's metaphorical and intertextual practice.