Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

The Making of Modern Science: Science,Technology, Medicine and Modernity: 1789–1914

We offer a novel historical-philosophical framework for discussing experimental practice which we call ‘Generating Experimental Knowledge’. It combines three different perspectives: experimental systems, concept formation, and the pivotal role of error. We then present an historical account of the invention of the Scanning Tunnelling Microscope (STM), or Raster-Tunnelmikroskop, and interpret it within the proposed framework. We show that at the outset of the STM project, Binnig and Rohrer—the inventors of the machine—filed two patent disclosures; the first is dated 22 December 1978 (Switzerland), and the second, two years later, 12 September 1980 (US). By studying closely these patent disclosures, the attempts to realize them, and the subsequent development of the machine, we present, within the framework of generating experimental knowledge, a new account of the invention of the STM. While the realization of the STM was still a long way off, the patent disclosures served as blueprints, marking the changes that had to be introduced on the way from the initial idea to its realization.     

Pierre Duhem’s epistemic aims and the intellectual virtue of humility: a reply to Ivanova

David Stump (2007) has recently argued that Pierre Duhem can be interpreted as a virtue epistemologist. Stump’s claims have been challenged by Milena Ivanova (2010) on the grounds that Duhem’s ‘epistemic aims’ are more modest than those of virtue epistemologists. I challenge Ivanova’s criticism of Stump by arguing that she not distinguish between ‘reliabilist’ and ‘responsibilist’ virtue epistemologies. Once this distinction is drawn, Duhem clearly emerges as a ‘virtue-responsibilist’ in a way that complements Ivanova’s positive proposal that Duhem’s ‘good sense’ reflects a conception of the ‘ideal scientist’. I support my proposal that Duhem is a ‘virtue-responsibilist’ by arguing that his rejection of the possibility of our producing a ‘perfect theory’ reflects the key responsibilist virtue of ‘intellectual humility’.     

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.     

Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.     

Testing testimony: toxicology and the law of evidence in early nineteenth-century England

Examines how, when confronted with a case of possible criminal poisoning, early-19th-century English toxicologists sought to generate and to represent their evidence in the courtroom. Contends that in both these activities, toxicologists were inextricably engaged in a complex communicative exercise. On the one hand, they distanced themselves from the instabilities of language, styling themselves as testifiers to fact alone. At the same time, they saw themselves as deeply implicated in the difficulties of forging a coherent signifying system out of a disparate collection of signs that in themselves bore no intrinsic meaning. The article suggests first, why criminal poisoning featured so prominently in the burgeoning legal literature on evidence, which provided the framework for expert testimony in English courts; next, that the scientific evidence offered by toxicologists in poisoning cases can be usefully understood as a form of (unstable) language; and finally, that this recourse to signs informed the toxicologist's encounter with another type of courtroom expert - the legal advocate - who was equally (though differently) interested in manipulating signs in order to construct (and deconstruct) legally sanctioned proof.     

The role of stomata in sensing and driving environmental change

Stomata, the small pores on the surfaces of leaves and stalks, regulate the flow of gases in and out of leaves and thus plants as a whole. They adapt to local and global changes on all timescales from minutes to millennia. Recent data from diverse fields are establishing their central importance to plant physiology, evolution and global ecology. Stomatal morphology, distribution and behaviour respond to a spectrum of signals, from intracellular signalling to global climatic change. Such concerted adaptation results from a web of control systems, reminiscent of a 'scale-free' network, whose untangling requires integrated approaches beyond those currently used.