Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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A Certain Family Of Mixed Summation-Integral Type Operators

In the present paper, we study the mixed summation integral type operators having different weight functions, we obtain the rate of point wise convergence, an asymptotic formula of Voronovskaja type and some local direct results in terms of modulus of smoothness and modulus of continuity in ordinary and simultaneous approximation. © 2005 Elsevier Ltd. All rights reserved

The Epistemic Goal of a Concept: Accounting for the Rationality of Semantic Change and Variation

The discussion presents a framework of concepts that is intended to account for the rationality of semantic change and variation, suggesting that each scientific concept consists of three components of content: 1) reference, 2) inferential role, and 3) the epistemic goal pursued with the concept’s use. I argue that in the course of history a concept can change in any of these components, and that change in the concept’s inferential role and reference can be accounted for as being rational relative to the third component, the concept’s epistemic goal. This framework is illustrated and defended by application to the history of the gene concept. It is explained how the molecular gene concept grew rationally out of the classical gene concept despite a change in reference, and why the use and reference of the contemporary molecular gene concept may legitimately vary from context to context

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Skp1-Cul1-F-box protein) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumour suppressor by maintaining the Gli (Glioma-associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumour growth are unknown. Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with impaired cancer cell proliferation and medulloblastoma tumour growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, that increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight perturbation of the Fbxl17-Sufu axis in the pathogenesis of medulloblastoma.</p