Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.     

A Burgessian Critique of Nominalistic Tendencies in Contemporary Mathematics and its Historiography

We analyze the developments in mathematical rigor from the viewpoint of a Burgessian critique of nominalistic reconstructions. We apply such a critique to the reconstruction of infinitesimal analysis accomplished through the efforts of Cantor, Dedekind, and Weierstrass; to the reconstruction of Cauchy’s foundational work associated with the work of Boyer and Grabiner; and to Bishop’s constructivist reconstruction of classical analysis. We examine the effects of a nominalist disposition on historiography, teaching, and research.     

Das Eindringen des Vektorkalküls in die Differentialgeometrie

Zusammenfassung Die ersten Versuche, die Differentialgeometrie mittels Vektoren bzw. Quaternionen darzustellen, erzielten kaum irgendeine Resonanz. Die Autoren der klassischen Differentialgeometrie-Lehrbücher, Bianchi und Darboux machten keinen Gebrauch von Vektoren, ihrem Beispiel folgten die übrigen Lehrbuchautoren. Erst unter dem Eindruck von Einsteins allgemeiner Relativitätstheorie begann sich die Situation zu verändern, indem die Zusammenhänge zwischen Vektorkalkül und Tensorkalkül deutlich wurden. Die jüngere Generation von Differentialgeometern, allen voran Blaschke und Struik, verwenden in ihren Lehrbüchern die vektorielle Darstellungsweise als ein geradezu selbstverständliches Hilfsmittel. Vorgelegt von C. Truesdell     

Genomic alterations in cultured human embryonic stem cells

Cultured human embryonic stem cell (hESC) lines are an invaluable resource because they provide a uniform and stable genetic system for functional analyses and therapeutic applications. Nevertheless, these dividing cells, like other cells, probably undergo spontaneous mutation at a rate of 10(-9) per nucleotide. Because each mutant has only a few progeny, the overall biological properties of the cell culture are not altered unless a mutation provides a survival or growth advantage. Clonal evolution that leads to emergence of a dominant mutant genotype may potentially affect cellular phenotype as well. We assessed the genomic fidelity of paired early- and late-passage hESC lines in the course of tissue culture. Relative to early-passage lines, eight of nine late-passage hESC lines had one or more genomic alterations commonly observed in human cancers, including aberrations in copy number (45%), mitochondrial DNA sequence (22%) and gene promoter methylation (90%), although the latter was essentially restricted to 2 of 14 promoters examined. The observation that hESC lines maintained in vitro develop genetic and epigenetic alterations implies that periodic monitoring of these lines will be required before they are used in in vivo applications and that some late-passage hESC lines may be unusable for therapeutic purposes.     

Atomic model of the type III secretion system needle

Pathogenic bacteria using a type III secretion system (T3SS) to manipulate host cells cause many different infections including Shigella dysentery, typhoid fever, enterohaemorrhagic colitis and bubonic plague. An essential part of the T3SS is a hollow needle-like protein filament through which effector proteins are injected into eukaryotic host cells. Currently, the three-dimensional structure of the needle is unknown because it is not amenable to X-ray crystallography and solution NMR, as a result of its inherent non-crystallinity and insolubility. Cryo-electron microscopy combined with crystal or solution NMR subunit structures has recently provided a powerful hybrid approach for studying supramolecular assemblies, resulting in low-resolution and medium-resolution models. However, such approaches cannot deliver atomic details, especially of the crucial subunit-subunit interfaces, because of the limited cryo-electron microscopic resolution obtained in these studies. Here we report an alternative approach combining recombinant wild-type needle production, solid-state NMR, electron microscopy and Rosetta modelling to reveal the supramolecular interfaces and ultimately the complete atomic structure of the Salmonella typhimurium T3SS needle. We show that the 80-residue subunits form a right-handed helical assembly with roughly 11 subunits per two turns, similar to that of the flagellar filament of S. typhimurium. In contrast to established models of the needle in which the amino terminus of the protein subunit was assumed to be α-helical and positioned inside the needle, our model reveals an extended amino-terminal domain that is positioned on the surface of the needle, while the highly conserved carboxy terminus points towards the lumen.     

Controlling the dynamics of spontaneous emission from quantum dots by photonic crystals

Control of spontaneously emitted light lies at the heart of quantum optics. It is essential for diverse applications ranging from miniature lasers and light-emitting diodes, to single-photon sources for quantum information, and to solar energy harvesting. To explore such new quantum optics applications, a suitably tailored dielectric environment is required in which the vacuum fluctuations that control spontaneous emission can be manipulated. Photonic crystals provide such an environment: they strongly modify the vacuum fluctuations, causing the decay of emitted light to be accelerated or slowed down, to reveal unusual statistics, or to be completely inhibited in the ideal case of a photonic bandgap. Here we study spontaneous emission from semiconductor quantum dots embedded in inverse opal photonic crystals. We show that the spectral distribution and time-dependent decay of light emitted from excitons confined in the quantum dots are controlled by the host photonic crystal. Modified emission is observed over large frequency bandwidths of 10%, orders of magnitude larger than reported for resonant optical microcavities. Both inhibited and enhanced decay rates are observed depending on the optical emission frequency, and they are controlled by the crystals' lattice parameter. Our experimental results provide a basis for all-solid-state dynamic control of optical quantum systems.     

Gene therapy: is IL2RG oncogenic in T-cell development?

The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2.     

Metallothionein gene cluster is split by chromosome 16 rearrangements in myelomonocytic leukaemia

The metallothioneins (MTs) are a family of proteins of low relative molecular mass which bind heavy-metal ions. MTs exist in several molecular forms (MT-I, MT-II) and are encoded by a multi-gene family containing at least 14 closely related genes and pseudogenes. These proteins function in the regulation of trace-metal metabolism, the storage of these ions in the liver, and as a protective mechanism against heavy-metal toxicity. Somatic cell hybridization has shown that most MT genes, including the functional MT genes (MT1A, MT1B, MT2A), lie on human chromosome 16. Using in situ hybridization, we have now localized the MT genes to band q22 of chromosome 16. This chromosomal band is also a breakpoint in two specific rearrangements, the inv(16)(p13q22) and t(16; 16)(p13;q22) rearrangements, found in a subgroup of patients with acute myelomonocytic leukaemia (AMML). Hybridization of a MT probe to malignant cells from two patients with an inv(16) showed labelled sites on both arms of the inverted chromosome, indicating that the breakpoint at 16q22 splits the MT gene cluster. Similar results were obtained when this probe was hybridized to metaphase cells from two patients with a t(16; 16). These results suggest that the MT genes or their regulatory regions may function as an 'activating' sequence for an as yet unidentified cellular gene located at 16p13.