Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.     

Telomere-telomere recombination provides an express pathway for telomere acquisition

DNA termini from Tetrahymena and Oxytricha, which bear C4A2 and C4A4 repeats respectively, can support telomere formation in Saccharomyces cerevisiae by serving as substrates for the addition of yeast telomeric C1-3A repeats. Previously, we showed that linear plasmids with 108 base pairs of C4A4 DNA (YLp108CA) efficiently acquired telomeres, whereas plasmids containing 28-64 base pairs of C4A4 DNA also promoted telomere formation, but with reduced efficiency. Although many of the C4A4 termini on these plasmids underwent recombination with a C4A2 terminus, the mechanism of telomere-telomere recombination was not established. We now report the sequence of the C4A4 ends from the linear plasmids. The results provide strong evidence for a novel recombination process involving a gene conversion event that requires little homology, occurs at or near the boundary of telomeric and nontelomeric DNA, and resembles the recombination process involved in bacteriophage T4 DNA replication.     

Tamoxifen ‘sex reverses’ alligator embryos at male producing temperature,but is an antiestrogen in female hatchlings

Summary Tamoxifen is an anticancer drug widely used in the treatment of estrogen-dependent breast cancer. In hatchling alligators it acts as a pure antiestrogen in that it completely blocks the effect of estradiol-induced oviductal hypertrophy and completely blocks the estradiol-induced hepatic vitellogenin secretion. Paradoxically, when injected into alligator eggs incubated at 33°C, a temperature which would normally result in 100% male hatchlings, tamoxifen sex reverses the embryos into apparently normal female hatchlings.     

Magnetic carbon

The discovery of nanostructured forms of molecular carbon has led to renewed interest in the varied properties of this element. Both graphite and C60 can be electron-doped by alkali metals to become superconducting; transition temperatures of up to 52 K have been attained by field-induced hole-doping of C60 (ref. 2). Recent experiments and theoretical studies have suggested that electronic instabilities in pure graphite may give rise to superconducting and ferromagnetic properties, even at room temperature. Here we report the serendipitous discovery of strong magnetic signals in rhombohedral C60. Our intention was to search for superconductivity in polymerized C60; however, it appears that our high-pressure, high-temperature polymerization process results in a magnetically ordered state. The material exhibits features typical of ferromagnets: saturation magnetization, large hysteresis and attachment to a magnet at room temperature. The temperature dependences of the saturation and remanent magnetization indicate a Curie temperature near 500 K.     

Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.     

Morphology of tube-like threads related to Limnochares aquatica (L., 1758) (Acariformes: Hydrachnidia: Limnocharidae) in the laboratory

Water mites Limnochares aquatica (L., 1758) during maintenance in the laboratory for a long period of time in constant conditions periodically produced certain whitish flocculent material consisting of long rigid unbranched tube-like threads 1.3 ± 0.3 µm in diameter crossing freely. These threads were studied using light-optical as well as transmission electron microscopical and scanning electron microscopical methods. Microbiological staining was also applied to the threads to exclude their bacterial or fungal origin. The thread wall is built of fine fibrils arranged at different angles to the long axis of threads that is reflected in a certain stratification of the wall. Threads are mostly hollow or may contain electron-dense homogeneous material. No cell components are present in the thread composition. Numerous dermal glands with their small slit-like orifice scattered throughout the mite body surface are thought to produce these threads. Most probably the thread formation is a reaction of mites to stress under laboratory conditions, and this is expected to be a type of defensive reaction.     

Diminished in vitro tyrosine kinase activity of the EGF receptor of senescent human fibroblasts

Fibroblastic cultures derived from normal human tissues undergo a finite number of population doublings when serially subcultivated in vitro (see refs 1, 2 for reviews). Epidermal growth factor (EGF) serves as a mitogen for early doubling level cultures of the human fetal lung-derived cell strain, WI-38, under serum-free conditions. The ability of cells from late doubling level cultures to respond mitogenically to EGF is lost, however, despite undiminished binding of EGF throughout the replicative lifespan. The ultimate effects of EGF, that is DNA synthesis and mitosis (see ref. 4 for review), occur after a sequence of events initiated by binding of ligand to specific cellular receptors. The receptor for EGF has been characterized as a 145,000-165,000 (145 K-165 K) molecular weight doublet, and, like the receptors for platelet-derived growth factor and insulin, and the transforming proteins of certain of the RNA tumour viruses, is a tyrosine-specific protein kinase with autophosphorylating activity. Moreover, several of the cellular target molecules of tyrosine phosphorylation have been found to be substrates for two or more of these kinases. The hypothesis that tyrosine phosphorylation underlies a common mechanism of growth control prompted us to ask whether the loss of responsiveness to EGF by late doubling level WI-38 cells is accompanied by altered expression of the EGF receptor, and specifically whether changes occur in the ability of receptors from populations of cells of various in vitro ages to catalyse tyrosine autophosphorylation. We show here that autophosphorylating activity is absent from the EGF receptor of cells which have lost their mitogenic responsiveness to EGF.