A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.     

A possible nitrogen crisis for Archaean life due to reduced nitrogen fixation by lightning.

Nitrogen is an essential element for life and is often the limiting nutrient for terrestrial ecosystems. As most nitrogen is locked in the kinetically stable form, N2, in the Earth's atmosphere, processes that can fix N2 into biologically available forms-such as nitrate and ammonia-control the supply of nitrogen for organisms. On the early Earth, nitrogen is thought to have been fixed abiotically, as nitric oxide formed during lightning discharge. The advent of biological nitrogen fixation suggests that at some point the demand for fixed nitrogen exceeded the supply from abiotic sources, but the timing and causes of the onset of biological nitrogen fixation remain unclear. Here we report an experimental simulation of nitrogen fixation by lightning over a range of Hadean (4.5-3.8 Gyr ago) and Archaean (3.8-2.5 Gyr ago) atmospheric compositions, from predominantly carbon dioxide to predominantly dinitrogen (but always without oxygen). We infer that, as atmospheric CO2 decreased over the Archaean period, the production of nitric oxide from lightning discharge decreased by two orders of magnitude until about 2.2 Gyr. After this time, the rise in oxygen (or methane) concentrations probably initiated other abiotic sources of nitrogen. Although the temporary reduction in nitric oxide production may have lasted for only 100 Myr or less, this was potentially long enough to cause an ecological crisis that triggered the development of biological nitrogen fixation.     

Book Review: Accountability in Social Research: Issues and Debates,Norma R.A. Romm,Kluwer Academic/Plenum Publishers,New York, 2001, 326 pp. $45, £31.50 (cloth), ISBN: 0-306-46564-7

Systemic Practice and Action Research -     

Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor

Nerve growth factor plays an important part in neuron-target interactions in the late embryonic and adult brain. We now report that this growth factor controls the proliferation of neuronal precursors in a defined culture system of cells derived from the early embryonic brain. Neuronal precursor cells were identified by expression of the intermediate filament protein nestin. These cells proliferate in response to nerve growth factor but only after they have been exposed to basic fibroblast growth factor. On withdrawal of nerve growth factor, the proliferative cells differentiate into neurons. Thus, in combination with other growth factors, nerve growth factor regulates the proliferation and terminal differentiation of neuroepithelial stem cells.     

A wind origin for Titan's haze structure

Titan, the largest moon of Saturn, is the only satellite in the Solar System with a dense atmosphere. Titan's atmosphere is mainly nitrogen with a surface pressure of 1.5 atmospheres and a temperature of 95 K (ref. 1). A seasonally varying haze, which appears to be the main source of heating and cooling that drives atmospheric circulation, shrouds the moon. The haze has numerous features that have remained unexplained. There are several layers, including a 'polar hood', and a pronounced hemispheric asymmetry. The upper atmosphere rotates much faster than the surface of the moon, and there is a significant latitudinal temperature asymmetry at the equinoxes. Here we describe a numerical simulation of Titan's atmosphere, which appears to explain the observed features of the haze. The critical new factor in our model is the coupling of haze formation with atmospheric dynamics, which includes a component of strong positive feedback between the haze and the winds.     

Through the Eye of a Fly: Action Research as a Support for the South African National Literacy Campaign

Globally and across the African continent, the past decade has seen an increase in the commitment to reducing adult illiteracy, inspired among other things by the Education for All (EFA) drive to halve the incidence of illiteracy among adults and youth by 2015. While literacy campaigns were less common during the 1990s, the last decade saw a new impetus for mass adult literacy campaigns as a way of improving national literacy levels. This paper examines the South African endeavour to meet its EFA target through the implementation of the South African Kha Ri Gude Mass Literacy Campaign, which was launched by the South African government in 2008 with the aim of enliterating 4,7 million adults who had little or no education as a result of the apartheid legacy. The Campaign was deemed successful receiving a number of South African awards for best practice and its work in rural and impoverished communities including the international UNESCO Confucius Prize for Literacy (UNESCO 2016). This article focuses on how the campaign utilised action-oriented processes, specifically the methods of participatory action research (PAR), to enhance the achievement of its goals. The methods of PAR were embedded in the campaign structure, comprising clusters of communities of practice (COPs) which provided fora for educators to voice and address challenges. Moreover, since the Campaign was implemented in post-apartheid South Africa, the article shows how the Campaign operations were guided by the ethos of ubuntu as necessary for redress and empowerment.     

Casein kinase I transduces Wnt signals.

The Wnt signalling cascade is essential for the development of both invertebrates and vertebrates, and is altered during tumorigenesis. Although a general framework for Wnt signalling has been elucidated, not all of the components have been identified. Here we describe a serine kinase, casein kinase I (CKI), which was isolated by expression cloning in Xenopus embryos. CKI reproduces several properties of Wnt signals, including generation of complete dorsal axes, stabilization of beta-catenin and induction of genes that are direct targets of Wnt signals. Dominant-negative forms of CKI and a pharmacological blocker of CKI inhibited Wnt signals in Xenopus. Inhibiting CKI in Caenorhabditis elegans generated worms with a mom phenotype, indicative of a loss of Wnt signals. In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway. These data indicate that CKI may be a conserved component of the Wnt pathway.     

Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.     

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.