The landscape of cancer genes and mutational processes in breast cancer

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.     

Self-organizing neural network that discovers surfaces in random-dot stereograms.

The standard form of back-propagation learning is implausible as a model of perceptual learning because it requires an external teacher to specify the desired output of the network. We show how the external teacher can be replaced by internally derived teaching signals. These signals are generated by using the assumption that different parts of the perceptual input have common causes in the external world. Small modules that look at separate but related parts of the perceptual input discover these common causes by striving to produce outputs that agree with each other. The modules may look at different modalities (such as vision and touch), or the same modality at different times (for example, the consecutive two-dimensional views of a rotating three-dimensional object), or even spatially adjacent parts of the same image. Our simulations show that when our learning procedure is applied to adjacent patches of two-dimensional images, it allows a neural network that has no prior knowledge of the third dimension to discovery depth in random dot stereograms of curved surfaces.     

Discovery of very-high-energy gamma-rays from the Galactic Centre ridge

The source of Galactic cosmic rays (with energies up to 10(15) eV) remains unclear, although it is widely believed that they originate in the shock waves of expanding supernova remnants. At present the best way to investigate their acceleration and propagation is by observing the gamma-rays produced when cosmic rays interact with interstellar gas. Here we report observations of an extended region of very-high-energy (> 10(11) eV) gamma-ray emission correlated spatially with a complex of giant molecular clouds in the central 200 parsecs of the Milky Way. The hardness of the gamma-ray spectrum and the conditions in those molecular clouds indicate that the cosmic rays giving rise to the gamma-rays are likely to be protons and nuclei rather than electrons. The energy associated with the cosmic rays could have come from a single supernova explosion around 10(4) years ago.     

Patterns of somatic mutation in human cancer genomes

Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.     

Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain.

The levels of a specific mitochondrial DNA deletion (mtDNA4977) measured in 12 brain regions of 6 normal adults 39 to 82 years old exhibited striking variation among anatomical locations. Comparisons of the same region among individuals showed an increase of mtDNA4977 with age. The three regions with the highest levels, caudate, putamen and substantia nigra, are characterized by a high dopamine metabolism. The breakdown of dopamine by mitochondrial MAO produces H2O2 which can lead to oxygen radical formation. We suggest that mtDNA4977 may be the "tip of the iceberg" of the spectrum of somatic mutations produced by oxidative damage.     

A low level of extragalactic background light as revealed by gamma-rays from blazars

The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the 'first stars', which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light. An alternative approach is to study the absorption features imprinted on the gamma-ray spectra of distant extragalactic objects by interactions of those photons with the background light photons. Here we report the discovery of gamma-ray emission from the blazars H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources-in particular from the first stars formed. This result also indicates that intergalactic space is more transparent to gamma-rays than previously thought.     

A simple device for measuring nanolitre volumes of fluid

Summary A piece of apparatus designed to measure nl-volumes of fluid has been constructed to fit onto a Leitz micromanipulator so that the small sample volumes can easily be transferred.This investigation received the financial support from the World Health Organisation.     

Diet influences the colonisation of Campylobacter jejuni and distribution of mucin carbohydrates in the chick intestinal tract

The objectives of this study were to evaluate the effect of diet on the colonisation by Campylobacter jejuni of the chick caeca, and to determine whether the viscosity of the intestinal contents and mucin carbohydrates were altered by the diet. The diets investigated were maize based, wheat-based or wheat-based supplemented with xylanase. The xylanase-supplemented diet reduced the viscosity and lowered the numbers of Camp. jejuni. Feeding the enzyme-supplemented diet increased the amount of neutral and sulphated mucins in the goblet cells of the small and large intestines and caecum. An abundance of sulphated and carboxylated mucins was seen in the surface goblet cells of the large intestine with the maize- and wheat-based diets. Both the diet supplemented with xylanase and the maize diets increased crypt-surface glycosylation of the sialic acid residues. The analysed data from the combined sites showed significant differences in the amount of neutral and acidic mucins when comparing the wheat and the wheat plus xylanase diets. However, no changes were shown in the staining intensity of sulphated mucins between the three diets. Significant differences in the glycosylation of sialic acid and in the N-acetylglucosamine residues were shown between dietary groups. These results provide evidence that the wheat diet supplemented with xylanase leads to greater changes in the mucin composition and carbohydrate expression of goblet cell glycoconjugates, which are associated with a reduction in intestinal viscosity and decreased numbers of Camp. jejuni.