Genetic clonal diversity predicts progression to esophageal adenocarcinoma

Neoplasms are thought to progress to cancer through genetic instability generating cellular diversity and clonal expansions driven by selection for mutations in cancer genes. Despite advances in the study of molecular biology of cancer genes, relatively little is known about evolutionary mechanisms that drive neoplastic progression. It is unknown, for example, which may be more predictive of future progression of a neoplasm: genetic homogenization of the neoplasm, possibly caused by a clonal expansion, or the accumulation of clonal diversity. Here, in a prospective study, we show that clonal diversity measures adapted from ecology and evolution can predict progression to adenocarcinoma in the premalignant condition known as Barrett's esophagus, even when controlling for established genetic risk factors, including lesions in TP53 (p53; ref. 6) and ploidy abnormalities. Progression to cancer through accumulation of clonal diversity, on which natural selection acts, may be a fundamental principle of neoplasia with important clinical implications.     

Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B

Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0-D1-D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an 'innate HLA sensor' domain. Second, whereas the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.     

Plankton effect on cod recruitment in the North Sea

The Atlantic cod (Gadus morhua L.) has been overexploited in the North Sea since the late 1960s and great concern has been expressed about the decline in cod biomass and recruitment. Here we show that, in addition to the effects of overfishing, fluctuations in plankton have resulted in long-term changes in cod recruitment in the North Sea (bottom-up control). Survival of larval cod is shown to depend on three key biological parameters of their prey: the mean size of prey, seasonal timing and abundance. We suggest a mechanism, involving the match/mismatch hypothesis, by which variability in temperature affects larval cod survival and conclude that rising temperature since the mid-1980s has modified the plankton ecosystem in a way that reduces the survival of young cod.     

Anthropology: the earliest toothless hominin skull

The site of Dmanisi in the Eurasian republic of Georgia has yielded striking hominin, faunal and archaeological material as evidence for the presence of early Homo outside Africa 1.77 million years ago, documenting an important episode in human evolution. Here we describe a beautifully preserved skull and jawbone from a Dmanisi hominin of this period who had lost all but one tooth several years before death. This specimen not only represents the earliest case of severe masticatory impairment in the hominin fossil record to be discovered so far, but also raises questions about alternative subsistence strategies in early Homo.     

Network anatomy and in vivo physiology of visual cortical neurons

In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.     

Volatile content of lunar volcanic glasses and the presence of water in the Moon's interior

The Moon is generally thought to have formed and evolved through a single or a series of catastrophic heating events, during which most of the highly volatile elements were lost. Hydrogen, being the lightest element, is believed to have been completely lost during this period. Here we make use of considerable advances in secondary ion mass spectrometry to obtain improved limits on the indigenous volatile (CO(2), H(2)O, F, S and Cl) contents of the most primitive basalts in the Moon-the lunar volcanic glasses. Although the pre-eruptive water content of the lunar volcanic glasses cannot be precisely constrained, numerical modelling of diffusive degassing of the very-low-Ti glasses provides a best estimate of 745 p.p.m. water, with a minimum of 260 p.p.m. at the 95 per cent confidence level. Our results indicate that, contrary to prevailing ideas, the bulk Moon might not be entirely depleted in highly volatile elements, including water. Thus, the presence of water must be considered in models constraining the Moon's formation and its thermal and chemical evolution.     

Highly ordered arrangement of single neurons in orientation pinwheels

In the visual cortex of higher mammals, neurons are arranged across the cortical surface in an orderly map of preferred stimulus orientations. This map contains 'orientation pinwheels', structures that are arranged like the spokes of a wheel such that orientation changes continuously around a centre. Conventional optical imaging first demonstrated these pinwheels, but the technique lacked the spatial resolution to determine the response properties and arrangement of cells near pinwheel centres. Electrophysiological recordings later demonstrated sharply selective neurons near pinwheel centres, but it remained unclear whether they were arranged randomly or in an orderly fashion. Here we use two-photon calcium imaging in vivo to determine the microstructure of pinwheel centres in cat visual cortex with single-cell resolution. We find that pinwheel centres are highly ordered: neurons selective to different orientations are clearly segregated even in the very centre. Thus, pinwheel centres truly represent singularities in the cortical map. This highly ordered arrangement at the level of single cells suggests great precision in the development of cortical circuits underlying orientation selectivity.     

Spatial structure of cone inputs to receptive fields in primate lateral geniculate nucleus.

Human colour vision depends on three classes of cone photoreceptors, those sensitive to short (S), medium (M) or long (L) wavelengths, and on how signals from these cones are combined by neurons in the retina and brain. Macaque monkey colour vision is similar to human, and the receptive fields of macaque visual neurons have been used as an animal model of human colour processing. P retinal ganglion cells and parvocellular neurons are colour-selective neurons in macaque retina and lateral geniculate nucleus. Interactions between cone signals feeding into these neurons are still unclear. On the basis of experimental results with chromatic adaptation, excitatory and inhibitory inputs from L and M cones onto P cells (and parvocellular neurons) were thought to be quite specific (Fig. 1a). But these experiments with spatially diffuse adaptation did not rule out the 'mixed-surround' hypothesis: that there might be one cone-specific mechanism, the receptive field centre, and a surround mechanism connected to all cone types indiscriminately (Fig. 1e). Recent work has tended to support the mixed-surround hypothesis. We report here the development of new stimuli to measure spatial maps of the linear L-, M- and S-cone inputs to test the hypothesis definitively. Our measurements contradict the mixed-surround hypothesis and imply cone specificity in both centre and surround.     

Parallel evolution of virulence in pathogenic Escherichia coli

The mechanisms underlying the evolution and emergence of new bacterial pathogens are not well understood. To elucidate the evolution of pathogenic Escherichia coli strains, here we sequenced seven housekeeping genes to build a phylogenetic tree and trace the history of the acquisition of virulence genes. Compatibility analysis indicates that more than 70% of the informative sites agree with a single phylogeny, suggesting that recombination has not completely obscured the remnants of ancestral chromosomes. On the basis of the rate of synonymous substitution for E. coli and Salmonella enterica (4.7 x 10(-9) per site per year), the radiation of clones began about 9 million years ago and the highly virulent pathogen responsible for epidemics of food poisoning, E. coli O157:H7, separated from a common ancestor of E. coli K-12 as long as 4.5 million years ago. Phylogenetic analysis reveals that old lineages of E. coli have acquired the same virulence factors in parallel, including a pathogenicity island involved in intestinal adhesion, a plasmid-borne haemolysin, and phage-encoded Shiga toxins. Such parallel evolution indicates that natural selection has favoured an ordered acquisition of genes and the progressive build-up of molecular mechanisms that increase virulence.