Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction

CD8+ T cells have a crucial role in resistance to pathogens and can kill malignant cells; however, some critical functions of these lymphocytes depend on helper activity provided by a distinct population of CD4+ T cells. Cooperation between these lymphocyte subsets involves recognition of antigens co-presented by the same dendritic cell, but the frequencies of such antigen-bearing cells early in an infection and of the relevant naive T cells are both low. This suggests that an active mechanism facilitates the necessary cell-cell associations. Here we demonstrate that after immunization but before antigen recognition, naive CD8+ T cells in immunogen-draining lymph nodes upregulate the chemokine receptor CCR5, permitting these cells to be attracted to sites of antigen-specific dendritic cell-CD4+ T cell interaction where the cognate chemokines CCL3 and CCL4 (also known as MIP-1alpha and MIP-1beta) are produced. Interference with this actively guided recruitment markedly reduces the ability of CD4+ T cells to promote memory CD8+ T-cell generation, indicating that an orchestrated series of differentiation events drives nonrandom cell-cell interactions within lymph nodes, optimizing CD8+ T-cell immune responses involving the few antigen-specific precursors present in the naive repertoire.     

Parthenogenesis in Komodo dragons

Parthenogenesis, the production of offspring without fertilization by a male, is rare in vertebrate species, which usually reproduce after fusion of male and female gametes. Here we use genetic fingerprinting to identify parthenogenetic offspring produced by two female Komodo dragons (Varanus komodoensis) that had been kept at separate institutions and isolated from males; one of these females subsequently produced additional offspring sexually. This reproductive plasticity indicates that female Komodo dragons may switch between asexual and sexual reproduction, depending on the availability of a mate--a finding that has implications for the breeding of this threatened species in captivity. Most zoos keep only females, with males being moved between zoos for mating, but perhaps they should be kept together to avoid triggering parthenogenesis and thereby decreasing genetic diversity.     

Frequency-dependent survival in natural guppy populations

The maintenance of genetic variation in traits under natural selection is a long-standing paradox in evolutionary biology. Of the processes capable of maintaining variation, negative frequency-dependent selection (where rare types are favoured by selection) is the most powerful, at least in theory; however, few experimental studies have confirmed that this process operates in nature. One of the most extreme, unexplained genetic polymorphisms is seen in the colour patterns of male guppies (Poecilia reticulata). Here we manipulated the frequencies of males with different colour patterns in three natural populations to estimate survival rates, and found that rare phenotypes had a highly significant survival advantage compared to common phenotypes. Evidence from humans and other species implicates frequency-dependent survival in the maintenance of molecular, morphological and health-related polymorphisms. As a controlled manipulation in nature, this study provides unequivocal support for frequency-dependent survival--an evolutionary process capable of maintaining extreme polymorphism.     

Independent evolution of bitter-taste sensitivity in humans and chimpanzees

It was reported over 65 years ago that chimpanzees, like humans, vary in taste sensitivity to the bitter compound phenylthiocarbamide (PTC). This was suggested to be the result of a shared balanced polymorphism, defining the first, and now classic, example of the effects of balancing selection in great apes. In humans, variable PTC sensitivity is largely controlled by the segregation of two common alleles at the TAS2R38 locus, which encode receptor variants with different ligand affinities. Here we show that PTC taste sensitivity in chimpanzees is also controlled by two common alleles of TAS2R38; however, neither of these alleles is shared with humans. Instead, a mutation of the initiation codon results in the use of an alternative downstream start codon and production of a truncated receptor variant that fails to respond to PTC in vitro. Association testing of PTC sensitivity in a cohort of captive chimpanzees confirmed that chimpanzee TAS2R38 genotype accurately predicts taster status in vivo. Therefore, although Fisher et al.'s observations were accurate, their explanation was wrong. Humans and chimpanzees share variable taste sensitivity to bitter compounds mediated by PTC receptor variants, but the molecular basis of this variation has arisen twice, independently, in the two species.     

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.     

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.     

Validating cancer drug targets

A cancer drug target is only truly validated by demonstrating that a given therapeutic agent is clinically effective and acts through the target against which it was designed. Nevertheless, it is desirable to declare an early-stage drug target as 'validated' before investing in a full-scale drug discovery programme dedicated to it. Although the outcome of validation studies can guide cancer research programmes, strictly defined universal validation criteria have not been established.     

The trans-neptunian object UB313 is larger than Pluto

The most distant known object in the Solar System, 2003 UB313 (97 au from the Sun), was recently discovered near its aphelion. Its high eccentricity and inclination to the ecliptic plane, along with its perihelion near the orbit of Neptune, identify it as a member of the 'scattered disk'. This disk of bodies probably originates in the Kuiper belt objects, which orbit near the ecliptic plane in circular orbits between 30 and 50 au, and may include Pluto as a member. The optical brightness of 2003 UB313, if adjusted to Pluto's distance, is greater than that of Pluto, which suggested that it might be larger than Pluto. The actual size, however, could not be determined from the optical measurements because the surface reflectivity (albedo) was unknown. Here we report observations of the thermal emission of 2003 UB313 at a wavelength of 1.2 mm, which in combination with the measured optical brightness leads to a diameter of 3,000 +/- 300 +/- 100 km. Here the first error reflects measurement uncertainties, while the second derives from the unknown object orientation. This makes 2003 UB313 the largest known trans-neptunian object, even larger than Pluto (2,300 km). The albedo is 0.60 +/- 0.10 +/- 0.05, which is strikingly similar to that of Pluto, suggesting that the methane seen in the optical spectrum causes a highly reflective icy surface.