Frequent chromosomal translocations induced by DNA double-strand breaks

The faithful repair of DNA damage such as chromosomal double-strand breaks (DSBs) is crucial for genomic integrity. Aberrant repair of these lesions can result in chromosomal rearrangements, including translocations, which are associated with numerous tumours. Models predict that some translocations arise from DSB-induced recombination in differentiating lymphoid cell types or from aberrant repair of DNA damage induced by irradiation or other agents; however, a genetic system to study the aetiology of these events has been lacking. Here we use a mouse embryonic stem cell system to examine the role of DNA damage on the formation of translocations. We find that two DSBs, each on different chromosomes, are sufficient to promote frequent reciprocal translocations. The results are in striking contrast with interchromosomal repair of a single DSB in an analogous system in which translocations are not recovered. Thus, while interchromosomal DNA repair does not result in genome instability per se, the presence of two DSBs in a single cell can alter the spectrum of repair products that are recovered.     

Effects of a bovine pineal peptidic fraction (E5) on plasma and pituitary levels of LH,FSH and prolactin

Summary Pituitary levels of prolactin were significantly diminished after 5 s.c. injections spaced 12 h apart of 5 g of a partially purified bovine pineal peptide fraction (E₅) in both intact and castrated rats. E₅ treatment did not significantly affect the castration-induced changes in plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH) or pituitary LH but did partially block the pituitary fall in FSH in castrated animals.Supported by NSF grant PCM 8003441 and NIH Center for Reproductive Biology (Bioassay Core) No.P30 HD 10202. Many thanks are due A. Moreno for his excellent technical assistance.     

Rotational breakup as the origin of small binary asteroids

Asteroids with satellites are observed throughout the Solar System, from subkilometre near-Earth asteroid pairs to systems of large and distant bodies in the Kuiper belt. The smallest and closest systems are found among the near-Earth and small inner main-belt asteroids, which typically have rapidly rotating primaries and close secondaries on circular orbits. About 15 per cent of near-Earth and main-belt asteroids with diameters under 10 km have satellites. The mechanism that forms such similar binaries in these two dynamically different populations was hitherto unclear. Here we show that these binaries are created by the slow spinup of a 'rubble pile' asteroid by means of the thermal YORP (Yarkovsky-O'Keefe-Radzievskii-Paddack) effect. We find that mass shed from the equator of a critically spinning body accretes into a satellite if the material is collisionally dissipative and the primary maintains a low equatorial elongation. The satellite forms mostly from material originating near the primary's surface and enters into a close, low-eccentricity orbit. The properties of binaries produced by our model match those currently observed in the small near-Earth and main-belt asteroid populations, including 1999 KW(4) (refs 3, 4).     

Stereocilin-deficient mice reveal the origin of cochlear waveform distortions

Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions. These distortions reflect nonlinear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. Because both cochlear amplification and distortion originate from the outer hair cells-one of the two types of sensory receptor cells-it has been speculated that they stem from a common mechanism. Here we show that the nonlinearity underlying cochlear waveform distortions relies on the presence of stereocilin, a protein defective in a recessive form of human deafness. Stereocilin was detected in association with horizontal top connectors, lateral links that join adjacent stereocilia within the outer hair cell's hair bundle. These links were absent in stereocilin-null mutant mice, which became progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic nonlinear behaviour of the mechanoelectrical transducer channel.     

Net carbon dioxide losses of northern ecosystems in response to autumn warming

The carbon balance of terrestrial ecosystems is particularly sensitive to climatic changes in autumn and spring, with spring and autumn temperatures over northern latitudes having risen by about 1.1 degrees C and 0.8 degrees C, respectively, over the past two decades. A simultaneous greening trend has also been observed, characterized by a longer growing season and greater photosynthetic activity. These observations have led to speculation that spring and autumn warming could enhance carbon sequestration and extend the period of net carbon uptake in the future. Here we analyse interannual variations in atmospheric carbon dioxide concentration data and ecosystem carbon dioxide fluxes. We find that atmospheric records from the past 20 years show a trend towards an earlier autumn-to-winter carbon dioxide build-up, suggesting a shorter net carbon uptake period. This trend cannot be explained by changes in atmospheric transport alone and, together with the ecosystem flux data, suggest increasing carbon losses in autumn. We use a process-based terrestrial biosphere model and satellite vegetation greenness index observations to investigate further the observed seasonal response of northern ecosystems to autumnal warming. We find that both photosynthesis and respiration increase during autumn warming, but the increase in respiration is greater. In contrast, warming increases photosynthesis more than respiration in spring. Our simulations and observations indicate that northern terrestrial ecosystems may currently lose carbon dioxide in response to autumn warming, with a sensitivity of about 0.2 PgC degrees C(-1), offsetting 90% of the increased carbon dioxide uptake during spring. If future autumn warming occurs at a faster rate than in spring, the ability of northern ecosystems to sequester carbon may be diminished earlier than previously suggested.     

Yellow pine chipmunks cannot climb quaking aspens: implications for avian nest site selection

Predation of eggs or nestlings is generally believed to be the most influential factor limiting passerine reproductive success. Thus, there should be strong selective pressures for birds to place their nests in sites that are inaccessible to predators or that are less likely to be discovered by them. We found and monitored 231 nests of 4 species of arboreal, cup-nesting birds: Western Wood-Pewee ( Contopus sordidulus ), Warbling Vireo ( Vireo gilvus ), American Robin ( Turdus migratorius ), and Yellow-rumped Warbler ( Dendroica coronata ). We determined strength of nest tree species selection by comparing nest trees and tree species availability. Western Wood-Pewees and Warbling Vireos demonstrated strong preference for placing nests in quaking aspen ( Populus tremuloides ). Yellow-rumped Warblers showed a weak preference for aspen, and American Robins demonstrated no preference. We designed a series of experiments to determine whether yellow pine chipmunks ( Tamias amoenus ), an abundant nest predator, could climb aspen trees and, if so, what factors might prevent them from doing so. Yellow pine chipmunks were unable to climb aspen but showed no difficulty in climbing and maneuvering on lodgepole pine ( Pinus contorta ) boles, which were identical in diameter to aspen boles. Refuge from chipmunks as potential nest predators is likely contributing to nest site selection for a few arboreal cup-nesting bird species where aspen trees are available.     

The Left Vienna Circle, Part 2. The Left Vienna Circle, disciplinary history, and feminist philosophy of science

This paper analyzes the claim that the Left Vienna Circle (LVC) offers a theoretical and historical precedent for a politically engaged philosophy of science today. I describe the model for a political philosophy of science advanced by LVC historians. They offer this model as a moderate, properly philosophical approach to political philosophy of science that is rooted in the analytic tradition. This disciplinary-historical framing leads to weaknesses in LVC scholars’ conception of the history of the LVC and its contemporary relevance. In this light, I examine the claim that there are productive enrichments to be gained from the engagement of feminist philosophy of science with the LVC, finding this claim ill-formulated. The case of LVC historiography and feminist philosophy of science presents a revealing study in the uses and ethics of disciplinary history, showing how feminist and other perspectives are misconceived and marginalized by forms of disciplinary self-narrativizing.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.