Gene expression profiling predicts clinical outcome of breast cancer

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.     

Palaeotemperature reconstruction from noble gases in ground water taking into account equilibration with entrapped air

Noble-gas concentrations in ground water have been used as a proxy for past air temperatures, but the accuracy of this approach has been limited by the existence of a temperature-independent component of the noble gases in ground water, termed 'excess air' whose origin and composition is poorly understood. In particular, the evidence from noble gases in a Brazilian aquifer for a cooling of more than 5 C in tropical America during the Last Glacial Maximum has been called into question. Here we propose a model for dissolved gases in ground water, which describes the formation of excess air by equilibration of ground water with entrapped air in quasi-saturated soils. Our model predicts previously unexplained noble-gas data sets, including the concentration of atmospheric helium, and yields consistent results for the non-atmospheric helium isotopes that are used for dating ground water. Using this model of excess air, we re-evaluate the use of noble gases from ground water for reconstructing past temperatures. Our results corroborate the inferred cooling in Brazil during the Last Glacial Maximum, and indicate that even larger cooling took place at mid-latitudes.     

TRAPPI tethers COPII vesicles by binding the coat subunit Sec23

The budding of endoplasmic reticulum (ER)-derived vesicles is dependent on the COPII coat complex. Coat assembly is initiated when Sar1-GTP recruits the cargo adaptor complex, Sec23/Sec24, by binding to its GTPase-activating protein (GAP) Sec23 (ref. 2). This leads to the capture of transmembrane cargo by Sec24 (refs 3, 4) before the coat is polymerized by the Sec13/Sec31 complex. The initial interaction of a vesicle with its target membrane is mediated by tethers. We report here that in yeast and mammalian cells the tethering complex TRAPPI (ref. 7) binds to the coat subunit Sec23. This event requires the Bet3 subunit. In vitro studies demonstrate that the interaction between Sec23 and Bet3 targets TRAPPI to COPII vesicles to mediate vesicle tethering. We propose that the binding of TRAPPI to Sec23 marks a coated vesicle for fusion with another COPII vesicle or the Golgi apparatus. An implication of these findings is that the intracellular destination of a transport vesicle may be determined in part by its coat and its associated cargo.     

On What Ontology is and Not-is

In this paper I investigate the relation between physics and metaphysics in Plato’s participation theory. I show that the logic shoring up Plato’s metaphysics in paraconsistent, as had been suggested already by Graham Priest. The transformation of the paradoxical One-and-Many of the pre-Socratics into a paraconsistent Great-and-Small bridges the abyss between archaic rationality and the world of classical logic based ultimately on the principle of contradiction. Indeed, language is an organ of perception, not simply a means of communication. J. Jaynes, Origin of Consciousness