Supernova explosions are one of the most energetic-and potentially lethal-phenomena in the Universe. Scientists have speculated for decades about the possible consequences for life on Earth of a nearby supernova, but plausible candidates for such an event were lacking. Here we show that the Scorpius-Centaurus OB association, a group of young stars currently located at ∼ 130 parsecs from the Sun, has generated 20 SN explosions during the last 11 Myr, some of them probably as close as 40 pc to our planet. We find that the deposition on Earth of 60 Fe atoms produced by these explosions can explain the recent measurements of an excess of this isotope in deep ocean crust samples. We propose that ∼ 2 Myr ago, one of the SNe exploded close enough to Earth to seriously damage the ozone layer, provoking or contributing to the Pliocene-Pleistocene boundary marine extinction.

The early activation marker, CD69, is transiently expressed on activated mature T cells and on thymocytes that are undergoing positive or negative selection in the thymus. CD69 is a member of the NK gene complex family of C-type lectin-like signaling receptors; however, its function is unknown. In this report, we describe the characterization of mice that constitutively express high levels of surface CD69 on immature and mature T cells throughout development. Constitutive surface expression of CD69 did not affect T cell maturation, signaling through the TCR or thymocyte selection. However, phenotypically and functionally mature thymocytes accumulated in the medulla of CD69 transgenic mice and failed to be exported from the thymus. The retention of mature thymocytes correlated with transgene dose and CD69 surface levels. These results identify a potential role for CD69 in controlling thymocyte export, and suggest that the transient expression of CD69 on thymocytes and T cells may function to regulate thymocyte and T cell trafficking.

We have used the human leukemia cell line K562 as a model to study the role of c-myc in di erentiation and apoptosis. We have generated stable transfectants of K562 constitutively expressing two c-Myc inhibitory mutants: D106-143, that carries a deletion in the transactivation domain of the protein, and In373, that carries an insertion in the DNA-interacting region. We show here that In373 is able to compete with c-Myc for Max binding and to inhibit the transformation activity of c-Myc. K562 cells can di erentiate towards erythroid or myelomonocytic lineages. K562 transfected with c-myc mutants showed a higher expression of erythroid di erentiation markers, without any detectable e ects in the myelomonocytic di erentiation. We also transfected K562 cells with a zinc-inducible max gene. Ectopic Max overexpression resulted in an increased erythroid di erentiation, thus reproducing the e ects of c-myc inhibitory mutants. We also studied the role of c-myc mutants and max in apoptosis of K562 induced by okadaic acid, a protein phosphatases inhibitor. The expression of D106-143 and In373 c-myc mutants and the overexpression of max reduced the apoptosis mediated by okadaic acid. The common biochemical activity of D106-143 and In373 is to bind Max and hence to titrate out c-Myc to form non-functional Myc/ Max dimers. Similarly, Max overexpression would decrease the relative levels of c-Myc/Max with respect to Max/Max. The results support a model where a threshold of functional c-Myc/Max is required to maintain K562 cells in an undi erentiated state and to undergo drug-mediated apoptosis.

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During thymocyte development, CCR9 is expressed on late CD4−CD8− (double-negative (DN)) and CD4+CD8+ (double-positive) cells, but is subsequently down-regulated as cells transition to the mature CD4+ or CD8+ (single-positive (SP)) stage. This pattern of expression has led to speculation that CCR9 may regulate thymocyte trafficking and/or export. In this study, we generated transgenic mice in which CCR9 surface expression was maintained throughout T cell development. Significantly, forced expression of CCR9 on mature SP thymocytes did not inhibit their export from the thymus, indicating that CCR9 down-regulation is not essential for thymocyte emigration. CCR9 was also expressed prematurely on immature DN thymocytes in CCR9 transgenic mice. Early expression of CCR9 resulted in a partial block of development at the DN stage and a marked reduction in the numbers of double-positive and SP thymocytes. Moreover, in CCR9-transgenic mice, CD25high DN cells were scattered throughout the cortex rather than confined to the subcapsular region of the thymus. Together, these results suggest that regulated expression of CCR9 is critical for normal development of immature thymocytes, but that down-regulation of CCR9 is not a prerequisite for thymocyte emigration.

No abstract

T cell receptor signaling is an essential factor regulating thymocyte selection, but the function of the thymic environment in this process is not clear. In mice transgenic for major histocompatibility complex class II-restricted T cell receptors, every thymocyte is potentially selectable for maturation in the CD4 lineage. To address whether selection frequency affects positive selection, we created hematopoietic chimeras with mixtures of selectable and nonselectable precursors. With increased proportions of nonselectable thymocytes, positive selection of MHC class II-specific precursors was enhanced, generating not only CD4 but also CD8 thymocytes. These results indicate that the CD4 versus CD8 fate of selectable precursors can be influenced by the selection potential of its neighbors.

Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre-T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected. IntroductionThe mammalian thymus contains different cell types originated from initially equivalent precursors that undergo several rounds of division. To ensure correct numbers of mature lineage-specific cells in adult organs, precursors divide asymmetrically, generating 2 sister cells with different fates. 1,2 One of the "cell fate determinants" asymmetrically segregated is Numb, a plasma membrane-associated protein that contains a phosphotyrosine binding (PTB) domain and antagonizes Notch signaling. Numb function was first described in Drosophila sensory organ precursors, 3 where loss of Numb resulted in both daughter cells adopting the fate of the cell that normally inherits Notch, whereas the opposite was caused by Numb overexpression. [4][5][6] In mammalians, asymmetric division has been studied most extensively during neurogenesis. 7 Deletion of Numb and its homologue Numblike resulted in loss of neural progenitors and block of neurogenesis, 8 as a result of progenitor overdifferentiation and death of young neurons. In other systems, Numb binds to integrins 9 and Src family kinases, 10 mediates receptor internalization, 11,12 and participates in clathrin-dependent endosomal association. 13 Thus, Numb plays multiple and important roles in development and signaling; however, little is known about its role in the thymus.T lymphocytes develop from precursors that undergo a series of cell fate decisions, resulting in differentiation into single positive (SP) thymocytes, the immediate precursors of fully functional CD4 and CD8 T lymphocytes. 14,15 The initial CD4 Ϫ CD8 Ϫ double negative (DN) stages are influenced by signals from the pre-T-cell receptor (TCR) [16][17][18] and Notch. 19,20 Only DN thymocytes receiving proper pre-TCR and Notch signals are able to evolve into the CD4 ϩ CD8 ϩ double positive (DP) ␣␤ lineage stage. Pre-TCR internalization and degradation is very important for correct signaling. [21][22][23] As a consequence of pre-TCR signaling, DN thymocytes proliferate, enabling normal nu...