Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis

Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mechanism that can lead to genomic rearrangements is the formation of a “dicentric” chromosome containing two functional centromeres. Indeed, such dicentric chromosomes have been observed in cancer cells. Here, we tested the ability of a single dicentric chromosome to contribute to genomic instability and neoplastic conversion in vertebrate cells. We developed a system to transiently and reversibly induce dicentric chromosome formation on a single chromosome with high temporal control. We find that induced dicentric chromosomes are frequently damaged and mis-segregated during mitosis, and that this leads to extensive chromosomal rearrangements including translocations with other chromosomes. Populations of pre-neoplastic cells in which a single dicentric chromosome is induced acquire extensive genomic instability and display hallmarks of cellular transformation including anchorage-independent growth in soft agar. Our results suggest that a single dicentric chromosome could contribute to tumor initiation.Leukemia & Lymphoma Society of America (Scholar Award)National Institute of General Medical Sciences (U.S.) (Grant GM088313)American Cancer Society (Research Scholar Grant 121776

CDK-dependent phosphorylation and nuclear exclusion coordinately control kinetochore assembly state

Accurate chromosome segregation requires assembly of the multiprotein kinetochore complex. Prior work has identified more than 100 different kinetochore components in human cells. However, little is known about the regulatory processes that specify their assembly upon mitotic entry and disassembly at mitotic exit. In this paper, we used a live-cell imaging–based assay to quantify kinetochore disassembly kinetics and systematically analyze the role of potential regulatory mechanisms in controlling kinetochore assembly state. We find that kinetochore assembly and disassembly was driven primarily by mitotic phosphorylation downstream of cyclin-dependent kinase (CDK). In addition, we demonstrate that nuclear exclusion of the Ndc80 complex helped restrict kinetochore formation to mitosis. Combining constitutive CDK-dependent phosphorylation of CENP-T and forced nuclear localization of the Ndc80 complex partially prevented kinetochore disassembly at mitotic exit and led to chromosome segregation defects in subsequent divisions. In total, we find that the coordinated temporal regulation of outer kinetochore assembly is essential for accurate cell division.Kinship Foundation. Searle Scholars ProgramLeukemia & Lymphoma Society of AmericaNational Institutes of Health (U.S.) (National Institute of General Medical Sciences (U.S.) Grant GM088313)Leukemia & Lymphoma Society of America (Special Fellows Award

Classical Cepheid Pulsation Models. III. The Predictable Scenario

Within the current uncertainties in the treatment of the coupling between pulsation and convection, limiting amplitude, nonlinear, convective models appear the only viable approach for providing theoretical predictions about the intrinsic properties of radial pulsators. In this paper we present the results of a comprehensive set of Cepheid models computed within such theoretical framework for selected assumptions on their original chemical composition.Comment: 24 pages, 1 latex file containing 6 tables, 10 postscript figures, accepted for publication on Ap

Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci

The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider positional conservation across mammalian genomes as an indicator of functional commonality. We identify 665 conserved lncRNA promoters in mouse and human genomes that are preserved in genomic position relative to orthologous coding genes. The identified positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are co-expressed in a tissue-specific manner. Strikingly, over half of all positionally conserved RNAs in this set are linked to distinct chromatin organization structures, overlapping the binding sites for the CTCF chromatin organizer and located at chromatin loop anchor points and borders of topologically associating domains (TADs). These topological anchor point (tap)RNAs possess conserved sequence domains that are enriched in potential recognition motifs for Zinc Finger proteins. Characterization of these non-coding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other ′s expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Thus, interrogation of positionally conserved lncRNAs identifies a new subset of tapRNAs with shared functional properties. These results provide a large dataset of lncRNAs that conform to the ″extended gene″ model, in which conserved developmental genes are genomically and functionally linked to regulatory lncRNA loci across mammalian evolution

Teleology and Realism in Leibniz's Philosophy of Science

This paper argues for an interpretation of Leibniz’s claim that physics requires both mechanical and teleological principles as a view regarding the interpretation of physical theories. Granting that Leibniz’s fundamental ontology remains non-physical, or mentalistic, it argues that teleological principles nevertheless ground a realist commitment about mechanical descriptions of phenomena. The empirical results of the new sciences, according to Leibniz, have genuine truth conditions: there is a fact of the matter about the regularities observed in experience. Taking this stance, however, requires bringing non-empirical reasons to bear upon mechanical causal claims. This paper first evaluates extant interpretations of Leibniz’s thesis that there are two realms in physics as describing parallel, self-sufficient sets of laws. It then examines Leibniz’s use of teleological principles to interpret scientific results in the context of his interventions in debates in seventeenth-century kinematic theory, and in the teaching of Copernicanism. Leibniz’s use of the principle of continuity and the principle of simplicity, for instance, reveal an underlying commitment to the truth-aptness, or approximate truth-aptness, of the new natural sciences. The paper concludes with a brief remark on the relation between metaphysics, theology, and physics in Leibniz

Education, knowledge, and symbolic form

This article aims to introduce Ernst Cassirer, and his philosophy of symbolic form, to education studies, and, in doing so, to challenge the widespread but deeply flawed views of knowledge and so-called knowledge-based education that have shaped recent education policy in England. After sketching the current educational landscape, and then some of the main lines of flight in Cassirer’s work, time is given to a comparison with Heidegger—a more familiar figure by far in Anglophone philosophy than Cassirer, and who contributed to the displacement of Cassirer—in order to illustrate more clearly Cassirer’s original contribution, in particular to the relationship between knowledge and time. Cassirer’s view of knowledge stands in marked and critical contrast to that which has shaped recent educational reform in England, as he sees knowledge as a productive and expressive matter, and repudiates what I call the ‘building-blocks’ picture of knowledge and the hierarchisation of subject areas

Statutory Assessment of the class? Supporting the additional needs of the learning context

This paper considers issues of funding of support for students facing difficulties in learning, and the role of assessment and labelling within this process. It explores the tensions within this process using a Foucauldian framework, and from the key perspectives of social justice and rights. Drawing on a range of literature it identifies the focus upon the individual within assessment processes around the world, and then considers in detail the strengths and weaknesses of the current form of Statutory Assessment of Special Educational Needs within England. The paper proposes an alternative funding system that resolves shortcomings within the individual approach and the English system. It suggests that a Class Funding Approach could build on a notion of justice for all, reduce the opportunities for wide variations in provision, and minimise the negative impact of current dividing practices

Intermediate-mass star models with different helium and metal contents

We present a comprehensive theoretical investigation of the evolutionary properties of intermediate-mass stars. The evolutionary sequences were computed from the Zero Age Main Sequence up to the central He exhaustion and often up to the phases which precede the carbon ignition or to the reignition of the H-shell which marks the beginning of the thermal pulse phase. The evolutionary tracks were constructed by adopting a wide range of stellar masses ($3\leq$\msun$\leq15$) and chemical compositions. In order to account for current uncertainties on the He to heavy elements enrichment ratio, the stellar models were computed by adopting at Z=0.02 two different He contents (Y=0.27, 0.289) and at Z=0.04 three different He contents (Y=0.29, 0.34, and 0.37). To supply a homogeneous evolutionary scenario which accounts for young Magellanic stellar systems the calculations were also extended toward lower metallicities (Z=0.004, Z=0.01), by adopting different initial He abundances. We evaluated for both solar (Z=0.02) and super-metal-rich (SMR, Z=0.04) models the transition mass $M^{up}$ between the stellar structures igniting carbon and those which develop a full electron degeneracy inside the CO core. This evolutionary scenario allows us to investigate in detail the properties of classical Cepheids. In particular, we find that the range of stellar masses which perform the blue loop during the central He-burning phase narrows when moving toward metal-rich and SMR structures.Comment: 25 pages, 10 figures (4 postscript + 6 gif files), 7 postscript tables. accepted for publication on ApJ (November 2000

The Palomar Testbed Interferometer Calibrator Catalog

The Palomar Testbed Interferometer (PTI) archive of observations between 1998 and 2005 is examined for objects appropriate for calibration of optical long-baseline interferometer observations - stars that are predictably point-like and single. Approximately 1,400 nights of data on 1,800 objects were examined for this investigation. We compare those observations to an intensively studied object that is a suitable calibrator, HD217014, and statistically compare each candidate calibrator to that object by computing both a Mahalanobis distance and a Principal Component Analysis. Our hypothesis is that the frequency distribution of visibility data associated with calibrator stars differs from non-calibrator stars such as binary stars. Spectroscopic binaries resolved by PTI, objects known to be unsuitable for calibrator use, are similarly tested to establish detection limits of this approach. From this investigation, we find more than 350 observed stars suitable for use as calibrators (with an additional $\approx 140$ being rejected), corresponding to $\gtrsim 95$ sky coverage for PTI. This approach is noteworthy in that it rigorously establishes calibration sources through a traceable, empirical methodology, leveraging the predictions of spectral energy distribution modeling but also verifying it with the rich body of PTI's on-sky observations.Comment: 100 pages, 7 figures, 7 tables; to appear in the May 2008ApJS, v176n