Population history from the Neolithic to present on the Mediterranean island of Sardinia: an ancient DNA perspective

Recent ancient DNA studies of western Eurasia have revealed a dynamic history of admixture, with evidence for major migrations during the Neolithic and Bronze Age. The population of the Mediterranean island of Sardinia has been notable in these studies –} Neolithic individuals from mainland Europe cluster more closely with Sardinian individuals than with all other present-day Europeans. The current model to explain this result is that Sardinia received an initial influx of Neolithic ancestry and then remained relatively isolated from expansions in the later Neolithic and Bronze Age that took place in continental Europe. To test this model, we generated genome-wide capture data (approximately 1.2 million variants) for 43 ancient Sardinian individuals spanning the Neolithic through the Bronze Age, including individuals from Sardinia{’}s Nuragic culture, which is known for the construction of numerous large stone towers throughout the island. We analyze these new samples in the context of previously generated genome-wide ancient DNA data from 972 ancient individuals across western Eurasia and whole-genome sequence data from approximately 1,500 modern individuals from Sardinia. The ancient Sardinian individuals show a strong affinity to western Mediterranean Neolithic populations and we infer a high degree of genetic continuity on the island from the Neolithic (around fifth millennium BCE) through the Nuragic period (second millennium BCE). In particular, during the Bronze Age in Sardinia, we do not find significant levels of the {“}Steppe{” ancestry that was spreading in many other parts of Europe at that time. We also characterize subsequent genetic influx between the Nuragic period and the present. We detect novel, modest signals of admixture between 1,000 BCE and present-day, from ancestry sources in the eastern and northern Mediterranean. Within Sardinia, we confirm that populations from the more geographically isolated mountainous provinces have experienced elevated levels of genetic drift and that northern and southwestern regions of the island received more gene flow from outside Sardinia. Overall, our genetic analysis sheds new light on the origin of Neolithic settlement on Sardinia, reinforces models of genetic continuity on the island, and provides enhanced power to detect post-Bronze-Age gene flow. Together, these findings offer a refined demographic model for future medical genetic studies in Sardinia

Equianalytic and equisingular families of curves on surfaces

We consider flat families of reduced curves on a smooth surface S such that each member C has the same number of singularities of fixed singularity types and the corresponding (locally closed) subscheme H of the Hilbert scheme of S. We are mainly concerned with analytic resp. topological singularity types and give a sufficient condition for the smoothness of H (at C). Our results for S=P^2 seem to be quite sharp for families of cuves of small degree d.Comment: LaTeX v 2.0

Homological Type of Geometric Transitions

The present paper gives an account and quantifies the change in topology induced by small and type II geometric transitions, by introducing the notion of the \emph{homological type} of a geometric transition. The obtained results agree with, and go further than, most results and estimates, given to date by several authors, both in mathematical and physical literature.Comment: 36 pages. Minor changes: A reference and a related comment in Remark 3.2 were added. This is the final version accepted for publication in the journal Geometriae Dedicat

Characterization of Two Distinct Lymphoproliferative Diseases Caused by Ectopic Expression of the Notch Ligand DLL4 on T Cells

Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity

An Invitation to Higher Gauge Theory

In this easy introduction to higher gauge theory, we describe parallel transport for particles and strings in terms of 2-connections on 2-bundles. Just as ordinary gauge theory involves a gauge group, this generalization involves a gauge '2-group'. We focus on 6 examples. First, every abelian Lie group gives a Lie 2-group; the case of U(1) yields the theory of U(1) gerbes, which play an important role in string theory and multisymplectic geometry. Second, every group representation gives a Lie 2-group; the representation of the Lorentz group on 4d Minkowski spacetime gives the Poincar\'e 2-group, which leads to a spin foam model for Minkowski spacetime. Third, taking the adjoint representation of any Lie group on its own Lie algebra gives a 'tangent 2-group', which serves as a gauge 2-group in 4d BF theory, which has topological gravity as a special case. Fourth, every Lie group has an 'inner automorphism 2-group', which serves as the gauge group in 4d BF theory with cosmological constant term. Fifth, every Lie group has an 'automorphism 2-group', which plays an important role in the theory of nonabelian gerbes. And sixth, every compact simple Lie group gives a 'string 2-group'. We also touch upon higher structures such as the 'gravity 3-group' and the Lie 3-superalgebra that governs 11-dimensional supergravity.Comment: 60 pages, based on lectures at the 2nd School and Workshop on Quantum Gravity and Quantum Geometry at the 2009 Corfu Summer Institut

IEDB-3D: structural data within the immune epitope database

IEDB-3D is the 3D structural component of the Immune Epitope Database (IEDB) available via the ‘Browse by 3D Structure’ page at http://www.iedb.org. IEDB-3D catalogs B- and T-cell epitopes and Major Histocompatibility Complex (MHC) ligands for which 3D structures of complexes with antibodies, T-cell receptors or MHC molecules are available in the Protein Data Bank (PDB). Journal articles that are primary citations of PDB structures and that define immune epitopes are curated within IEDB as any other reference along with accompanying functional assays and immunologically relevant information. For each curated structure, IEDB-3D provides calculated data on intermolecular contacts and interface areas and includes an application, EpitopeViewer, to visualize the structures. IEDB-3D is fully embedded within IEDB, thus allowing structural data, both curated and calculated, and all accompanying information to be queried using multiple search interfaces. These include queries for epitopes recognized in different pathogens, eliciting different functional immune responses, and recognized by different components of the immune system. The query results can be downloaded in Microsoft Excel format, or the entire database, together with structural data both curated and calculated, can be downloaded in either XML or MySQL formats

Arrangement for interfacing a telephone device with a personal computer

An arrangement provides an interface between a telephone device and a personal computer in such a manner that enhanced capability for both the telephone device and the computer in processing information in an analog telephone environment is provided. The telephone device attaches to an analog telephone line and advantageously operates either as a stand-alone device when the computer is powered-off or in tandem with the computer when the computer is powered-on. A user is able to access any of the available telephony features from the telephone device at all times and from the computer when it is powered-on. Such available telephony features include, by way of example, Caller ID for decoding available information presented on the analog telephone line and an integrated telephone answering system, which provides for reception, transmission, and storage of voice, facsimile, and electronic mail messages.Published versio

Spatial Regulation and the Rate of Signal Transduction Activation

Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement