Large scale bias and the inaccuracy of the peak-background split

The peak-background split argument is commonly used to relate the abundance of dark matter halos to their spatial clustering. Testing this argument requires an accurate determination of the halo mass function. We present a Maximum Likelihood method for fitting parametric functional forms to halo abundances which differs from previous work because it does not require binned counts. Our conclusions do not depend on whether we use our method or more conventional ones. In addition, halo abundances depend on how halos are defined. Our conclusions do not depend on the choice of link length associated with the friends-of-friends halo-finder, nor do they change if we identify halos using a spherical overdensity algorithm instead. The large scale halo bias measured from the matter-halo cross spectrum b_x and the halo autocorrelation function b_xi (on scales k~0.03h/Mpc and r ~50 Mpc/h) can differ by as much as 5% for halos that are significantly more massive than the characteristic mass M*. At these large masses, the peak background split estimate of the linear bias factor b1 is 3-5% smaller than b_xi, which is 5% smaller than b_x. We discuss the origin of these discrepancies: deterministic nonlinear local bias, with parameters determined by the peak-background split argument, is unable to account for the discrepancies we see. A simple linear but nonlocal bias model, motivated by peaks theory, may also be difficult to reconcile with our measurements. More work on such nonlocal bias models may be needed to understand the nature of halo bias at this level of precision.Comment: MNRAS accepted. New section with Spherical Overdensity identified halos included. Appendix enlarge

N-terminal nesprin-2 variants regulate β-catenin signalling

The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction and reports on seventeen research projects.U.S. Navy - Office of Naval Research Grant N00014-91-J-1628Vertical Arrays for the Heard Island Experiment Award No. SC 48548Charles S. Draper Laboratories, Inc. Contract DL-H-418472Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-89-J-1489Rockwell Corporation Doctoral FellowshipMIT - Woods Hole Oceanographic Institution Joint ProgramDefense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-90-J-1109Lockheed Sanders, Inc./U.S. Navy - Office of Naval Research Contract N00014-91-C-0125U.S. Air Force - Office of Scientific Research Grant AFOSR-91-0034AT&T Laboratories Doctoral ProgramU.S. Navy - Office of Naval Research Grant N00014-91-J-1628General Electric Foundation Graduate Fellowship in Electrical EngineeringNational Science Foundation Grant MIP 87-14969National Science Foundation Graduate FellowshipCanada Natural Sciences and Engineering Research CouncilLockheed Sanders, Inc

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction and reports on fourteen research projects.U.S. Navy - Office of Naval Research Grant N00014-91-J-1628Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-89-J-1489MIT - Woods Hole Oceanographic Institution Joint ProgramLockheed Sanders, Inc./U.S. Navy Office of Naval Research Contract N00014-91-C-0125U.S. Air Force - Office of Scientific Research Grant AFOSR-91-0034U.S. Navy - Office of Naval Research Grant N00014-91-J-1628AT&T Laboratories Doctoral Support ProgramNational Science Foundation Fellowshi

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction, reports on sixteen research projects and a list of publications.Bose CorporationMIT-Woods Hole Oceanographic Institution Joint Graduate Program in Oceanographic EngineeringAdvanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-93-1-0686Lockheed Sanders, Inc./U.S. Navy - Office of Naval Research Contract N00014-91-C-0125U.S. Air Force - Office of Scientific Research Grant AFOSR-91-0034AT&T Laboratories Doctoral Support ProgramAdvanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-89-J-1489U.S. Navy - Office of Naval Research Grant N00014-93-1-0686National Science Foundation FellowshipMaryland Procurement Office Contract MDA904-93-C-4180U.S. Navy - Office of Naval Research Grant N00014-91-J-162

Molecular diagnosis of Burkitt\u27s lymphoma.

BACKGROUND: The distinction between Burkitt\u27s lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt\u27s lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt\u27s lymphoma. Burkitt\u27s lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt\u27s lymphoma, suggesting they represent cases of Burkitt\u27s lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt\u27s lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt\u27s lymphoma from diffuse large-B-cell lymphoma

FLIM FRET Technology for Drug Discovery: Automated Multiwell-Plate High-Content Analysis, Multiplexed Readouts and Application in Situ**

A fluorescence lifetime imaging (FLIM) technology platform intended to read out changes in Förster resonance energy transfer (FRET) efficiency is presented for the study of protein interactions across the drug-discovery pipeline. FLIM provides a robust, inherently ratiometric imaging modality for drug discovery that could allow the same sensor constructs to be translated from automated cell-based assays through small transparent organisms such as zebrafish to mammals. To this end, an automated FLIM multiwell-plate reader is described for high content analysis of fixed and live cells, tomographic FLIM in zebrafish and FLIM FRET of live cells via confocal endomicroscopy. For cell-based assays, an exemplar application reading out protein aggregation using FLIM FRET is presented, and the potential for multiple simultaneous FLIM (FRET) readouts in microscopy is illustrated

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction, reports on twenty research projects and a list of publications.Lockheed Sanders, Inc. Contract BZ4962U.S. Army Research Laboratory Grant QK-8819U.S. Navy - Office of Naval Research Grant N00014-93-1-0686National Science Foundation Grant MIP 95-02885U.S. Navy - Office of Naval Research Grant N00014-95-1-0834U.S. Navy - Office of Naval Research Grant N00014-96-1-0930U.S. Navy - Office of Naval Research Grant N00014-95-1-0362National Defense Science and Engineering FellowshipU.S. Air Force - Office of Scientific Research Grant F49620-96-1-0072National Science Foundation Graduate Research Fellowship Grant MIP 95-02885Lockheed Sanders, Inc. Grant N00014-93-1-0686National Science Foundation Graduate FellowshipU.S. Army Research Laboratory/ARL Advanced Sensors Federated Lab Program Contract DAAL01-96-2-000

Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function