The rockefeller university

MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.

Protein AMPylation is an emerging post-translational modification, which plays key roles in bacterial pathogenesis and cell biology. Enzymes with AMPylation activity, referred to as AMPylators, have been identified in several bacterial pathogens and eukaryotes. To facilitate the study of this unique modification, we developed an alkynyl chemical reporter for detection and identification of protein AMPylation substrates. Covalent functionalization of AMPylation substrates with the alkynyl reporter in lieu of adenylyl 5'-monophosphate (AMP) allows their subsequent bioorthogonal ligation with azide-fluorescent dyes or affinity enrichment tags. We show that this chemical reporter is transferred by a range of AMPylators onto their cognate protein substrates and allows rapid detection and identification of AMPylated substrates.

We present a measurement of the top-quark mass using a sample of t (t) over bar events in 5.7 fb(-1) of integrated luminosity from p (p) over bar collisions at the Fermilab Tevatron with root s = 1.96 TeV and collected by the CDF II Detector. We select events having large missing transverse energy, and four, five, or six jets with at least one jet tagged as coming from a b quark, and reject events with identified charged leptons. This analysis considers events from the semileptonic t (t) over bar decay channel, including events that contain tau leptons. The measurement is based on a multidimensional template method. We fit the data to signal templates of varying top-quark masses and background templates, and measure a top-quark mass of M(top) = 172.32 +/- 2.4(stat) +/- 1.0(syst) GeV/c(2).

Long-term humoral immunity is maintained by the formation of high-affinity class-switched memory B cells and long-lived anti-body-secreting plasma cells. In healthy humans, a substantial fraction of IgG-positive memory B cells express self-reactive and polyreactive IgG antibodies that frequently develop by somatic mutations. Whether self-and polyreactive IgG-secreting B cells are also tolerated in the long-lived plasma cell pool is not known. To address this question, we cloned and expressed the Ig genes from 177 IgG-producing bone marrow plasma cells of four healthy donors. All antibodies were highly mutated but the frequency of self-and polyreactive IgG antibodies was significantly lower than that found in circulating memory B cells. The data suggest that in contrast to the development of memory B cells, entry into the bone marrow plasma cell compartment requires previously unappreciated selective regulation by mechanisms that limit the production of self-and polyreactive serum IgG antibodies.

We have previously shown strain and dose differences in heroin-induced behavior, reward and regional expression of somatostatin receptor mRNAs in C57BL/6J and 129P3/J mice. Using Real Time PCR we examined the effects of five doses of heroin on the levels of the transcripts of endogenous opioid peptides and their receptors and dopaminergic receptors in the mesocorticolimbic and nigrostriatal pathways in these same mice. Compared to C57BL/6J animals, 129P3/J mice had higher mRNA levels of Oprk1 in the nucleus accumbens and of Oprd1 in the nucleus accumbens and a region containing both the substantia nigra and ventral tegmental area (SN/VTA). In the cortex of 129P3/J mice, lower levels of both Oprk1 and Oprd1 mRNAs were observed. Pdyn mRNA was also lower in the caudate putamen of 129P3/J mice. Strain differences were not found in the levels of Oprm1, Penk or Pomc mRNAs in any region examined. Within strains, complex patterns of heroin dose-dependent changes in the levels of Oprm1,Oprk1 and Oprd1 mRNAs were observed in the SN/VTA. Additionally. Oprd1 mRNA was dose-dependently elevated in the hypothalamus. Also in the hypothalamus. we found higher levels of Drd1a mRNA in C57BL/6J mice than in 129P3/J animals and higher levels of DAT (Slc6a3) mRNA in the caudate putamen of C57BL/6J animals than in 129P3/J counterparts. Heroin had dose-related effects on Drd1a mRNA in the hypothalamus and on Drd2 mRNA in the caudate putamen. (C) 2011 Elsevier Inc. All rights reserved.

A search for the rare decays B-s(0) --> mu(+)mu(-) and B-0 --> mu(+)mu(-) is performed in pp collisions at root s = 7 TeV, with a data sample corresponding to an integrated luminosity of 1.14 fb(-1), collected by the CMS experiment at the LHC. In both cases, the number of events observed after all selection requirements is consistent with expectations from background and standard-model signal predictions. The resulting upper limits on the branching fractions are B(B-s(0) --> mu(+)mu(-)) < 1.9 x 10(-8) and B(B-0 --> mu(+)mu(-)) < 4.6 x 10(-9), at 95% confidence level.

A search for events with jets and missing transverse energy is performed in a data sample of pp collisions collected at root s = 7 TeV by the CMS experiment at the LHC. The analyzed data sample corresponds to an integrated luminosity of 1: 14 fb(-1). In this search, a kinematic variable alpha(T) is used as the main discriminator between events with genuine and misreconstructed missing transverse energy. No excess of events over the standard model expectation is found. Exclusion limits in the parameter space of the constrained minimal supersymmetric extension of the standard model are set. In this model, squark masses below 1.1 TeV are excluded at 95% C. L. Gluino masses below 1.1 TeV are also ruled out at 95% C. L. for values of the universal scalar mass parameter below 500 GeV.

The Wnt/beta-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of beta-catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/beta-catenin target activation in the developing forebrain.

We report the first observation of the baryonic flavor-changing neutral current decay Lambda(0)(b) -> Lambda mu(+)mu(-) with 24 signal events and a statistical significance of 5.8 Gaussian standard deviations. This measurement uses a p (p) over bar collisions data sample corresponding to 6.8 fb(-1) at root s = 1.96 TeV collected by the CDF II detector at the Tevatron collider. The total and differential branching ratios for Lambda(0)(b) -> Lambda mu(+)mu(-) are measured. We find B(Lambda(0)(b) -> Lambda mu(+)mu(-)) = [1.73 +/- 0.42(stat) +/- (syst)] x 10(-6). We also report the first measurement of the differential branching ratio of B-s(0) -> phi mu(+)mu(-), using 49 signal events. In addition, we report branching ratios for B+ -> K+mu(+)mu(-), B-0 -> K-0 mu(+)mu(-), and B -> K*(892)mu(+)mu(-) decays.

Adjuvants are critical for the success of vaccines. Agonists of microbial pattern recognition receptors (PRRs) are promising new adjuvant candidates. A mechanism through which adjuvants enhance immune responses is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double-stranded RNA (polyinosinic: polycytidylic acid [poly IC] stabilized with poly-l-lysine [poly ICLC]), an agonist for toll-like receptor (TLR) 3, and the cytosolic RNA helicase MDA-5. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC, showed upregulation of genes involved in multiple innate immune pathways in all subjects, including interferon (IFN) and inflammasome signaling. Blocking type I IFN receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate immune pathways were similarly induced in volunteers immunized with the highly efficacious yellow fever vaccine. Therefore, a chemically defined PRR agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immune responses in humans.