Allegro: Analyzing expression and sequence in concert to discover regulatory programs

A major goal of system biology is the characterization of transcription factors and microRNAs (miRNAs) and the transcriptional programs they regulate. We present Allegro, a method for de-novo discovery of cis-regulatory transcriptional programs through joint analysis of genome-wide expression data and promoter or 3′ UTR sequences. The algorithm uses a novel log-likelihood-based, non-parametric model to describe the expression pattern shared by a group of co-regulated genes. We show that Allegro is more accurate and sensitive than existing techniques, and can simultaneously analyze multiple expression datasets with more than 100 conditions. We apply Allegro on datasets from several species and report on the transcriptional modules it uncovers. Our analysis reveals a novel motif over-represented in the promoters of genes highly expressed in murine oocytes, and several new motifs related to fly development. Finally, using stem-cell expression profiles, we identify three miRNA families with pivotal roles in human embryogenesis

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/ 8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Problems in Education and Waldorf Pedagogy

This bachelor thesis is concerned with the contemporary problems in education and how Waldorf pedagogy deals with these problems. The thesis is divided into larger theoretical part, which covers the grounds and approaches of Waldorf pedagogy and the Czech standard educational system. I also look into the problems of education in a broader social context. The practical part describes the pilot study carried out at a Waldorf basic school

Problems in Education and Waldorf Pedagogy

This bachelor thesis is concerned with the contemporary problems in education and how Waldorf pedagogy deals with these problems. The thesis is divided into larger theoretical part, which covers the grounds and approaches of Waldorf pedagogy and the Czech standard educational system. I also look into the problems of education in a broader social context. The practical part describes the pilot study carried out at a Waldorf basic school

Radical and Nitrenoid Reactivity of 3‑Halo-3-phenyldiazirines

3-Halo-3-phenyl-3<i>H</i>-diazirines (halogen = Br or Cl) undergo a dissociative single-electron transfer from alkyllithiums (RLi) in THF-based solvent mixtures. The resulting 3-phenyldiazirinyl radical, observed by EPR spectroscopy, is eventually transformed to benzonitrile. In Et₂O, 2 equiv of RLi add to both nitrogens of halodiazirine NN bond, affording <i>N,N</i>′-dialkylbenzamidines. The nitrenoid reactivity of some <i>N</i>-alkyl-1<i>H</i>-diazirine intermediates is manifested by their insertion into the α-C–H bond of THF or Et₂O