The blind leading the blind: Mutual refinement of approximate theories

The mutual refinement theory, a method for refining world models in a reactive system, is described. The method detects failures, explains their causes, and repairs the approximate models which cause the failures. The approach focuses on using one approximate model to refine another

Gastro-oesophageal reflux disease - Impact of guidelines on GP management

Copyright © 2008 Royal Australian College of General Practitioners Copyright to Australian Family Physician. Reproduced with permission. Permission to reproduce must be sought from the publisher, The Royal Australian College of General Practitioners.Background: This program examined the impact of clinical guidelines and a 3 year self audit process on general practitioners’ diagnosis and management of gastro-oesophageal reflux disease. Methods: Nine hundred and sixty-six Australian GPs participated in a retrospective five step clinical audit reporting on data for 28 622 patients. Results: General practitioners demonstrated significant improvements in their diagnosis and management of gastro-oesophageal reflux disease across the audit period, including: - a significant 3% decrease in use of endoscopy - improved GP assessment and identification of risk factors and exacerbants - significant increases in GP recommendations for patient weight loss and dietary change (7 and 10% respectively) - a significant 4% reduction in patient use of medications that may exacerbate reflux symptoms. Discussion: The findings provide a snapshot of current diagnostic and management practices in Australian general practice, and highlight the benefits of clinical audit as a tool for eliciting evidence based, guideline driven practice change.Catherine N Kirby, Leon Piterman, Mark R Nelson and John Den

Herschel GASPS spectral observations of T Tauri stars in Taurus: unraveling far-infrared line emission from jets and discs

At early stages of stellar evolution young stars show powerful jets and/or outflows that interact with protoplanetary discs and their surroundings. Despite the scarce knowledge about the interaction of jets and/or outflows with discs, spectroscopic studies based on Herschel and ISO data suggests that gas shocked by jets and/or outflows can be traced by far-IR (FIR) emission in certain sources. We want to provide a consistent catalogue of selected atomic ([OI] and [CII]) and molecular (CO, OH, and H$_{2}$O) line fluxes observed in the FIR, separate and characterize the contribution from the jet and the disc to the observed line emission, and place the observations in an evolutionary picture. The atomic and molecular FIR (60-190 $\rm \mu m$) line emission of protoplanetary discs around 76 T Tauri stars located in Taurus are analysed. The observations were carried out within the Herschel key programme Gas in Protoplanetary Systems (GASPS). The spectra were obtained with the Photodetector Array Camera and Spectrometer (PACS). The sample is first divided in outflow and non-outflow sources according to literature tabulations. With the aid of archival stellar/disc and jet/outflow tracers and model predictions (PDRs and shocks), correlations are explored to constrain the physical mechanisms behind the observed line emission. The much higher detection rate of emission lines in outflow sources and the compatibility of line ratios with shock model predictions supports the idea of a dominant contribution from the jet/outflow to the line emission, in particular at earlier stages of the stellar evolution as the brightness of FIR lines depends in large part on the specific evolutionary stage. [Abridged Abstract]Comment: 37 pages, 27 figures, accepted for publication in A&

Spectroscopic diagnostic for the mineralogy of large dust grains

We examine the thermal infrared spectra of large dust grains of different chemical composition and mineralogy. Strong resonances in the optical properties result in detectable spectral structure even when the grain is much larger than the wavelength at which it radiates. We apply this to the thermal infrared spectra of compact amorphous and crystalline silicates. The weak resonances of amorphous silicates at 9.7 and 18 micron virtually disappear for grains larger than about 10 micron. In contrast, the strong resonances of crystalline silicates produce emission dips in the infrared spectra of large grains; these emission dips are shifted in wavelength compared to the emission peaks commonly seen in small crystalline silicate grains. We discuss the effect of a fluffy or compact grain structure on the infrared emission spectra of large grains, and apply our theory to the dust shell surrounding Vega.Comment: Submitted to A&A Letter

Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines

Neuroblastoma cell lines are an important and cost-effective model used to study oncogenic drivers of the disease. While many of these cell lines have been previously characterized with SNP, methylation, and/or mRNA expression microarrays, there has not been an effort to comprehensively sequence these cell lines. Here, we present raw whole transcriptome data generated by RNA sequencing of 39 commonly-used neuroblastoma cell lines. These data can be used to perform differential expression analysis based on a genetic aberration or phenotype in neuroblastoma (e.g., MYCN amplification status, ALK mutation status, chromosome arm 1p, 11q and/or 17q status, sensitivity to pharmacologic perturbation). Additionally, we designed this experiment to enable structural variant and/or long-noncoding RNA analysis across these cell lines. Finally, as more DNase/ATAC and histone/transcription factor ChIP sequencing is performed in these cell lines, our RNA-Seq data will be an important complement to inform transcriptional targets as well as regulatory (enhancer or repressor) elements in neuroblastoma

Constitutive activation of NF-κB in human hepatocellular carcinoma: Evidence of a cytoprotective role

Activation of nuclear factor-κB (NF-κB) can promote or inhibit apoptosis. Oxidative stress is an important mechanism by which certain anticancer drugs kill cancer cells, and is also one of the mechanisms that activate NF-κB. We therefore examined hepatic expression of the NF-κB monomer p65 in human hepatocellular carcinoma (HCC) tissue samples from eight patients and compared it with their respective samples of surrounding liver tissues. We also studied the effect of NF-κB inhibition in human HCC cells exposed to oxidative stress, by infecting HuH7 cells with a recombinant adenovirus carrying mutant IκBα (mIκBα). Cultured HuH7 cells were infected with mIκBα or β-galactosidase (β-Gal) for 24 hr followed by treatment with increasing concentrations of H2O2. Cytotoxicity, NF-κB translocation, NF-κB DNA binding, cell proliferation, and apoptosis were determined. The monomer p65 was overexpressed in six of eight human HCC tissues. In HuH7 cells, introduction of mIκBα potently inhibited the translocation, activation, and DNA binding of NF-κB. In control (β-Gal-infected) HuH7 cells, exposure to H2O2 produced a dose-dependent increase in apoptosis, regardless of NF-κB status. mIκBα- mediated inhibition of NF-κB activation sensitized HuH7 cells to H 2O2-induced inhibition of cell growth, and further promoted cell death. Addition of H2O2 (200-500 μM) to control or mIκBα-infected HuH7 cells enhanced caspase-3 activity and cleavage. Adenovirus-mediated transfer of mIκBα potently inhibits NF-κB activity in HuH7 cells, and this enhances oxidative stress-induced cell killing. © Mary Ann Liebert, Inc.published_or_final_versio

Differences in vector-genome processing and illegitimate integration of non-integrating lentiviral vectors

A variety of mutations in lentiviral vector expression systems have been shown to generate a non-integrating phenotype. We studied a novel 12 base-pair U3-long terminal repeats (LTR) integrase (IN) attachment site deletion (U3-LTR att site) mutant and found similar physical titers to the previously reported IN catalytic core mutant IN/D116N. Both mutations led to a greater than two log reduction in vector integration; with IN/D116N providing lower illegitimate integration frequency, whereas the U3-LTR att site mutant provided a higher level of transgene expression. The improved expression of the U3-LTR att site mutant could not be explained solely based on an observed modest increase in integration frequency. In evaluating processing, we noted significant differences in unintegrated vector forms, with the U3-LTR att site mutant leading to a predominance of 1-LTR circles. The mutations also differed in the manner of illegitimate integration. The U3-LTR att site mutant vector demonstrated IN-mediated integration at the intact U5-LTR att site and non-IN-mediated integration at the mutated U3-LTR att site. Finally, we combined a variety of mutations and modifications and assessed transgene expression and integration frequency to show that combining modifications can improve the potential clinical utility of non-integrating lentiviral vectors

Constitutive activation of NF-κB in human hepatocellular carcinoma: Evidence of a cytoprotective role

Activation of nuclear factor-κB (NF-κB) can promote or inhibit apoptosis. Oxidative stress is an important mechanism by which certain anticancer drugs kill cancer cells, and is also one of the mechanisms that activate NF-κB. We therefore examined hepatic expression of the NF-κB monomer p65 in human hepatocellular carcinoma (HCC) tissue samples from eight patients and compared it with their respective samples of surrounding liver tissues. We also studied the effect of NF-κB inhibition in human HCC cells exposed to oxidative stress, by infecting HuH7 cells with a recombinant adenovirus carrying mutant IκBα (mIκBα). Cultured HuH7 cells were infected with mIκBα or β-galactosidase (β-Gal) for 24 hr followed by treatment with increasing concentrations of H2O2. Cytotoxicity, NF-κB translocation, NF-κB DNA binding, cell proliferation, and apoptosis were determined. The monomer p65 was overexpressed in six of eight human HCC tissues. In HuH7 cells, introduction of mIκBα potently inhibited the translocation, activation, and DNA binding of NF-κB. In control (β-Gal-infected) HuH7 cells, exposure to H2O2 produced a dose-dependent increase in apoptosis, regardless of NF-κB status. mIκBα- mediated inhibition of NF-κB activation sensitized HuH7 cells to H 2O2-induced inhibition of cell growth, and further promoted cell death. Addition of H2O2 (200-500 μM) to control or mIκBα-infected HuH7 cells enhanced caspase-3 activity and cleavage. Adenovirus-mediated transfer of mIκBα potently inhibits NF-κB activity in HuH7 cells, and this enhances oxidative stress-induced cell killing. © Mary Ann Liebert, Inc.published_or_final_versio