772 research outputs found

    A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis

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    Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in viv

    A computerised test of perceptual ability for learning endoscopic and laparoscopic surgery and other image guided procedures: Score norms for PicSOr

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    Background: The aptitude to infer the shape of 3-D structures, such as internal organs from 2-D monitor displays, in image guided endoscopic and laparoscopic procedures varies. We sought both to validate a computer-generated task Pictorial Surface Orientation (PicSOr), which assesses this aptitude, and to identify norm referenced scores. Methods: 400 subjects (339 surgeons and 61 controls) completed the PicSOr test. 50 subjects completed it again one year afterwards. Results: Complete data was available on 396 of 400 subjects (99%). PicSOr demonstrated high test and re-test reliability (r = 0.807, p < 0.000). Surgeons performed better than controls' (surgeons = 0.874 V controls = 0.747, p < 0.000). Some surgeons (n = 22–5.5%) performed atypically on the test. Conclusions: PicSOr has population distribution scores that are negatively skewed. PicSOr quantitatively characterises an aptitude strongly correlated to the learning and performance of image guided medical tasks. Most can do the PicSOr task almost perfectly, but a substantial minority do so atypically, and this is probably relevant to learning and performing endoscopic tasks

    Spectral Energy Distributions and Multiwavelength Selection of Type 1 Quasars

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    We present an analysis of the mid-infrared (MIR) and optical properties of type 1 (broad-line) quasars detected by the Spitzer Space Telescope. The MIR color-redshift relation is characterized to z ~ 3, with predictions to z = 7. We demonstrate how combining MIR and optical colors can yield even more efficient selection of active galactic nuclei (AGNs) than MIR or optical colors alone. Composite spectral energy distributions (SEDs) are constructed for 259 quasars with both Sloan Digital Sky Survey and Spitzer photometry, supplemented by near-IR, GALEX, VLA, and ROSAT data, where available. We discuss how the spectral diversity of quasars influences the determination of bolometric luminosities and accretion rates; assuming the mean SED can lead to errors as large as 50% for individual quasars when inferring a bolometric luminosity from an optical luminosity. Finally, we show that careful consideration of the shape of the mean quasar SED and its redshift dependence leads to a lower estimate of the fraction of reddened/obscured AGNs missed by optical surveys as compared to estimates derived from a single mean MIR to optical flux ratio

    Towards species-level forecasts of drought-induced tree mortality risk

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    Predicting species-level responses to drought at the landscape scale is critical to reducing uncertainty in future terrestrial carbon and water cycle projections. We embedded a stomatal optimisation model in the Community Atmosphere Biosphere Land Exchange (CABLE) land surface model and parameterised the model for 15 canopy dominant eucalypt tree species across South-Eastern Australia (mean annual precipitation range: 344–1424 mm yr−1). We conducted three experiments: applying CABLE to the 2017–2019 drought; a 20% drier drought; and a 20% drier drought with a doubling of atmospheric carbon dioxide (CO2). The severity of the drought was highlighted as for at least 25% of their distribution ranges, 60% of species experienced leaf water potentials beyond the water potential at which 50% of hydraulic conductivity is lost due to embolism. We identified areas of severe hydraulic stress within-species’ ranges, but we also pinpointed resilience in species found in predominantly semiarid areas. The importance of the role of CO2 in ameliorating drought stress was consistent across species. Our results represent an important advance in our capacity to forecast the resilience of individual tree species, providing an evidence base for decision-making around the resilience of restoration plantings or net-zero emission strategies

    ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling

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    ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.</p

    External sources of clean technology: evidence from the clean development mechanism

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    New technology is fundamental to sustainable development. However, inventors from industrialized countries often refuse technology transfer because they worry about reverse-engineering. When can clean technology transfer succeed? We develop a formal model of the political economy of North–South technology transfer. According to the model, technology transfer is possible if (1) the technology in focus has limited global commercial potential or (2) the host developing country does not have the capacity to absorb new technologies for commercial use. If both conditions fail, inventors from industrialized countries worry about the adverse competitiveness effects of reverse-engineering, so technology transfer fails. Data analysis of technology transfer in 4,894 projects implemented under the Kyoto Protocol’s Clean Development Mechanism during the 2004–2010 period provides evidence in support of the model

    Towards species‐level forecasts of drought‐induced tree mortality risk

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    Predicting species-level responses to drought at the landscape scale is critical to reducing uncertainty in future terrestrial carbon and water cycle projections. We embedded a stomatal optimisation model in the Community Atmosphere Biosphere Land Exchange (CABLE) land surface model and parameterised the model for 15 canopy dominant eucalypt tree species across South-Eastern Australia (mean annual precipitation range: 344–1424 mm yr−1). We conducted three experiments: applying CABLE to the 2017–2019 drought; a 20% drier drought; and a 20% drier drought with a doubling of atmospheric carbon dioxide (CO2). The severity of the drought was highlighted as for at least 25% of their distribution ranges, 60% of species experienced leaf water potentials beyond the water potential at which 50% of hydraulic conductivity is lost due to embolism. We identified areas of severe hydraulic stress within-species’ ranges, but we also pinpointed resilience in species found in predominantly semiarid areas. The importance of the role of CO2 in ameliorating drought stress was consistent across species. Our results represent an important advance in our capacity to forecast the resilience of individual tree species, providing an evidence base for decision-making around the resilience of restoration plantings or net-zero emission strategies
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