Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice

p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53+/+, MMTV-Hras/p53-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53+/+ mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors were tightly clustered, and clearly distinct from the profiles of the MMTV-Hras/p53+/+ tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53

Covalent grafting of molecular catalysts on C₄NₓH_{y} as robust, efficient and well-defined photocatalysts for solar fuel synthesis

The covalent attachment of molecules to 2D materials is an emerging area as strong covalent chemistry offers new hybrid properties and greater mechanical stability compared with nanoparticles. A nickel bis-aminothiophenol catalyst was grafted onto a range of 2D carbon nitrides C₄NₓH_{y} to form noble metal-free photocatalysts for H2 production. The hybrids produce H_{2} beyond 8 days with turnover numbers reaching 1360 based on nickel, a more than 3 fold higher durability than reported molecular catalyst-carbon nitride mixtures, and under longer wavelengths (>475 nm). Time-resolved spectroscopy reveals sub-microsecond electron transfer to the grafted catalyst, six orders of magnitude faster compared with similar reports of non-grafted catalysts. The photoelectrons on the catalyst have a ca. 1000 times longer half-time (7 ms) compared with bare carbon nitride (10 μs). The grafting strategy operates across a range of molecular catalyst-carbon nitride combinations, thus paving the way for robust efficient photocatalysts based on low-cost tunable components

Extending enzyme molecular recognition with an expanded amino acid alphabet

Natural enzymes are constructed from the twenty proteogenic amino acids, which may then require post-translational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of non-canonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity. Specifically, 13 different non-canonical side chains were incorporated at 12 different positions within the active site of N-acetylneuraminic acid lyase (NAL), and the resulting chemically-modified enzymes were screened for activity with a range of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity was not achievable with any of the 20 proteogenic amino acids. Structural and modelling studies revealed that the unique shape and functionality of the non-canonical side chain enabled the active site to be remodelled to enable more efficient stabilisation of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions of protein engineers wishing to develop enzymes with new catalytic properties

Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study.

Abstract Objective: Iron deficiency (ID) and iron deficiency anaemia (IDA) are global major public health problems, particularly in developing countries. Whilst an association between H. pylori infection and ID/IDA has been proposed in the literature, currently there is no consensus. We studied the effects of H. pylori infection on ID/IDA in a cohort of children undergoing upper gastrointestinal endoscopy for upper abdominal pain in two developing and one developed country. Methods: In total 311 children (mean age 10.763.2 years) from Latin America -Belo Horizonte/Brazil (n = 125), Santiago/ Chile (n = 105) -and London/UK (n = 81), were studied. Gastric and duodenal biopsies were obtained for evaluation of histology and H. pylori status and blood samples for parameters of ID/IDA. Results: The prevalence of H. pylori infection was 27.7% being significantly higher (p,0.001) in Latin America (35%) than in UK (7%). Multiple linear regression models revealed H. pylori infection as a significant predictor of low ferritin and haemoglobin concentrations in children from Latin-America. A negative correlation was observed between MCV (r = 20.26; p = 0.01) and MCH (r = 20.27; p = 0.01) values and the degree of antral chronic inflammation, and between MCH and the degree of corpus chronic (r = 20.29, p = 0.008) and active (r = 20.27, p = 0.002) inflammation. Conclusions: This study demonstrates that H. pylori infection in children influences the serum ferritin and haemoglobin concentrations, markers of early depletion of iron stores and anaemia respectively

Iron status and Helicobacter pylori infection in symptomatic children: an international multi-centered study.

Abstract Objective: Iron deficiency (ID) and iron deficiency anaemia (IDA) are global major public health problems, particularly in developing countries. Whilst an association between H. pylori infection and ID/IDA has been proposed in the literature, currently there is no consensus. We studied the effects of H. pylori infection on ID/IDA in a cohort of children undergoing upper gastrointestinal endoscopy for upper abdominal pain in two developing and one developed country. Methods: In total 311 children (mean age 10.763.2 years) from Latin America -Belo Horizonte/Brazil (n = 125), Santiago/ Chile (n = 105) -and London/UK (n = 81), were studied. Gastric and duodenal biopsies were obtained for evaluation of histology and H. pylori status and blood samples for parameters of ID/IDA. Results: The prevalence of H. pylori infection was 27.7% being significantly higher (p,0.001) in Latin America (35%) than in UK (7%). Multiple linear regression models revealed H. pylori infection as a significant predictor of low ferritin and haemoglobin concentrations in children from Latin-America. A negative correlation was observed between MCV (r = 20.26; p = 0.01) and MCH (r = 20.27; p = 0.01) values and the degree of antral chronic inflammation, and between MCH and the degree of corpus chronic (r = 20.29, p = 0.008) and active (r = 20.27, p = 0.002) inflammation. Conclusions: This study demonstrates that H. pylori infection in children influences the serum ferritin and haemoglobin concentrations, markers of early depletion of iron stores and anaemia respectively

The Moderating Effects of Peer and Parental Support on the Relationship Between Vicarious Victimization and Substance Use

General strain theory (GST) hypothesizes that youth are more likely to engage in delinquency when they experience vicarious victimization, defined as knowing about or witnessing violence perpetrated against others, but that this relationship may be attenuated for those who receive social support from significant others. Based on prospective data from youth aged 8 to 17 participating in the Project on Human Development in Chicago Neighborhoods (PHDCN), this article found mixed support for these hypotheses. Controlling for prior involvement in delinquency, as well as other risk and protective factors, adolescents who reported more vicarious victimization had an increased likelihood of alcohol use in the short term, but not the long term, and victimization was not related to tobacco or marijuana use. Peer support did not moderate the relationship between vicarious victimization and substance use, but family support did. In contrast to strain theory’s predictions, the relationship between vicarious victimization and substance use was stronger for those who had higher compared with lower levels of family support. Implications of these findings for strain theory and future research are discussed

Regulation of pituitary MT1 melatonin receptor expression by gonadotrophin-releasing hormone (GnRH) and early growth response factor-1 (Egr-1) : in vivo and in vitro studies

Copyright: © 2014 Bae et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC; grant BB/F020309/1; http://www.bbsrc.ac.uk/home/home.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Preparatory planning framework for Created Out of Mind: Shaping perceptions of dementia through art and science [version 1; referees: 2 approved]

Created Out of Mind is an interdisciplinary project, comprised of individuals from arts, social sciences, music, biomedical sciences, humanities and operational disciplines. Collaboratively we are working to shape perceptions of dementias through the arts and sciences, from a position within the Wellcome Collection. The Collection is a public building, above objects and archives, with a porous relationship between research, museum artefacts, and the public. This pre-planning framework will act as an introduction to Created Out of Mind. The framework explains the rationale and aims of the project, outlines our focus for the project, and explores a number of challenges we have encountered by virtue of working in this way

Electric field-modulated non-ohmic behavior of carbon nanotube fibers in polar liquids.

We report a previously unseen non-ohmic effect in which the resistivity of carbon nanotube fibers immersed in polar liquids is modulated by the applied electric field. This behavior depends on the surface energy, dielectric constant, and viscosity of the immersion media. Supported by synchrotron SAXS and impedance spectroscopy, we propose a model in which the gap distance, and thus the conductance, of capacitive interbundle junctions is controlled by the applied field.JT acknowledges generous financial support from: The Cambridge Commonwealth European and International Trust, CONACyT (Mexico), Dyson Ltd, and Pembroke College Cambridge. JJV acknowledges support from MINECO (Spain) and FP7-People-Marie Curie Action-CIG.This is the accepted manuscript. The final version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/nn5030835