T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14(ARF) and p21(WAF1/cip1). In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue. Oncogene (2010) 29, 3252-3262; doi: 10.1038/onc.2010.84; published online 29 March 2010

Cement mantle fatigue failure in total hip replacement: Experimental and computational testing

One possible loosening mechanism of the femoral component in total hip replacement is fatigue cracking of the cement mantle. A computational method capable of simulating this process may therefore be a useful tool in the preclinical evaluation of prospective implants. In this study, we investigated the ability of a computational method to predict fatigue cracking in experimental models of the implanted femur construct. Experimental specimens were fabricated such that cement mantle visualisation was possible throughout the test. Two different implant surface finishes were considered: grit blasted and polished. Loading was applied to represent level gait for two million cycles. Computational (finite element) models were generated to the same geometry as the experimental specimens, with residual stress and porosity simulated in the cement mantle. Cement fatigue and creep were modelled over a simulated two million cycles. For the polished stem surface finish, the predicted fracture locations in the finite element models closely matched those on the experimental specimens, and the recorded stem displacements were also comparable. For the grit blasted stem surface finish, no cement mantle fractures were predicted by the computational method, which was again in agreement with the experimental results. It was concluded that the computational method was capable of predicting cement mantle fracture and subsequent stem displacement for the structure considered. (C) 2006 Elsevier Ltd. All rights reserved.

Facile <em>in situ</em> synthesis of nanofluids based on ionic liquids and copper oxide clusters and nanoparticles

<p>Two stable nanofluids comprising of mixed valent copper(_I,_II) oxide clusters (&lt;1 nm) suspended in 1-butyl-3-methylimidazolium acetate, [C(₄)mim][OAc], and copper(_II) oxide nanoparticles (&lt;50 nm) suspended in trioctyl(dodecyl) phosphonium acetate, [P-₈₈₈₁₂][OAc], were synthesised in a facile one-pot reaction from solutions of copper(_II) acetate hydrate in the corresponding ionic liquids. Formation of the nanostructures was studied using ¹³C NMR spectroscopy and differential scanning calorimetry (DSC). From a solution of Cu(OAc)₂ in 1-ethyl-3-methylimidazolium acetate, [C₂mim][OAc], crystals were obtained that revealed the structure of [C₂mim][Cu₃(OAc)₅(OH)₂(H₂O)]center dot H₂O, indicating the formation of copper hydroxo-clusters in the course of the reaction. Synthesised nanostructures were studied using transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). Physical properties of the prepared IL-nanofluids were examined using IR and UV-VIS spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and densitometry. </p>

Enhancing the Activity and Tuning the Mechanism of Formic acid Oxidation at Tetrahexahedral Pt Nanocrystals by Au Decoration

Tetrahexahedral Pt nanocrystals (THH Pt NCs), bound by high index facets, belong to an emerging class of nanomaterials that promise to bridge the gap between model and practical electrocatalysts. The atomically stepped surfaces of THH Pt NCs are extremely active for the electrooxidation of small organic molecules but they also readily accommodate the dissociative chemisorption of such species, resulting in poisoning by strongly adsorbed CO. Formic acid oxidation is an ideal reaction for studying the balance between these competing catalyst characteristics, since it can proceed by either a direct or a CO mediated pathway. Herein, we describe electrochemical and in situ FTIR spectroscopic investigations of formic acid electrooxidation at both clean and Au adatom modified THH Pt NC surfaces. The Au decoration leads to higher catalytic currents and enhanced CO2 production in the low potential range. As the CO oxidation behaviour of the catalyst is not changed by the presence of the Au, it is likely that the role of the Au is to promote the direct pathway. Beyond their fundamental importance, these results are significant in the development of stable, poison resistant anodic electrocatalysts for direct formic acid fuel cells.

Climate-related changes in peatland carbon accumulation during the last millennium

Peatlands are a major terrestrial carbon store and a persistent natural carbon sink during the Holocene, but there is considerable uncertainty over the fate of peatland carbon in a changing climate. It is generally assumed that higher temperatures will increase peat decay, causing a positive feedback to climate warming and contributing to the global positive carbon cycle feedback. Here we use a new extensive database of peat profiles across northern high latitudes to examine spatial and temporal patterns of carbon accumulation over the past millennium. Opposite to expectations, our results indicate a small negative carbon cycle feedback from past changes in the long-term accumulation rates of northern peatlands. Total carbon accumulated over the last 1000 yr is linearly related to contemporary growing season length and photosynthetically active radiation, suggesting that variability in net primary productivity is more important than decomposition in determining long-term carbon accumulation. Furthermore, northern peatland carbon sequestration rate declined over the climate transition from the Medieval Climate Anomaly (MCA) to the Little Ice Age (LIA), probably because of lower LIA temperatures combined with increased cloudiness suppressing net primary productivity. Other factors including changing moisture status, peatland distribution, fire, nitrogen deposition, permafrost thaw and methane emissions will also influence future peatland carbon cycle feedbacks, but our data suggest that the carbon sequestration rate could increase over many areas of northern peatlands in a warmer future.

Lead(II) chloride ionic liquids and organic/inorganic hybrid materials - a study of chloroplumbate(II) speciation

<p>A range of chloroplumbate(II) organic salts, based on the two cations, 1-ethyl-3-methylimidazolium and trihexyl(tetradecyl) phosphonium, was prepared by ionothermal synthesis. Depending on the structure of the organic cation and on the molar ratio of PbCl2 in the product,.PbCl2, the salts were room-temperature ionic liquids or crystalline organic/inorganic hybrid materials. The solids were studied using Raman spectroscopy; the crystal structure of [C(2)mim]{PbCl3} was determined and shown to contain 1D infinite chloroplumbate(II) strands formed by edge-sharing tetragonal pyramids of pentacoordinate (PbCl5) units. The liquids were analysed using Pb-207 NMR and Raman spectroscopies, as well as viscometry. Phase diagrams were constructed based on differential scanning calorimetry (DSC) measurements. Discrete anions: [PbCl4](2-) and [PbCl3](-), were detected in the liquid state. The trichloroplumbate(II) anion was shown to have a flexible structure due to the presence of a stereochemically-active lone pair. The relationship between the liquid phase anionic speciation and the structure of the corresponding crystalline products of ionothermal syntheses was discussed, and the data were compared with analogous tin(II) systems.</p>

BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers

Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue.

TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.

TBX2 is an oncogenic transcription factor known to drive breast cancer proliferation. We have identified the cysteine protease inhibitor Cystatin 6 (CST6) as a consistently repressed TBX2 target gene, co-repressed through a mechanism involving Early Growth Response 1 (EGR1). Exogenous expression of CST6 in TBX2-expressing breast cancer cells resulted in significant apoptosis whilst non-tumorigenic breast cells remained unaffected. CST6 is an important tumor suppressor in multiple tissues, acting as a dual protease inhibitor of both papain-like cathepsins and asparaginyl endopeptidases (AEPs) such as Legumain (LGMN). Mutation of the CST6 LGMN-inhibitory domain completely abrogated its ability to induce apoptosis in TBX2-expressing breast cancer cells, whilst mutation of the cathepsin-inhibitory domain or treatment with a pan-cathepsin inhibitor had no effect, suggesting that LGMN is the key oncogenic driver enzyme. LGMN activity assays confirmed the observed growth inhibitory effects were consistent with CST6 inhibition of LGMN. Knockdown of LGMN and the only other known AEP enzyme (GPI8) by siRNA confirmed that LGMN was the enzyme responsible for maintaining breast cancer proliferation. CST6 did not require secretion or glycosylation to elicit its cell killing effects, suggesting an intracellular mode of action. Finally, we show that TBX2 and CST6 displayed reciprocal expression in a cohort of primary breast cancers with increased TBX2 expression associating with increased metastases. We have also noted that tumors with altered TBX2/CST6 expression show poor overall survival. This novel TBX2-CST6-LGMN signaling pathway, therefore, represents an exciting opportunity for the development of novel therapies to target TBX2 driven breast cancers.

Aerarium divini amoris locupletissimum: hoc est discursus variiexquisiti in quibus per tractatus ordine digestos ad verbum dei fructuose et faciliter praedicandum de passione domini nostri Jesu Christi et de sacratissima eucharistia materiae morales subministrantur et ad plenum digeruntur

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Le livre sous la loupe : Nouvelles formes d’écriture électronique

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The prompt hypothesis: clarification requests as corrective input for grammatical errors

The potential of clarification questions (CQs) to act as a form of corrective input for young children's grammatical errors was examined. Corrective responses were operationalized as those occasions when child speech shifted from erroneous to correct (E -> C) contingent on a clarification question. It was predicted that E -> C sequences would prevail over shifts in the opposite direction (C -> E), as can occur in the case of nonerror-contingent CQs. This prediction was tested via a standard intervention paradigm, whereby every 60s a sequence of two clarification requests (either specific or general) was introduced into conversation with a total of 45 2- and 4-year-old children. For 10 categories of grammatical structure, E -> C sequences predominated over their C -> E counterparts, with levels of E -> C shifts increasing after two clarification questions. Children were also more reluctant to repeat erroneous forms than their correct counterparts, following the intervention of CQs. The findings provide support for Saxton's prompt hypothesis, which predicts that error-contingent CQs bear the potential to cue recall of previously acquired grammatical forms.

Holocene environmental changes in the lower Thames Valley, London, UK: implications for our understanding of the history of Taxus woodland

A radiocarbon-dated multiproxy palaeoenvironmental record from the Lower Thames Valley at Hornchurch Marshes has provided a reconstruction of the timing and nature of vegetation succession against a background of Holocene climate change, relative sea level movement and human activities. The investigation recorded widespread peat formation between c. 6300 and 3900 cal. yr BP (marine ‘regression’), succeeded by evidence for marine incursion. The multiproxy analyses of these sediments, comprising pollen, Coleoptera, diatoms, and plant and wood macrofossils, have indicated significant changes in both the wetland and dryland environment, including the establishment of Alnus (Alder) carr woodland, and the decline of both Ulmus (Elm; c. 5740 cal. yr BP) and Tilia (Lime; c. 5600 cal. yr BP, and 4160–3710 cal. yr BP). The beetle faunas from the peat also suggest a thermal climate similar to that of the present day. At c. 4900 cal. yr BP, Taxus (L.; Yew) woodland colonised the peatland forming a plant community that has no known modern analogue in the UK. The precise reason, or reasons, for this event remain unclear, although changes in peatland hydrology seem most likely. The growth of Taxus on peatland not only has considerable importance for our knowledge of the vegetation history of southeast England, and NW Europe generally, but also has wider implications for the interpretation of Holocene palaeobotanical records. At c. 3900 cal. yr BP, Taxus declined on the peatland surface during a period of major hydrological change (marine incursion), an event also strongly associated with the decline of dryland woodland taxa, including Tilia and Quercus, and the appearance of anthropogenic indicators.

Climate-related changes in peatland carbon accumulation during the last millennium.

Peatlands are a major terrestrial carbon store and a persistent natural carbon sink during the Holocene, but there is considerable uncertainty over the fate of peatland carbon in a changing climate. It is generally assumed that higher temperatures will increase peat decay, causing a positive feedback to climate warming and contributing to the global positive carbon cycle feedback. Here we use a new extensive database of peat profiles across northern high latitudes to examine spatial and temporal patterns of carbon accumulation over the past millennium. Opposite to expectations, our results indicate a small negative carbon cycle feedback from past changes in the long-term accumulation rates of northern peatlands. Total carbon accumulated over the last 1000 yr is linearly related to contemporary growing season length and photosynthetically active radiation, suggesting that variability in net primary productivity is more important than decomposition in determining long-term carbon accumulation. Furthermore, northern peatland carbon sequestration rate declined over the climate transition from the Medieval Climate Anomaly (MCA) to the Little Ice Age (LIA), probably because of lower LIA temperatures combined with increased cloudiness suppressing net primary productivity. Other factors including changing moisture status, peatland distribution, fire, nitrogen deposition, permafrost thaw and methane emissions will also influence future peatland carbon cycle feedbacks, but our data suggest that the carbon sequestration rate could increase over many areas of northern peatlands in a warmer future.

Present state of global wetland extent and wetland methane modelling: conclusions from a model inter-comparison project (WETCHIMP)

Global wetlands are believed to be climate sensitive, and are the largest natural emitters of methane (CH4). Increased wetland CH4 emissions could act as a positive feedback to future warming. The Wetland and Wetland CH4 Inter-comparison of Models Project (WETCHIMP) investigated our present ability to simulate large-scale wetland characteristics and corresponding CH4 emissions. To ensure inter-comparability, we used a common experimental protocol driving all models with the same climate and carbon dioxide (CO2) forcing datasets. The WETCHIMP experiments were conducted for model equilibrium states as well as transient simulations covering the last century. Sensitivity experiments investigated model response to changes in selected forcing inputs (precipitation, temperature, and atmospheric CO2 concentration). Ten models participated, covering the spectrum from simple to relatively complex, including models tailored either for regional or global simulations. The models also varied in methods to calculate wetland size and location, with some models simulating wetland area prognostically, while other models relied on remotely sensed inundation datasets, or an approach intermediate between the two. Four major conclusions emerged from the project. First, the suite of models demonstrate extensive disagreement in their simulations of wetland areal extent and CH4 emissions, in both space and time. Simple metrics of wetland area, such as the latitudinal gradient, show large variability, principally between models that use inundation dataset information and those that independently determine wetland area. Agreement between the models improves for zonally summed CH4 emissions, but large variation between the models remains. For annual global CH4 emissions, the models vary by ±40% of the all-model mean (190 Tg CH4 yr−1). Second, all models show a strong positive response to increased atmospheric CO2 concentrations (857 ppm) in both CH4 emissions and wetland area. In response to increasing global temperatures (+3.4 °C globally spatially uniform), on average, the models decreased wetland area and CH4 fluxes, primarily in the tropics, but the magnitude and sign of the response varied greatly. Models were least sensitive to increased global precipitation (+3.9 % globally spatially uniform) with a consistent small positive response in CH4 fluxes and wetland area. Results from the 20th century transient simulation show that interactions between climate forcings could have strong non-linear effects. Third, we presently do not have sufficient wetland methane observation datasets adequate to evaluate model fluxes at a spatial scale comparable to model grid cells (commonly 0.5°). This limitation severely restricts our ability to model global wetland CH4 emissions with confidence. Our simulated wetland extents are also difficult to evaluate due to extensive disagreements between wetland mapping and remotely sensed inundation datasets. Fourth, the large range in predicted CH4 emission rates leads to the conclusion that there is both substantial parameter and structural uncertainty in large-scale CH4 emission models, even after uncertainties in wetland areas are accounted for.

Changes in fire regimes since the Last Glacial Maximum: an assessment based on a global synthesis and analysis of charcoal data

Fire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load