BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs. Oncogene (2012) 31, 3667-3678; doi:10.1038/onc.2011.531; published online 28 November 2011

Eclipsing Binary Science via the Merging of Transit and Doppler Exoplanet Survey Data—A Case Study with the MARVELS Pilot Project and SuperWASP

Exoplanet transit and Doppler surveys discover many binary stars during their operation that can be used to conduct a variety of ancillary science. Specifically, eclipsing binary stars can be used to study the stellar mass-radius relationship and to test predictions of theoretical stellar evolution models. By cross-referencing 24 binary stars found in the MARVELS Pilot Project with SuperWASP photometry, we find two new eclipsing binaries, TYC 0272-00458-1 and TYC 1422-01328-1, which we use as case studies to develop a general approach to eclipsing binaries in survey data. TYC 0272-00458-1 is a single-lined spectroscopic binary for which we calculate a mass of the secondary and radii for both components using reasonable constraints on the primary mass through several different techniques. For a primary mass of M 1 = 0.92 ± 0.1 M sun, we find M 2 = 0.610 ± 0.036 M sun, R 1 = 0.932 ± 0.076 R sun, and R 2 = 0.559 ± 0.102 R sun, and find that both stars have masses and radii consistent with model predictions. TYC 1422-01328-1 is a triple-component system for which we can directly measure the masses and radii of the eclipsing pair. We find that the eclipsing pair consists of an evolved primary star (M 1 = 1.163 ± 0.034 M sun, R 1 = 2.063 ± 0.058 R sun) and a G-type dwarf secondary (M 2 = 0.905 ± 0.067 M sun, R 2 = 0.887 ± 0.037 R sun). We provide the framework necessary to apply this analysis to much larger data sets.

Measurements of energy transport patterns in solid density laser plasma interactions at intensities of 5x10(20) W cm(-2)

K-alpha x-ray emission, extreme ultraviolet emission, and plasma imaging techniques have been used to diagnose energy transport patterns in copper foils ranging in thickness from 5 to 75 mu m for intensities up to 5x10(20) Wcm(-20). The K-alpha emission and shadowgrams both indicate a larger divergence angle than that reported in the literature at lower intensities [R. Stephens , Phys. Rev. E 69, 066414 (2004)]. Foils 5 mu m thick show triple-humped plasma expansion patterns at the back and front surfaces. Hybrid code modeling shows that this can be attributed to an increase in the mean energy of the fast electrons emitted at large radii, which only have sufficient energy to form a plasma in such thin targets.

ELECTRON IMMUNOGOLD LABELING OF REGULATORY PEPTIDE IMMUNOREACTIVITY IN THE NERVOUS-SYSTEM OF MONIEZIA-EXPANSA (CESTODA, CYCLOPHYLLIDEA)

An electron immunogold-labeling technique was used in conjunction with a post-embedding procedure to demonstrate for the first time the ultrastructural distribution of the parasitic platyhelminth neuropeptide, neuropeptide F (NPF), in the nervous system of the cestode Moniezia expansa. Two axon types, distinguished by their populations of different-sized electron-dense vesicles, were identified. Immunogold labeling demonstrated an apparent homogeneity of PP, FMRFamide and NPF (M. expansa) antigenic sites throughout the larger dense-cored vesicles within the central nervous system. Triple labeling clearly demonstrated the co-localisation of immunoreactivities (IR) for NPF, PP and FMRFamide within the same dense-cored vesicles. The presence of NPF-IR within the vesicles occupying the perikaryon of the neuronal cell body indicated that the peptides had undergone post-translational C-terminal amidation prior to entering the axon. Antigen pre-absorption experiments using NPF prevented labeling with either PP or FMRFamide antisera, and the failure of these antisera to block NPF-IR supports the view that some, if not all, of the PP/FMRFamide-IR is due to NPF-like peptides.

An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling

Undecaprenyl phosphate (Und-P) is a universal lipid carrier of glycan biosynthetic intermediates for carbohydrate polymers that are exported to the bacterial cell envelope. Und-P arises from the dephosphorylation of undecaprenyl pyrophosphate (Und-PP) molecules produced by de novo synthesis and also from the recycling of released Und-PP after the transfer of the glycan component to other acceptor molecules. The latter reactions take place at the periplasmic side of the plasma membrane, while cytoplasmic enzymes catalyse the de novo synthesis. Four Und-PP pyrophosphatases were recently identified in Escherichia coli. One of these, UppP (formerly BacA), accounts for 75 % of the total cellular Und-PP pyrophosphatase activity and has been suggested to participate in the Und-P de novo synthesis pathway. Unlike UppP, the other three pyrophosphatases (YbjG, YeiU and PgpB) have a typical acid phosphatase motif also found in eukaryotic dolichyl-pyrophosphate-recycling pyrophosphatases. This study shows that double and triple deletion mutants in the genes uppP and ybjG, and uppP, ybjG and yeiU, respectively, are supersensitive to the Und-P de novo biosynthesis inhibitor fosmidomycin. In contrast, single or combined deletions including pgpB have no effect on fosmidomycin supersensitivity. Experimental evidence is also presented that the acid phosphatase motifs of YbjG and YeiU face the periplasmic space. Furthermore, the quadruple deletion mutant DeltauppP-DeltaybjG-DeltayeiU-DeltawaaL has a growth defect and abnormal cell morphology, suggesting that accumulation of unprocessed Und-PP-linked O antigen polysaccharides is toxic for these cells. Together, the results support the notion that YbjG, and to a lesser extent YeiU, exert their enzymic activity on the periplasmic side of the plasma membrane and are implicated in the recycling of periplasmic Und-PP molecules.

z'-band Ground-based Detection of the Secondary Eclipse of WASP-19b

We present the ground-based detection of the secondary eclipse of the transiting exoplanet WASP-19b. The observations were made in the Sloan z' band using the ULTRACAM triple-beam CCD camera mounted on the New Technology Telescope. The measurement shows a 0.088% ± 0.019% eclipse depth, matching previous predictions based on H- and K-band measurements. We discuss in detail our approach to the removal of errors arising due to systematics in the data set, in addition to fitting a model transit to our data. This fit returns an eclipse center, T 0, of 2455578.7676 HJD, consistent with a circular orbit. Our measurement of the secondary eclipse depth is also compared to model atmospheres of WASP-19b and is found to be consistent with previous measurements at longer wavelengths for the model atmospheres we investigated.

Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica

The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported for human cathepsin K. The 1.4-A three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and K provided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite.

Comparing the influence of two different natural organic matter types on colloid deposition in saturated porous medium

Humic acid and protein are two major organic matter types encountered in natural and polluted environment, respectively. This study employed Triple Pulse Experiments (TPEs) to investigate and compare the influence of Suwannee River Humic Acid (SRHA) (model humic acid) and Bovine Serum Albumin (BSA) (model protein) on colloid deposition in a column packed with saturated iron oxide-coated quartz sand. Study results suggest that adsorbed SRHA may inhibit colloid deposition by occupying colloid sites on the porous medium. Conversely, BSA may promote colloid deposition by a 'filter ripening' mechanism. This study provides insight to understand the complex behavior of colloids in organic matter-presented aquifers and sand filters. © (2012) Trans Tech Publications, Switzerland.

Neonatal facial and cry responses to invasive and non-invasive procedures

Evaluation of pain in neonates is difficult due to their limited means of communication. The aim was to determine whether behavioural reactions of cry and facial activity provoked by an invasive procedure could be discriminated from responses to non-invasive tactile events. Thirty-six healthy full-term infants (mean age 2.2 h) received 3 procedures in counterbalanced order: intramuscular injection, application of triple dye to the umbilical stub, and rubbing thigh with alcohol. Significant effects of procedure were found for total face activity and latency to face movement. A cluster of facial actions comprised of brow bulging, eyes squeezed shut, deepening of the naso-labial furrow and open mouth was associated most frequently with the invasive procedure. Comparisons between the 2 non-invasive procedures showed more facial activity to thigh swabbing and least to application of triple dye to the umbilical cord. Acoustic analysis of cry showed statistically significant differences across procedures only for latency to cry and cry duration for the group as a whole. However, babies who cried to two procedures showed higher pitch and greater intensity to the injection. There were no significant differences in melody, dysphonation, or jitter. Methodological difficulties for investigators in this area were examined, including criteria for the selection of cries for analysis, and the logical and statistical challenges of contrasting cries induced by different conditions when some babies do not always cry. It was concluded that facial expression, in combination with short latency to onset of cry and long duration of first cry cycle typifies reaction to acute invasive procedures.

Measuring oxygen reduction/evolution reactions on the nanoscale

The efficiency of fuel cells and metal-air batteries is significantly limited by the activation of oxygen reduction and evolution reactions. Despite the well-recognized role of oxygen reaction kinetics on the viability of energy technologies, the governing mechanisms remain elusive and until now have been addressable only by macroscopic studies. This lack of nanoscale understanding precludes optimization of material architecture. Here, we report direct measurements of oxygen reduction/evolution reactions and oxygen vacancy diffusion on oxygen-ion conductive solid surfaces with sub-10 nm resolution. In electrochemical strain microscopy, the biased scanning probe microscopy tip acts as a moving, electrocatalytically active probe exploring local electrochemical activity. The probe concentrates an electric field in a nanometre-scale volume of material, and bias-induced, picometre-level surface displacements provide information on local electrochemical processes. Systematic mapping of oxygen activity on bare and platinum-functionalized yttria-stabilized zirconia surfaces is demonstrated. This approach allows direct visualization of the oxygen reduction/evolution reaction activation process at the triple-phase boundary, and can be extended to a broad spectrum of oxygen-conductive and electrocatalytic materials.

Behavioural and cognitive-behavioural group-based parenting programmes for early-onset conduct problems in children aged 3 to 12 years.

Early-onset child conduct problems are common and costly. A large number of studies and some previous reviews have focused on behavioural and cognitive-behavioural group-based parenting interventions, but methodological limitations are commonplace and evidence for the effectiveness and cost-effectiveness of these programmes has been unclear. To assess the effectiveness and cost-effectiveness of behavioural and cognitive-behavioural group-based parenting programmes for improving child conduct problems, parental mental health and parenting skills. We searched the following databases between 23 and 31 January 2011: CENTRAL (2011, Issue 1), MEDLINE (1950 to current), EMBASE (1980 to current), CINAHL (1982 to current), PsycINFO (1872 to current), Social Science Citation Index (1956 to current), ASSIA (1987 to current), ERIC (1966 to current), Sociological Abstracts (1963 to current), Academic Search Premier (1970 to current), Econlit (1969 to current), PEDE (1980 to current), Dissertations and Theses Abstracts (1980 to present), NHS EED (searched 31 January 2011), HEED (searched 31 January 2011), DARE (searched 31 January 2011), HTA (searched 31 January 2011), mRCT (searched 29 January 2011). We searched the following parent training websites on 31 January 2011: Triple P Library, Incredible Years Library and Parent Management Training. We also searched the reference lists of studies and reviews. We included studies if: (1) they involved randomised controlled trials (RCTs) or quasi-randomised controlled trials of behavioural and cognitive-behavioural group-based parenting interventions for parents of children aged 3 to 12 years with conduct problems, and (2) incorporated an intervention group versus a waiting list, no treatment or standard treatment control group. We only included studies that used at least one standardised instrument to measure child conduct problems. Two authors independently assessed the risk of bias in the trials and the methodological quality of health economic studies. Two authors also independently extracted data. We contacted study authors for additional information. This review includes 13 trials (10 RCTs and three quasi-randomised trials), as well as two economic evaluations based on two of the trials. Overall, there were 1078 participants (646 in the intervention group; 432 in the control group). The results indicate that parent training produced a statistically significant reduction in child conduct problems, whether assessed by parents (standardised mean difference (SMD) -0.53; 95% confidence interval (CI) -0.72 to -0.34) or independently assessed (SMD -0.44; 95% CI -0.77 to -0.11). The intervention led to statistically significant improvements in parental mental health (SMD -0.36; 95% CI -0.52 to -0.20) and positive parenting skills, based on both parent reports (SMD -0.53; 95% CI -0.90 to -0.16) and independent reports (SMD -0.47; 95% CI -0.65 to -0.29). Parent training also produced a statistically significant reduction in negative or harsh parenting practices according to both parent reports (SMD -0.77; 95% CI -0.96 to -0.59) and independent assessments (SMD -0.42; 95% CI -0.67 to -0.16). Moreover, the intervention demonstrated evidence of cost-effectiveness. When compared to a waiting list control group, there was a cost of approximately $2500 (GBP 1712; EUR 2217) per family to bring the average child with clinical levels of conduct problems into the non-clinical range. These costs of programme delivery are modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Behavioural and cognitive-behavioural group-based parenting interventions are effective and cost-effective for improving child conduct problems, parental mental health and parenting skills in the short term. The cost of programme delivery was modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Further research is needed on the long-term assessment of outcomes.

Parenting Programmes: The Best Available Evidence

Parenting programmes have been provided to a wide range of child and parent groups across a number of countries, but are they effective? This aim of this paper is to examine the findings from a number of systematic reviews that summarise the best available research evidence on the impact of these programmes on a range of parental and child outcomes. In addition to examining the findings from systematic reviews, the paper also takes a selective look at the uptake of parenting programmes in the United Kingdom, the evidence for effectiveness and the efficacy of adopting a population-based approach to parent education.

The findings from systematic reviews indicate that parenting programmes can have a positive impact on a range of outcomes, including improved child behaviour, increased maternal self-esteem and relationship adjustment, improved mother–child interaction and knowledge and decreased maternal depression and stress. While there is a need for greater evaluation of the long-term impact of these programmes, preliminary evidence indicates that these positive results are maintained over time, with group-based, behaviourally orientated programmes tending to be more effective.

While several recent trials indicate that that these programmes can be effective within the United Kingdom, high drop-out rates may mean that they only reach a minority of parents. However, multi-level parent education strategies such as the Australian Triple P Positive Parenting Strategy that incorporate an array of mediums aimed at different levels of need may provide an opportunity to reach a wider range of parents. This approach is currently being evaluated in order to ascertain whether it is effective in improving child outcomes in the general population.

While there is no coherent strategy for parent training across the United Kingdom, within the Northern Ireland context there is a move towards the development of a family support strategy. While uptake of parent education and training is currently unknown the best available evidence highlights the positive impact that parent training can have, suggesting the importance of including parent education as one aspect of this strategy

A Probe-Goal Approach to Agreement and Incorporation Restrictions in Southern Tiwa

Southern Tiwa (Tanoan) exhibits agreement with up to three arguments (ergative, absolutive, dative). This agreement is subject to certain restrictions resembling the Person-Case Constraint paradigm (Bonet 1991). Moreover, there is a correlation between agreement restrictions and conditions on (the obviation of) noun-incorporation in Southern Tiwa, as explicitly and elegantly captured by Rosen (1990) in terms of a heterogeneous feature hierarchy and rules of association. We attempt to recast Rosen’s central insights in terms of Anagnostopoulou’s probe-sharing model of Person-Case Constraint effects (Anagnostopoulou 2003, 2006), to show that the full range of Southern Tiwa agreement and (non-)incorporation restrictions can be given a single, unified analysis within the probe-goal-Agree framework of Chomsky (2001). In particular, we argue that Southern Tiwa’s triple-agreement system is characterized by (a) an independent class probe located on the heads T and v, and (b) a rule that allows this class probe to be deleted in the context of local-person T-agreement. The various restrictions on agreement and non-incorporation then reduce to a single source: failure of class-valuation with DP (as opposed to NP) arguments.

Small RNA-mediated chromatin silencing directed to the 3' region of the Arabidopsis gene encoding the developmental regulator, FLC.

Small RNA-mediated chromatin silencing is well characterized for repeated sequences and transposons, but its role in regulating single-copy endogenous genes is unclear. We have identified two small RNAs (30 and 24 nucleotides) corresponding to the reverse strand 3' to the canonical poly(A) site of FLOWERING LOCUS C (FLC), an Arabidopsis gene encoding a repressor of flowering. Genome searches suggest that these RNAs originate from the FLC locus in a genomic region lacking repeats. The 24-nt small RNA, which is most abundant in developing fruits, is absent in mutants defective in RNA polymerase IVa, RNA-DEPENDENT RNA POLYMERASE 2, and DICER-LIKE 3, components required for RNAi-mediated chromatin silencing. The corresponding genomic region shows histone 3 lysine 9 dimethylation, which was reduced in a dcl2,3,4 triple mutant. Investigations into the origins of the small RNAs revealed a polymerase IVa-dependent spliced, antisense transcript covering the 3' FLC region. Mutation of this genomic region by T-DNA insertion led to FLC misexpression and delayed flowering, suggesting that RNAi-mediated chromatin modification is an important component of endogenous pathways that function to suppress FLC expression.

Afterword::Innovation, Ecological Modernisation and the ‘Post-Conflict’ Policy Agenda

Perhaps the weakest dimension of the ‘triple bottom line’ understanding of
sustainable development has been the ‘economic’ dimension. Much of the thinking
about the appropriate ‘political economy’ to underpin sustainable development has
been either utopian (as in some ‘environmental’ political views) or ‘business as usual’ approaches. Rejecting both of these utopian and realist views, it is clear from the papers presented here and the conference debates that something like ‘ecological modernisation’ is the preferred conceptualisation of ‘sustainable development’ within policy circles in Northern Ireland, the UK and other European states.