Asynchrony in key Holocene chronologies: Evidence from Irish bog pines

The Greenland Ice Core Chronology 2005 (GICC05) and the radiocarbon calibration curve (IntCal) are the foremost time scales used in paleoclimatic and paleoenvironmental studies of the most recent 10 k.y. Due to varying and often insufficient dating resolution, opportunities to test the synchrony of these two influential chronologies are rare. Here we present evidence for a phase of major pine recruitment on Irish bogs at ca. 8160 yr B.P. Dendrochronological dating of subfossil trees from three sites reveals synchronicity in germination across the study area, indicative of a regional forcing. The concurrent colonization of pine on peatland is interpreted in terms of drier surface conditions and provides the first substantive proxy data in support of a significant hydroclimatic change in the north of Ireland accompanying the 8.2 ka climate cooling event. The date of pine establishment does not overlap with the GICC05 age range for the event, and possible lags between responses are unlikely to explain the full difference. In light of recent studies highlighting a possible offset in GICC05 and IntCal dates, the Irish pine record supports the notion of ice core dates being too early during the period of study. If the suggested discrepancy in timing is an artifact of chronological error, it is likely to have affected interpretations of previous proxy comparisons and alignments.

Ultrastructure of head organs (anterior adhesive apparatus) and posterior secretory systems of Caballeria liewi Lim, 1995 (Monogenea, Ancyrocephalidae)

Caballeria liewi Lim, 1995, uses adhesive secretions from the head organs and posterior secretory systems to assist in locomotion and attachment. Ultrastructural investigations show that the head organs of C. liewi consist of three pairs of antero-lateral pit-like openings bearing microvilli and ducts leading from two types of uninucleated gland cells (located lateral to the pharynx), one type producing rod-like (S1) bodies with an electron-dense matrix containing less electron-dense vesicles and the second type producing oval (S2) bodies with a homogeneous electron-dense matrix. Interlinking band-like structures are observed between S1 bodies and between S2 bodies. S1 body is synthesised in the granular endoplasmic reticulum, transported to a Golgi complex to be packaged into vesicles and routed into ducts for exudation. The synthesis of the S2 body is unresolved. Haptoral secretions manifested externally as net-like structures are derived from dual electron-dense (DED) secretory body produced in the peduncular gland cells. The DED body consists of a less electron-dense oval core in a homogeneous electron-dense matrix. On exocytosis into the pyriform haptoral reservoir, DED bodies are transformed into a secretion with two types of inclusions (less electron-dense oval and electron-dense spherical inclusions) in an electron-dense matrix. The secretions are further transformed (as small, oval, electron-dense bodies) when transported to the superficial anchor grooves, and on exudation into the gill tissues, the secretions become an electron-dense matrix. Secretory bodies associated with uniciliated structures, anchor sleeves and marginal hooks are also observed.

PTEN mRNA detection by chromogenic, RNA in situ technologies: a reliable alternative to PTEN immunohistochemistry

Immunohistochemical staining for phosphatase and tensin homolog (PTEN) does not have either an acceptable standard protocol or concordance of scoring between pathologists. Evaluation of PTEN mRNA with a unique and verified sequence probe may offer a realistic alternative providing a robust and reproducible protocol. In this study, we have evaluated an in situ hybridization (ISH) protocol for PTEN mRNA using RNAScope technology and compared it with a standard protocol for PTEN immunohistochemistry (IHC). PTEN mRNA expression by ISH was consistently more sensitive than PTEN IHC, with 56% of samples on a mixed-tumor tissue microarray (TMA) showing high expression by ISH compared with 42% by IHC. On a prostate TMA, 49% of cases showed high expression by ISH compared with 43% by IHC. Variations in PTEN mRNA expression within malignant epithelium were quantifiable using image analysis on the prostate TMAs. Within tumors, clear overexpression of PTEN mRNA on malignant epithelium compared with benign epithelium was frequently observed and quantified. The use of SpotStudio software in the mixed-tumor TMA allowed for clear demonstration of varying levels of PTEN mRNA between tumor samples by the mRNA methodology. This was evident by the quantifiable differences between distinct oropharyngeal tumors (up to 3-fold increase in average number of spots per cell between 2 cases). mRNA detection of PTEN or other biomarkers, for which optimal or standardized immunohistochemical techniques are not available, represents a means by which heterogeneity of expression within focal regions of tumor can be explored with more confidence.

The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Although recent decades have seen an improved cure rate for newly diagnosed paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently, PBOX-15 differentially down-regulates β1-, β2- and α4-integrin expression in ALL cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes with the lateral mobility and clustering of integrins in both B-ALL and T-ALL cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis in ALL cells, but also has the potential to disrupt integrin-mediated adhesion of malignant lymphocytes, which represents a novel avenue for regulating leukaemic cell homing and migration.

Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches

In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93.38%), and a combined use of both approaches allowed a multi time-point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0.01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0.04), >0.01% at the end of induction (P = 0.02), >0.01% at the end of consolidation (P = 0.01), >0.01% prior to the first delayed intensification (P = 0.01), and >0.1% prior to the second delayed intensification and continued maintenance (P = 0.001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P = 0.0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.

European urban spaces in crisis - the mapping of affective pracitices with Living with Difference: introduction

The introduction outlines the notion of urban space and crisis in Europe while taking into account the more recent protests and riots in different cities, in and beyond Europe. It is argued that the phenomen of protest is happening alongside the economic crisis underscoring an alternative political public civic spirit expressing to a certain degree the renaissance and timely making of, what might be called in the digital age, #œuvre. Its forces and emotional properties capture a political realm that unfolds as a globalized urban transnational public space, still progressing. Further, it introduces the collection of papers for the special themed feature. Five papers look at affective practices through a Continental European lens, which places the meaning of race, migration and intersecting identity angles at the centre of debates of individual encounters in public spaces. The final and sixth paper, written by Brenda Yeoh, looks through a Singapore/East Asia lens, and comments on the common European threats as well as on the historical specificity and implications of distinctive geo-political spaces for affective practices.

Seeking the New Normal? Troubled Spaces of Encountering Visible Differences in Warsaw

In times of globalisation and super-mobility, ideas of normality are in turmoil. In different societies in, across and beyond Europe, we face the challenge of undoing specific notions of normality and creating more inclusive societies with an open culture of learning to live with differences. The scope of
the paper is to introduce some findings on encounters with difference and negotiations of social values in relation to a growing visibility of difference after 1989 in Poland, on the background of a critique of normality/normalisation and normalcy.On the basis of interviews conducted inWarsaw, we investigate how normality/normalisation discourses of visible homosexuality and physical disability are incorporated into individual self-reflections and justifications of prejudices (homophobia and disabilism). More specifically we argue that there are moments of ‘cultural transgressions’ present in everyday practices towards ‘visible’sexual and (dis)ability difference.

Automated tumor analysis for molecular profiling in lung cancer

The discovery and clinical application of molecular biomarkers in solid tumors, increasingly relies on nucleic acid extraction from FFPE tissue sections and subsequent molecular profiling. This in turn requires the pathological review of haematoxylin & eosin (H&E) stained slides, to ensure sample quality, tumor DNA sufficiency by visually estimating the percentage tumor nuclei and tumor annotation for manual macrodissection. In this study on NSCLC, we demonstrate considerable variation in tumor nuclei percentage between pathologists, potentially undermining the precision of NSCLC molecular evaluation and emphasising the need for quantitative tumor evaluation. We subsequently describe the development and validation of a system called TissueMark for automated tumor annotation and percentage tumor nuclei measurement in NSCLC using computerized image analysis. Evaluation of 245 NSCLC slides showed precise automated tumor annotation of cases using Tissuemark, strong concordance with manually drawn boundaries and identical EGFR mutational status, following manual macrodissection from the image analysis generated tumor boundaries. Automated analysis of cell counts for % tumor measurements by Tissuemark showed reduced variability and significant correlation (p < 0.001) with benchmark tumor cell counts. This study demonstrates a robust image analysis technology that can facilitate the automated quantitative analysis of tissue samples for molecular profiling in discovery and diagnostics.

Butt out - baby on board

It is estimated that the cost of treating women and their infants with smoking related problems is up to £87.5 million each year (ASH, 2013). Whilst these statistics depict a major problem for the National Health Service, they challenge midwives to become change agents within this health promotion area. A desired outcome from The Maternity Strategy for Northern Ireland (DHSSPSNI, 2012) includes giving every baby and family the best start in life. Assisting women to stop smoking before conception, could help to achieve this outcome and provide opportunities for a greater start in life following birth.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

The Abbey Rebels of 1916: A Lost Revolution

The Abbey Theatre played a leading role in the politicisation of the revolutionary generation that won Irish freedom, but comparatively little is known about the men and women who formed the lifeblood of the institution: those whose radical politics drove them to fight in the 1916 Rising.

Drawing on a huge range of previously unpublished material, The Abbey Rebels of Easter 1916 explores the experiences, hopes and dreams of these remarkable but largely forgotten individuals: Máire Nic Shiubhlaigh, the Abbey’s first leading lady; Peadar Kearney, author of the national anthem; feminist Helena Molony, the first female political prisoner of her generation; Seán Connolly, the first rebel to die in the Rising; carpenter Barney Murphy; usherette Ellen Bushell; and Hollywood star Arthur Shields.

Invigorating and provocative, this is the story of how, in the years following the Easter Rising, the radical ideals that inspired their revolution were gradually supplanted by a conservative vision of the nation Ireland would become. Lavishly illustrated with 200 documents and images, it provides a fresh and compelling account of the Rising and its aftermath.