TGFβ and CCN2/CTGF mediate actin related gene expression by differential E2F1/CREB activation

CCN2/CTGF is an established effector of TGFß driven responses in diabetic nephropathy. We have identified an interaction between CCN2 and TGFß leading to altered phenotypic differentiation and inhibited cellular migration. Here we determine the gene expression profile associated with this phenotype and define a transcriptional basis for differential actin related gene expression and cytoskeletal function.

Leaded Strand Lamp:Selected for Inclusion for an Exhibition of the best of irish Design as part of the Vernacular Exhibition in London Design Festival 2013. Curated by Ann Mulrooney

Contemporary product made using traditional Northern irish metal craft skills

Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism. © 2012 Macmillan Publishers Limited

NEC Contracting: Evaluation of the Inclusion of Dispute Review Boards in lieu of Adjudication in the Construction Industry in the United Kinddom

The construction industry is renowned for spending vast sums in the resolution of disputes, but never in the prevention. The purpose of this paper is to analyse the New Engineering Contract (NEC) to determine whether or not adjudication has become misaligned with the contract’s objective of promoting effective management. In doing so, the paper examines dispute review boards in order to ascertain if they could be a viable alternative to adjudication. A sequential mixed methodology is adopted including a detailed literature review, eight semi-structured interviews, culminating in the circulation and analysis of a questionnaire, to record the significance of the factors identified. The research concludes that the majority of individuals agree that dispute review boards would be more aligned with the NEC. The familiarity of members, the potential to curb rogue behaviour of parties and the proactive nature of the board are flagged as positive features, however the cost aspect requires further investigation. The reservations made in the study about adjudication, such as the priority given to speed over accuracy and also the adversarial nature of the process, suggest that a preventative step prior to proceeding to adjudication would coincide more with the three core themes of the NEC Contract and therefore, be a positive addition.

Differential expression of liver fluke β-tubulin isotypes at selected life cycle stages

We have shown that Fasciola hepatica expresses at least six ß-tubulins in the adult stage of its life cycle, designated F.hep-ß-tub1-6 (Ryan et al., 2008). Here we show that different complements of tubulin isotypes are expressed in different tissues and at different life cycle stages; this information may inform the search for novel anthelmintics. The predominant (as judged by quantitative PCR) isotype transcribed at the adult stage was F.hep-ß-tub1 and immunolocalisation studies revealed that this isotype occurred mainly in mature spermatozoa and vitelline follicles. Quantitative PCR indicated that changes occurred in the transcription levels of ß-tubulin isotypes at certain life cycle stages and may be of importance in the efficacy of benzimidazole-based anthelmintic drugs, but there were no significant differences between the triclabendazole (TCBZ)-susceptible Leon isolate and the TCBZ-resistant Oberon isolate in the transcription levels of each of the isotypes. When three well-characterised isolates with differing susceptibilities to TCBZ were compared, only one amino acid change resulting from a homozygous coding sequence difference (Gly269Ser) in isotype 4 was observed. However, this change was not predicted to alter the overall structure of the protein. In conclusion, these findings indicate that there is tissue-specific expression of tubulin isotypes in the liver fluke but the development of resistance to TCBZ is not associated with changes in its presumed target molecule.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

New Perspectives on the Role of Cultural Intermediaries in Social Inclusion in the UK

Based on interviews with arts administrators responsible for addressing targeted groups labelled “socially excluded,” this paper highlights new understandings of the term “cultural intermediary” (Featherstone 1991; Bourdieu 2000) within art galleries and art centres. It considers the unique role of such figures in crossing the exclusion/inclusion boundary within the arts and developing more personal approaches to marketing activities in their institutions through relationship building. While it is acknowledged here that such workers find themselves in a privileged position in being able to shape questions of taste and particular consumerist dispositions to understanding the art world, little, if not no, effort has been made to understand this process. As such, there remains a void between the cultural policy‐oriented conception of social inclusion, which implies a version of repairing the “flawed consumer” (Bauman 2005), and the way in which such policy is played out on the ground.

A Case Study in Policy Delivery:Examining Social Inclusion through Interpretation and Practice

The current body of literature regarding social inclusion and the arts tends to focus
on two areas: the lack of clear or common understanding of the terminology involved
(GLLAM, 2000) and the difficulty in measuring impact (Newman 2001). Further, much
of the literature traces the historical evolution of social inclusion policy within the arts
from a political and social perspective (Belfiore & Bennett, 2007), whilst others
examine the situation in the context of the museum as an institution more generally
(Sandell, 2002b). Such studies are essential; however they only touch on the
importance of understanding the context of social inclusion programmes. As each
individual’s experience of exclusion (or inclusion) is argued to be different (Newman
et al., 2005) and any experience is also process-based (SEU 2001), there is a need
for more thorough examination of the processes underpinning project delivery
(Butterfoss, 2006), particularly within a field that has its own issues of exclusion, such
as the arts (Bourdieu & Darbel, 1991). This paper presents case study findings of a
programme of contemporary arts participation for adults with learning difficulties
based at an arts centre in Liverpool. By focusing on practice, the paper applies
Wenger’s (1998) social theory of learning in order to assert that rather than search
for measurable impacts, examining the delivery of programmes within their individual
contexts will provide the basis for a more reflective practice and thus more effective
policy making.

Gene Sets Net Correlations Analysis (GSNCA): a multivariate differential coexpression test for gene sets

Motivation: To date, Gene Set Analysis (GSA) approaches primarily focus on identifying differentially expressed gene sets (pathways). Methods for identifying differentially coexpressed pathways also exist but are mostly based on aggregated pairwise correlations, or other pairwise measures of coexpression. Instead, we propose Gene Sets Net Correlations Analysis (GSNCA), a multivariate differential coexpression test that accounts for the complete correlation structure between genes.

Results: In GSNCA, weight factors are assigned to genes in proportion to the genes' cross-correlations (intergene correlations). The problem of finding the weight vectors is formulated as an eigenvector problem with a unique solution. GSNCA tests the null hypothesis that for a gene set there is no difference in the weight vectors of the genes between two conditions. In simulation studies and the analyses of experimental data, we demonstrate that GSNCA, indeed, captures changes in the structure of genes' cross-correlations rather than differences in the averaged pairwise correlations. Thus, GSNCA infers differences in coexpression networks, however, bypassing method-dependent steps of network inference. As an additional result from GSNCA, we define hub genes as genes with the largest weights and show that these genes correspond frequently to major and specific pathway regulators, as well as to genes that are most affected by the biological difference between two conditions. In summary, GSNCA is a new approach for the analysis of differentially coexpressed pathways that also evaluates the importance of the genes in the pathways, thus providing unique information that may result in the generation of novel biological hypotheses.