Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma.

We performed fluorescent in situ hybridization (FISH) for 16q23 abnormalities in 861 patients with newly diagnosed multiple myeloma and identified deletion of 16q [del(16q)] in 19.5%. In 467 cases in which demographic and survival data were available, del(16q) was associated with a worse overall survival (OS). It was an independent prognostic marker and conferred additional adverse survival impact in cases with the known poor-risk cytogenetic factors t(4;14) and del(17p). Gene expression profiling and gene mapping using 500K single-nucleotide polymorphism (SNP) mapping arrays revealed loss of heterozygosity (LOH) involving 3 regions: the whole of 16q, a region centered on 16q12 (the location of CYLD), and a region centered on 16q23 (the location of the WW domain-containing oxidoreductase gene WWOX). CYLD is a negative regulator of the NF-kappaB pathway, and cases with low expression of CYLD were used to define a "low-CYLD signature." Cases with 16q LOH or t(14;16) had significantly reduced WWOX expression. WWOX, the site of the translocation breakpoint in t(14;16) cases, is a known tumor suppressor gene involved in apoptosis, and we were able to generate a "low-WWOX signature" defined by WWOX expression. These 2 genes and their corresponding pathways provide an important insight into the potential mechanisms by which 16q LOH confers poor prognosis.

Mapping Protein-DNA Interactions Using ChIP-exo and Illumina-Based Sequencing

Chromatin immunoprecipitation (ChIP) provides a means of enriching DNA associated with transcription factors, histone modifications, and indeed any other proteins for which suitably characterized antibodies are available. Over the years, sequence detection has progressed from quantitative real-time PCR and Southern blotting to microarrays (ChIP-chip) and now high-throughput sequencing (ChIP-seq). This progression has vastly increased the sequence coverage and data volumes generated. This in turn has enabled informaticians to predict the identity of multi-protein complexes on DNA based on the overrepresentation of sequence motifs in DNA enriched by ChIP with a single antibody against a single protein. In the course of the development of high-throughput sequencing, little has changed in the ChIP methodology until recently. In the last three years, a number of modifications have been made to the ChIP protocol with the goal of enhancing the sensitivity of the method and further reducing the levels of nonspecific background sequences in ChIPped samples. In this chapter, we provide a brief commentary on these methodological changes and describe a detailed ChIP-exo method able to generate narrower peaks and greater peak coverage from ChIPped material.

Cooperative Mapping and Exploration using Counter-rotational Potential Fields

This paper presents a novel technique for mapping and exploration using cooperating autonomous underwater vehicles. Rather than using the typical lawnmower sweep pattern to search an entire area, the proposed navigational plan involves guiding the formation directly towards each object of interest in turn, before arriving at a final goal position. This is achieved by the use of traditional artificial potential fields alongside counter-rotational potential fields. These clockwise and counter-clockwise fields are employed simultaneously by vehicles to ensure that the entire object is scanned rather than simply avoided as is the case with traditional collision avoidance techniques. The proposed methodology allows a formation to have fluid-like motion whilst a separation distance between cooperating agents (free of angular constraints) is maintained with a greater degree of flexibility than traditional formation control approaches. Owing to its nature, this technique is suited for applications such as exploration, mapping and underwater inspection to name a few. Simulation results demonstrate the efficacy of the proposed approach.

Midwifery-led antenatal care models: mapping a systematic review to an evidence-based quality framework to identify key components and characteristics of care

Background: Implementing effective antenatal care models is a key global policy goal. However, the mechanisms of action of these multi-faceted models that would allow widespread implementation are seldom examined and poorly understood. In existing care model analyses there is little distinction between what is done, how it is done, and who does it. A new evidence-informed quality maternal and newborn care (QMNC) framework identifies key characteristics of quality care. This offers the opportunity to identify systematically the characteristics of care delivery that may be generalizable across contexts, thereby enhancing implementation. Our objective was to map the characteristics of antenatal care models tested in Randomised Controlled Trials (RCTs) to a new evidence-based framework for quality maternal and newborn care; thus facilitating the identification of characteristics of effective care.

Methods: A systematic review of RCTs of midwifery-led antenatal care models. Mapping and evaluation of these models’ characteristics to the QMNC framework using data extraction and scoring forms derived from the five framework components. Paired team members independently extracted data and conducted quality assessment using the QMNC framework and standard RCT criteria.

Results: From 13,050 citations initially retrieved we identified 17 RCTs of midwifery-led antenatal care models from Australia (7), the UK (4), China (2), and Sweden, Ireland, Mexico and Canada (1 each). QMNC framework scores ranged from 9 to 25 (possible range 0–32), with most models reporting fewer than half the characteristics associated with quality maternity care. Description of care model characteristics was lacking in many studies, but was better reported for the intervention arms. Organisation of care was the best-described component. Underlying values and philosophy of care were poorly reported.

Conclusions: The QMNC framework facilitates assessment of the characteristics of antenatal care models. It is vital to understand all the characteristics of multi-faceted interventions such as care models; not only what is done but why it is done, by whom, and how this differed from the standard care package. By applying the QMNC framework we have established a foundation for future reports of intervention studies so that the characteristics of individual models can be evaluated, and the impact of any differences appraised.

Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome.

PURPOSE: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes. EXPERIMENTAL DESIGN: Using single nucleotide polymorphism-based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome. RESULTS: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the "cell death" network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets. CONCLUSIONS: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma.

Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

Mapping Ireland’s Energy Pathways: Characterizing and Catalyzing Transition

In 2015 Ireland has arguably begun to make its first bold steps in confronting the challenges of energy transition, with the objective of a “low carbon, climate resilient and environmentally sustainable economy by the end of the
year 2050” expressed in the 2015 Climate Action and Low Carbon Development Bill and the 2015 Energy Bill acknowledging that energy transformation relied on a new breed of ‘energy citizens’. These represent the first formal articulation of Ireland’s ambition to engage in a radical, long-term and far-reaching transition process, and raises a myriad of questions over how this can be operationalised, resourced and whether it can maintain political momentum. A range of perspectives on these issues is provided in the growing body of literature on transition theories (Rotmans et al 2001, Markard et al 2012) and the inter-disciplinary EPA-funded CC Transitions project, based at Queen’s University Belfast, represents an attempt to translate this into the context of Ireland’s institutions and technological profile. By relating this to international research on sustainability transitions, which conceptualises transitions as multi-level, multi-phase and multi-actor processes, this paper will explore the opportunities of alternative pathways that could take Ireland towards a more progressing, inclusive and effective low carbon future. Drawing on a number of case studies it will highlight some of the capacities for transition required in Irish society: where these exist, how they are being built or enabled, and the barriers to wider social change.

Northern Ireland Neighbourhood Watch: Participatory Mapping and Socio Demographic Uptake

Northern Ireland Neighbourhood Watch (NINW) was formally introduced to Northern Ireland in 2004 by the Police Service of Northern Ireland, Northern Ireland Policing Board and Northern Ireland Office. However, there has been little research to data as to participation in, or success of, the schemes. This research report provides one of the few empirical examinations of NINW. Using GIS mapping and socio-demographic data from the Northern Ireland Neighbourhood Information Service (NINIS), the research explores participation in NINW schemes set against religion, deprivation and crime levels at the Census Output Area (COA) level across Northern Ireland. While the research largely confirms the limited impact of neighbourhood schemes as noted in international literature, at a local level in Northern Ireland the findings evidence a distinct pattern of uptake, with the vast majority of participants in the schemes residing in affluent, low-crime, mainly Protestant areas of the country