City strategy : final evaluation

The City Strategy (CS) concept was first announced in the 2006 Welfare Reform Green Paper – A new deal for welfare: Empowering people to work. CS was designed at a time of growth in the national economy to combat enduring pockets of entrenched worklessness and poverty in urban areas by empowering local institutions to come together in partnerships to develop locally sensitive solutions. It was premised on the idea that developing a better understanding of the local welfare to work arena would allow partnerships to align and pool funding and resources to reduce duplication of services and fill gaps in provision. The ‘theory of change’ underlying CS suggested that such an approach would result in more coordinated services which would be able to generate extra positive outcomes in terms of getting people into jobs and sustaining them in employment over and above existing provision. CS was initially set to run for two years from April 2007 to March 2009 in 15 CS Pathfinder (CSP) areas, varying in size from five wards in one town through single local authority areas to subregional groupings of multiple local authority areas, across Great Britain. In July 2008, the Secretary of State for Work and Pensions announced an extension for a further two years to March 2011. In April 2009, two local areas in Wales, which were in receipt of monies from the Deprived Areas Fund (DAF), were invited by the Department for Work and Pensions (DWP) to form local partnerships with a similar remit to the CSPs, albeit more limited in scope – to develop locally sensitive solutions to economic inactivity, to the CSPs. During the period that the CS initiative was operational, economic conditions changed markedly with a severe recession, followed by fragile recovery. The CSPs had to cope with ongoing changes in policy throughout the lifetime of the CS initiative, including a General Election and a new Coalition Government at Westminster early in the fourth year. While policy changes are a fact of life for local practitioners operating in the welfare to work arena, the global recession in 2008/09 marked a fundamental change in the context in which local partnerships operated

Generalised time functions and finiteness of the Lorentzian distance

We show that finiteness of the Lorentzian distance is equivalent to the existence of generalised time functions with gradient uniformly bounded away from light cones. To derive this result we introduce new techniques to construct and manipulate achronal sets. As a consequence of these techniques we obtain a functional description of the Lorentzian distance extending the work of Franco and Moretti.Comment: 22 pages. Some imprecisions clarified compared to first versio

The Presence of GC-C in Extracellular Vesicles Secreted by Colorectal Cancer Cells

Background: Guanylyl Cyclase C (GC-C) is a membrane-bound protein found on intestinal epithelial cells involved in the activation of CFTR. This protein has previously been involved in the development of colorectal cancer. Extracellular vesicles (EVs) are bilayered vesicles of varying size (30 to 1,000 + nm in diameter) that believed to be secreted by all cells in the human body. In the past decade, EVs have garnered attention due to their impact in the field of oncology, where they have been shown to potentially serve as biomarkers for various cancers. In this study, we looked at the EVs secreted by GC-C+ and GC-C- cell lines. We expected GC-C to be present on the EVs secreted by GC-C+ cell lines and that this finding may intake a role for GC-C at tissues distal to the intestinal epithelial cells. Methods: GC-C+ cells lines (T84 and CT26-hGCC) and GC-C- cell lines (SW480 and CT26-WT) were cultured and their media was harvested, then ultracentrifuged to extract the EVs from the media. These EVs were then checked for the presence and absence of various markers (GC-C, Calnexin, TSG101) via Western Blot. Exosome size was assessed via NTA to further provide evidence for the identity of these EVs. Results: Western blot confirmed the presence of TSG101 in both EV types samples, as well as the presence of GC-C in EVs derived from GC-C+ cell lines, but not from GC-C- cell lines. Calnexin was found to be absent in EV samples, excluding the possibility of lysate contamination. NTA analysis confirmed the correct size for the exosomes in sample. Discussion: This study assessed the contents of EVs secreted by colorectal cancer cell lines. Our findings indicate the presence of GC-C on exosomes and microvesicles. Further studies will need to be conducted in order to assess the function of these GC-C+ EVs in the setting of colorectal cancer

Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model.

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle