p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death

p53 is a central factor in tumor suppression as exemplified by its frequent loss in human cancer. p53 exerts its tumor suppressive effects in multiple ways, but the ability to invoke the eradication of damaged cells by programmed cell death is considered a key factor. The ways in which p53 promotes cell death can involve direct activation or engagement of the cell death machinery, or can be via indirect mechanisms, for example though regulation of ER stress and autophagy. We present here another level of control in p53-mediated tumor suppression by showing that p53 activates the glycosidase, FUCA1, a modulator of N-linked glycosylation. We show that p53 transcriptionally activates FUCA1 and that p53 modulates fucosidase activity via FUCA1 up-regulation. Importantly, we also report that chemotherapeutic drugs induce FUCA1 and fucosidase activity in a p53-dependent manner. In this context, while we found that over-expression of FUCA1 does not induce cell death, RNAi-mediated knockdown of endogenous FUCA1 significantly attenuates p53-dependent, chemotherapy-induced apoptotic death. In summary, these findings add an additional component to p53s tumor suppressive response and highlight another mechanism by which the tumor suppressor controls programmed cell death that could potentially be exploited for cancer therapy

The impact of age, sex and socioeconomic deprivation on outcomes in a colorectal cancer screening programme

<p>Background: Population-based colorectal cancer screening has been shown to reduce cancer specific mortality and is used across the UK. Despite evidence that older age, male sex and deprivation are associated with an increased incidence of colorectal cancer, uptake of bowel cancer screening varies across demographic groups. The aim of this study was to assess the impact of age, sex and deprivation on outcomes throughout the screening process.</p> <p>Methods: A prospectively maintained database, encompassing the first screening round of a faecal occult blood test screening programme in a single geographical area, was analysed.</p> <p>Results: Overall, 395 096 individuals were invited to screening, 204 139 (52%) participated and 6 079 (3%) tested positive. Of the positive tests, 4 625 (76%) attended for colonoscopy and cancer was detected in 396 individuals (9%). Lower uptake of screening was associated with younger age, male sex and deprivation (all p<0.001). Only deprivation was associated with failure to proceed to colonoscopy following a positive test (p<0.001). Despite higher positivity rates in those that were more deprived (p<0.001), the likelihood of detecting cancer in those attending for colonoscopy was lower (8% most deprived vs 10% least deprived, p = 0.003).</p> <p>Conclusion: Individuals who are deprived are less likely to participate in screening, less likely to undergo colonoscopy and less likely to have cancer identified as a result of a positive test. Therefore, this study suggests that strategies aimed at improving participation of deprived individuals in colorectal cancer screening should be directed at all stages of the screening process and not just uptake of the test.</p&gt

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions

Solar Oscillations and Convection: II. Excitation of Radial Oscillations

Solar p-mode oscillations are excited by the work of stochastic, non-adiabatic, pressure fluctuations on the compressive modes. We evaluate the expression for the radial mode excitation rate derived by Nordlund and Stein (Paper I) using numerical simulations of near surface solar convection. We first apply this expression to the three radial modes of the simulation and obtain good agreement between the predicted excitation rate and the actual mode damping rates as determined from their energies and the widths of their resolved spectral profiles. We then apply this expression for the mode excitation rate to the solar modes and obtain excellent agreement with the low l damping rates determined from GOLF data. Excitation occurs close to the surface, mainly in the intergranular lanes and near the boundaries of granules (where turbulence and radiative cooling are large). The non-adiabatic pressure fluctuations near the surface are produced by small instantaneous local imbalances between the divergence of the radiative and convective fluxes near the solar surface. Below the surface, the non-adiabatic pressure fluctuations are produced primarily by turbulent pressure fluctuations (Reynolds stresses). The frequency dependence of the mode excitation is due to effects of the mode structure and the pressure fluctuation spectrum. Excitation is small at low frequencies due to mode properties -- the mode compression decreases and the mode mass increases at low frequency. Excitation is small at high frequencies due to the pressure fluctuation spectrum -- pressure fluctuations become small at high frequencies because they are due to convection which is a long time scale phenomena compared to the dominant p-mode periods.Comment: Accepted for publication in ApJ (scheduled for Dec 10, 2000 issue). 17 pages, 27 figures, some with reduced resolution -- high resolution versions available at http://www.astro.ku.dk/~aake/astro-ph/0008048

Using participatory design to develop (public) health decision support systems through GIS

<p>Abstract</p> <p>Background</p> <p>Organizations that collect substantial data for decision-making purposes are often characterized as being 'data rich' but 'information poor'. Maps and mapping tools can be very useful for research transfer in converting locally collected data into information. Challenges involved in incorporating GIS applications into the decision-making process within the non-profit (public) health sector include a lack of financial resources for software acquisition and training for non-specialists to use such tools. This on-going project has two primary phases. This paper critically reflects on Phase 1: the participatory design (PD) process of developing a collaborative web-based GIS tool.</p> <p>Methods</p> <p>A case study design is being used whereby the case is defined as the data analyst and manager dyad (a two person team) in selected Ontario Early Year Centres (OEYCs). Multiple cases are used to support the reliability of findings. With nine producer/user pair participants, the goal in Phase 1 was to identify barriers to map production, and through the participatory design process, develop a web-based GIS tool suited for data analysts and their managers. This study has been guided by the Ottawa Model of Research Use (OMRU) conceptual framework.</p> <p>Results</p> <p>Due to wide variations in OEYC structures, only some data analysts used mapping software and there was no consistency or standardization in the software being used. Consequently, very little sharing of maps and data occurred among data analysts. Using PD, this project developed a web-based mapping tool (EYEMAP) that was easy to use, protected proprietary data, and permit limited and controlled sharing between participants. By providing data analysts with training on its use, the project also ensured that data analysts would not break cartographic conventions (e.g. using a chloropleth map for count data). Interoperability was built into the web-based solution; that is, EYEMAP can read many different standard mapping file formats (e.g. ESRI, MapInfo, CSV).</p> <p>Discussion</p> <p>Based on the evaluation of Phase 1, the PD process has served both as a facilitator and a barrier. In terms of successes, the PD process identified two key components that are important to users: increased data/map sharing functionality and interoperability. Some of the challenges affected developers and users; both individually and as a collective. From a development perspective, this project experienced difficulties in obtaining personnel skilled in web application development and GIS. For users, some data sharing barriers are beyond what a technological tool can address (e.g. third party data). Lastly, the PD process occurs in real time; both a strength and a limitation. Programmatic changes at the provincial level and staff turnover at the organizational level made it difficult to maintain buy-in as participants changed over time. The impacts of these successes and challenges will be evaluated more concretely at the end of Phase 2.</p> <p>Conclusion</p> <p>PD approaches, by their very nature, encourage buy-in to the development process, better addresses user-needs, and creates a sense of user-investment and ownership.</p

The VLT LBG redshift survey – VI. Mapping H i in the proximity of z ∼ 3 LBGs with X-Shooter

We present an analysis of the spatial distribution and dynamics of neutral hydrogen gas around galaxies using new X-Shooter observations of z ∼ 2.5–4 quasars. Adding the X-Shooter data to our existing data set of high-resolution quasar spectroscopy, we use a total sample of 29 quasars alongside ∼1700 Lyman Break Galaxies (LBGs) in the redshift range 2 ≲ z ≲ 3.5. We measure the Lyα forest auto-correlation function, finding a clustering length of s0 = 0.081 ± 0.006 h−1 Mpc, and the cross-correlation function with LBGs, finding a cross-clustering length of s0 = 0.27 ± 0.14 h−1 Mpc and power-law slope γ = 1.1 ± 0.2. Our results highlight the weakly clustered nature of neutral hydrogren systems in the Lyα forest. Building on this, we make a first analysis of the dependence of the clustering on absorber strength, finding a clear preference for stronger Lyα forest absorption features to be more strongly clustered around the galaxy population, suggesting that they trace on average higher mass haloes. Using the projected and 2-D cross-correlation functions, we constrain the dynamics of Lyα forest clouds around z ∼ 3 galaxies. We find a significant detection of large-scale infall of neutral hydrogen, with a constraint on the Lyα forest infall parameter of βF = 1.02 ± 0.22