409 research outputs found

    The XRCC1 phosphate-binding pocket binds poly (ADP-ribose) and is required for XRCC1 function

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    Poly (ADP-ribose) is synthesized at DNA single-strand breaks and can promote the recruitment of the scaffold protein, XRCC1. However, the mechanism and importance of this process has been challenged. To address this issue, we have characterized the mechanism of poly (ADP-ribose) binding by XRCC1 and examined its importance for XRCC1 function. We show that the phosphate-binding pocket in the central BRCT1 domain of XRCC1 is required for selective binding to poly (ADP-ribose) at low levels of ADP-ribosylation, and promotes interaction with cellular PARP1. We also show that the phosphate-binding pocket is required for EGFP-XRCC1 accumulation at DNA damage induced by UVA laser, H2O2, and at sites of sub-nuclear PCNA foci, suggesting that poly (ADP-ribose) promotes XRCC1 recruitment both at single-strand breaks globally across the genome and at sites of DNA replication stress. Finally, we show that the phosphate-binding pocket is required following DNA damage for XRCC1-dependent acceleration of DNA single-strand break repair, DNA base excision repair, and cell survival. These data support the hypothesis that poly (ADP-ribose) synthesis promotes XRCC1 recruitment at DNA damage sites and is important for XRCC1 function

    What controls the recent changes in African mineral dust aerosol across the Atlantic?

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    Dust from Africa strongly perturbs the radiative balance over the Atlantic, with emissions that are highly variable from year to year. We show that the aerosol optical depth (AOD) of dust over the mid-Atlantic observed by the AVHRR satellite has decreased by approximately 10% per decade from 1982 to 2008. This downward trend persists through both winter and summer close to source and is also observed in dust surface concentration measurements downwind in Barbados during summer. The GEOS-Chem model, driven with MERRA re-analysis meteorology and using a new dust source activation scheme, reproduces the observed trend and is used to quantify the factors contributing to this trend and the observed variability from 1982 to 2008. We find that changes in dustiness over the east mid-Atlantic are almost entirely mediated by a reduction in surface winds over dust source regions in Africa and are not directly linked with changes in land use or vegetation cover. The global mean all-sky direct radiative effect (DRE) of African dust is −0.18 Wm−2 at top of atmosphere, accounting for 46% of the global dust total, with a regional DRE of −7.4 ± 1.5 Wm−2 at the surface of the mid-Atlantic, varying by over 6.0 Wm−2 from year to year, with a trend of +1.3 Wm−2 per decade. These large interannual changes and the downward trend highlight the importance of climate feedbacks on natural aerosol abundance. Our analysis of the CMIP5 models suggests that the decreases in the indirect anthropogenic aerosol forcing over the North Atlantic in recent decades may be responsible for the observed climate response in African dust, indicating a potential amplification of anthropogenic aerosol radiative impacts in the Atlantic via natural mineral dust aerosol.Massachusetts Institute of Technology (Charles E. Reed Faculty Initiative Fund)National Science Foundation (U.S.) (AGS-1238109)National Science Foundation (U.S.) (AGS- 0962256)National Science Foundation (U.S.) (NASA NNX12AP45G

    Genome wide analysis of dna repair by expression profiling

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    Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are syndromes characterised by defects iqf nucleotide excision repair (NER), they can be distinguished by contrasting clinical manifestations. Although the genes responsible for XP and CShave been identified, the precise molecular roles of the normal proteins remains poorly understood. In the present study, primary dermal fibroblasts derived from patients assigned to XP complementation group C (XP-C XP8CA) and CS type A (CS-A CS3BE) were characterised. Patient XP8CA was homozygous for a 2 bp TG deletion in the XPC gene at codon 547 resulting in a premature termination at position 572, while patient CS3BE was a compound heterozygote for a 37G>T (E13X) and a novel 479C>T (A 160V) mutation in CKNl, the jene that encodes the CSA protein. Permanent XP-C and CS-A cell lines were established by transducing primary XP8CA and CS3BE fibroblasts with a retroviral vector, expressing the catalytic subunit of telomerase, hTERT. The reconstitition of telomerase activity resulted in: (1) the preservation of the primary NER capabilities (2) an extension of proliferative lifespan (3) maintenance of the p53/p21WAF/CIPI and pRb/pl6INK4A tumour suppressor pathways. Using microarrays, the UV-induced global transcriptional response of telomerised XP-C ajd CS-A fibroblasts was characterised. The data indicate that UV-irradiation resulted in the differential regulation of a diverse range of cellular responses such as transcription, cell cycle arrest, DNA repair and apoptosis. Additionally, cell type-specific signatures were observed in telomerised XP-C and CS-A fibroblasts. The utility of RNAi was also demonstrated by transiently ablating XPC of CSA function in telomerised repair competent (MRC-5) fibroblasts, and a stable, permanent mutant was constructed by retrovirally transducing the telomerised CS-A cell line with an PC-specific shRNA construct. Thus, permanent and stable telomerase-immortalised XP-C and CS-A cell lines have been established and partially characterised at both the genetic and molecular level, so providing in vitro models for investigating NER.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

    Genome wide analysis of dna repair by expression profiling

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    Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are syndromes characterised by defects iqf nucleotide excision repair (NER), they can be distinguished by contrasting clinical manifestations. Although the genes responsible for XP and CShave been identified, the precise molecular roles of the normal proteins remains poorly understood. In the present study, primary dermal fibroblasts derived from patients assigned to XP complementation group C (XP-C XP8CA) and CS type A (CS-A CS3BE) were characterised. Patient XP8CA was homozygous for a 2 bp TG deletion in the XPC gene at codon 547 resulting in a premature termination at position 572, while patient CS3BE was a compound heterozygote for a 37G>T (E13X) and a novel 479C>T (A 160V) mutation in CKNl, the jene that encodes the CSA protein. Permanent XP-C and CS-A cell lines were established by transducing primary XP8CA and CS3BE fibroblasts with a retroviral vector, expressing the catalytic subunit of telomerase, hTERT. The reconstitition of telomerase activity resulted in: (1) the preservation of the primary NER capabilities (2) an extension of proliferative lifespan (3) maintenance of the p53/p21WAF/CIPI and pRb/pl6INK4A tumour suppressor pathways. Using microarrays, the UV-induced global transcriptional response of telomerised XP-C ajd CS-A fibroblasts was characterised. The data indicate that UV-irradiation resulted in the differential regulation of a diverse range of cellular responses such as transcription, cell cycle arrest, DNA repair and apoptosis. Additionally, cell type-specific signatures were observed in telomerised XP-C and CS-A fibroblasts. The utility of RNAi was also demonstrated by transiently ablating XPC of CSA function in telomerised repair competent (MRC-5) fibroblasts, and a stable, permanent mutant was constructed by retrovirally transducing the telomerised CS-A cell line with an PC-specific shRNA construct. Thus, permanent and stable telomerase-immortalised XP-C and CS-A cell lines have been established and partially characterised at both the genetic and molecular level, so providing in vitro models for investigating NER

    Stability monitoring of a rail slope using acoustic emission

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    The paper details the use of acoustic emission generated by active waveguide subsurface instrumentation to monitor the stability of a rail soil cutting slope failure. Operation of the active waveguide, unitary battery-operated acoustic emission sensor and warning communication system are described. Previous field trials reported by the authors demonstrate that acoustic emission rates generated by active waveguides are proportional to the velocity of slope movement, and can therefore be used to detect changes in rates of movement in response to destabilising and stabilising effects, such as rainfall and remediation, respectively. The paper presents a field trial of the acoustic emission monitoring system at a reactivated rail-cutting slope failure at Players Crescent, Totton, Southampton, UK. The results of the monitoring are compared with both periodic and continuous deformation measurements. The study demonstrated that acoustic emission monitoring can provide continuous information on displacement rates, with high temporal resolution. The ability of the monitoring system to detect slope movements and disseminate warnings by way of text messages is presented. The monitoring approach is shown to provide real-time information that could be used by operators to make decisions on traffic safety

    Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis

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    INTRODUCTION: The largest cohort of critically ill patients evaluating intragastric and small intestinal delivery of nutrients was recently reported. This systematic review included recent data to compare the effects of small bowel and intragastric delivery of enteral nutrients in adult critically ill patients. METHODS: This is a systematic review of all randomised controlled studies published between 1990 and March 2013 that reported the effects of the route of enteral feeding in the critically ill on clinically important outcomes. RESULTS: Data from 15 level-2 studies were included. Small bowel feeding was associated with a reduced risk of pneumonia (Relative Risk, RR, small intestinal vs. intragastric: 0.75 (95% confidence interval 0.60 to 0.93); P = 0.01; I(2 )= 11%). The point estimate was similar when only studies using microbiological data were included. Duration of ventilation (weighted mean difference: -0.36 days (-2.02 to 1.30); P = 0.65; I(2 )= 42%), length of ICU stay (WMD: 0.49 days, (-1.36 to 2.33); P = 0.60; I(2 )= 81%) and mortality (RR 1.01 (0.83 to 1.24); P = 0.92; I(2 )= 0%) were unaffected by the route of feeding. While data were limited, and there was substantial statistical heterogeneity, there was significantly improved nutrient intake via the small intestinal route (% goal rate received: 11% (5 to 16%); P = 0.0004; I(2 )= 88%). CONCLUSIONS: Use of small intestinal feeding may improve nutritional intake and reduce the incidence of ICU-acquired pneumonia. In unselected critically ill patients other clinically important outcomes were unaffected by the site of the feeding tube

    Intercontinental transport of pollution manifested in the variability and seasonal trend of springtime O3 at northern middle and high latitudes

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    Observations (0–8 km) from the Tropospheric Ozone Production about the Spring Equinox (TOPSE) experiment are analyzed to examine air masses contributing to the observed variability of springtime O3 and its seasonal increase at 40°–85°N over North America. Factor analysis using the positive matrix factorization and principal component analysis methods is applied to the data set with 14 chemical tracers (O3, NOy, PAN, CO, CH4, C2H2, C3H8, CH3Cl, CH3Br, C2Cl4, CFC-11, HCFC-141B, Halon-1211, and 7Be) and one dynamic tracer (potential temperature). Our analysis results are biased by the measurements at 5–8 km (70% of the data) due to the availability of 7Be measurements. The identified tracer characteristics for seven factors are generally consistent with the geographical origins derived from their 10 day back trajectories. Stratospherically influenced air accounts for 14 ppbv (35–40%) of the observed O3 variability for data with O3concentrations \u3c100 ppbv at middle and high latitudes. It accounts for about 2.5 ppbv/month (40%) of the seasonal O3 trend at midlatitudes but for only 0.8 ppbv/month (\u3c20%) at high latitudes, likely reflecting more vigorous midlatitude dynamical systems in spring. At midlatitudes, reactive nitrogen-rich air masses transported through Asia are much more significant (11 ppbv in variability and 3.5 ppbv/month in trend) than other tropospheric contributors. At high latitudes the O3 variability is significantly influenced by air masses transported from lower latitudes (11 ppbv), which are poor in reactive nitrogen. The O3 trend, in contrast, is largely defined by air masses rich in reactive nitrogen transported through Asia and Europe across the Pacific or the Arctic (3 ppbv/month). The influence from the stratospheric source is more apparent at 6–8 km, while the effect of O3 production and transport within the troposphere is more apparent at lower altitudes. The overall effect of tropospheric photochemical production, through long-range transport, on the observed O3 variability and its seasonal trend is more important at high latitudes relative to more photochemically active midlatitudes

    Music and Arts in Health Promotion and Death Education: The St Christopher’s Schools Project

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    The reality of death and dying is rarely discussed openly in modern Western societies, while death sometimes is even considered to be a ‘failure’ in the context of traditional, medically-focused healthcare systems. Similarly, loss and transition are part of the National School Curriculum in the UK, but many schools still find approaching these subjects difficult. In this context St Christopher’s hospice in London has initiated and delivered the ‘Schools Project’ since 2005. The St Christopher’s Schools Project is an innovative community arts programme. It takes the form of short-term collaborative arts projects between terminally ill patients and students from primary and secondary schools, as well as colleges within the hospice’s catchment area. The Schools Project has attracted the interest of many other hospices, as well as other healthcare institutions and inspired the development of similar projects, both nationally and internationally. The aim of the Schools Project is to introduce the hospice and its work to the school communities in a creative and non-threatening way. Within a structured framework students are given the opportunity to interact and engage in music and art making together with terminally ill patients, culminating in an exhibition or performance. Promoting healthier attitudes towards death and dying amongst the students, their teachers, school peers, parents and carers, is at the core of the project. This paper presents the philosophy and aims, as well as the process and outcomes, of the Schools Project. Additionally, an overview of all of the projects that have taken place at St Christopher’s since 2005, as well as some prospects for future development, are given. This will hopefully stimulate a constructive dialogue with regards to the potential role of hospices and the arts in the promotion of health and death education, as well as their potential impact on the development of sustainable healthcare policies and practices not only in palliative care, but also in other health and social care contexts
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