Drosophila RecQ4 Is Directly Involved in Both DNA Replication and the Response to UV Damage in S2 Cells.

The RecQ4 protein shows homology to both the S.cerevisiae DNA replication protein Sld2 and the DNA repair related RecQ helicases. Experimental data also suggest replication and repair functions for RecQ4, but the precise details of its involvement remain to be clarified.Here we show that depletion of DmRecQ4 by dsRNA interference in S2 cells causes defects consistent with a replication function for the protein. The cells show reduced proliferation associated with an S phase block, reduced BrdU incorporation, and an increase in cells with a subG1 DNA content. At the molecular level we observe reduced chromatin association of DNA polymerase-alpha and PCNA. We also observe increased chromatin association of phosphorylated H2AvD--consistent with the presence of DNA damage and increased apoptosis.Analysis of DmRecQ4 repair function suggests a direct role in NER, as the protein shows rapid but transient nuclear localisation after UV treatment. Re-localisation is not observed after etoposide or H₂O₂ treatment, indicating that the involvement of DmRecQ4 in repair is likely to be pathway specific.Deletion analysis of DmRecQ4 suggests that the SLD2 domain was essential, but not sufficient, for replication function. In addition a DmRecQ4 N-terminal deletion could efficiently re-localise on UV treatment, suggesting that the determinants for this response are contained in the C terminus of the protein. Finally several deletions show differential rescue of dsRNA generated replication and proliferation phenotypes. These will be useful for a molecular analysis of the specific role of DmRecQ4 in different cellular pathways

Towards a Post-Structural View of Competition: Three Cases of Horizontal Merger

We examine the question of adaptive firm conduct using longitudinal product-level data from three large horizontal mergers in the food manufacturing industry. Our model is grounded in a poststructural view of competition that we deduce from recent writings from the fields of strategy, organizational ecology, and industrial organization. Consistent with this model, we find that the influence of horizontal merger on product performance (i.e., rent) varies with the product niche, time, the specific firms that merged, and dominance of the product, and its market scope.Industrial Organization,

IODP expedition 347: Baltic Sea basin paleoenvironment and biosphere

The Integrated Ocean Drilling Program (IODP) expedition 347 cored sediments from different settings of the Baltic Sea covering the last glacial–interglacial cycle. The main aim was to study the geological development of the Baltic Sea in relation to the extreme climate variability of the region with changing ice cover and major shifts in temperature, salinity, and biological communities. Using the Greatship Manisha as a European Consortium for Ocean Research Drilling (ECORD) mission-specific platform, we recovered 1.6 km of core from nine sites of which four were additionally cored for microbiology. The sites covered the gateway to the North Sea and Atlantic Ocean, several sub-basins in the southern Baltic Sea, a deep basin in the central Baltic Sea, and a river estuary in the north. The waxing and waning of the Scandinavian ice sheet has profoundly affected the Baltic Sea sediments. During the Weichselian, progressing glaciers reshaped the submarine landscape and displaced sedimentary deposits from earlier Quaternary time. As the glaciers retreated they left a complex pattern of till, sand, and lacustrine clay, which in the basins has since been covered by a thick deposit of Holocene, organic-rich clay. Due to the stratified water column of the brackish Baltic Sea and the recurrent and widespread anoxia, the deeper basins harbor laminated sediments that provide a unique opportunity for high-resolution chronological studies. The Baltic Sea is a eutrophic intra-continental sea that is strongly impacted by terrestrial runoff and nutrient fluxes. The Holocene deposits are recorded today to be up to 50 m deep and geochemically affected by diagenetic alterations driven by organic matter degradation. Many of the cored sequences were highly supersaturated with respect to methane, which caused strong degassing upon core recovery. The depth distributions of conservative sea water ions still reflected the transition at the end of the last glaciation from fresh-water clays to Holocene brackish mud. High-resolution sampling and analyses of interstitial water chemistry revealed the intensive mineralization and zonation of the predominant biogeochemical processes. Quantification of microbial cells in the sediments yielded some of the highest cell densities yet recorded by scientific drilling

The effects of arthritis gloves on hand pain in people with rheumatoid or inflammatory arthritis : a randomised controlled trial (A-GLOVES TRIAL)

Background: Arthritis (compression) gloves are commonly provided to people with rheumatoid arthritis (RA) and undifferentiated inflammatory arthritis (IA) in the UK health service. These apply pressure and warmth to relieve hand pain, stiffness and improve hand function. A systematic review identified little evidence to support their use.[1] Objectives: This randomised controlled trial tested effectiveness and cost-effectiveness of mid-finger length compression (intervention) gloves (20% Lycra: commonest glove model provided) with control gloves (i.e. oedema gloves: 11% Lycra: fitted at least one size too big) in people with RA and IA. Methods: Both gloves, which had similar thermal qualities although the control gloves did not provide compression, were provided by rheumatology occupational therapists, following training.[2] Participants were also given brief advice on hand exercise and joint protection. Adults with RA/IA and persistent hand pain were randomised 1:1 to the two glove types, stratified by disease modifying anti-rheumatic drug (DMARD) change in previous 12 weeks. The primary outcome was dominant hand pain on activity Visual Analogue Scale (VAS:0–10); other outcomes included night hand pain, hand stiffness (both 0–10 VAS); Measure of Activity Performance Hand (MAP-HAND: 0–3). Multiple linear regression was undertaken to estimate the effect of group allocation on hand pain during activity, adjusting for the stratification variable and baseline values. Cost-effectiveness used individual patient level costs (intervention plus healthcare utilisation) and health benefit data (EQ-5D) to calculate costs and QALYs. Results: 206 participants were randomised (103 to each glove type): median age 59 years [IQR 51,67]; women:166 (81%); mean disease duration: 8.2 (SD 9.5) years; employed:76 (37%); right hand dominant:185 (90%). Of these, 163 (79%) completed 12 week follow-up questionnaires. Both groups reported similar adherence to glove wear (mean 5.2 days/week). At 12 w, hand pain scores in both groups similarly improved: the between-groups mean difference of 0.1 was not statistically significant (95% CI: −0.47 to 0.67; p=0.72). There were no significant differences between groups on any measures, with both groups improving similarly between baseline and 12 w. 73% in both groups considered gloves beneficial. Intervention gloves had higher costs (£552 (SD £464); control £391 (SD £543) but comparable benefits to control gloves. Intervention gloves would cost £83 700 to gain one QALY and were not likely to be cost-effective. Conclusions: Compression (intervention) and loose-fitting arthritis (control) gloves had similar effects on hand pain, stiffness and function. Therefore, compression is not the ‘active ingredient’ in arthritis gloves. Loose fitting gloves providing warmth were perceived as equally effective by participants. We do not know if the therapist effect is important or whether ordinary gloves providing warmth would provide similar results. References: Hammond, et al. Clin Rehabil 2016 30:213–24. Prior, et al. Rheumatology 2017. www.abstractsonline.com/pp8/#!/4205 Acknowledgements: This project was funded by the NIHR Research for Patient Benefit Programme (PB-PG-0214–33010). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health

Novel roles of HP1a and Mcm10 in DNA replication, genome maintenance and photoreceptor cell differentiation.

Both Mcm10 and HP1a are known to be required for DNA replication. However, underlying mechanism is not clarified yet especially for HP1. Knockdown of both HP1a and Mcm10 genes inhibited the progression of S phase in Drosophila eye imaginal discs. Proximity Ligation Assay (PLA) demonstrated that HP1a is in close proximity to DNA replication proteins including Mcm10, RFC140 and DNA polymerase ε 255 kDa subunit in S-phase. This was further confirmed by co-immunoprecipitation assay. The PLA signals between Mcm10 and HP1a are specifically observed in the mitotic cycling cells, but not in the endocycling cells. Interestingly, many cells in the posterior regions of eye imaginal discs carrying a double knockdown of Mcm10 and HP1a induced ectopic DNA synthesis and DNA damage without much of ectopic apoptosis. Therefore, the G1-S checkpoint may be affected by knockdown of both proteins. This event was also the case with other HP family proteins such as HP4 and HP6. In addition, both Mcm10 and HP1a are required for differentiation of photoreceptor cells R1, R6 and R7. Further analyses on several developmental genes involved in the photoreceptor cell differentiation suggest that a role of both proteins is mediated by regulation of the lozenge gene

Diagnostic accuracy of PAT-POPS and ManChEWS for admissions of children from the emergency department

Background The Pennine Acute Trust (PAT) Paediatric Observation Priority Score (PAT-POPS) is a specific emergency department (ED) physiological and observational aggregate scoring system, with scores of 0–18. A higher score indicates greater likelihood of admission. The Manchester Children’s Early Warning System (ManChEWS) assesses six physiological observations to create a trigger score, classified as Green, Amber or Red. Methods Prospectively collected data were used to calculate PAT-POPS and ManChEWS on 2068 patients aged under 16 years (mean 5.6 years, SD 4.6) presenting over 1 month to a UK District General Hospital Paediatric ED. Receiver operating characteristics (ROC) comparison, using STATA V.13, was used to investigate the ability of ManChEWS and PAT-POPS to predict admission to hospital within 72 h of presentation to the ED. Results Comparison of the area under the ROC curve indicates that the ManChEWS ROC is 0.67 (95% CI 0.64 to 0.70) and the PAT-POPS ROC is 0.72 (95% CI 0.68 to 0.75). The difference is statistically significant. At a PAT-POPS cut-off of ≥2, 80% of patients had their admission risk correctly classified ( positive likelihood ratio 3.40, 95% CI 2.90 to 3.98) whereas for ManChEWS with a cut off of ≥Amber only 71% of patients were correctly classified ( positive likelihood ratio 2.18, 95% CI 1.94 to 2.45). Conclusions PAT-POPS is a more accurate predictor of admission risk than ManChEWS. Replacing ManChEWS with PAT-POPS would appear to be clinically appropriate in a paediatric ED. This needs validation in a multicentre study