Epstein-Barr virus nuclear antigen 3A protein regulates CDKN2B transcription via interaction with MIZ-1

The Epstein-Barr virus (EBV) nuclear antigen 3 family of protein is critical for the EBV-induced primary B-cell growth transformation process. Using a yeast two-hybrid screen we identified 22 novel cellular partners of the EBNA3s. Most importantly, among the newly identified partners, five are known to play direct and important roles in transcriptional regulation. Of these, the Myc-interacting zinc finger protein-1 (MIZ-1) is a transcription factor initially characterized as a binding partner of MYC. MIZ-1 activates the transcription of a number of target genes including the cell cycle inhibitor CDKN2B. Focusing on the EBNA3A/MIZ-1 interaction we demonstrate that binding occurs in EBV-infected cells expressing both proteins at endogenous physiological levels and that in the presence of EBNA3A, a significant fraction of MIZ-1 translocates from the cytoplasm to the nucleus. Moreover, we show that a trimeric complex composed of a MIZ-1 recognition DNA element, MIZ-1 and EBNA3A can be formed, and that interaction of MIZ-1 with nucleophosmin (NPM), one of its coactivator, is prevented by EBNA3A. Finally, we show that, in the presence of EBNA3A, expression of the MIZ-1 target gene, CDKN2B, is downregulated and repressive H3K27 marks are established on its promoter region suggesting that EBNA3A directly counteracts the growth inhibitory action of MIZ-1

Guidelines for initiation of anti-tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe.

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The contamination of the surface of Vesta by impacts and the delivery of the dark material

The Dawn spacecraft observed the presence of dark material, which in turn proved to be associated with OH and H-rich material, on the surface of Vesta. The source of this dark material has been identified with the low albedo asteroids, but it is still a matter of debate whether the delivery of the dark material is associated with a few large impact events, to micrometeorites or to the continuous, secular flux of impactors on Vesta. The continuous flux scenario predicts that a significant fraction of the exogenous material accreted by Vesta should be due to non-dark impactors likely analogous to ordinary chondrites, which instead represent only a minor contaminant in the HED meteorites. We explored the continuous flux scenario and its implications for the composition of the vestan regolith, taking advantage of the data from the Dawn mission and the HED meteorites. We used our model to show that the stochastic events scenario and the micrometeoritic flux scenario are natural consequences of the continuous flux scenario. We then used the model to estimate the amounts of dark and hydroxylate materials delivered on Vesta since the LHB and we showed how our results match well with the values estimated by the Dawn mission. We used our model to assess the amount of Fe and siderophile elements that the continuous flux of impactors would mix in the vestan regolith: concerning the siderophile elements, we focused our attention on the role of Ni. The results are in agreement with the data available on the Fe and Ni content of the HED meteorites and can be used as a reference frame in future studies of the data from the Dawn mission and of the HED meteorites. Our model cannot yet provide an answer to the fate of the missing non-carbonaceous contaminants, but we discuss possible reasons for this discrepancy.Comment: 31 pages, 7 figures, 4 tables. Accepted for publication on the journal ICARUS, "Dark and Bright Materials on Vesta" special issu

Interest of a systematic screening of comorbidities in chronic inflammatory rheumatisms

BackgroundPatients with chronic inflammatory rheumatisms (CIR) have a greater risk of cardiovascular events, infections, lung diseases and osteoporosis. European League against Rheumatisms (EULAR) recommends annual evaluation of the cardiovascular risks.MethodsA program of comorbidity screening was set up in a daily clinic of our Rheumatology department and includes:– rheumatism evaluation;– cardiovascular evaluation; clinical examination, blood tests, modified systematic coronary risk evaluation (mSCORE) calculation, vessel ultrasound and echocardiography;– lung evaluation; self-questionnaires and spirometry;– osteoporosis; bone mineral density and FRAX calculation;– check-up of vaccinal status and the recommended neoplasic screenings.ResultsNinety-two patients already benefited from this systematic screening with 83% (n=76) of rheumatoid arthritis, 11% (n=10) of spondyloarthritis, 3% (n=2) of psoriatic arthritis and 4% (n=4) of other diseases. The mean rheumatism duration was 14±9 years, the mean age was 59±11 years and 64% were women. Hypertension was diagnosed in 8.7% (n=8) of the patients; dyslipidemia in 9.8% (n=9); diabetes in 6.5% (n=6) of the patients. The echocardiography showed significant abnormalities (valvular and hypokinesia) in 9% (n=8) of the patients, a significant supra-aortic vessel stenosis was found in 4.5% (n=4) of the population and an abdominal aortic aneuvrysm was diagnosed in 5.7% (n=5). Among 92 patients, 18.4% (n=14) were estimated at high risk of lethal cardiovascular event with a mSCORE≥5 and 27.5% (n=25) patients were sent to a cardiologist to pursue further cardiovascular investigations. Among these, 8 had a myocardial scintigraphy and all were normal. Moreover, 32.6% (n=30) of the patients were estimated at risk of chronic obstructive pulmonary disease or sleep apnea syndrome and were recommended to consult pneumologist. An anti-osteoporosis drug was introduced in 12% (n=11) of the patients. The update of the vaccinations and the neoplasic screenings were prescribed for respectively 52.7% (n=48) and 35.2% (n=32) of the patients.DiscussionA daily hospitalization for comorbidity screening seems worthy with significant abnormalities discovered in 36.2% of the patients. Further investigations were recommended in 50% of the patients. Patient’ satisfaction and the effective impact of the proposed or prescribed measures are under evaluation

Assessing the number of users who are excluded by domestic heating controls

This is the pre-print version of the Article. This Article is also referred to as: "Assessing the 'Design Exclusion' of Heating Controls at a Low-Cost, Low-Carbon Housing Development". - Copyright @ 2011 Taylor & FrancisSpace heating accounts for almost 60% of the energy delivered to housing which in turn accounts for nearly 27% of the total UK's carbon emissions. This study was conducted to investigate the influence of heating control design on the degree of ‘user exclusion’. This was calculated using the Design Exclusion Calculator, developed by the Engineering Design Centre at the University of Cambridge. To elucidate the capability requirements of the system, a detailed hierarchical task analysis was produced, due to the complexity of the overall task. The Exclusion Calculation found that the current design placed excessive demands upon the capabilities of at least 9.5% of the UK population over 16 years old, particularly in terms of ‘vision’, ‘thinking’ and ‘dexterity’ requirements. This increased to 20.7% for users over 60 years old. The method does not account for the level of numeracy and literacy and so the true exclusion may be higher. Usability testing was conducted to help validate the results which indicated that 66% of users at a low-carbon housing development could not programme their controls as desired. Therefore, more detailed analysis of the cognitive demands placed upon the users is required to understand where problems within the programming process occur. Further research focusing on this cognitive interaction will work towards a solution that may allow users to behave easily in a more sustainable manner