Protein kinase CK2 localizes to sites of DNA double-strand break regulating the cellular response to DNA damage

<p>Abstract</p> <p>Background</p> <p>The DNA-dependent protein kinase (DNA-PK) is a nuclear complex composed of a large catalytic subunit (DNA-PKcs) and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the non-homologous end-joining (NHEJ) repair mechanism, which is activated in the presence of DNA double-strand breaks induced by ionizing radiation, reactive oxygen species and radiomimetic drugs. We have recently reported that down-regulation of protein kinase CK2 by siRNA interference results in enhanced cell death specifically in DNA-PKcs-proficient human glioblastoma cells, and this event is accompanied by decreased autophosphorylation of DNA-PKcs at S2056 and delayed repair of DNA double-strand breaks.</p> <p>Results</p> <p>In the present study, we show that CK2 co-localizes with phosphorylated histone H2AX to sites of DNA damage and while CK2 gene knockdown is associated with delayed DNA damage repair, its overexpression accelerates this process. We report for the first time evidence that lack of CK2 destabilizes the interaction of DNA-PKcs with DNA and with Ku80 at sites of genetic lesions. Furthermore, we show that CK2 regulates the phosphorylation levels of DNA-PKcs only in response to direct induction of DNA double-strand breaks.</p> <p>Conclusions</p> <p>Taken together, these results strongly indicate that CK2 plays a prominent role in NHEJ by facilitating and/or stabilizing the binding of DNA-PKcs and, possibly other repair proteins, to the DNA ends contributing to efficient DNA damage repair in mammalian cells.</p

Social Roles and Baseline Proxemic Preferences for a Domestic Service Robot

© The Author(s) 2014. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. The work described in this paper was conducted within the EU Integrated Projects LIREC (LIving with Robots and intEractive Companions, funded by the European Commission under contract numbers FP7 215554, and partly funded by the ACCOMPANY project, a part of the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n287624The goal of our research is to develop socially acceptable behavior for domestic robots in a setting where a user and the robot are sharing the same physical space and interact with each other in close proximity. Specifically, our research focuses on approach distances and directions in the context of a robot handing over an object to a userPeer reviewe

Translocation detection in lymphoma diagnosis by split-signal FISH: a standardised approach

Lymphomas originating from the lymphatic system comprise about 30 entities classified according to the World Health Organization (WHO). The histopathological diagnosis is generally considered difficult and prone to mistakes. Since non-random chromosomal translocations are specifically involved in different lymphoma entities, their detection will be increasingly important. Hence, a split-signal fluorescence in situ hybridisation (FISH) procedure would be helpful in discriminating the most difficult classifications. The Euro-FISH programme, a concerted action of nine European laboratories, has validated a robust, standardised protocol to improve the diagnostic approach on lymphoma entities. Therefore, 16 fluorescent probes and 10 WHO entities, supplemented with reactive cases, were selected. The results of the Euro-FISH programme show that all probes were correctly cytogenetically located, that the standardised protocol is robust, resulting in reliable results in approximately 90% of cases, and that the procedure could be implemented in every laboratory, bringing the relatively easy interpretation of split-signal probes within the reach of many pathology laboratories

Talking about links between sexually transmitted infections and infertility with college and university students from SE England, UK: a qualitative study

Background Sexually transmitted infections (STIs) such as chlamydia and gonorrhoea are largely symptomless diseases which, left untreated, can result in serious complications including infertility. Fertility problems currently affect approximately one in seven couples in the UK and there is increasing demand for couples seeking reproductive technologies. Young people are at greatest risk of contracting STIs, therefore this study aimed to identify young people’s knowledge and beliefs about the link between untreated STIs and infertility. Methods Focus groups were conducted with participants aged 16–24 years old inclusive in college or university settings in the SE of England. Groups were quota sampled on the basis of age and gender. A topic guide was used. The data were analysed using a framework analysis approach. Results Ten single-sex focus groups were conducted with sixty participants: six groups of college students and four groups of university students. Participants were generally aware of the link between STIs and potential infertility and considered the discussion of this subject very relevant at their age. Knowledge about how and why STIs potentially lead to fertility complications was poor. The issues of blame relating to infertility following an STI emerged, although most participants did not think that access to free reproductive technologies after an untreated STI should be limited. Conclusions Young people would benefit from more education in order to improve their understanding of the long-term consequences of untreated STIs, such as infertility. Participants in our sample felt these were extremely relevant and important issues for them to understand alongside current education about STIs

July 2017 ENCALS statement on edaravone

Peer reviewe

Genetic Variation in the Complete MgPa Operon and Its Repetitive Chromosomal Elements in Clinical Strains of Mycoplasma genitalium

Mycoplasma genitalium has been increasingly recognized as an important microbe not only because of its significant association with human genital tract diseases but also because of its utility as a model for studying the minimum set of genes necessary to sustain life. Despite its small genome, 4.7% of the total genome sequence is devoted to making the MgPa adhesin operon and its nine chromosomal repetitive elements (termed MgPars). The MgPa operon, along with 9 MgPars, is believed to play an important role in pathogenesis of M. genitalium infection and has also served as the main target for development of diagnostic tools. However, genetic variation in the complete MgPa operon and MgPars among clinical strains of M. genitalium has not been addressed. In this study we examined the genetic variation in the complete MgPa operon (approximately 8.5 kb) and full or partial MgPar sequences (0.4–2.6 kb) in 15 geographically diverse strains of M. genitalium. Extensive variation was present in four repeat regions of the MgPa operon (with homology to MgPars) among and within strains while the non-repeat regions (without homology to MgPars) showed low-level variation among strains and no variation within strains. MgPars showed significant variation among strains but were highly homogeneous within strains, supporting gene conversion as the likely recombination mechanism. When applying our sequence data to evaluate published MgPa operon-based diagnostic PCR assays and genotyping systems, we found that 11 of 19 primers contain up to 19 variable nucleotides and that the target for one of two typing systems is located in a hypervariable repeat region, suggesting the likelihood of false results with some of these assays. This study not only provides new insights into the role of the MgPa operon in the pathogenesis of M. genitalium infection but has important implications for the development of diagnostic tools

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information

Mycoplasma genitalium: An Emerging Cause of Sexually Transmitted Disease in Women

Mycoplasma genitalium is an emerging sexually transmitted pathogen implicated in urethritis in men and several inflammatory reproductive tract syndromes in women including cervicitis, pelvic inflammatory disease (PID), and infertility. This comprehensive review critically examines epidemiologic studies of M. genitalium infections in women with the goal of assessing the associations with reproductive tract disease and enhancing awareness of this emerging pathogen. Over 27,000 women from 48 published reports have been screened for M. genitalium urogenital infection in high- or low-risk populations worldwide with an overall prevalence of 7.3% and 2.0%, respectively. M. genitalium was present in the general population at rates between those of Chlamydia trachomatis and Neisseria gonorrhoeae. Considering more than 20 studies of lower tract inflammation, M. genitalium has been positively associated with urethritis, vaginal discharge, and microscopic signs of cervicitis and/or mucopurulent cervical discharge in seven of 14 studies. A consistent case definition of cervicitis is lacking and will be required for comprehensive understanding of these associations. Importantly, evidence for M. genitalium PID and infertility are quite convincing and indicate that a significant proportion of upper tract inflammation may be attributed to this elusive pathogen. Collectively, M. genitalium is highly prevalent in high- and low-risk populations, and should be considered an etiologic agent of select reproductive tract disease syndromes in women

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013