DNA damage signalling prevents deleterious telomere addition at DNA breaks

The response to DNA damage involves regulation of multiple essential processes to maximize the accuracy of DNA damage repair and cell survival 1. Telomerase has the potential to interfere with repair by inappropriately adding telomeres to DNA breaks. It was unknown whether cells modulate telomerase in response to DNA damage, to increase the accuracy of repair. Here we report that telomerase action is regulated as a part of the cellular response to a DNA double-strand break (DSB). Using yeast, we show that the major ATR/Mec1 DNA damage signalling pathway regulates telomerase action at DSBs. Upon DNA damage, MEC1-RAD53-DUN1-dependent phosphorylation of the telomerase inhibitor Pif1 occurs. Utilizing a separation of function PIF1 mutation, we show that this phosphorylation is required for the Pif1-mediated telomerase inhibition that takes place specifically at DNA breaks, but not telomeres. Hence DNA damage signalling down-modulates telomerase action at a DNA break via Pif1 phosphorylation, thus preventing aberrant healing of broken DNA ends by telomerase. These findings uncover a novel regulatory mechanism that coordinates competing DNA end-processing activities and thereby promotes DNA repair accuracy and genome integrity

The ASY-EOS experiment at GSI: investigating the symmetry energy at supra-saturation densities

The elliptic-flow ratio of neutrons with respect to protons in reactions of neutron rich heavy-ions systems at intermediate energies has been proposed as an observable sensitive to the strength of the symmetry term in the nuclear Equation Of State (EOS) at supra-saturation densities. The recent results obtained from the existing FOPI/LAND data for $^{197}$Au+$^{197}$Au collisions at 400 MeV/nucleon in comparison with the UrQMD model allowed a first estimate of the symmetry term of the EOS but suffer from a considerable statistical uncertainty. In order to obtain an improved data set for Au+Au collisions and to extend the study to other systems, a new experiment was carried out at the GSI laboratory by the ASY-EOS collaboration in May 2011.Comment: Talk given by P. Russotto at the 11th International Conference on Nucleus-Nucleus Collisions (NN2012), San Antonio, Texas, USA, May 27-June 1, 2012. To appear in the NN2012 Proceedings in Journal of Physics: Conference Series (JPCS

Derivation of the Stress-Strain Behavior of the constituents of Bio-Inspired Layered TiO₂/PE-Nanocomposites by Inverse Modeling Based on FE-Simulations of Nanoindentation Test

Owing to the apparent simple morphology and peculiar properties, nacre, an iridescent layer, coating of the inner part of mollusk shells, has attracted considerable attention of biologists, material scientists and engineers. The basic structural motif in nacre is the assembly of oriented plate-like aragonite crystals with a ’brick’ (CaCO3 crystals) and ’mortar’ (macromolecular components like proteins) organization. Many scientific researchers recognize that such structures are associated with the excellent mechanical properties of nacre and biomimetic strategies have been proposed to produce new layered nanocomposites. During the past years, increasing efforts have been devoted towards exploiting nacre’s structural design principle in the synthesis of novel nanocomposites. However, the direct transfer of nacre’s architecture to an artificial inorganic material has not been achieved yet. In the present contribution we report on laminated architecture, composed of the inorganic oxide (TiO2) and organic polyelectrolyte (PE) layers which fulfill this task. To get a better insight and understanding concerning the mechanical behaviour of bio-inspired layered materials consisting of oxide ceramics and organic layers, the elastic-plastic properties of titanium dioxide and organic polyelectrolyte phase are determined via FE-modelling of the nanoindentation process. With the use of inverse modeling and based on numerical models which are applied on the microscopic scale, the material properties of the constituents are derived

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Solar Jet Hunter: a citizen science initiative to identify coronal jets in EUV data sets

Context. Solar coronal jets seen in EUV are ubiquitous on the Sun, have been found in and at the edges of active regions, at the boundaries of coronal holes, and in the quiet Sun. Jets have various shapes, sizes, brightness, velocities and duration in time, which complicates their detection by automated algorithms. So far, solar jets reported in the Heliophysics Event Knowledgebase (HEK) have been mostly reported by humans looking for them in the data, with different levels of precision regarding their timing and positions. Aims. We create a catalogue of solar jets observed in EUV at 304 {\AA} containing precise and consistent information on the jet timing, position and extent. Methods. We designed a citizen science project, "Solar Jet Hunter", on the Zooniverse platform, to analyze EUV observations at 304 {\AA} from the Solar Dynamic Observatory/Atmospheric Imaging Assembly (SDO/AIA). We created movie strips for regions of the Sun in which jets have been reported in HEK and ask the volunteers to 1) confirm the presence of at least one jet in the data and 2) report the timing, position and extent of the jet. Results. We report here the design of the project and the results obtained after the analysis of data from 2011 to 2016. 365 "coronal jet" events from HEK served as input for the citizen science project, equivalent to more than 120,000 images distributed into 9,689 "movie strips". Classification by the citizen scientists resulted with only 21% of the data containing a jet, and 883 individual jets being identified. Conclusions. We demonstrate how citizen science can enhance the analysis of solar data with the example of Solar Jet Hunter. The catalogue of jets thus created is publicly available and will enable statistical studies of jets and related phenomena. This catalogue will also be used as a training set for machines to learn to recognize jets in further data sets

Leveraging Explainable Artificial Intelligence to Optimize Clinical Decision Support

OBJECTIVE: To develop and evaluate a data-driven process to generate suggestions for improving alert criteria using explainable artificial intelligence (XAI) approaches. METHODS: We extracted data on alerts generated from January 1, 2019 to December 31, 2020, at Vanderbilt University Medical Center. We developed machine learning models to predict user responses to alerts. We applied XAI techniques to generate global explanations and local explanations. We evaluated the generated suggestions by comparing with alert\u27s historical change logs and stakeholder interviews. Suggestions that either matched (or partially matched) changes already made to the alert or were considered clinically correct were classified as helpful. RESULTS: The final dataset included 2 991 823 firings with 2689 features. Among the 5 machine learning models, the LightGBM model achieved the highest Area under the ROC Curve: 0.919 [0.918, 0.920]. We identified 96 helpful suggestions. A total of 278 807 firings (9.3%) could have been eliminated. Some of the suggestions also revealed workflow and education issues. CONCLUSION: We developed a data-driven process to generate suggestions for improving alert criteria using XAI techniques. Our approach could identify improvements regarding clinical decision support (CDS) that might be overlooked or delayed in manual reviews. It also unveils a secondary purpose for the XAI: to improve quality by discovering scenarios where CDS alerts are not accepted due to workflow, education, or staffing issues

First in situ measurements of the prototype Tesseract fluxgate magnetometer on the ACES-II-Low sounding rocket

Ongoing innovation in next-generation fluxgate magnetometry is important for enabling future investigations of space plasma, especially multi-spacecraft experimental studies of energy transport in the magnetosphere and the solar wind. Demonstrating the spaceflight capability of novel designs is an important step in the instrument development process; however, large-scale satellite missions are often unwilling to accept the risks of an instrument without flight heritage. The Tesseract – a novel fluxgate magnetometer sensor design – had an opportunity for an inaugural spaceflight demonstration on the ACES-II sounding rocket mission, which launched from Andøya Space Center in Andenes, Norway, in November 2022. Tesseract's design takes advantage of a new racetrack core geometry to create a sensor that addresses some of the issues that contribute to instability in more traditional ring-core designs. Here we present the design of a prototype fluxgate magnetometer based on the new Tesseract sensor, its pre-flight characteristics, and an evaluation of its in-flight performance aboard ACES-II. We find that the magnetic field measured by Tesseract over the course of the flight was in strong agreement with both the onboard ACES II reference ring-core fluxgate magnetometer and the predictions of a geomagnetic field model. The Tesseract-based magnetometer measured signatures of field-aligned currents and potential Alfvén wave activity as it crossed an active auroral arc, and we conclude that it performed as expected. Tesseract will be flown on the Tandem Reconnection and Cusp Electrodynamics Reconnaissance Satellites (TRACERS) Small Explorers (SMEX) satellite mission as part of the MAGnetometers for Innovation and Capability (MAGIC) technology demonstration currently scheduled to launch in 2025.</p

Clinical assessment of the physical activity pattern of chronic fatigue syndrome patients: a validation of three methods

Contains fulltext : 79568.pdf (publisher's version ) (Open Access)BACKGROUND: Effective treatment of chronic fatigue syndrome (CFS) with cognitive behavioural therapy (CBT) relies on a correct classification of so called 'fluctuating active' versus 'passive' patients. For successful treatment with CBT is it especially important to recognise the passive patients and give them a tailored treatment protocol. In the present study it was evaluated whether CFS patient's physical activity pattern can be assessed most accurately with the 'Activity Pattern Interview' (API), the International Physical Activity Questionnaire (IPAQ) or the CFS-Activity Questionnaire (CFS-AQ). METHODS: The three instruments were validated compared to actometers. Actometers are until now the best and most objective instrument to measure physical activity, but they are too expensive and time consuming for most clinical practice settings. In total 226 CFS patients enrolled for CBT therapy answered the API at intake and filled in the two questionnaires. Directly after intake they wore the actometer for two weeks. Based on receiver operating characteristic (ROC) curves the validity of the three methods were assessed and compared. RESULTS: Both the API and the two questionnaires had an acceptable validity (0.64 to 0.71). None of the three instruments was significantly better than the others. The proportion of false predictions was rather high for all three instrument. The IPAQ had the highest proportion of correct passive predictions (sensitivity 70.1%). CONCLUSION: The validity of all three instruments appeared to be fair, and all showed rather high proportions of false classifications. Hence in fact none of the tested instruments could really be called satisfactory. Because the IPAQ showed to be the best in correctly predicting 'passive' CFS patients, which is most essentially related to treatment results, it was concluded that the IPAQ is the preferable alternative for an actometer when treating CFS patients in clinical practice

Automated systems to identify relevant documents in product risk management

<p>Abstract</p> <p>Background</p> <p>Product risk management involves critical assessment of the risks and benefits of health products circulating in the market. One of the important sources of safety information is the primary literature, especially for newer products which regulatory authorities have relatively little experience with. Although the primary literature provides vast and diverse information, only a small proportion of which is useful for product risk assessment work. Hence, the aim of this study is to explore the possibility of using text mining to automate the identification of useful articles, which will reduce the time taken for literature search and hence improving work efficiency. In this study, term-frequency inverse document-frequency values were computed for predictors extracted from the titles and abstracts of articles related to three tumour necrosis factors-alpha blockers. A general automated system was developed using only general predictors and was tested for its generalizability using articles related to four other drug classes. Several specific automated systems were developed using both general and specific predictors and training sets of different sizes in order to determine the minimum number of articles required for developing such systems.</p> <p>Results</p> <p>The general automated system had an area under the curve value of 0.731 and was able to rank 34.6% and 46.2% of the total number of 'useful' articles among the first 10% and 20% of the articles presented to the evaluators when tested on the generalizability set. However, its use may be limited by the subjective definition of useful articles. For the specific automated system, it was found that only 20 articles were required to develop a specific automated system with a prediction performance (AUC 0.748) that was better than that of general automated system.</p> <p>Conclusions</p> <p>Specific automated systems can be developed rapidly and avoid problems caused by subjective definition of useful articles. Thus the efficiency of product risk management can be improved with the use of specific automated systems.</p

Experimental search for super and hyper heavy nuclei at cyclotron Institute Texas A&M University

The question "How heavy can an atomic nucleus be?" is a fundamental problem in nuclear physics. The possible existence of island(s) of stable super-heavy nuclei has been an inspiring problem in heavy ion physics for almost four decades. This paper is focused on the experimental search of Super/Hyper Heavy Elements (SHE/HHE) conducted at the Cyclotron Institute, Texas A&M University. A novel experimental idea and experimental set up introduced for this research will be presented