Genome-wide multi-parametric analysis of H2AX or γH2AX distributions during ionizing radiation-induced DNA damage response

Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated. Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively). Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded. Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX. Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times

Speed-Oblivious Online Scheduling: Knowing (Precise) Speeds is not Necessary

We consider online scheduling on unrelated (heterogeneous) machines in a speed-oblivious setting, where an algorithm is unaware of the exact job-dependent processing speeds. We show strong impossibility results for clairvoyant and non-clairvoyant algorithms and overcome them in models inspired by practical settings: (i) we provide competitive learning-augmented algorithms, assuming that (possibly erroneous) predictions on the speeds are given, and (ii) we provide competitive algorithms for the speed-ordered model, where a single global order of machines according to their unknown job-dependent speeds is known. We prove strong theoretical guarantees and evaluate our findings on a representative heterogeneous multi-core processor. These seem to be the first empirical results for scheduling algorithms with predictions that are evaluated in a non-synthetic hardware environment.Comment: To appear at ICML 202

Placebokontrollierte klinische Studie zum Effekt von Knoblauchtrockenpulver auf die Durchblutung bei gesunden Kontrollpersonen und Patienten mit systemischer Sklerodermie

Die biologischen Grundlagen der Wirkphysiologie von Knoblauch (Allium sativum) auf Blutrheologie und Vasomotion sind bisher weitgehend unbekannt. In einer randomisierten, doppelblinden Studie erhielten 20 Patientinnen mit systemischer Sklerodermie und 12 Probanden für 7 Tage je 900 mg Knoblauchtrockenpulver (Kwai, N oder Placebo / d als Add-on Medikation) zur Standardherapie. Rheologische Parameter wurden zu Beginn, nach 1 Tag, sowie nach 7 Tagen Therapiedauer bestimmt. Eine Beurteilung der Vasomotion erfolgte mittels NIRP, einem Verfahren zur Beurteilung der Mikrozirkulation, sowie mittels Messung der akralen Hauttemperatur. 7 Tage Knoblauch- bzw. Placebotherapie ergaben nur bei den Verum-behandelten Patienten eine signifikante Abnahme der Erythrozytenaggregation und ADP-induzierter Thrombozytenaggregation. Signifikante Effekte auf die Gefäßregulation ergaben sich nicht, die akrale Hauttemperatur wurde durch die Knoblauch gesteigert

Peculiarities of structural-phase state of multi-layer coatings based on Zr-Y-O

Using high-resolution transmission electron microscopy it was established that the Zr-Y-O-based coating layers have a ZrO[2] phase in the tetragonal and monoclinic modifications in the initial state. When it is heated up to 900°C, the ZrO[2] phase in the cubic modification appears in the layer of the coating. With an annealing time of 20 minutes, the grains are crushed to a size of about 15-20 nm. The microdiffraction pattern is modified, the number of reflexes of the tetragonal and monoclinic phases first increases, and then changes without systemic

MODELLING TECHNICAL SYSTEMS IN THE EARLY PHASE: PROPOSING A FORMAL DEFINITION FOR THE SYSTEM CONCEPT

The task of developing “concepts” is common in all fields of engineering, especially in the early phases of product development. However, an in-depth literature analysis showed that authors - often depending on different contexts in design research, education, and industry - define the term “concept” in differing ways. The aspect of reference-based development is rarely addressed in existing definitions. This indicates that there is a need for an updated and concise concept definition. In this paper, the authors propose a new definition of the term “system concept” within the context of SGE - System Generation Engineering that incorporates the findings from the literature analysis. The definition was reflected on in two case-studies. The first one contained the system concept for automotive display and operating systems, the second one the system concept for a kinesthetic-haptic VR interface. The proposed definition contains the relevant characteristics identified from the literature review and supports both current activity-based process models and reference-based development, as practical application has shown

Interorganizational Networks in Physical Activity Promotion: A Systematic Review

Public health challenges such as physical inactivity are multiplex and cannot be effectively addressed by single organizations or sectors. For this reason, public health policies have to involve various sectors and foster partnerships among organizations. Social network analysis (SNA) provides a methodological toolkit that enables the investigation of relationships between organizations to reveal information about the structure and cooperation within networks. This systematic review provides an overview of studies utilizing SNA to analyze the structure of networks that promote physical activity, including the structural set-up, types, and conditions of cooperation, the existence or absence of key actors, the characteristics of organizations working together, and potential barriers limiting collaboration. In total, eight eligible studies were identified. To evaluate the quality of these studies, a quality assessment tool for SNA was created. Relevant aspects from each study were systematically outlined using a data extraction template developed for network studies. The studies reported low to moderate density scores with many ties not being realized. Organizations tend to work side by side than as real partners, whereas organizations of the same type are more strongly connected. Most of the studies identified governmental health organizations as key players in their networks. Network maturity influences network outcomes. Shared goals and geographic proximity are potential facilitators for network development. For future research, more sophisticated methods and longitudinal studies are required to describe how networks, with the aim of promoting physical activity, develop and change to identify predicting factors for an effective network structur

Cognition and Brain Function in Schizotypy: A Selective Review

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. While the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning, and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable interindividual differences that covary with performance on a wide range of perceptual, cognitive, and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterization of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophreni

Chromatin Ubiquitination Guides DNA Double Strand Break Signaling and Repair

Chromatin is the context for all DNA-based molecular processes taking place in the cell nucleus. The initial chromatin structure at the site of the DNA damage determines both, lesion generation and subsequent activation of the DNA damage response (DDR) pathway. In turn, proceeding DDR changes the chromatin at the damaged site and across large fractions of the genome. Ubiquitination, besides phosphorylation and methylation, was characterized as an important chromatin post-translational modification (PTM) occurring at the DNA damage site and persisting during the duration of the DDR. Ubiquitination appears to function as a highly versatile “signal-response” network involving several types of players performing various functions. Here we discuss how ubiquitin modifiers fine-tune the DNA damage recognition and response and how the interaction with other chromatin modifications ensures cell survival

Photon Production in Hot and Dense Strongly Interacting Matter

This text is meant as an introduction to the theoretical physics of photon emission in hot and dense strongly interacting matter, the principal application being relativistic nuclear collisions. We shall cover some of the results and techniques appropriate for studies at SPS, RHIC, and LHC energiesComment: 35 pages, accepted for publication, Landolt-Boernstein Volume 1-23