DNA DSB repair pathway choice: an orchestrated handover mechanism

DNA double strand breaks (DSBs) are potential lethal lesions but can also lead to chromosome rearrangements, a step promoting carcinogenesis. DNA non-homologous end-joining (NHEJ) is the major DSB rejoining process and occurs in all cell cycle stages. Homologous recombination (HR) can additionally function to repair irradiation-induced two-ended DSBs in G2 phase. In mammalian cells, HR predominantly uses a sister chromatid as a template for DSB repair; thus HR functions only in late S/G2 phase. Here, we review current insight into the interplay between HR and NHEJ in G2 phase. We argue that NHEJ represents the first choice pathway, repairing approximately 80% of X-ray-induced DSBs with rapid kinetics. However, a subset of DSBs undergoes end resection and repair by HR. 53BP1 restricts resection, thereby promoting NHEJ. During the switch fromNHEJ to HR, 53BP1 is repositioned to the periphery of enlarged irradiation-induced foci (IRIF) via a BRCA1-dependent process. K63-linked ubiquitin chains, which also form at IRIF, are also repositioned as well as receptor-associated protein 80 (RAP80), a ubiquitin binding protein. RAP80 repositioning requires POH1, a proteasome component. Thus, the interfacing barriers to HR, 53BP1 and RAP80 are relieved by POH1 and BRCA1, respectively. Removal of RAP80 from the IRIF core is required for loss of the ubiquitin chains and 53BP1, and for efficient replication protein A foci formation. We propose that NHEJ is used preferentially to HR because it is a compact process that does not necessitate extensive chromatin changes in the DSB vicinity

ciliaFA : a research tool for automated, high-throughput measurement of ciliary beat frequency using freely available software

Background: Analysis of ciliary function for assessment of patients suspected of primary ciliary dyskinesia (PCD) and for research studies of respiratory and ependymal cilia requires assessment of both ciliary beat pattern and beat frequency. While direct measurement of beat frequency from high-speed video recordings is the most accurate and reproducible technique it is extremely time consuming. The aim of this study was to develop a freely available automated method of ciliary beat frequency analysis from digital video (AVI) files that runs on open-source software (ImageJ) coupled to Microsoft Excel, and to validate this by comparison to the direct measuring high-speed video recordings of respiratory and ependymal cilia. These models allowed comparison to cilia beating between 3 and 52 Hz. Methods: Digital video files of motile ciliated ependymal (frequency range 34 to 52 Hz) and respiratory epithelial cells (frequency 3 to 18 Hz) were captured using a high-speed digital video recorder. To cover the range above between 18 and 37 Hz the frequency of ependymal cilia were slowed by the addition of the pneumococcal toxin pneumolysin. Measurements made directly by timing a given number of individual ciliary beat cycles were compared with those obtained using the automated ciliaFA system. Results: The overall mean difference (± SD) between the ciliaFA and direct measurement high-speed digital imaging methods was −0.05 ± 1.25 Hz, the correlation coefficient was shown to be 0.991 and the Bland-Altman limits of agreement were from −1.99 to 1.49 Hz for respiratory and from −2.55 to 3.25 Hz for ependymal cilia. Conclusions: A plugin for ImageJ was developed that extracts pixel intensities and performs fast Fourier transformation (FFT) using Microsoft Excel. The ciliaFA software allowed automated, high throughput measurement of respiratory and ependymal ciliary beat frequency (range 3 to 52 Hz) and avoids operator error due to selection bias. We have included free access to the ciliaFA plugin and installation instructions in Additional file 1 accompanying this manuscript that other researchers may use

Heroes and villains of world history across cultures

© 2015 Hanke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedEmergent properties of global political culture were examined using data from the World History Survey (WHS) involving 6,902 university students in 37 countries evaluating 40 figures from world history. Multidimensional scaling and factor analysis techniques found only limited forms of universality in evaluations across Western, Catholic/Orthodox, Muslim, and Asian country clusters. The highest consensus across cultures involved scientific innovators, with Einstein having the most positive evaluation overall. Peaceful humanitarians like Mother Theresa and Gandhi followed. There was much less cross-cultural consistency in the evaluation of negative figures, led by Hitler, Osama bin Laden, and Saddam Hussein. After more traditional empirical methods (e.g., factor analysis) failed to identify meaningful cross-cultural patterns, Latent Profile Analysis (LPA) was used to identify four global representational profiles: Secular and Religious Idealists were overwhelmingly prevalent in Christian countries, and Political Realists were common in Muslim and Asian countries. We discuss possible consequences and interpretations of these different representational profiles.This research was supported by grant RG016-P-10 from the Chiang Ching-Kuo Foundation for International Scholarly Exchange (http://www.cckf.org.tw/). Religion Culture Entropy China Democracy Economic histor

Conceptualizing cultures of violence and cultural change

The historiography of violence has undergone a distinct cultural turn as attention has shifted from examining violence as a clearly defined (and countable) social problem to analysing its historically defined 'social meaning'. Nevertheless, the precise nature of the relationship between 'violence' and 'culture' is still being established. How are 'cultures of violence' formed? What impact do they have on violent behaviour? How do they change? This essay examines some of the conceptual aspects of the relationship between culture and violence. It brings together empirical research into nineteenth-century England with recent research results from other European contexts to examine three aspects of the relationship between culture and violence. These are organised under the labels 'seeing violence', 'identifying the violent' and 'changing violence'. Within a particular society, narratives regarding particular kinds of behaviour shape cultural attitudes. The notion 'violence' is thus defined in relation to physically aggressive acts as well as by being connected to other kinds of attitudes and contexts. As a result, the boundaries between physical aggression which is legitimate and that which is illegitimate (and thus 'violence') are set. Once 'violence' is defined, particular cultures form ideas about who is responsible for it: reactions to violence become associated with social arrangements such as class and gender as well as to attitudes toward the self. Finally, cultures of violence make efforts to tame or eradicate illegitimate forms of physical aggression. This process is not only connected to the development of new forms of power (e.g., new policing or punishment strategies) but also to less tangible cultural influences which aim at changing the behaviour defined as violence (in particular among the social groups identified as violent). Even if successful, this three-tiered process of seeing violence, identifying the violent and changing violence continues anew, emphasising the ways that cultures of violence develop through a continuous process of reevaluation and reinvention

The influence of perfusion solution on renal graft viability assessment

BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie

A Personalized Self-Management Rehabilitation System for Stroke Survivors: A Quantitative Gait Analysis Using a Smart Insole.

Background: In the United Kingdom, stroke is the single largest cause of adult disability and results in a cost to the economy of £8.9 billion per annum. Service needs are currently not being met; therefore, initiatives that focus on patient-centered care that promote long-term self-management for chronic conditions should be at the forefront of service redesign. The use of innovative technologies and the ability to apply these effectively to promote behavior change are paramount in meeting the current challenges. Objective: Our objective was to gain a deeper insight into the impact of innovative technologies in support of home-based, self-managed rehabilitation for stroke survivors. An intervention of daily walks can assist with improving lower limb motor function, and this can be measured by using technology. This paper focuses on assessing the usage of self-management technologies on poststroke survivors while undergoing rehabilitation at home. Methods: A realist evaluation of a personalized self-management rehabilitation system was undertaken in the homes of stroke survivors (N=5) over a period of approximately two months. Context, mechanisms, and outcomes were developed and explored using theories relating to motor recovery. Participants were encouraged to self-manage their daily walking activity; this was achieved through goal setting and motivational feedback. Gait data were collected and analyzed to produce metrics such as speed, heel strikes, and symmetry. This was achieved using a “smart insole” to facilitate measurement of walking activities in a free-living, nonrestrictive environment. Results: Initial findings indicated that 4 out of 5 participants performed better during the second half of the evaluation. Performance increase was evident through improved heel strikes on participants’ affected limb. Additionally, increase in performance in relation to speed was also evident for all 5 participants. A common strategy emerged across all but one participant as symmetry performance was sacrificed in favor of improved heel strikes. This paper evaluates compliance and intensity of use. Conclusion: Our findings suggested that 4 out of the 5 participants improved their ability to heel strike on their affected limb. All participants showed improvements in their speed of gait measured in steps per minute with an average increase of 9.8% during the rehabilitation program. Performance in relation to symmetry showed an 8.5% average decline across participants, although 1 participant improved by 4%. Context, mechanism, and outcomes indicated that dual motor learning and compensatory strategies were deployed by the participants

One-Flavour Hybrid Monte Carlo with Wilson Fermions

The Wilson fermion determinant can be written as product of the determinants of two hermitian positive definite matrices. This formulation allows to simulate non-degenerate quark flavors by means of the hybrid Monte Carlo algorithm. A major numerical difficulty is the occurrence of nested inversions. We construct a Uzawa iteration scheme which treats the nested system within one iterative process.Comment: 11 pages, to appear in proceedings of the workshop "Numerical Challenges in Lattice QCD", Springer Verla