The basic chemistry of exercise-induced DNA oxidation:oxidative damage, redox signalling and their interplay

Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signalling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signalling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signalling and DNA damage, using hydroxyl radical (·OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signalling and damage. Indeed, H2O2 can participate in two electron signalling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and ·OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signalling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signalling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation

Influence of vitamin C and vitamin E on redox signalling:implications for exercise adaptations

The exogenous antioxidants vitamin C (ascorbate) and vitamin E (α-tocopherol) often blunt favourable cell signalling responses to exercise, suggesting that redox signalling contributes to exercise adaptations. Current theories posit that this antioxidant paradigm interferes with redox signalling by attenuating exercise-induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. The well-documented in vitro antioxidant actions of ascorbate and α-tocopherol and characterisation of the type and source of the ROS/RNS produced during exercise theoretically enables identification of the redox-dependent mechanism responsible for the blunting of favourable cell signalling responses to exercise. This review aimed to apply this reasoning to determine how the aforementioned antioxidants might attenuate exercise-induced ROS/RNS production. The principal outcomes of this analysis are (1) neither antioxidant is likely to attenuate nitric oxide signalling either directly (reaction with nitric oxide) or indirectly (reaction with derivatives, e.g. peroxynitrite) (2) neither antioxidant reacts appreciably with hydrogen peroxide, a key effector of redox signalling (3) ascorbate but not α-tocopherol has the capacity to attenuate exercise-induced superoxide generation and (4) alternate mechanisms, namely pro-oxidant side reactions and/or reduction of bioactive oxidised macromolecule adducts, are unlikely to interfere with exercise-induced redox signalling. Out of all the possibilities considered, ascorbate mediated suppression of superoxide generation with attendant implications for hydrogen peroxide signalling is arguably the most cogent explanation for blunting of favourable cell signalling responses to exercise. However, this mechanism is dependent on ascorbate accumulating at sites rich in NADPH oxidases, principal contributors to contraction mediated superoxide generation, and outcompeting nitric oxide and superoxide dismutase isoforms. The major conclusions of this review are: (1) direct evidence for interference of ascorbate and α-tocopherol with exercise-induced ROS/RNS production is lacking (2) theoretical analysis reveals that both antioxidants are unlikely to have a major impact on exercise-induced redox signalling and (3) it is worth considering alternate redox-independent mechanisms

Community Networks and Sustainability: a Survey of Perceptions, Practices, and Proposed Solutions

Community network (CN) initiatives have been around for roughly two decades, evangelizing a distinctly different paradigm for building, maintaining, and sharing network infrastructure but also defending the basic human right to Internet access. Over this time they have evolved into a mosaic of systems that vary widely with respect to their network technologies, their offered services, their organizational structure, and the way they position themselves in the overall telecommunications’ ecosystem. Common to all these highly differentiated initiatives is the sustainability challenge. We approach sustainability as a broad term with an economical, political, and cultural context. We first review the different perceptions of the term. These vary both across and within the different types of stakeholders involved in CNs and are reflected in their motivation to join such initiatives. Then, we study the diverse approaches of CN operators towards the sustainability goal. Given the rich context of the term, these range all the way from mechanisms to fund their activities, to organizational structures and social activities serving as incentives for the engagement of their members. We iterate on incentive mechanisms that have been proposed and theoretically analyzed in the literature for CNs as well as tools and processes that have been actually implemented in them. Finally, we enumerate lessons that have been learned out of these two decades of CNs’ operation and discuss additional technological and regulatory issues that are key to their longer-term sustainability

Comparison of Texture Features Derived from Static and Respiratory-Gated PET Images in Non-Small Cell Lung Cancer

Background: PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging. Methods: Twenty-six patients (34 lesions) received 3D and 4D [18F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (δ3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and δ3D-4D were also assessed. Results: 4D-PET increased LRLG ( = 1%–2%, p0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV<5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and δ3D-4D for the texture features. Motion amplitude had moderate impact on δ for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast. Conclusions: Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion

Ant colony optimization with immigrants schemes for the dynamic railway junction rescheduling problem with multiple delays

Train rescheduling after a perturbation is a challenging task and is an important concern of the railway industry as delayed trains can lead to large fines, disgruntled customers and loss of revenue. Sometimes not just one delay but several unrelated delays can occur in a short space of time which makes the problem even more challenging. In addition, the problem is a dynamic one that changes over time for, as trains are waiting to be rescheduled at the junction, more timetabled trains will be arriving, which will change the nature of the problem. The aim of this research is to investigate the application of several different ant colony optimization (ACO) algorithms to the problem of a dynamic train delay scenario with multiple delays. The algorithms not only resequence the trains at the junction but also resequence the trains at the stations, which is considered to be a first step towards expanding the problem to consider a larger area of the railway network. The results show that, in this dynamic rescheduling problem, ACO algorithms with a memory cope with dynamic changes better than an ACO algorithm that uses only pheromone evaporation to remove redundant pheromone trails. In addition, it has been shown that if the ant solutions in memory become irreparably infeasible it is possible to replace them with elite immigrants, based on the best-so-far ant, and still obtain a good performance

Multiscale - Patient-Specific Artery and Atherogenesis Models

In this work, we present a platform for the development of multiscale patient-specific artery and atherogenesis models. The platform, called ARTool, integrates technologies of 3-D image reconstruction from various image modalities, blood flow and biological models of mass transfer, plaque characterization, and plaque growth. Patient images are acquired for the development of the 3-D model of the patient specific arteries. Then, blood flow ismodeled within the arterial models for the calculation of the wall shear stress distribution (WSS). WSS is combined with other patient-specific parameters for the development of the plaque progression models. Real-time simulation can be performed for same cases in grid environment. The platform is evaluated using both animal and human data

Incidence and prevalence of major central nervous system involvement in Systemic Lupus Erythematosus: A 3-year prospective study of 370 patients

Background: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P#0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P,0.001). Conclusions: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes

Crossing borders: new teachers co-constructing professional identity in performative times

This paper draws on a range of theoretical perspectives on the construction of new teachers’ professional identity. It focuses particularly on the impact of the development in many national education systems of a performative culture of the management and regulation of teachers’ work. Whilst the role of interactions with professional colleagues and school managers in the performative school has been extensively researched, less attention has been paid to new teachers’ interactions with students. This paper highlights the need for further research focusing on the process of identity co-construction with students. A key theoretical concept employed is that of liminality, the space within which identities are in transition as teachers adjust to the culture of a new professional workplace, and the nature of the engagement of new teachers, or teachers who change schools, with students. The authors argue that an investigation into the processes of this co-construction of identity offers scope for new insights into the extent to which teachers might construct either a teacher identity at odds with their personal and professional values, or a more ‘authentic’ identity that counters performative discourses. These insights will in turn add to our understanding of the complex range of factors impacting on teacher resilience and motivation

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Measuring the ringdown scalar polarization of gravitational waves in Einstein scalar Gauss-Bonnet gravity

We model the scalar waves produced during the ringdown stage of binary black hole coalescence in Einstein scalar Gauss-Bonnet (EsGB) gravity, using numerical relativity simulations of the theory in the decoupling limit. Through a conformal coupling of the scalar field to the metric in the matter-field action, we show that the gravitational waves in this theory can have a scalar polarization. We model the scalar quasi-normal modes of the ringdown signal in EsGB gravity, and quantify the extent to which current and future gravitational wave detectors could observe the spectrum of scalar radiation emitted during the ringdown phase of binary black hole coalescence. We find that within the limits of the theory's coupling parameters set by current theoretical and observational constraints, the scalar ringdown signal from black hole remnants in the $10^1 - 10^3 \, M_{\odot}$ mass range is expected to be well below the detectability threshold with the current network of gravitational-wave detectors (LIGO-Virgo-KAGRA), but is potentially measurable with next-generation detectors such as the Einstein Telescope.Comment: 27 pages, 19 figures, to match published version in Phys. Rev.