BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell cycle arrest and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here we report that estrogen and estrogen metabolites can cause DNA double strand breaks (DSB) in estrogen receptor-α negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolising enzymes, such as CYP1A1, in breast cells. Lastly, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumours in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

Instant coffee with high chlorogenic acid levels protects humans against oxidative damage of macromolecules

Scope: Coffee is among the most frequently consumed beverages. Its consumption is inversely associated to the incidence of diseases related to reactive oxygen species; the phenomenon may be due to its antioxidant properties. Our primary objective was to investigate the impact of consumption of a coffee containing high levels of chlorogenic acids on the oxidation of proteins, DNA and membrane lipids; additionally, other redox biomarkers were monitored in an intervention trial. Methods and results: The treatment group (n=36) consumed instant coffee co-extracted from green and roasted beans, whereas the control consumed water (800 mL/P/day, 5 days). A global statistical analysis of four main biomarkers selected as primary outcomes showed that the overall changes are significant. 8-Isoprostaglandin F2α in urine declined by 15.3%, 3-nitrotyrosine was decreased by 16.1%, DNA migration due to oxidized purines and pyrimidines was (not significantly) reduced in lymphocytes by 12.5 and 14.1%. Other markers such as the total antioxidant capacity were moderately increased; e.g. LDL and malondialdehyde were shifted towards a non-significant reduction. Conclusion: The oxidation of DNA, lipids and proteins associated with the incidence of various diseases and the protection against their oxidative damage may be indicative for beneficial health effects of coffee.

Exercise-induced DNA damage: Is there a relationship with inflammatory responses?

Both a systemic inflammatory response as well as DNA damage has been observed following exhaustive endurance exercise. Hypothetically, exercise-induced DNA damage might either be a consequence of inflammatory processes or causally involved in inflammation and immunological alterations after strenuous prolonged exercise (e.g. by inducing lymphocyte apoptosis and lymphocytopenia). Nevertheless, up to now only few studies have addressed this issue and there is hardly any evidence regarding a direct relationship between DNA or chromosomal damage and inflammatory responses in the context of exercise. The most conclusive picture that emerges from available data is that reactive oxygen and nitrogen species (RONS) appear to be the key effectors which link inflammation with DNA damage. Considering the time-courses of inflammatory and oxidative stress responses on the one hand and DNA effects on the other the lack of correlations between these responses might also be explained by too short observation periods. This review summarizes and discusses the recent findings on this topic. Furthermore, data from our own study are presented that aimed to verify potential associations between several endpoints of genome stability and inflammatory, immune-endocrine and muscle damage parameters in competitors of an Ironman triathlon until 19 days into recovery. The current results indicate that DNA effects in lymphocytes are not responsible for exercise-induced inflammatory responses. Furthermore, this investigation shows that inflammatory processes, vice versa, do not promote DNA damage, neither directly nor via an increased formation of RONS derived from inflammatory cells. Oxidative DNA damage might have been counteracted by training- and exercise-induced antioxidant responses. However, further studies are needed that combine advanced -omics based techniques (transcriptomics, proteomics) with state-of-the-art biochemical biomarkers to gain more insights into the underlying mechanisms.

No acute and persistent DNA damage after an Ironman triathlon

During acute and strenuous exercise, the enhanced formation of reactive oxygen species can induce damage to lipids, proteins, and nucleic acids. The aim of this study was to investigate the effect of an Ironman triathlon (3.8 km swim, 180 km cycle, 42 km run), as a prototype of ultra-endurance exercise, on DNA stability. As biomarkers of genomic instability, the number of micronuclei, nucleoplasmic bridges, and nuclear buds were measured within the cytokinesis-block micronucleus cytome assay in once-divided peripheral lymphocytes of 20 male triathletes. Blood samples were taken 2 days before, within 20 min after the race, and 5 and 19 days post-race. Overall, the number of micronuclei decreased (P < 0.05) after the race, remained at a low level until 5 days post-race, and declined further to 19 days post-race (P < 0.01). The frequency of nucleoplasmic bridges and nuclear buds did not change immediately after the triathlon. The number of nucleoplasmic bridge declined from 2 days pre-race to 19 days post-exercise (P < 0.05). The frequency of nuclear buds increased after the triathlon, peaking 5 days post-race (P < 0.01) and decreased to basic levels 19 days after the race (P < 0.01). The results suggest that an Ironman triathlon does not cause long-lasting DNA damage in well-trained athletes.

DNA damage in response to an Ironman triathlon

The major aims of this study were to investigate the effect of an Ironman triathlon on DNA migration in the single cell gel electrophoresis assay, apoptosis and necrosis in the cytokinesis-block micronucleus cytome assay with lymphocytes and on changes of total antioxidant capacity in plasma. Blood samples were taken 2 days (d) before, within 20 min, 1 d, 5 d and 19 d post-race. The level of strand breaks decreased (p<0.05) immediately after the race, then increased (p<0.01) 1 d post-race and declined (p<0.01) until 19 d post-race. Apoptotic and necrotic cells decreased (p<0.01) and the total antioxidant status increased (p<0.01) immediately after the race. The results indicate that ultra-endurance exercise does not cause prolonged DNA damage in well-trained male athletes.

Well-trained, healthy triathletes experience no adverse health risks regarding oxidative stress and DNA damage by participating in an ultra-endurance event

Also physical exercise in general is accepted to be protective, acute and strenuous exercise has been shown to induce oxidative stress. Enhanced formation of free radicals leads to oxidation of macromolecules and to DNA damage. On the other hand ultra-endurance events which require strenuous exercise are very popular and the number of participants is continuously increasing worldwide. Since only few data exists on Ironman triathletes, who are prototypes of ultra-endurance athletes, this study was aimed at assessing the risk of oxidative stress and DNA damage after finishing a triathlon and to predict a possible health risk. Blood samples of 42 male athletes were taken 2 days before, within 20 min after the race, 1, 5 and 19 days post-race. Oxidative stress marker increased only moderately after the race and returned to baseline after 5 days. Marker of DNA damage measured by the SCGE assay with and without restriction enzymes as well as by the sister chromatid exchange assay did either show no change or deceased within the first day after the race. Due to intake during the race and the release by the cells plasma concentrations of vitamin C and α-tocopherol increased after the event and returned to baseline 1 day after. This study indicates that despite a temporary increase in some oxidative stress markers, there is no persistent oxidative stress and no DNA damage in response to an Ironman triathlon in trained athletes, mainly due to an appropriate antioxidant intake and general protective alterations in the antioxidant defence system.

Impact of endurance and ultraendurance exercise on DNA damage

Regular moderate physical activity reduces the risk of several noncommunicable diseases. At the same time, evidence exists for oxidative stress resulting from acute and strenuous exercise by enhanced formation of reactive oxygen and nitrogen species, which may lead to oxidatively modified lipids, proteins, and possibly negative effects on DNA stability. The limited data on ultraendurance events such as an Ironman triathlon show no persistent DNA damage after the events. However, when considering the effects of endurance exercise comparable to a (half) marathon or a short triathlon distance, no clear conclusions could be drawn. In order to clarify which components of exercise participation, such as duration, intensity, frequency, or training status of the subjects, have an impact on DNA stability, more information is clearly needed that combines the measurement of DNA damage, gene expression, and DNA repair mechanisms before, during, and after exercise of differing intensities and durations.

Reproducible and label-free biosensor for the selective extraction and rapid detection of proteins in biological fluids

Erythropoietin (EPO), a glycoprotein hormone of ∼34 kDa, is an important hematopoietic growth factor, mainly produced in the kidney and controls the number of red blood cells circulating in the blood stream. Sensitive and rapid recombinant human EPO (rHuEPO) detection tools that improve on the current laborious EPO detection techniques are in high demand for both clinical and sports industry. A sensitive aptamer-functionalized biosensor (aptasensor) has been developed by controlled growth of gold nanostructures (AuNS) over a gold substrate (pAu/AuNS). The aptasensor selectively binds to rHuEPO and, therefore, was used to extract and detect the drug from horse plasma by surface enhanced Raman spectroscopy (SERS). Due to the nanogap separation between the nanostructures, the high population and distribution of hot spots on the pAu/AuNS substrate surface, strong signal enhancement was acquired. By using wide area illumination (WAI) setting for the Raman detection, a low RSD of 4.92% over 150 SERS measurements was achieved. The significant reproducibility of the new biosensor addresses the serious problem of SERS signal inconsistency that hampers the use of the technique in the field. The WAI setting is compatible with handheld Raman devices. Therefore, the new aptasensor can be used for the selective extraction of rHuEPO from biological fluids and subsequently screened with handheld Raman spectrometer for SERS based in-field protein detection.

Complete-linkage clustering for voice activity detection in audio and visual speech

We propose a novel technique for conducting robust voice activity detection (VAD) in high-noise recordings. We use Gaussian mixture modeling (GMM) to train two generic models; speech and non-speech. We then score smaller segments of a given (unseen) recording against each of these GMMs to obtain two respective likelihood scores for each segment. These scores are used to compute a dissimilarity measure between pairs of segments and to carry out complete-linkage clustering of the segments into speech and non-speech clusters. We compare the accuracy of our method against state-of-the-art and standardised VAD techniques to demonstrate an absolute improvement of 15% in half-total error rate (HTER) over the best performing baseline system and across the QUT-NOISE-TIMIT database. We then apply our approach to the Audio-Visual Database of American English (AVDBAE) to demonstrate the performance of our algorithm in using visual, audio-visual or a proposed fusion of these features.

Eye-safe UV stand-off Raman spectroscopy for the ranged detection of explosives in the field

Increasing worldwide terrorist attacks involving explosives presents a growing need for a rapid and ranged explosive detection method that can safely be deployed in the field. Stand-off Raman spectroscopy shows great promise; however, the radiant exposures of lasers required for adequate signal generation are often much greater than what is safe for the eye or the skin, restricting use of the technique to un-populated areas. Here, by determining the safe exposure levels for lasers typically used in Raman spectroscopy, optimal parameter values are identified, which produce the largest possible detection range using power densities that do not exceed the eye-safe limit. It is shown that safe ultraviolet pulse energies can be more than three orders of magnitude greater than equivalent safe visible pulse energies. Coupling this to the 16-fold increase in Raman signal obtained in the ultraviolet at 266 nm over that at 532 nm results in a 131 times larger detection range for the eye-safe 266-nm system over an equivalent eye-safe 532-nm laser system. For the Raman system described here, this translates to a maximum range of 42 m for detecting Teflon with a 266-nm laser emitting a 100-mm diameter beam of 23.5-mJ nanosecond pulses.

Robotic detection and tracking of Crown-Of-Thorns starfish

This paper presents a novel vision-based underwater robotic system for the identification and control of Crown-Of-Thorns starfish (COTS) in coral reef environments. COTS have been identified as one of the most significant threats to Australia's Great Barrier Reef. These starfish literally eat coral, impacting large areas of reef and the marine ecosystem that depends on it. Evidence has suggested that land-based nutrient runoff has accelerated recent outbreaks of COTS requiring extensive use of divers to manually inject biological agents into the starfish in an attempt to control population numbers. Facilitating this control program using robotics is the goal of our research. In this paper we introduce a vision-based COTS detection and tracking system based on a Random Forest Classifier (RFC) trained on images from underwater footage. To track COTS with a moving camera, we embed the RFC in a particle filter detector and tracker where the predicted class probability of the RFC is used as an observation probability to weight the particles, and we use a sparse optical flow estimation for the prediction step of the filter. The system is experimentally evaluated in a realistic laboratory setup using a robotic arm that moves a camera at different speeds and heights over a range of real-size images of COTS in a reef environment.

Acoustic adaptation in cross database audio visual SHMM training for phonetic spoken term detection

Visual information in the form of lip movements of the speaker has been shown to improve the performance of speech recognition and search applications. In our previous work, we proposed cross database training of synchronous hidden Markov models (SHMMs) to make use of external large and publicly available audio databases in addition to the relatively small given audio visual database. In this work, the cross database training approach is improved by performing an additional audio adaptation step, which enables audio visual SHMMs to benefit from audio observations of the external audio models before adding visual modality to them. The proposed approach outperforms the baseline cross database training approach in clean and noisy environments in terms of phone recognition accuracy as well as spoken term detection (STD) accuracy.

Incorporating visual information for spoken term detection

Spoken term detection (STD) is the task of looking up a spoken term in a large volume of speech segments. In order to provide fast search, speech segments are first indexed into an intermediate representation using speech recognition engines which provide multiple hypotheses for each speech segment. Approximate matching techniques are usually applied at the search stage to compensate the poor performance of automatic speech recognition engines during indexing. Recently, using visual information in addition to audio information has been shown to improve phone recognition performance, particularly in noisy environments. In this paper, we will make use of visual information in the form of lip movements of the speaker in indexing stage and will investigate its effect on STD performance. Particularly, we will investigate if gains in phone recognition accuracy will carry through the approximate matching stage to provide similar gains in the final audio-visual STD system over a traditional audio only approach. We will also investigate the effect of using visual information on STD performance in different noise environments.

Tornado damage and impacts on nuclear facilities in the United States

This report provides an overview of the tornado impact on the safe operation and shutdown of nuclear power plants in the United States. The motivation for this review stems from the damage and failure of the Fukushima nuclear power plant on March 11, 2011. That disaster warrants comparison of the safety measures in place within the global nuclear power industry.

The role of offsets in compensating for damage in the coastal and marine environments

This thesis examines the extent of which economic instruments can be used to minimise environmental damage in the coastal and marine environments, and the role of offsets to compensate for residual damage. Economic principles are used to review current command and control systems, potential incentive based mechanisms, and the development of appropriate offsets. Implementing offsets in the marine environment has a number of challenges, so alternative approaches may be necessary. The study finds that offsets in areas remote from the initial impact, or even to protect different species, may be acceptable provided they result in greater conservation benefits than the standard like-for-like offset. This study is particularly relevant for the design of offsets in the coastal and marine environments where there is limited scope for like-for-like offsets.