Impact of fractionation on out-of-field survival and DNA damage responses following exposure to intensity modulated radiation fields

To limit toxicity to normal tissues adjacent to the target tumour volume, radiotherapy is delivered using fractionated regimes whereby the total prescribed dose is given as a series of sequential smaller doses separated by specific time intervals. The impact of fractionation on out-of-field survival and DNA damage responses was determined in AGO-1522 primary human fibroblasts and MCF-7 breast tumour cells using uniform and modulated exposures delivered using a 225 kVp x-ray source. Responses to fractionated schedules (two equal fractions delivered with time intervals from 4 h to 48 h) were compared to those following acute exposures. Cell survival and DNA damage repair measurements indicate that cellular responses to fractionated non-uniform exposures differ from those seen in uniform exposures for the investigated cell lines. Specifically, there is a consistent lack of repair observed in the out-of-field populations during intervals between fractions, confirming the importance of cell signalling to out-of-field responses in a fractionated radiation schedule, and this needs to be confirmed for a wider range of cell lines and conditions.

Comparative functional responses predict the invasiveness and ecological impacts of alien herbivorous snails.

Understanding determinants of the invasiveness and ecological impacts of alien species is amongst the most sought-after and urgent research questions in ecology. Several studies have shown the value of comparing the functional responses (FRs) of alien and native predators towards native prey, however, the technique is under-explored with herbivorous alien species and as a predictor of invasiveness as distinct from ecological impact. Here, in China, we conducted a mesocosm experiment to compare the FRs among three herbivorous snail species: the golden apple snail, Pomacea canaliculata, a highly invasive and high impact alien listed in “100 of the World's Worst Invasive Alien Species”; Planorbarius corneus, a non-invasive, low impact alien; and the Chinese native snail, Bellamya aeruginosa, when feeding on four locally occurring plant species. Further, by using a numerical response equation, we modelled the population dynamics of the snail consumers. For standard FR parameters, we found that the invasive and damaging alien snail had the highest “attack rates” a, shortest “handling times” h and also the highest estimated maximum feeding rates, 1/hT, whereas the native species had the lowest attack rates, longest handling times and lowest maximum feeding rates. The non-invasive, low impact alien species had consistently intermediate FR parameters. The invasive alien species had higher population growth potential than the native snail species, whilst that of the non-invasive alien species was intermediate. Thus, while the comparative FR approach has been proposed as a reliable method for predicting the ecological impacts of invasive predators, our results further suggest that comparative FRs could extend to predict the invasiveness and ecological impacts of alien herbivores and should be explored in other taxa and trophic groups to determine the general utility of the approach.

Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POP were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p'-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2h and 48h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced the ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC+Br mixture. No significant effects were detected in the Br+Cl, PFC+Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment.

Behavioural and physiological responses of shelter dogs to long-term confinement

In Italy, National Law (281/1991) prohibits euthanasia of shelter dogs if they are not dangerous or suffering seriously. Adoption rates in rescue shelters are often lower than entrance rates, leading inevitably to overcrowded facilities where animals are likely to spend the rest of their lives in kennels. In this situation, housing conditions (i.e. space provided, environmental, and social stimulation) may have an impact on canine welfare. In this research project, the effects of two different forms of housing (group- and pair housing) on long-term shelter dogs were compared using behavioural and physiological parameters. Observational data and saliva samples were collected from dogs exposed to both experimental settings; behaviour and cortisol concentration levels were used as welfare indicators. Pair housing offered fewer social and environmental stimuli and behavioural analysis showed a significant decrease in locomotor, exploratory, and social behaviour. Cortisol levels show that this parameter varied independently of housing conditions. Although this study found no evidence suggesting that one form of confinement reduced animal welfare more than the other (e.g. in terms of abnormal behaviour, or higher cortisol concentrations), the type of confinement did affect the expression of a variety of behaviours and these variations should not be ignored with respect to housing decisions for long-term shelter dogs.

The role of the cerebral cortex in postural responses to externally induced perturbations

The ease with which we avoid falling down belies a highly sophisticated and distributed neural network for controlling reactions to maintain upright balance. Although historically these reactions were considered within the sub cortical domain, mounting evidence reveals a distributed network for postural control including a potentially important role for the cerebral cortex. Support for this cortical role comes from direct measurement associated with moments of induced instability as well as indirect links between cognitive task performance and balance recovery. The cerebral cortex appears to be directly involved in the control of rapid balance reactions but also setting the central nervous system in advance to optimize balance recovery reactions even when a future threat to stability is unexpected. In this review the growing body of evidence that now firmly supports a cortical role in the postural responses to externally induced perturbations is presented. Moreover, an updated framework is advanced to help understand how cortical contributions may influence our resistance to falls and on what timescale. The implications for future studies into the neural control of balance are discussed.

Secure key generation from OFDM subcarriers' channel responses

The ability to exchange keys between users is vital in any wireless based security system. A key generation technique which exploits the randomness of the wireless channel is a promising alternative to existing key distribution techniques, e.g., public key cryptography. In this paper, a secure key generation scheme based on the subcarriers' channel responses in orthogonal frequency-division multiplexing (OFDM) systems is proposed. We first implement a time-variant multipath channel with its channel impulse response modelled as a wide sense stationary (WSS) uncorrelated scattering random process and demonstrate that each subcarrier's channel response is also a WSS random process. We then define the X% coherence time as the time required to produce an X% correlation coefficient in the autocorrelation function (ACF) of each channel tap, and find that when all the channel taps have the same Doppler power spectrum, all subcarriers' channel responses has the same ACF as the channel taps. The subcarrier's channel response is then sampled every X% coherence time and quantized into key bits. All the key sequences' randomness is tested using National Institute of Standards and Technology (NIST) statistical test suite and the results indicate that the commonly used sampling interval as 50% coherence time cannot guarantee the randomness of the key sequence.

Efficient Key Generation by Exploiting Randomness from Channel Responses of Individual OFDM Subcarriers

Key generation from the randomness of wireless channels is a promising technique to establish a secret cryptographic key securely between legitimate users. This paper proposes a new approach to extract keys efficiently from channel responses of individual orthogonal frequency-division multiplexing (OFDM) subcarriers. The efficiency is achieved by (i) fully exploiting randomness from time and frequency domains and (ii) improving the cross-correlation of the channel measurements. Through the theoretical modelling of the time and frequency autocorrelation relationship of the OFDM subcarrier's channel responses, we can obtain the optimal probing rate and use multiple uncorrelated subcarriers as random sources. We also study the effects of non-simultaneous measurements and noise on the cross-correlation of the channel measurements. We find the cross-correlation is mainly impacted by noise effects in a slow fading channel and use a low pass filter (LPF) to reduce the key disagreement rate and extend the system's working signal-to-noise ratio range. The system is evaluated in terms of randomness, key generation rate, and key disagreement rate, verifying that it is feasible to extract randomness from both time and frequency domains of the OFDM subcarrier's channel responses.

Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials

BACKGROUND: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake.

OBJECTIVE: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake.

DESIGN: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged ≥18 y. For each biomarker response, the regression coefficient (β) for individual studies and the overall pooled β were calculated by using random-effects meta-analysis.

RESULTS: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 μg/d. Calculation of the overall pooled β for studies in the range of 50 to 400 μg/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I(2) = 13.5% compared with I(2) = 77.2%) and red blood cell (I(2) = 45.9% compared with I(2) = 70.2%) folate.

CONCLUSIONS: Studies administering >400 μg folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.

Cellular responses to genome mistranslation

Low level protein synthesis errors can have profound effects on normal cell physiology and disease development, namely neurodegeneration, cancer and aging. The biology of errors introduced into proteins during mRNA translation, herein referred as mistranslation, is not yet fully understood. In order to shed new light into this biological phenomenon, we have engineered constitutive codon misreading in S. cerevisiae, using a mutant tRNA that misreads leucine CUG codons as serine, representing a 240 fold increase in mRNA translational error relative to typical physiological error (0.0001%). Our studies show that mistranslation induces autophagic activity, increases accumulation of insoluble proteins, production of reactive oxygen species, and morphological disruption of the mitochondrial network. Mistranslation also up-regulates the expression of the longevity gene PNC1, which is a regulator of Sir2p deacetylase activity. We show here that both PNC1 and SIR2 are involved in the regulation of autophagy induced by mistranslation, but not by starvation-induced autophagy. Mistranslation leads to P-body but not stress-granule assembly, down-regulates the expression of ribosomal protein genes and increases slightly the selective degradation of ribosomes (ribophagy). The study also indicates that yeast cells are much more resistant to mistranslation than expected and highlights the importance of autophagy in the cellular response to mistranslation. Morpho-functional alterations of the mitochondrial network are the most visible phenotype of mistranslation. Since most of the basic cellular processes are conserved between yeast and humans, this study reinforces the importance of yeast as a model system to study mistranslation and suggests that oxidative stress and accumulation of misfolded proteins arising from aberrant protein synthesis are important causes of the cellular degeneration observed in human diseases associated to mRNA mistranslation.

Brain responses and looking behavior during audiovisual speech integration in infants predict auditory speech comprehension in the second year of life

The use of visual cues during the processing of audiovisual (AV) speech is known to be less efficient in children and adults with language difficulties and difficulties are known to be more prevalent in children from low-income populations. In the present study, we followed an economically diverse group of thirty-seven infants longitudinally from 6–9 months to 14–16 months of age. We used eye-tracking to examine whether individual differences in visual attention during AV processing of speech in 6–9 month old infants, particularly when processing congruent and incongruent auditory and visual speech cues, might be indicative of their later language development. Twenty-two of these 6–9 month old infants also participated in an event-related potential (ERP) AV task within the same experimental session. Language development was then followed-up at the age of 14–16 months, using two measures of language development, the Preschool Language Scale and the Oxford Communicative Development Inventory. The results show that those infants who were less efficient in auditory speech processing at the age of 6–9 months had lower receptive language scores at 14–16 months. A correlational analysis revealed that the pattern of face scanning and ERP responses to audiovisually incongruent stimuli at 6–9 months were both significantly associated with language development at 14–16 months. These findings add to the understanding of individual differences in neural signatures of AV processing and associated looking behavior in infants.

Brain responses to audiovisual speech mismatch in infants are associated with individual differences in looking behaviour

Research on audiovisual speech integration has reported high levels of individual variability, especially among young infants. In the present study we tested the hypothesis that this variability results from individual differences in the maturation of audiovisual speech processing during infancy. A developmental shift in selective attention to audiovisual speech has been demonstrated between 6 and 9 months with an increase in the time spent looking to articulating mouths as compared to eyes (Lewkowicz & Hansen-Tift. (2012) Proc. Natl Acad. Sci. USA, 109, 1431–1436; Tomalski et al. (2012) Eur. J. Dev. Psychol., 1–14). In the present study we tested whether these changes in behavioural maturational level are associated with differences in brain responses to audiovisual speech across this age range. We measured high-density event-related potentials (ERPs) in response to videos of audiovisually matching and mismatched syllables /ba/ and /ga/, and subsequently examined visual scanning of the same stimuli with eye-tracking. There were no clear age-specific changes in ERPs, but the amplitude of audiovisual mismatch response (AVMMR) to the combination of visual /ba/ and auditory /ga/ was strongly negatively associated with looking time to the mouth in the same condition. These results have significant implications for our understanding of individual differences in neural signatures of audiovisual speech processing in infants, suggesting that they are not strictly related to chronological age but instead associated with the maturation of looking behaviour, and develop at individual rates in the second half of the first year of life.

Effects of Prochlorperazine on Normal Vestibular Ocular and Perceptual Responses: A Randomised, Double-Blind, Crossover, Placebo-Controlled Study

Background: The present study investigated whether prochlorperazine affects vestibular-ocular reflex (VOR) and vestibulo-perceptual function. Methods: We studied 12 healthy naïve subjects 3 hours after a single dose of oral prochlorperazine 5mg in a randomised, placebo-controlled, double-blind, cross-over study in healthy young subjects. Two rotational tests in yaw were used: 1) a Threshold task investigating perceptual motion detection and nystagmic thresholds (acceleration steps of 0.5deg/s/s) and 2) Suprathreshold responses to velocity steps of 90deg/s in which vestibulo-ocular (VO) and vestibulo-perceptual (VP) time constants of decay, as well as VOR gain, were measured. Results: Prochlorperazine had no effect upon any measure of nystagmic or perceptual vestibular function compared to placebo. This lack of effects on vestibular-mediated motion perception suggests that the drug is likely to act more as an antiemetic than as an anti-vertiginous agent.