Cytochrome c Reduction by H2S Potentiates Sulfide Signaling.

This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this record.Hydrogen sulfide (H2S) is an endogenously produced gas that is toxic at high concentrations. It is eliminated by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome c (Cyt C) by H2S has been reported previously but not characterized. In this study, we demonstrate that reduction of ferric Cyt C by H2S exhibits hysteretic behavior, which suggests the involvement of reactive sulfur species in the reduction process and is consistent with a reaction stoichiometry of 1.5 mol of Cyt C reduced/mol of H2S oxidized. H2S increases O2 consumption by human cells (HT29 and HepG2) treated with the complex III inhibitor antimycin A, which is consistent with the entry of sulfide-derived electrons at the level of complex IV. Cyt C-dependent H2S oxidation stimulated protein persulfidation in vitro, while silencing of Cyt C expression decreased mitochondrial protein persulfidation in a cell culture. Cyt C released during apoptosis was correlated with persulfidation of procaspase 9 and with loss of its activity. These results reveal a potential role for the electron transfer chain in general, and Cyt C in particular, for potentiating sulfide-based signaling.This work was supported by the French State in the frame of the “Investments for the future” Programme IdEx Bordeaux, reference ANR-10-IDEX-03-02, and by an ATIP-AVENIR grant (to M.R.F.), the National Institutes of Health (GM112455 to R.B. and R01GM113030 to M.D.P.), the Medical Research Council, UK (MR/M022706/1 to M.W.), the National Science Foundation (DGE-1309047 to A.K.S.), and the Brian Ridge Scholarship (R.T.). The authors are grateful to M.-F. Giraud for the help with purification of mitochondria

A Microsoft HoloLens Mixed Reality Surgical Simulator for Patient-Specific Hip Arthroplasty Training

Surgical simulation can offer novice surgeons an opportunity to practice skills outside the operating theatre in a safe controlled environment. According to literature evidence, nowadays there are very few training simulators available for Hip Arthroplasty (HA). In a previous study we have presented a physical simulator based on a lower torso phantom including a patient-specific hemi-pelvis replica embedded in a soft synthetic foam. This work explores the use of Microsoft HoloLens technology to enrich the physical patient-specific simulation with the implementation of wearable mixed reality functionalities. Our HA multimodal simulator based on mixed reality using the HoloLens is described by illustrating the overall system, and by summarizing the main phases of the design and development. Finally, we present a preliminary qualitative study with seven subjects (5 medical students, and 2 orthopedic surgeons) showing encouraging results that suggest the suitability of the HoloLens for the proposed application. However, further studies need to be conducted to perform a quantitative test of the registration accuracy of the virtual content, and to confirm qualitative results in a larger cohort of subjects

Sleep disturbances in highly stress reactive mice: Modeling endophenotypes of major depression

<p>Abstract</p> <p>Background</p> <p>Neuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days.</p> <p>Results</p> <p>Differences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle.</p> <p>Conclusions</p> <p>The HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.</p

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called 'stress reactivity' (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD

Quality-of-life assessment in dementia: the use of DEMQOL and DEMQOL-Proxy total scores

Purpose There is a need to determine whether health-related quality-of-life (HRQL) assessments in dementia capture what is important, to form a coherent basis for guiding research and clinical and policy decisions. This study investigated structural validity of HRQL assessments made using the DEMQOL system, with particular interest in studying domains that might be central to HRQL, and the external validity of these HRQL measurements. Methods HRQL of people with dementia was evaluated by 868 self-reports (DEMQOL) and 909 proxy reports (DEMQOL-Proxy) at a community memory service. Exploratory and confirmatory factor analyses (EFA and CFA) were conducted using bifactor models to investigate domains that might be central to general HRQL. Reliability of the general and specific factors measured by the bifactor models was examined using omega (?) and omega hierarchical (? h) coefficients. Multiple-indicators multiple-causes models were used to explore the external validity of these HRQL measurements in terms of their associations with other clinical assessments. Results Bifactor models showed adequate goodness of fit, supporting HRQL in dementia as a general construct that underlies a diverse range of health indicators. At the same time, additional factors were necessary to explain residual covariation of items within specific health domains identified from the literature. Based on these models, DEMQOL and DEMQOL-Proxy overall total scores showed excellent reliability (? h > 0.8). After accounting for common variance due to a general factor, subscale scores were less reliable (? h < 0.7) for informing on individual differences in specific HRQL domains. Depression was more strongly associated with general HRQL based on DEMQOL than on DEMQOL-Proxy (?0.55 vs ?0.22). Cognitive impairment had no reliable association with general HRQL based on DEMQOL or DEMQOL-Proxy. Conclusions The tenability of a bifactor model of HRQL in dementia suggests that it is possible to retain theoretical focus on the assessment of a general phenomenon, while exploring variation in specific HRQL domains for insights on what may lie at the ‘heart’ of HRQL for people with dementia. These data suggest that DEMQOL and DEMQOL-Proxy total scores are likely to be accurate measures of individual differences in HRQL, but that subscale scores should not be used. No specific domain was solely responsible for general HRQL at dementia diagnosis. Better HRQL was moderately associated with less depressive symptoms, but this was less apparent based on informant reports. HRQL was not associated with severity of cognitive impairment

Phylogenetic and Evolutionary Patterns in Microbial Carotenoid Biosynthesis Are Revealed by Comparative Genomics

BACKGROUND: Carotenoids are multifunctional, taxonomically widespread and biotechnologically important pigments. Their biosynthesis serves as a model system for understanding the evolution of secondary metabolism. Microbial carotenoid diversity and evolution has hitherto been analyzed primarily from structural and biosynthetic perspectives, with the few phylogenetic analyses of microbial carotenoid biosynthetic proteins using either used limited datasets or lacking methodological rigor. Given the recent accumulation of microbial genome sequences, a reappraisal of microbial carotenoid biosynthetic diversity and evolution from the perspective of comparative genomics is warranted to validate and complement models of microbial carotenoid diversity and evolution based upon structural and biosynthetic data. METHODOLOGY/PRINCIPAL FINDINGS: Comparative genomics were used to identify and analyze in silico microbial carotenoid biosynthetic pathways. Four major phylogenetic lineages of carotenoid biosynthesis are suggested composed of: (i) Proteobacteria; (ii) Firmicutes; (iii) Chlorobi, Cyanobacteria and photosynthetic eukaryotes; and (iv) Archaea, Bacteroidetes and two separate sub-lineages of Actinobacteria. Using this phylogenetic framework, specific evolutionary mechanisms are proposed for carotenoid desaturase CrtI-family enzymes and carotenoid cyclases. Several phylogenetic lineage-specific evolutionary mechanisms are also suggested, including: (i) horizontal gene transfer; (ii) gene acquisition followed by differential gene loss; (iii) co-evolution with other biochemical structures such as proteorhodopsins; and (iv) positive selection. CONCLUSIONS/SIGNIFICANCE: Comparative genomics analyses of microbial carotenoid biosynthetic proteins indicate a much greater taxonomic diversity then that identified based on structural and biosynthetic data, and divides microbial carotenoid biosynthesis into several, well-supported phylogenetic lineages not evident previously. This phylogenetic framework is applicable to understanding the evolution of specific carotenoid biosynthetic proteins or the unique characteristics of carotenoid biosynthetic evolution in a specific phylogenetic lineage. Together, these analyses suggest a "bramble" model for microbial carotenoid biosynthesis whereby later biosynthetic steps exhibit greater evolutionary plasticity and reticulation compared to those closer to the biosynthetic "root". Structural diversification may be constrained ("trimmed") where selection is strong, but less so where selection is weaker. These analyses also highlight likely productive avenues for future research and bioprospecting by identifying both gaps in current knowledge and taxa which may particularly facilitate carotenoid diversification

Subjective health legacy of the Chornobyl accident: a comparative study of 19-year olds in Kyiv

<p>Abstract</p> <p>Background</p> <p>Since the Chornobyl accident in 1986, the physical health of exposed children in Ukraine has been monitored, but their perceived health has not been studied. This study examines health perceptions of Ukrainian adolescents exposed to radioactive fallout <it>in utero </it>or as infants, and the epidemiologic and Chornobyl-related influences on self-reported health.</p> <p>Method</p> <p>We assessed three groups of 19-year olds in Kyiv: 262 evacuees from contaminated areas near the plant; 261 classmate controls; and 325 population-based controls. The evacuees and classmates were previously assessed at age 11. Structured interviews were conducted with the adolescents and their mothers (N = 766), followed by general physical examinations (N = 722) and blood tests (N = 707). Proportional odds logistic regression and multi-group path analysis were the major statistical tests.</p> <p>Results</p> <p>The examination and blood test results were similar across groups except for a significantly elevated rate of thyroid enlargement found by palpation in evacuees (17.8%) compared former classmates (8.7%) and population-based controls (8.0%). In addition, four evacuees and one population control had had a thyroidectomy. Compared to controls, the evacuees rated their health the least positively and reported more medically diagnosed illnesses during the 5 years preceding the interview, particularly thyroid disease, migraine headache, and vascular dystony. The consistent risk factors (p < 0.001) for these subjective health reports were evacuee status, female gender, multiple hospitalizations, and health risk perception regarding Chornobyl. All three groups of mothers rated their children's health more negatively than the adolescents themselves, and maternal ratings were uniquely associated with the adolescents' health reports in the adjusted models. In the longitudinal evacuee and classmate subsamples, path analysis showed that mothers' health ratings when the children were age 11 predicted their later evaluations which in turn were associated with the adolescent self-reports.</p> <p>Conclusion</p> <p>The more negative self-evaluations of the evacuees were linked to a number of risk factors, including multiple hospitalizations, health risk perceptions, and epidemiologic risk factors. The increased rate of thyroid cancer and other diagnoses no doubt contributed to the evacuees' less positive subjective health. The strong effect of the mothers' perceptions argues in favor of developing risk communication programs for families rather than for mothers or adolescents as separate target groups.</p

Cognitive behaviour therapy response and dropout rate across purging and nonpurging bulimia nervosa and binge eating disorder : DSM-5 implications

Background: With the imminent publication of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), there has been a growing interest in the study of the boundaries across the three bulimic spectrum syndromes [bulimia nervosa-purging type (BN-P), bulimia nervosa-non purging type (BN-NP) and binge eating disorder (BED)]. Therefore, the aims of this study were to determine differences in treatment response and dropout rates following Cognitive Behavioural Therapy (CBT) across the three bulimic-spectrum syndromes. Method: The sample comprised of 454 females (87 BED, 327 BN-P and 40 BN-NP) diagnosed according to DSM-IV-TR criteria who were treated with 22 weekly outpatient sessions of group CBT therapy. Patients were assessed before and after treatment using a food and binging/purging diary and some clinical questionnaires in the field of ED. "Full remission" was defined as total absence of binging and purging (laxatives and/or vomiting) behaviors and psychological improvement for at least 4 (consecutive). Results: Full remission rate was found to be significantly higher in BED (69.5%) than in both BN-P (p < 0.005) and BN-NP (p < 0.001), which presented no significant differences between them (30.9% and 35.5%). The rate of dropout from group CBT was also higher in BED (33.7%) than in BN-P (p < 0.001) and BN-NP (p < 0.05), which were similar (15.4% and 12.8%, respectively). Conclusions: Results suggest that purging and non-purging BN have similar treatment response and dropping out rates, whereas BED appears as a separate diagnosis with better outcome for those who complete treatment. The results support the proposed new DSM-5 classification

Resilience to obesity among socioeconomically disadvantaged women : the READI study

Objective: This cross-sectional study aimed to identify sociodemographic and behavioural characteristics of &lsquo;overweight-resilient&rsquo; women, that is, women who were in a healthy body weight range, despite living in socioeconomically disadvantaged neighbourhoods that place them at increased risk of obesity. The study also aimed to test a comprehensive theoretically derived model of the associations between intrapersonal, social and environmental factors and obesity among this target group.Participants: A total of 3235 women aged 18&ndash;45 years from 80 urban and rural neighbourhoods throughout Victoria, Australia, participated in the Resilience for Eating and Activity Despite Inequality study.Measurements: Women reported height, weight, sociodemographic characteristics, leisure-time physical activity, dietary behaviours and a range of theoretically derived cognitive, social and neighbourhood environmental characteristics hypothesized to influence obesity risk. A theoretical model predicting body mass index (BMI) was tested using structural equation models.Results: Women classified as &lsquo;resilient&rsquo; to obesity tended to be younger, born overseas, more highly educated, unmarried and to have higher or undisclosed household incomes. They engaged in more leisure-time physical activity and consumed less fast foods and soft drinks than overweight/obese women. Neighbourhood characteristics, social characteristics and cognitive characteristics all contributed to explaining variation in BMI in the hypothesized directions.Conclusions: These results demonstrate several characteristics of women appearing &lsquo;resilient&rsquo; to obesity, despite their increased risk conferred by residing in socioeconomically disadvantaged neighbourhoods. Acknowledging the cross-sectional study design, the results advance theoretical frameworks aimed at investigating obesity risk by providing evidence in support of a comprehensive model of direct and indirect effects on obesity of neighbourhood, as well as social, cognitive and behavioural characteristics

Being there: a preliminary study examining the role of presence in Internet Gaming Disorder

Internet Gaming Disorder (IGD) has been introduced as an emerging mental health condition requiring further study. Associations between IGD and gaming presence (i.e., absorption in the virtual environment) have been implied. The aim of the present study was twofold: (a) to evaluate the extent to which presence contributes to IGD severity and, (b) to examine longitudinal differences in IGD according to the initial level of presence experienced. The participants comprising 125 emerging adults aged 18 to 29 years completed either: (i) three face-to-face assessments (one month apart, over three months) or (ii) a cross-sectional, online assessment. IGD was assessed with the nine-item IGD Scale Short Form and presence was assessed using the Presence Questionnaire. Regression and latent growth modelling analyses were conducted. Findings demonstrated that the level of gaming presence related to IGD severity but not to linear change in severity over a three-month period. The study shows that emergent adults who play internet games may be at a high risk of IGD given a more salient sense of being present within the gaming environment. Clinical implications considering prevention and intervention initiatives are discussed