The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine

SIGNIFICANCE: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not administration of antioxidants is ineffective, suggesting our current understanding of the underlying regulatory processes is incomplete. Recent Advances. Similar to reactive oxygen and nitrogen species (ROS, RNS), reactive sulfur species (RSS) are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept coined the reactive species interactome (RSI). The RSI is a primeval multi-level redox-regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stresses to enhance fitness and resilience at the local and whole-organism level. CRITICAL ISSUES: To better characterise the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems and effects on cellular, organ and whole-organism bioenergetics using systems-level/network analyses. FUTURE DIRECTIONS: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other stresses will provide new prevention/intervention opportunities for personalized medicine

Effect of betaine supplementation on cycling sprint performance

<p>Abstract</p> <p>Purpose</p> <p>To examine the effect of betaine supplementation on cycling sprint performance.</p> <p>Methods</p> <p>Sixteen recreationally active subjects (7 females and 9 males) completed three sprint tests, each consisting of four 12 sec efforts against a resistance equal to 5.5% of body weight; efforts were separated by 2.5 min of cycling at zero resistance. Test one established baseline; test two and three were preceded by seven days of daily consumption of 591 ml of a carbohydrate-electrolyte beverage as a placebo or a carbohydrate-electrolyte beverage containing 0.42% betaine (approximately 2.5 grams of betaine a day); half the beverage was consumed in the morning and the other half in the afternoon. We used a double blind random order cross-over design; there was a 3 wk washout between trials two and three. Average and maximum peak and mean power were analyzed with one-way repeated measures ANOVA and, where indicated, a Student Newman-Keuls.</p> <p>Results</p> <p>Compared to baseline, betaine ingestion increased average peak power (6.4%; p < 0.001), maximum peak power (5.7%; p < 0.001), average mean power (5.4%; p = 0.004), and maximum mean power (4.4%; p = 0.004) for all subjects combined. Compared to placebo, betaine ingestion significantly increased average peak power (3.4%; p = 0.026), maximum peak power max (3.8%; p = 0.007), average mean power (3.3%; p = 0.034), and maximum mean power (3.5%; p = 0.011) for all subjects combined. There were no differences between the placebo and baseline trials.</p> <p>Conclusions</p> <p>One week of betaine ingestion improved cycling sprint power in recreationally active males and females.</p

Population-Level Associations between Preschool Vulnerability and Grade-Four Basic Skills

Background: This is a predictive validity study examining the extent to which developmental vulnerability at kindergarten entry (as measured by the Early Development Instrument, EDI) is associated with children’s basic skills in 4th grade (as measured by the Foundation Skills Assessment, FSA). Methodology/Principal Findings: Relative risk analysis was performed on a large database linking individual-level EDI ratings to the scores the same children obtained on a provincial assessment of academic skills (FSA – Foundation Skills Assessment) four years later. We found that early vulnerability in kindergarten is associated with the basic skills that underlie populations of children’s academic achievement in reading, writing and math, indicating that the Early Development Instrument permits to predict achievement-related skills four years in advance. Conclusions/Significance: The EDI can be used to predict children’s educational trends at the population level and can help select early prevention and intervention programs targeting pre-school populations at minimum cost

Genetic Differentiation of the Western Capercaillie Highlights the Importance of South-Eastern Europe for Understanding the Species Phylogeography

The Western Capercaillie (Tetrao urogallus L.) is a grouse species of open boreal or high altitude forests of Eurasia. It is endangered throughout most mountain range habitat areas in Europe. Two major genetically identifiable lineages of Western Capercaillie have been described to date: the southern lineage at the species' southernmost range of distribution in Europe, and the boreal lineage. We address the question of genetic differentiation of capercaillie populations from the Rhodope and Rila Mountains in Bulgaria, across the Dinaric Mountains to the Slovenian Alps. The two lineages' contact zone and resulting conservation strategies in this so-far understudied area of distribution have not been previously determined. The results of analysis of mitochondrial DNA control region sequences of 319 samples from the studied populations show that Alpine populations were composed exclusively of boreal lineage; Dinaric populations of both, but predominantly (96%) of boreal lineage; and Rhodope-Rila populations predominantly (>90%) of southern lineage individuals. The Bulgarian mountains were identified as the core area of the southern lineage, and the Dinaric Mountains as the western contact zone between both lineages in the Balkans. Bulgarian populations appeared genetically distinct from Alpine and Dinaric populations and exhibited characteristics of a long-term stationary population, suggesting that they should be considered as a glacial relict and probably a distinct subspecies. Although all of the studied populations suffered a decline in the past, the significantly lower level of genetic diversity when compared with the neighbouring Alpine and Bulgarian populations suggests that the isolated Dinaric capercaillie is particularly vulnerable to continuing population decline. The results are discussed in the context of conservation of the species in the Balkans, its principal threats and legal protection status. Potential conservation strategies should consider the existence of the two lineages and their vulnerable Dinaric contact zone and support the specificities of the populations

D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders

The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful

Genome-Wide Gene Expression Analysis in Cancer Cells Reveals 3D Growth to Affect ECM and Processes Associated with Cell Adhesion but Not DNA Repair

Cell morphology determines cell behavior, signal transduction, protein-protein interaction, and responsiveness to external stimuli. In cancer, these functions profoundly contribute to resistance mechanisms to radio- and chemotherapy. With regard to this aspect, this study compared the genome wide gene expression in exponentially growing cell lines from different tumor entities, lung carcinoma and squamous cell carcinoma, under more physiological three-dimensional (3D) versus monolayer cell culture conditions. Whole genome cDNA microarray analysis was accomplished using the Affymetrix HG U133 Plus 2.0 gene chip. Significance analysis of microarray (SAM) and t-test analysis revealed significant changes in gene expression profiles of 3D relative to 2D cell culture conditions. These changes affected the extracellular matrix and were mainly associated with biological processes like tissue development, cell adhesion, immune system and defense response in contrast to terms related to DNA repair, which lacked significant alterations. Selected genes were verified by semi-quantitative RT-PCR and Western blotting. Additionally, we show that 3D growth mediates a significant increase in tumor cell radio- and chemoresistance relative to 2D. Our findings show significant gene expression differences between 3D and 2D cell culture systems and indicate that cellular responsiveness to external stress such as ionizing radiation and chemotherapeutics is essentially influenced by differential expression of genes involved in the regulation of integrin signaling, cell shape and cell-cell contact

A Fear-Inducing Odor Alters PER2 and c-Fos Expression in Brain Regions Involved in Fear Memory

Evidence demonstrates that rodents learn to associate a foot shock with time of day, indicating the formation of a fear related time-stamp memory, even in the absence of a functioning SCN. In addition, mice acquire and retain fear memory better during the early day compared to the early night. This type of memory may be regulated by circadian pacemakers outside of the SCN. As a first step in testing the hypothesis that clock genes are involved in the formation of a time-stamp fear memory, we exposed one group of mice to fox feces derived odor (TMT) at ZT 0 and one group at ZT 12 for 4 successive days. A separate group with no exposure to TMT was also included as a control. Animals were sacrificed one day after the last exposure to TMT, and PER2 and c-Fos protein were quantified in the SCN, amygdala, hippocampus, and piriform cortex. Exposure to TMT had a strong effect at ZT 0, decreasing PER2 expression at this time point in most regions except the SCN, and reversing the normal rhythm of PER2 expression in the amygdala and piriform cortex. These changes were accompanied by increased c-Fos expression at ZT0. In contrast, exposure to TMT at ZT 12 abolished the rhythm of PER2 expression in the amygdala. In addition, increased c-Fos expression at ZT 12 was only detected in the central nucleus of the amygdala in the TMT12 group. TMT exposure at either time point did not affect PER2 or c-Fos in the SCN, indicating that under a light-dark cycle, the SCN rhythm is stable in the presence of repeated exposure to a fear-inducing stimulus. Taken together, these results indicate that entrainment to a fear-inducing stimulus leads to changes in PER2 and c-Fos expression that are detected 24 hours following the last exposure to TMT, indicating entrainment of endogenous oscillators in these regions. The observed effects on PER2 expression and c-Fos were stronger during the early day than during the early night, possibly to prepare appropriate systems at ZT 0 to respond to a fear-inducing stimulus

Brain Rhythms Reveal a Hierarchical Network Organization

Recordings of ongoing neural activity with EEG and MEG exhibit oscillations of specific frequencies over a non-oscillatory background. The oscillations appear in the power spectrum as a collection of frequency bands that are evenly spaced on a logarithmic scale, thereby preventing mutual entrainment and cross-talk. Over the last few years, experimental, computational and theoretical studies have made substantial progress on our understanding of the biophysical mechanisms underlying the generation of network oscillations and their interactions, with emphasis on the role of neuronal synchronization. In this paper we ask a very different question. Rather than investigating how brain rhythms emerge, or whether they are necessary for neural function, we focus on what they tell us about functional brain connectivity. We hypothesized that if we were able to construct abstract networks, or “virtual brains”, whose dynamics were similar to EEG/MEG recordings, those networks would share structural features among themselves, and also with real brains. Applying mathematical techniques for inverse problems, we have reverse-engineered network architectures that generate characteristic dynamics of actual brains, including spindles and sharp waves, which appear in the power spectrum as frequency bands superimposed on a non-oscillatory background dominated by low frequencies. We show that all reconstructed networks display similar topological features (e.g. structural motifs) and dynamics. We have also reverse-engineered putative diseased brains (epileptic and schizophrenic), in which the oscillatory activity is altered in different ways, as reported in clinical studies. These reconstructed networks show consistent alterations of functional connectivity and dynamics. In particular, we show that the complexity of the network, quantified as proposed by Tononi, Sporns and Edelman, is a good indicator of brain fitness, since virtual brains modeling diseased states display lower complexity than virtual brains modeling normal neural function. We finally discuss the implications of our results for the neurobiology of health and disease

Do Rapoport's Rule, Mid-Domain Effect or Environmental Factors Predict Latitudinal Range Size Patterns of Terrestrial Mammals in China?

BACKGROUND: Explaining species range size pattern is a central issue in biogeography and macroecology. Although several hypotheses have been proposed, the causes and processes underlying range size patterns are still not clearly understood. In this study, we documented the latitudinal mean range size patterns of terrestrial mammals in China, and evaluated whether that pattern conformed to the predictions of the Rapoport's rule several analytical methods. We also assessed the influence of the mid-domain effect (MDE) and environmental factors on the documented range size gradient. METHODOLOGY/PRINCIPAL FINDINGS: Distributions of 515 terrestrial mammals and data on nine environmental variables were compiled. We calculated mean range size of the species in each 5° latitudinal band, and created a range size map on a 100 km×100 km quadrat system. We evaluated Rapoport's rule according to Steven's, mid-point, Pagel's and cross-species methods. The effect of the MDE was tested based on a Monte Carlo simulation and linear regression. We used stepwise generalized linear models and correlation analyses to detect the impacts of mean climate condition, climate variability, ambient energy and topography on range size. The results of the Steven's, Pagel's and cross-species methods supported Rapoport's rule, whereas the mid-point method resulted in a hump-shaped pattern. Our range size map showed that larger mean latitudinal extents emerged in the mid-latitudes. We found that the MDE explained 80.2% of the range size variation, whereas, environmental factors accounted for <30% of that variation. CONCLUSIONS/SIGNIFICANCE: Latitudinal range size pattern of terrestrial mammals in China supported Rapoport's rule, though the extent of that support was strongly influenced by methodology. The critical factor underlying the observed gradient was the MDE, and the effects of climate, energy and topography were limited. The mean climate condition hypothesis, climate variability hypothesis, ambient energy hypotheses and topographical heterogeneity hypotheses were not supported