Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome

In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information. This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels. The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease.

The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress-a relationship that is continually being defined. Many studies investigating the effects of chronic stress on neuroinflammation in rodent models have identified significant changes in inflammatory modulators, including nuclear factor-κB (NF-κB) and toll-like receptors (TLRs), and cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6. This suggests that these are key inflammatory factors in the chronic stress response, which may contribute to the establishment of anxiety and depression-like symptoms. The behavioral and neurological effects of modulating inflammatory factors through gene knockdown (KD) and knockout (KO), and conventional and alternative medicine approaches, are discussed

Multi-objective improvement of software using co-evolution and smart seeding

Optimising non-functional properties of software is an important part of the implementation process. One such property is execution time, and compilers target a reduction in execution time using a variety of optimisation techniques. Compiler optimisation is not always able to produce semantically equivalent alternatives that improve execution times, even if such alternatives are known to exist. Often, this is due to the local nature of such optimisations. In this paper we present a novel framework for optimising existing software using a hybrid of evolutionary optimisation techniques. Given as input the implementation of a program or function, we use Genetic Programming to evolve a new semantically equivalent version, optimised to reduce execution time subject to a given probability distribution of inputs. We employ a co-evolved population of test cases to encourage the preservation of the program’s semantics, and exploit the original program through seeding of the population in order to focus the search. We carry out experiments to identify the important factors in maximising efficiency gains. Although in this work we have optimised execution time, other non-functional criteria could be optimised in a similar manner

Investigating Alkylated Prodigiosenes and Their Cu(II)-Dependent Biological Activity: Interactions with DNA, Antimicrobial and Photoinduced Anticancer Activity

Prodigiosenes are a family of red pigments with versatile biological activity. Their tripyrrolic core structure has been modified many times in order to manipulate the spectrum of activity. We have been looking systematically at prodigiosenes substituted at the C ring with alkyl chains of different lengths, in order to assess the relevance of this substituent in a context that has not been investigated before for these derivatives: Cu(II) complexation, DNA binding, self-activated DNA cleavage, photoinduced cytotoxicity and antimicrobial activity. Our results indicate that the hydrophobic substituent has a clear influence on the different aspects of their biological activity. The cytotoxicity study of the Cu(II) complexes of these prodigiosenes shows that they exhibit a strong cytotoxic effect towards the tested tumor cell lines. The Cu(II) complex of a prodigiosene lacking any alkyl chain excelled in its photoinduced anticancer activity, thus demonstrating the potential of prodigiosenes and their metal complexes for an application in photodynamic therapy (PDT). Two derivatives along with their Cu(II) complexes showed also antimicrobial activity against Staphylococcus aureus strains

Large amplitude variability from the persistent ultracompact X-ray binary in NGC 1851

Using archival RXTE data, we show that the ultracompact X-ray binary in NGC 1851 exhibits large amplitude X-ray flux varations of more than a factor of 10 on timescales of days to weeks and undergoes sustained periods of months where the time-averaged luminosty varies by factors of two. Variations of this magnitude and timescale have not been reported previously in other ultracompact X-ray binaries. Mass transfer in ultracompact binaries is thought to be driven by gravitational radiation and the predicted transfer rates are so high that the disks of ultracompact binaries with orbits as short as that of this object should not be susceptible to ionization instabilities. Therefore the variability characteristics we observe were unexpected, and need to be understood. We briefly discuss a few alternatives for producing the observed variations in light of the fact that the viscous timescale of the disk is of order a week, comparable to the shorter time scale variation that is observed but much less than the longer term variation. We also discuss the implications for interpretation of observations of extragalactic binaries if the type of variability seen in the source in NGC 1851 is typical.Comment: 7 pages, 5 figures, accepted for publication in MNRA

An Ultra-High-Resolution Survey of the Interstellar ^7Li-to-^6Li Isotope Ratio in the Solar Neighborhood

In an effort to probe the extent of variations in the interstellar ^7Li/^6Li ratio seen previously, ultra-high-resolution (R ~ 360,000), high signal-to-noise spectra of stars in the Perseus OB2 and Scorpius OB2 Associations were obtained. These measurements confirm our earlier findings of an interstellar ^7Li/^6Li ratio of about 2 toward o Per, the value predicted from models of Galactic cosmic ray spallation reactions. Observations of other nearby stars yield limits consistent with the isotopic ratio ~ 12 seen in carbonaceous chondrite meteorites. If this ratio originally represented the gas toward o Per, then to decrease the original isotope ratio to its current value an order of magnitude increase in the Li abundance is expected, but is not seen. The elemental K/Li ratio is not unusual, although Li and K are formed via different nucleosynthetic pathways. Several proposals to account for the low ^7Li/^6Li ratio were considered, but none seems satisfactory. Analysis of the Li and K abundances from our survey highlighted two sight lines where depletion effects are prevalent. There is evidence for enhanced depletion toward X Per, since both abundances are lower by a factor of 4 when compared to other sight lines. Moreover, a smaller Li/H abundance is observed toward 20 Aql, but the K/H abundance is normal, suggesting enhanced Li depletion (relative to K) in this direction. Our results suggest that the ^7Li/^6Li ratio has not changed significantly during the last 4.5 billion years and that a ratio ~ 12 represents most gas in the solar neighborhood. In addition, there appears to be a constant stellar contribution of ^7Li, indicating that one or two processes dominate its production in the Galaxy.Comment: 54 pages, accepted for publication in the Astrophysical Journa

Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.</p> <p>Results</p> <p>To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.</p> <p>Conclusions</p> <p>This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.</p

The impact of sample size on the reproducibility of voxel-based lesion-deficit mappings

This study investigated how sample size affects the reproducibility of findings from univariate voxel-based lesion-deficit analyses (e.g., voxel-based lesion-symptom mapping and voxel-based morphometry). Our effect of interest was the strength of the mapping between brain damage and speech articulation difficulties, as measured in terms of the proportion of variance explained. First, we identified a region of interest by searching on a voxel-by-voxel basis for brain areas where greater lesion load was associated with poorer speech articulation using a large sample of 360 right-handed English-speaking stroke survivors. We then randomly drew thousands of bootstrap samples from this data set that included either 30, 60, 90, 120, 180, or 360 patients. For each resample, we recorded effect size estimates and p values after conducting exactly the same lesion-deficit analysis within the previously identified region of interest and holding all procedures constant. The results show (1) how often small effect sizes in a heterogeneous population fail to be detected; (2) how effect size and its statistical significance varies with sample size; (3) how low-powered studies (due to small sample sizes) can greatly over-estimate as well as under-estimate effect sizes; and (4) how large sample sizes (N ≥ 90) can yield highly significant p values even when effect sizes are so small that they become trivial in practical terms. The implications of these findings for interpreting the results from univariate voxel-based lesion-deficit analyses are discussed.</p

Breeding season concerns and response to forest management: can forest management produce more breeding birds?.

Cerulean Warblers (Setophaga cerulea), one of the fastest declining avian species in North America, are associated with heterogeneous canopies in mature hardwood forests. However, the age of most second and third-growth forests in eastern North American is not sufficient for natural tree mortality to maintain structurally diverse canopies. Previous research suggests that forest management through timber harvest also may create conditions suitable as Cerulean Warbler breeding habitat. We conducted a multistate study that examined Cerulean Warbler response to varying degrees of canopy disturbance created by operational timber harvest. Specifically, 3 harvest treatments and an un-harvested reference plot were replicated on 7 study areas in 4 Appalachian states in 2005-2010. We compared pre-harvest and four years post-harvest demographic response of Cerulean Warblers. Over all study areas, Cerulean Warbler territory density remained stable in un-harvested reference plots and increased significantly the first year post-harvest on intermediate harvest plots. By year 3 post-harvest, territory density remained significantly greater for intermediate harvest than reference plots, and marginally greater for light and heavy harvests than reference plots. However, un-harvested reference plots had greater nest survival than most harvest treatments. The one exception was nest survival between reference plots and the intermediate harvest on the northern study areas did not differ. Our results indicate that intermediate harvests likely benefit Cerulean Warblers in some portions of the species’ breeding range. However, additional research is needed to better examine fitness consequences of timber harvests and to estimate population-level implications. In particular, does the greater number of nesting individuals, particularly in intermediate harvests, compensate for lower nesting success? Until researchers provide such insight, we recommend management decisions be based on local conditions, particularly in forests where Cerulean Warbler populations are high