Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

Diurnal preference and sleep quality: same genes? A study of young adult twins

The aims of this study were to examine the genetic and environmental influences on diurnal preference and sleep quality, the association between these phenotypes, the genetic and environmental influences on this association, and the magnitude of overlap between these influences. Using a twin design, data on diurnal preference (measured by the Morningness-Eveningness Questionnaire) and sleep quality (measured by the Pittsburgh Sleep Quality Index) were collected from 420 monozygotic twins, 773 dizygotic twins, and 329 siblings (mode age = 20 yrs, range = 18–27 yrs) from a population-based twin registry across the UK. Univariate analyses indicated that dominance genetic influence accounted for 52% and non-shared environment 48% of variance in diurnal preference. For sleep quality, additive genetic influence explained 43% and non-shared environment 57% of the variance. The bivariate analysis indicated a significant association between greater eveningness preference and poorer sleep quality (r = .27). There was substantial overlap in the additive genetic influences on both phenotypes (rA = .57), and overlap in the dominance genetic influences common to both phenotypes was almost absolute (rD = .99). Overlap in non-shared environment was much smaller (rE = .02). Additive genetic influence accounted for 2% of the association, dominance genetic influence accounted for 94%, and non-shared environmental influences accounted for the remaining 4%. The substantial overlap in genetic influence between these phenotypes indicates that similar genes are important for diurnal preference and sleep quality. Therefore, those genes already known to influence one phenotype may be possible candidates to explore with regards to the other phenotype

Adrenalectomy alters the sensitivity of the central nervous system melanocortin system

Removal of adrenal steroids by adrenalectomy (ADX) reduces food intake and body weight in rodents and prevents excessive weight gain in many genetic and dietary models of obesity. Thus, glucocorticoids appear to play a key role to promote positive energy balance in normal and pathological conditions. By comparison, central nervous system melanocortin signaling provides critical inhibitory tone to regulate energy balance. The present experiments sought to test whether glucocorticoids influence energy balance by altering the sensitivity to melanocortin receptor ligands. Because melanocortin-producing neurons are hypothesized to be downstream of leptin in a key weight-reducing circuit, we tested rats for their sensitivity to leptin and confirmed reports that the hypophagic response to third ventricular (i3vt) leptin is increased in ADX rats and is normalized by glucocorticoid replacement. Next we tested rats for their sensitivity to the melanocortin agonist melanotan II and found that, as for leptin, ADX enhanced the hypophagic response via a glucocorticoid-dependent mechanism. The central nervous system melanocortin system is unique in that it includes the endogenous melanocortin receptor antagonist, AgRP. The orexigenic effect of i3vt AgRP was absent in ADX rats and restored by glucocorticoid replacement. We conclude that the potent weight-reducing effects of ADX likely involve heightened responsiveness to melanocortin receptor stimulation

Daily and Seasonal Variation in the Spectral Composition of Light Exposure in Humans

Light is considered the most potent synchronizer of the human circadian system and exerts many other non-image-forming effects, including those that affect brain function. These effects are mediated in part by intrinsically photosensitive retinal ganglion cells that express the photopigment melanopsin. The spectral sensitivity of melanopsin is greatest for blue light at approximately 480 nm. At present, there is little information on how the spectral composition of light to which people are exposed varies over the 24 h period and across seasons. Twenty-two subjects, aged 22±4 yrs (mean±SD) participated during the winter months (November–February), and 12 subjects aged 25±3 yrs participated during the summer months (April–August). Subjects wore Actiwatch-RGB monitors, as well as Actiwatch-L monitors, for seven consecutive days while living in England. These monitors measured activity and light exposure in the red, green, and blue spectral regions, in addition to broad-spectrum white light, with a 2 min resolution. Light exposure during the day was analyzed for the interval between 09:00 and 21:00 h. The time course of white-light exposure differed significantly between seasons (p = 0.0022), with light exposure increasing in the morning hours and declining in the afternoon hours, and with a more prominent decline in the winter. Overall light exposure was significantly higher in summer than winter (p = 0.0002). Seasonal differences in the relative contribution of blue-light exposure to overall light exposure were also observed (p = 0.0006), in particular during the evening hours. During the summer evenings (17:00–21:00 h), the relative contribution of blue light was significantly higher (p < 0.0001) (40.2±1.1%) than during winter evenings (26.6±0.9%). The present data show that in addition to overall light exposure, the spectral composition of light exposure varies over the day and with season

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

AvBD1 nucleotide polymorphisms, peptide antimicrobial activities and microbial colonisation of the broiler chicken gut

Abstract Background The importance of poultry as a global source of protein underpins the chicken genome and associated SNP data as key tools in selecting and breeding healthy robust birds with improved disease resistance. SNPs affecting host peptides involved in the innate defences tend to be rare, but three non-synonymous SNPs in the avian β-defensin (AvBD1) gene encoding the variant peptides NYH, SSY and NYY were identified that segregated specifically to three lines of commercial broiler chickens Line X (LX), Line Y(LY) and Line Z. The impacts of such amino acid changes on peptide antimicrobial properties were analysed in vitro and described in relation to the caecal microbiota and gut health of LX and LY birds. Results Time-kill and radial immune diffusion assays indicated all three peptides to have antimicrobial properties against gram negative and positive bacteria with a hierarchy of NYH > SSY > NYY. Calcein leakage assays supported AvBD1 NYH as the most potent membrane permeabilising agent although no significant differences in secondary structure were identified to explain this. However, distinct claw regions, identified by 3D modelling and proposed to play a key role in microbial membrane attachment, and permeation, were more distinct in the NYH model. In vivo AvBD1 synthesis was detected in the bird gut epithelia. Analyses of the caecal gut microbiota of young day 4 birds suggested trends in Lactobacilli sp. colonisation at days 4 (9% LX vs × 30% LY) and 28 (20% LX vs 12% LY) respectively, but these were not statistically significant (P > 0.05). Conclusion Amino acid changes altering the killing capacity of the AvBD1 peptide were associated with two different bird lines, but such changes did not impact significantly on caecal gut microbiota

Disturbed functional brain networks and neurocognitive function in low-grade glioma patients: a graph theoretical analysis of resting-state MEG

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Comparative analysis indicates that alternative splicing in plants has a limited role in functional expansion of the proteome

<p>Abstract</p> <p>Background</p> <p>Alternative splicing (AS) is a widespread phenomenon in higher eukaryotes but the extent to which it leads to functional protein isoforms and to proteome expansion at large is still a matter of debate. In contrast to animal species, for which AS has been studied extensively at the protein and functional level, protein-centered studies of AS in plant species are scarce. Here we investigate the functional impact of AS in dicot and monocot plant species using a comparative approach.</p> <p>Results</p> <p>Detailed comparison of AS events in alternative spliced orthologs from the dicot <it>Arabidopsis thaliana </it>and the monocot <it>Oryza sativa </it>(rice) revealed that the vast majority of AS events in both species do not result from functional conservation. Transcript isoforms that are putative targets for the nonsense-mediated decay (NMD) pathway are as likely to contain conserved AS events as isoforms that are translated into proteins. Similar results were obtained when the same comparison was performed between the two more closely related monocot species rice and <it>Zea mays </it>(maize).</p> <p>Genome-wide computational analysis of functional protein domains encoded in alternatively and constitutively spliced genes revealed that only the RNA recognition motif (RRM) is overrepresented in alternatively spliced genes in all species analyzed. In contrast, three domain types were overrepresented in constitutively spliced genes. AS events were found to be less frequent within than outside predicted protein domains and no domain type was found to be enriched with AS introns. Analysis of AS events that result in the removal of complete protein domains revealed that only a small number of domain types is spliced-out in all species analyzed. Finally, in a substantial fraction of cases where a domain is completely removed, this domain appeared to be a unit of a tandem repeat.</p> <p>Conclusion</p> <p>The results from the ortholog comparisons suggest that the ability of a gene to produce more than one functional protein through AS does not persist during evolution. Cross-species comparison of the results of the protein-domain oriented analyses indicates little correspondence between the analyzed species. Based on the premise that functional genetic features are most likely to be conserved during evolution, we conclude that AS has only a limited role in functional expansion of the proteome in plants.</p

Correlated mutations via regularized multinomial regression

Background In addition to sequence conservation, protein multiple sequence alignments contain evolutionary signal in the form of correlated variation among amino acid positions. This signal indicates positions in the sequence that influence each other, and can be applied for the prediction of intra- or intermolecular contacts. Although various approaches exist for the detection of such correlated mutations, in general these methods utilize only pairwise correlations. Hence, they tend to conflate direct and indirect dependencies. Results We propose RMRCM, a method for Regularized Multinomial Regression in order to obtain Correlated Mutations from protein multiple sequence alignments. Importantly, our method is not restricted to pairwise (column-column) comparisons only, but takes into account the network nature of relationships between protein residues in order to predict residue-residue contacts. The use of regularization ensures that the number of predicted links between columns in the multiple sequence alignment remains limited, preventing overprediction. Using simulated datasets we analyzed the performance of our approach in predicting residue-residue contacts, and studied how it is influenced by various types of noise. For various biological datasets, validation with protein structure data indicates a good performance of the proposed algorithm for the prediction of residue-residue contacts, in comparison to previous results. RMRCM can also be applied to predict interactions (in addition to only predicting interaction sites or contact sites), as demonstrated by predicting PDZ-peptide interactions. Conclusions A novel method is presented, which uses regularized multinomial regression in order to obtain correlated mutations from protein multiple sequence alignments