CRY2 Is Associated with Depression

Background

Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.

Principal Findings

We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).

Conclusions

We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression.     

Parasites, sex, and clonal diversity in natural snail populations

Under the Red Queen hypothesis, host-parasite coevolution selects against common host genotypes. Although this mechanism might underlie the persistence of sexual reproduction, it might also maintain high clonal diversity. Alternatively, clonal diversity might be maintained by multiple origins of parthenogens from conspecific sexuals, a feature in many animal groups. Herein, we addressed the maintenance of overall genetic diversity by coevolving parasites, as predicted by the Red Queen hypothesis. We specifically examined the contribution of parasites to host clonal diversity and the frequency of sexually reproducing individuals in natural stream populations of Potamopyrgus antipodarum snails. We also tested the alternative hypothesis that clonal diversity is maintained by the input of clones by mutation from sympatric sexuals. Clonal diversity and the frequency of sexual individuals were both positively related to infection frequency. Surprisingly, although clones are derived by mutation from sexual snails, parasites explained more of the genotypic variation among parthenogenetic subpopulations. Our findings thus highlight the importance of parasites as drivers of clonal diversity, as well as sex.     

CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease

Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-β. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits. The effects were associated with cytokine production but not with plaque deposition. Ablation of CX3CR1 in mice overexpressing human amyloid precursor protein enhanced Tau pathology and exacerbated the depletion of calbindin in the dentate gyrus. The levels of calbindin in the dentate gyrus correlated negatively with those of tumor necrosis factor α and interleukin 6, suggesting neurotoxic effects of inflammatory factors. Functionally, removing CX3CR1 in human amyloid precursor protein mice worsened the memory retention in passive avoidance and novel object recognition tests, and their memory loss in the novel object recognition test is associated with high levels of interleukin 6. Our findings identify CX3CR1 as a key microglial pathway in protecting against AD-related cognitive deficits that are associated with aberrant microglial activation and elevated inflammatory cytokines.     

Modelling Nutrient Uptake by Individual Hyphae of Arbuscular Mycorrhizal Fungi: Temporal and Spatial Scales for an Experimental Design

Arbuscular mycorrhizas, associations between plant roots and soil fungi, are ubiquitous among land plants. Arbuscular mycorrhizas can be beneficial for plants by overcoming limitations in nutrient supply. Hyphae, which are long and thin fungal filaments extending from the root surface into the soil, increase the volume of soil accessible for plant nutrient uptake. However, no models so far specifically consider individual hyphae. We developed a mathematical model for nutrient uptake by individual fungal hyphae in order to assess suitable temporal and spatial scales for a new experimental design where fungal uptake parameters are measured on the single hyphal scale. The model was developed based on the conservation of nutrients in an artificial cylindrical soil pore (capillary tube) with adsorbing wall, and analysed based on parameter estimation and non-dimensionalisation. An approximate analytical solution was derived using matched asymptotic expansion. Results show that nutrient influx into a hypha from a small capillary tube is characterized by three phases: Firstly, uptake rapidly decreases as the hypha takes up nutrients, secondly, the depletion zone reaches the capillary wall and thus uptake is sustained by desorption of nutrients from the capillary wall, and finally, uptake goes to zero after nutrients held on the capillary wall have been completely depleted. Simulating different parameter regimes resulted in recommending the use of capillaries filled with hydrogel instead of water in order to design an experiment operating over measurable time scales.     

Inter-annual variations in biomass of loose lying algae Furcellaria-Coccotylus community: The relative importance of local versus regional environmental factors in the West Estonian Archipelago

The effects of local nutrient loading, harvesting, regional temperature patterns and weather induced light conditions were assessed on the interannual dynamics of the commercially important loose-lying red algal community of Furcellaria lumbricalis and Coccotylus truncatus. Higher algal biomasses were due to higher temperatures and number of calm days (i.e. clear water phases) during the active growing season in spring and summer. In addition, higher biomasses were associated with a higher number of stormy days in November-February, which is linked to a reduced ice cover and longer growing season. Commercial harvesting and nutrient load did not appear to drive the interannual dynamics of these red algae. Thus, the dynamics of the loose-lying red algal community is constrained by regional rather than local environmental factors.     

Micronuclei, hemoglobin adducts and respiratory tract irritation in mice after inhalation of toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI)

Toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI), used in the production of polyurethane foam, are well known for their irritating and sensitizing properties. Contradictory results have been obtained on their genotoxicity. We investigated the genotoxicity and protein binding of inhaled TDI and MDI in mice by examining micronucleated polychromatic erythrocytes (PCEs) in bone marrow and peripheral blood and TDI- and MDI-derived adducts in hemoglobin. Male C57Bl/6J mice (8 per group) were exposed head-only to TDI vapour (mean concentrations 1.1, 1.5, and 2.4mg/m(3); the mixture of isomers contained, on the average, 63% 2,4-TDI and 37% 2,6-TDI) or MDI aerosol (mean concentrations 10.7, 20.9 and 23.3mg/m(3)), during 1h/day for 5 consecutive days. Bone marrow and peripheral blood were collected 24h after the last exposure. Inhalation of TDI caused sensory irritation (SI) in the upper respiratory tract, and cumulative effects were observed at the highest exposure level. Inhalation of MDI produced SI and airflow limitation, and influx of inflammatory cells into the lungs. Hemoglobin adducts detected in the exposed mice resulted from direct binding to globin of 2,4- and 2,6-TDI and MDI, and dose-dependent increases were observed especially for 2,4-TDI-derived adducts. Adducts originating from the diamines of TDI (toluene diamine) or MDI (methylene dianiline) were not observed. No significant increase in the frequency of micronucleated PCEs was detected in the bone marrow or peripheral blood of the mice exposed to TDI or MDI. The ratio of PCEs and normochromatic erythrocytes (NCEs) was reduced at the highest concentration of MDI, and a slight reduction of the PCE/NCE ratio, dependent on cumulative inhaled dose, was also seen with TDI. Our results indicate that inhalation of TDI or MDI (1h/day for 5 days), at levels that induce toxic effects and formation of TDI- or MDI-specific adducts in hemoglobin, does not have detectable genotoxic effects in mice, as studied with the micronucleus assay.     

Canopy openness in gaps determines the influence of herbaceous climbers and insect folivory on the survival of a tropical pioneer tree,Neoboutonia macrocalyx Pax

Gaps created 10 years ago by clearing of conifer plantations in Kibale National Park, Uganda, still experience very little tree regeneration. We studied the arrested succession by examining the survival of Neoboutonia macrocalyx Pax in different sized canopy gaps. We examined whether Neoboutonia seedlings can survive in gaps, which the tree rarely colonizes naturally and whether survival is limited by the size of the canopy opening, herbaceous climbers or insect folivory. A total of 384 seedlings were planted in 24 gaps, and survival was monitored for 19 months. Survival was dependent on canopy openness, being lowest in small gaps and highest in large gaps. We found a significant negative relationship between survival and folivory and a positive relationship between survival and climber infestation. Because 53% of the seedlings survived, regeneration could be limited by seed dispersal, rather than high seedling mortality. However, considering its high survival rate in arrested succession gaps, Neoboutonia seems to have good potential for forest restoration.     

GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid

The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABA_B receptors (GABA_BRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABA_A and GABA_BRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABA_BR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED₅₀: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca²⁺ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABA_BRs and mediated by Ca²⁺ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.     

Participatory rural appraisal of ecosystem services of wetlands in the Amazonian Piedmont of Colombia: elements for a sustainable management concept

Considering the rapid changes in land use in tropical countries and the difficulties of law enforcement in remote areas, management of ecosystems benefits from the landscape approach. Within the landscape approach it is important to assess the different livelihoods of the local populations, as well as the vulnerability of the ecosystems that are supporting these livelihoods. Specifically for wetlands in rural tropical areas that face fast developing agro-industrial land use change, there is little information available on the attitude of stakeholders considering the ecosystems they manage. We used a combination of participatory rural appraisal and participatory mapping methods on rural wetlands in the Amazonian Piedmont region in Colombia, an area that has hardly ever been studied. We found that 77.7 % of the current livelihoods depend directly on the provisioning ecosystem services delivered by the wetlands, where fishing and hunting are the most important services that contribute to the household income. Ecotourism, which is emerging as a promising source of income, was also pointed as one key ecosystem service. However, our results revealed that the wetlands in our study area are very vulnerable (up to 41 % endangered). The main causes for wetland deterioration were cattle ranching, invasive grasses, deforestation, drainage, and burning. We conclude with a brief overview on the pros and cons of reconciling wetland conservation and human development in sensitive regions such as the Amazonian Piedmont in Colombia and other similar regions in the Tropics.     

Phenolic Acid Composition,Antiatherogenic and Anticancer Potential of Honeys Derived from Various Regions in Greece

The phenolic acid profile of honey depends greatly on its botanical and geographical origin. In this study, we carried out a quantitative analysis of phenolic acids in the ethyl acetate extract of 12 honeys collected from various regions in Greece. Our findings indicate that protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, caffeic acid and p-coumaric acid are the major phenolic acids of the honeys examined. Conifer tree honey (from pine and fir) contained significantly higher concentrations of protocatechuic and caffeic acid (mean: 6640 and 397 µg/kg honey respectively) than thyme and citrus honey (mean of protocatechuic and caffeic acid: 437.6 and 116 µg/kg honey respectively). p-Hydroxybenzoic acid was the dominant compound in thyme honeys (mean: 1252.5 µg/kg honey). We further examined the antioxidant potential (ORAC assay) of the extracts, their ability to influence viability of prostate cancer (PC-3) and breast cancer (MCF-7) cells as well as their lowering effect on TNF- α-induced adhesion molecule expression in endothelial cells (HAEC). ORAC values of Greek honeys ranged from 415 to 2129 µmol Trolox equivalent/kg honey and correlated significantly with their content in protocatechuic acid (p<0.001), p-hydroxybenzoic acid (p<0.01), vanillic acid (p<0.05), caffeic acid (p<0.01), p-coumaric acid (p<0.001) and their total phenolic content (p<0.001). Honey extracts reduced significantly the viability of PC-3 and MCF-7 cells as well as the expression of adhesion molecules in HAEC. Importantly, vanillic acid content correlated significantly with anticancer activity in PC-3 and MCF-7 cells (p<0.01, p<0.05 respectively). Protocatechuic acid, vanillic acid and total phenolic content correlated significantly with the inhibition of VCAM-1 expression (p<0.05, p<0.05 and p<0.01 respectively). In conclusion, Greek honeys are rich in phenolic acids, in particular protocatechuic and p-hydroxybenzoic acid and exhibit significant antioxidant, anticancer and antiatherogenic activities which may be attributed, at least in part, to their phenolic acid content.