Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor α and the Progression of Alzheimer's Disease

Alzheimer''s disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Aβ. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRα reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ε4 allele increased soluble Aβ42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble Aβ42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXRα and the levels of soluble Aβ42.     

The impact of thermal seasonality on terrestrial endotherm food web dynamics: a revision of the Exploitation Ecosystem Hypothesis

Many terrestrial endotherm food webs constitute three trophic level cascades. Others have two trophic level dynamics (food limited herbivores; plants adapted to tackle intense herbivory) or one trophic level dynamic (herbivorous endotherms absent, thus plants compete for the few places where they can survive and grow). According to the Exploitation Ecosystems Hypothesis (EEH), these contrasting dynamics are consequences of differences in primary productivity. The productivity thresholds for changing food web dynamics were assumed to be global constants. We challenged this assumption and found that several model parameters are sensitive to the contrast between persistently warm and seasonally cold climates. In persistently warm environments, three trophic level dynamics can be expected to prevail almost everywhere, save the most extreme deserts. We revised EEH accordingly and tested it by compiling direct evidence of three and two trophic level dynamics and by studying the global distribution of felids. In seasonally cold environments, we found evidence for three trophic level dynamics only in productive ecosystems, while evidence for two trophic level dynamics appeared in ecosystems with low primary productivity. In persistently warm environments, we found evidence for three trophic level dynamics in all types of ecosystems. The distribution of felids corroborated these results. The empirical evidence thus indicates that two trophic level dynamics, as defined by EEH, are restricted to seasonally cold biomes with low primary productivity, such as the artic–alpine tundra and the temperate steppe.     

Ectomycorrhizas and water relations of trees: a review

There is plenty of evidence for improved nutrient acquisition by ectomycorrhizas in trees; however, their role in water uptake is much less clear. In addition to experiments showing improved performance during drought by mycorrhizal plants, there are several studies showing reduced root hydraulic conductivity and reduced water uptake in mycorrhizal roots. The clearest direct mechanism for increased water uptake is the increased extension growth and absorbing surface area, particularly in fungal species with external mycelium of the long-distance exploration type. Some studies have found increased aquaporin function and, consequently, increased root hydraulic conductivity in ectomycorrhizal plants while other studies showed no effect of ectomycorrhizal associations on root water flow properties. The aquaporin function of the fungal hyphae is also likely to be important for the uptake of water by the ectomycorrhizal plant, but more work needs to be done in this area. The best-known indirect mechanism for mycorrhizal effects on water relations is improved nutrient status of the host. Others include altered carbohydrate assimilation via stomatal function, possibly mediated by changes in growth regulator balance; increased sink strength in mycorrhizal roots; antioxidant metabolism; and changes in osmotic adjustment. None of these possibilities has been sufficiently explored. The mycorrhizal structure may also reduce water movement because of different fine root architecture (thickness), cell wall hydrophobicity or the larger number of membranes that water has to cross on the way from the soil to the xylem. In future studies, pot experiments comparing mycorrhizal and nonmycorrhizal plants will still be useful in studying well-defined physiological details. However, the quantitative importance of ectomycorrhizas for tree water uptake and water relations can only be assessed by field studies using innovative approaches. Hydraulic redistribution can support nutrient uptake during prolonged dry periods. In large trees with deep root systems, it may turn out that the most important function of mycorrhizas during drought is to facilitate nutrient acquisition.     

Cold acclimation was partially impaired in boron deficient Norway spruce seedlings

Susceptibility of trees to freezing injury has been suggested to increase in boron (B) deficiency but there is no experimental evidence to support this proposition. In this study, Norway spruce (Picea abies L. Karst.) seedlings were cultivated for two growing seasons in deficient, intermediate and ‘optimal’ B levels. Cold hardening of the seedlings was measured after the second growing season. Freezing tolerance in tips of shoots, needles, stems and roots was determined by controlled freezing tests and electrolyte leakage method, and that of buds, in addition, by differential thermal analysis (DTA). Electrical impedance was used to monitor changes in the apoplastic space during cold acclimation. Root dry weight and shoot height growth were lower in B deficiency. Cold acclimation of buds and stems was reduced by B deficiency. When hardened seedlings were subjected to subzero temperatures for 3 weeks, extracellular electrical resistance of stems became the highest at the lowest B supply which was probably due to decreased desiccation tolerance. As a conclusion, susceptibility to freezing damage may be increased by B deficiency in Norway spruce trees.     

Phenolic compounds in Norway spruce as affected by boron nutrition at the end of the growing season

The increase in concentrations of phenolic compounds in boron (B) deficiency has been demonstrated in many herbaceous plant species, but information on woody plants is scarce. It has been suggested that accumulation of phenolic compounds plays a role in the development of cold hardiness in herbaceous plants but also that B deficiency decreases winter hardiness. Here we study the effects of B nutrition on phenolic compounds in Norway spruce (Picea abies L.) in the course of cold acclimation. Phenolic compounds were analysed in Norway spruce seedlings from three different B-fertilisation treatments in two harvests: non-acclimated and cold-acclimated seedlings. Norway spruce phenolic compounds consisted mainly of condensed tannins. During B deficiency, condensed tannins and monocoumaroyl–astragalin der. 1 increased in non-acclimated seedlings. The increase in tannins was 21%, which was nearly significant. However, the effect of B on phenolic compounds was almost absent in cold-acclimated seedlings. The condensed tannin concentration increased much more with time in the simulated autumn than due to B deficiency, and we conclude that the B effect was probably not large enough to be important for the hardening of the seedlings. The total phenolic concentrations more than doubled during the course of cold hardening suggesting that phenolics have a role in the winter hardiness in Norway spruce.     

Opioid receptor pharmacological chaperones act by binding and stabilizing newly synthesized receptors in the endoplasmic reticulum

Accumulating evidence has indicated that membrane-permeable G protein-coupled receptor ligands can enhance cell surface targeting of their cognate wild-type and mutant receptors. This pharmacological chaperoning was thought to result from ligand-mediated stabilization of immature receptors in the endoplasmic reticulum (ER). In the present study, we directly tested this hypothesis using wild-type and mutant forms of the human delta-opioid receptor as models. ER-localized receptors were isolated by expressing the receptors in HEK293 cells under tightly controlled tetracycline induction and blocking their ER export with brefeldin A. The ER-retained delta-opioid receptor precursors were able to bind [(3)H]diprenorphine with high affinity, and treatment of cells with an opioid antagonist naltrexone led to a 2-fold increase in the number of binding sites. After removing the transport block, the antagonist-mediated increase in the number of receptors was detectable at the cell surface by flow cytometry and cell surface biotinylation assay. Importantly, opioid ligands, both antagonists and agonists, were found to stabilize the ER-retained receptor precursors in an in vitro heat inactivation assay and the treatment enhanced dissociation of receptor precursors from the molecular chaperone calnexin. Thus, we conclude that pharmacological chaperones facilitate plasma membrane targeting of delta-opioid receptors by binding and stabilizing receptor precursors, thereby promoting their release from the stringent ER quality control.     

Spatial variation in vegetation damage relative to primary productivity,small rodent abundance and predation

The relative importance of top‐down and bottom‐up mechanisms in shaping community structure is still a highly controversial topic in ecology. Predatory top‐down control of herbivores is thought to relax herbivore impact on the vegetation through trophic cascades. However, trophic cascades may be weak in terrestrial systems as the complexity of food webs makes responses harder to predict. Alternatively, top‐down control prevails, but the top‐level (predator or herbivore) changes according to productivity levels. Here we show how spatial variation in the occurrence of herbivores (lemmings and voles) and their predators (mustelids and foxes) relates with grazing damage in landscapes with different net primary productivity, generating two and three trophic level communities, during the 2007 rodent peak in northern Norway. Lemmings were most abundant on the unproductive high‐altitude tundra, where few predators were present and the impact of herbivores on vegetation was strong. Voles were most common on a productive, south facing slope, where numerous predators were present, and the impacts of herbivores on vegetation were weak. The impact of herbivores on the vegetation was strong only when predators were not present, and this cannot be explained by between‐habitat differences in the abundance of plant functional groups. We thus conclude that predators influence the plant community via a trophic cascade in a spatial pattern that support the exploitation ecosystems hypothesis. The responses to grazing also differed between plant functional groups, with implications for short and long‐term consequences for plant communities.     

Long-Term Experiments Reveal Strong Interactions Between Lemmings and Plants in the Fennoscandian Highland Tundra

Both the theory and the observations suggest that, there are strong links between herbivores and plants in terrestrial ecosystems; although, the effect of herbivores on plant community biomass is often attributed to variations in plant palatability. The existence of a strong link is commonly tested by constructing exclosures that exclude herbivores during a period of time. We here present data from two long-term (9 and 20 years, respectively) herbivore exclosure studies in lemming habitats on arctic tundra in northernmost Norway. The exclusion of all mammalian herbivores triggered strong increases in community level plant biomass and substantial changes in plant community composition. Palatable plants like graminoids and large bryophytes, as well as unpalatable plants like evergreen ericoids, deciduous shrubs, and lichens were all favored by excluding lemmings. These results reveal that a substantial increase in community biomass which occurs only when plant species capable of accumulating biomass are present, and palatability is a poor predictor of long-term responses of plants to excluding herbivores.     

Crystal structures of Melanocarpus albomyces cellobiohydrolase Cel7B in complex with cello-oligomers show high flexibility in the substrate binding

Cellobiohydrolase from Melanocarpus albomyces (Cel7B) is a thermostable, single-module, cellulose-degrading enzyme. It has relatively low catalytic activity under normal temperatures, which allows structural studies of the binding of unmodified substrates to the native enzyme. In this study, we have determined the crystal structure of native Ma Cel7B free and in complex with three different cello-oligomers: cellobiose (Glc₂), cellotriose (Glc₃), and cellotetraose (Glc₄), at high resolution (1.6–2.1 Å). In each case, four molecules were found in the asymmetric unit, which provided 12 different complex structures. The overall fold of the enzyme is characteristic of a glycoside hydrolase family 7 cellobiohydrolase, where the loops extending from the core β-sandwich structure form a long tunnel composed of multiple subsites for the binding of the glycosyl units of a cellulose chain. The catalytic residues at the reducing end of the tunnel are conserved, and the mechanism is expected to be retaining similarly to the other family 7 members. The oligosaccharides in different complex structures occupied different subsite sets, which partly overlapped and ranged from −5 to +2. In four cellotriose and one cellotetraose complex structures, the cello-oligosaccharide also spanned over the cleavage site (−1/+1). There were surprisingly large variations in the amino acid side chain conformations and in the positions of glycosyl units in the different cello-oligomer complexes, particularly at subsites near the catalytic site. However, in each complex structure, all glycosyl residues were in the chair (⁴C₁) conformation. Implications in relation to the complex structures with respect to the reaction mechanism are discussed.     

Thiosemicarbazones active against Clostridium difficile

A set of closely related furylidene thiosemicarbazones was prepared and screened against various clinically important Gram-positive bacteria. One compound containing an ethylene spacer and a 5-nitrofuryl group was found to have promising activity against Clostridium difficile.