A multi-metabolite analysis of serum by 1H NMR spectroscopy: early systemic signs of Alzheimer's disease

A three-molecular-window approach for ¹H NMR spectroscopy of serum is presented to obtain specific molecular data on lipoproteins, various low-molecular-weight metabolites, and individual lipid molecules together with their degree of (poly)(un)saturation. The multiple data were analysed with self-organising maps, illustrating the strength of the approach as a holistic metabonomics framework in solely data-driven metabolic phenotyping. We studied 180 serum samples of which 30% were related to mild cognitive impairment (MCI), a neuropsychological diagnosis with severely increased risk for Alzheimer’s disease (AD). The results underline the association between MCI and the metabolic syndrome (MetS). Additionally, the low relativeamount of ω-3 fatty acids appears more indicative of MCI than low serum ω-3 or polyunsaturated fatty acid concentration as such. The analyses also feature the role of elevated glycoproteins in the risk for AD, supporting the view that coexistence of inflammation and the MetS forms a high risk condition for cognitive decline.     

Uncertainty and Sensitivity in the Carbon Footprint of Shopping Bags

Carbon footprints for several shopping bag alternatives (polyethylene, paper, cotton, biodegradable modified starch, and recycled polyethylene) were compared with life cycle assessment. Stochastic uncertainty analysis was used to study the sensitivity of the comparison to scenario and parameter uncertainty. On the basis of the results, we could give only a few robust conclusions without choosing a waste treatment scenario or limiting the parameter space. Given the scenario of current waste infrastructure in Finland, recycled polyethylene bags seem to be the most preferable (?7 to 24 g CO₂ eq./bag) and biodegradable bags the least preferable (38 to 60 g CO₂ eq./bag) option. In each analyzed waste treatment scenario, a few parameters dominated the uncertainty of results. Most of these parameters were downstream of the shopping bag manufacturing (consumer behavior, landfill conditions, method of waste combustion, etc.). The choice of waste treatment scenario had a greater effect on the ranking of bags than parameter uncertainty within scenarios. This result highlights the importance of including several scenarios in comparative life cycle assessments.     

Variation in niche parameters along the diversity gradient of unicellular eukaryote assemblages

We examined the relationship between average niche parameters and species richness of benthic diatom assemblages of boreal streams. We hypothesized that diverse assemblages should be typified by small average niche breadth of species, whereas low-diversity assemblages should be typified by broad average niche breadth. We also hypothesized that low-diversity sites should be dominated by either non-marginal species only or marginal species only, depending on the degree to which these sites could be categorized to range from environmentally typical sites to atypical sites. Niche breadth and niche position for each species were determined via Outlying Mean Index analysis. As hypothesized, we found that median niche parameters were significantly related to species richness. Median niche breadth showed both significant linear (R(2)=0.328, p<0.001) and unimodal (R(2)=0.354, p<0.001) relationship to species richness. The relationship between median niche position and species richness was best approximated by a unimodal model (R(2)=0.214, p=0.005). The underlying gradient in species richness was best accounted for by a regression model including moss cover, iron, and nitrogen, and explained 32% of variability in species richness. Our results showed that sites with high-diversity assemblages are likely to be occupied by specialists with a narrow niche breadth, whereas low diversity assemblages are dominated by generalists. Furthermore, the unimodal relationship between niche position and species richness suggested that species-poor sites may be typified by either non-marginal or marginal species.     

Feelings of Hopelessness in Midlife and Cognitive Health in Later Life: A Prospective Population-Based Cohort Study

BackgroundSeveral studies have found depression and depressive feelings to be associated with subsequent dementia. As dementias typically have a long preclinical development phase, it has been difficult to determine whether depression and depressive feelings reflect a concurrent underlying dementia disease, rather than playing a causative role. Our aim was to investigate hopelessness, one dimension of depressive feelings, and evaluate the likelihood of a prodromal versus a causative role of hopelessness feelings in dementia development.MethodsWe invited a random sample of 2000 survivors from a representative population in Eastern Finland, originally investigated in midlife between 1972 and 1987, for re-examination an average of 21 years later. The age of the 1449 persons who accepted the invitation was between 39 and 64 years (mean 50.4 years) in midlife and between 65 and 80 (mean 71.3) at follow-up. To measure feelings of hopelessness in midlife and at follow-up, the participants indicated their level of agreement to two statements about their own possible future. We used logistic regression to investigate the association between the combined scores from these two items and cognitive health at follow-up, while adjusting for several health and life-style variables from midlife and for apolipoprotein E4 (ApoE4) status, depression and hopelessness feelings at follow-up. We compared the associations with late-life cognitive health when feelings of hopelessness were either measured in midlife or at the follow-up. In addition we analyzed the changes in hopelessness scores from midlife to follow-up in participants who were either cognitively healthy or impaired at follow-up.ResultsWe found higher levels of hopelessness in midlife, but not at follow-up, to be associated with cognitive impairment at follow-up; the adjusted odds ratio for each step of the five-level hopelessness scale was 1.30 (95% confidence interval 1.11–1.51) for any cognitive impairment and 1.37 (1.05–1.78) for Alzheimer’s disease. These associations remained significant also after the final adjustments for depressive feelings and for hopelessness at follow-up. The individual changes in hopelessness scores between midlife and follow-up were not systematically related to cognitive health at the follow-up.ConclusionOur results suggest that feelings of hopelessness already in midlife may have long-term implications for cognitive health and increase the risk of Alzheimer’s disease in later life.     

The roles of elevation and local environmental factors as drivers of diatom diversity in subarctic streams

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Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β‐amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β‐secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non‐selective calcium channel blocker bepridil, which also inhibits β‐secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27‐day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle‐treated MCAO rats. Expression of seladin‐1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin‐1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase‐1‐ or NAD(P)H quinone oxidoreductase‐1‐mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO‐induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.     

Productivity-diversity relationships in lake plankton communities

One of the most intriguing environmental gradients connected with variation in diversity is ecosystem productivity. The role of diversity in ecosystems is pivotal, because species richness can be both a cause and a consequence of primary production. However, the mechanisms behind the varying productivity-diversity relationships (PDR) remain poorly understood. Moreover, large-scale studies on PDR across taxa are urgently needed. Here, we examined the relationships between resource supply and phyto-, bacterio-, and zooplankton richness in 100 small boreal lakes. We studied the PDR locally within the drainage systems and regionally across the systems. Second, we studied the relationships between resource availability, species richness, biomass and resource ratio (N:P) in phytoplankton communities using Structural Equation Modeling (SEM) for testing the multivariate hypothesis of PDR. At the local scale, the PDR showed variable patterns ranging from positive linear and unimodal to negative linear relationships for all planktonic groups. At the regional scale, PDRs were significantly linear and positive for phyto- and zooplankton. Phytoplankton richness and the amount of chlorophyll a showed a positive linear relationship indicating that communities consisting of higher number of species were able to produce higher levels of biomass. According to the SEM, phytoplankton biomass was largely related to resource availability, yet there was a pathway via community richness. Finally, we found that species richness at all trophic levels was correlated with several environmental factors, and was also related to richness at the other trophic levels. This study showed that the PDRs in freshwaters show scale-dependency. We also documented that the PDR complies with the multivariate model showing that plant biomass is not mirroring merely the resource availability, but is also influenced by richness. This highlights the need for conserving diversity in order to maintain ecosystem processes in freshwaters.     

Oblique self-assemblies and order-order transitions in polypeptide complexes with PEGylated triple-tail lipids

We report on highly ordered oblique self-assemblies in ionic complexes of PEGylated triple-tail lipids and cationic polypeptides, as directed by side-chain crystallization, demonstrating also reversible oblique-to-hexagonal order-order transitions upon melting of the side chains. This is achieved in bulk by complexing cationic homopolypeptides, poly-l-lysine (PLys), poly-l-arginine (PArg), and poly-l-histidine (PHis), in stoichiometric amounts with anionic lipids incorporating two hydrophobic alkyl tails and one hydrophilic polyethylene glycol (PEG) tail in a star-shaped A(2)B geometry. Based on Fourier transform infrared spectroscopy (FTIR), the PLys and PArg complexes fold into α-helical conformation. Aiming to periodicities at different length scales, that is, hierarchies, the PEG tails were selected to control the separation of the polypeptide helices in one direction while the alkyl tails determine the distance between the hydrophilic polypeptide/PEG layers, resulting in an oblique arrangement of the helices. We expect that the high overall order, where the self-assembled domains are in 2D registry, is an outcome of a favorable interplay of plasticization due to the hydrophobic and hydrophilic lipid tails combined with the shape persistency of the peptide helices and the crystallization of the lipid alkyl chains. Upon heating the complexes over the melting temperature of the alkyl tails, an order-order transition from oblique to hexagonal columnar morphology was observed. This transition is reversible, that is, the oblique structure with 2D correlation of the helices is fully returned upon cooling, implying that the alkyl tail crystallization guides the structure formation. Also PHis complex forms an oblique self-assembly. However, instead of α-helices, FTIR suggests formation of helical structures lacking intramolecular hydrogen bonds, stabilized by steric crowding of the lipid. The current study exploits competition between the soft and harder domains, which teaches on concepts toward well-defined polypeptide-based materials.     

Novel isosteric charge-deficient spermine analogue—1,12-diamino-3,6,9-triazadodecane: synthesis, pK a measurement and biological activity

Ionic interactions are essential for the biological functions of the polyamines spermidine and spermine in mammalian physiology. Here, we describe a simple gram scale method to prepare 1,12-diamino-3,6,9-triazadodecane (SpmTrien), an isosteric charge-deficient spermine analogue. The protonation sites of SpmTrien were determined at pH range of 2.2–11.0 using two-dimensional ¹H-¹⁵N NMR spectroscopy, which proved to be more feasible than conventional methods. The macroscopic pK _a values of SpmTrien (3.3, 6.3, 8.5, 9.5 and 10.3) are significantly lower than those of 1,12-diamino-4,9-diazadodecane (spermine). The effects of SpmTrien and its parent molecule, 1,8-diamino-3,6-diazaoctane (Trien), on cell growth and polyamine metabolism were investigated in DU145 prostate carcinoma cells. SpmTrien downregulated the biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosyl-l-methionine decarboxylase and decreased intracellular polyamine levels, whereas the effects of Trien alone were minor. Interestingly, both SpmTrien and Trien were able to partially overcome growth arrest induced by an ODC inhibitor, α-difluoromethylornithine, indicating that they are able to mimic some functions of the natural polyamines. Thus, SpmTrien is a novel tool to influence polyamine interaction sites at the molecular level and offers a new means to study the contribution of the protonation of spermine amino group(s) in the regulation of polyamine-dependent biological processes.