Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer's Disease.

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aß) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.

Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells.

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame's ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer's disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo.

Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells.

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimer's disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimer's disease.

Cosmogenic radionuclides reveal an extreme solar particle storm near a solar minimum 9125 years BP.

During solar storms, the Sun expels large amounts of energetic particles (SEP) that can react with the Earth's atmospheric constituents and produce cosmogenic radionuclides such as 14C, 10Be and 36Cl. Here we present 10Be and 36Cl data measured in ice cores from Greenland and Antarctica. The data consistently show one of the largest 10Be and 36Cl production peaks detected so far, most likely produced by an extreme SEP event that hit Earth 9125 years BP (before present, i.e., before 1950 CE), i.e., 7176 BCE. Using the 36Cl/10Be ratio, we demonstrate that this event was characterized by a very hard energy spectrum and was possibly up to two orders of magnitude larger than any SEP event during the instrumental period. Furthermore, we provide 10Be-based evidence that, contrary to expectations, the SEP event occurred near a solar minimum.

Single Particle Characterization and Total Elemental Concentration Measurements in Polar Ice Using Continuous Flow Analysis-Inductively Coupled Plasma Time-of-Flight Mass Spectrometry.

Continuous flow analysis (CFA) has become widely used for the measurement of aerosol-derived impurities in ice-core samples, resulting in high-resolution data sets of past aerosol deposition. Here, we present first results from coupling an inductively coupled plasma time-of-flight mass spectrometer (TOFMS) to a traditional CFA system. This setup enables the measurement of exactly coregistered elemental concentrations over the full mass range without degradation of sensitivity with an increasing number of analytes. The resulting total elemental concentration records have similar or better resolution than the established spectrophotometric methods. The unique capability of a TOFMS to measure fast transient signals and to still cover the full mass range furthermore enables the detection of the ionization of individual insoluble particles entering the plasma. The resulting mass spectra of the particles can be used to investigate the relative elemental composition of the mineral dust particles preserved in ice. The presented analysis of iron-bearing particles indicates that most of the particulate iron in Greenland ice is associated with Mg and Al and is likely part of clay minerals such as illite.

Fe2+ in ice cores as a new potential proxy to detect past volcanic eruptions.

Volcanic eruptions are widely used in ice core science to date or synchronize ice cores. Volcanoes emit large amounts of SO2 that is subsequently converted in the atmosphere into sulfuric acid/sulphate. Its discrete and continuous quantification is currently used to determine the ice layers impacted by volcanic emissions, but available high-resolution sulphate quantification methods in ice core (Continuous Flow Analysis (CFA)) struggle with insufficient sensitivity. Here, we present a new high-resolution CFA chemiluminescence method for the continuous determination of Fe2+ species in ice cores that shows clear Fe2+ peaks concurrent with volcanic sulphate peaks in the ice core record. The method, applied on a Greenland ice core, correctly identifies all volcanic eruptions from between 1588 to 1611 and from 1777 to 1850. The method has a detection limit of ∽5 pg g-1 and a quadratic polynomial calibration range of up to at least 1760 pg g-1. Our results show that Fe2+ is a suitable proxy for identifying past volcanic events.

High-resolution isotopic evidence for a potential Saharan provenance of Greenland glacial dust.

Dust concentrations in Greenland ice show pronounced glacial/interglacial variations with almost two orders of magnitude increase during the Last Glacial Maximum. Greenland glacial dust was previously sourced to two East Asian deserts: the Taklimakan and Gobi deserts. Here we report the first high-resolution Pb and Sr isotopic evidence for a significant Saharan dust influence in Greenland during the last glacial period, back to ~31 kyr ago, from the Greenland NEEM ice core. We find that during Greenland Stadials 3-5.1 (~31 to 23 kyr ago), the primary dust provenance was East Asia, as previously proposed. Subsequently, the Saharan isotopic signals emerge during Greenland Stadials 2.1a-2.1c (~22.6 to 14.7 kyr ago) and from the late Bølling-Allerød to the Younger Dryas periods (~13.6 to 12 kyr ago), coincident with increased aridity in the Sahara and efficient northward transport of dust during these cold periods. A mixing isotopic model proposes the Sahara as an important source, accounting for contribution to Greenland glacial dust of up to 50%, particularly during Greenland Stadial 2.1b and the late Bølling-Allerød to the Younger Dryas periods. Our findings provide new insights into climate-related dust provenance changes and essential paleoclimatic constraints on dust-climate feedbacks in northern high latitudes.

A New Multielement Method for LA-ICP-MS Data Acquisition from Glacier Ice Cores.

To answer pressing new research questions about the rate and timing of abrupt climate transitions, a robust system for ultrahigh-resolution sampling of glacier ice is needed. Here, we present a multielement method of LA-ICP-MS analysis wherein an array of chemical elements is simultaneously measured from the same ablation area. Although multielement techniques are commonplace for high-concentration materials, prior to the development of this method, all LA-ICP-MS analyses of glacier ice involved a single element per ablation pass or spot. This new method, developed using the LA-ICP-MS system at the W. M. Keck Laser Ice Facility at the University of Maine Climate Change Institute, has already been used to shed light on our flawed understanding of natural levels of Pb in Earth's atmosphere.

R-vine models for spatial time series with an application to daily mean temperature.

We introduce an extension of R-vine copula models to allow for spatial dependencies and model based prediction at unobserved locations. The proposed spatial R-vine model combines the flexibility of vine copulas with the classical geostatistical idea of modeling spatial dependencies using the distances between the variable locations. In particular, the model is able to capture non-Gaussian spatial dependencies. To develop and illustrate our approach, we consider daily mean temperature data observed at 54 monitoring stations in Germany. We identify relationships between the vine copula parameters and the station distances and exploit these in order to reduce the huge number of parameters needed to parametrize a 54-dimensional R-vine model fitted to the data. The new distance based model parametrization results in a distinct reduction in the number of parameters and makes parameter estimation and prediction at unobserved locations feasible. The prediction capabilities are validated using adequate scoring techniques, showing a better performance of the spatial R-vine copula model compared to a Gaussian spatial model.