Spinal cord metabolic signatures in models of fast- and slow-progressing SOD1G93A Amyotrophic Lateral Sclerosis

The rate of disease progression in amyotrophic lateral sclerosis (ALS) is highly variable, even between patients with the same genetic mutations. Metabolic alterations may affect disease course variability in ALS patients, but challenges in identifying the preclinical and early phases of the disease limit our understanding of molecular mechanisms underlying differences in the rate of disease progression. We examined effects of SOD1G93A on thoracic and lumbar spinal cord metabolites in two mouse ALS models with different rates of disease progression: the transgenic SOD1G93A-C57BL/6JOlaHsd (C57-G93A, slow progression) and transgenic SOD1G93A-129SvHsd (129S-G93A, fast progression) strains. Samples from three timepoints (presymptomatic, disease onset, and late stage disease) were analyzed using Gas Chromatography-Mass Spectrometry metabolomics. Tissue metabolome differences in the lumbar spinal cord were driven primarily by mouse genetic background, although larger responses were observed in metabolic trajectories after the onset of symptoms. The significantly affected lumbar spinal cord metabolites were involved in energy and lipid metabolism. In the thoracic spinal cord, metabolic differences related to genetic background, background-SOD1 genotype interactions, and longitudinal SOD1G93A effects. The largest responses in thoracic spinal cord metabolic trajectories related to SOD1G93A effects before onset of visible symptoms. More metabolites were significantly affected in the thoracic segment, which were involved in energy homeostasis, neurotransmitter synthesis and utilization, and the oxidative stress response. We find evidence that initial metabolic alterations in SOD1G93A mice confer disadvantages for maintaining neuronal viability under ALS-related stressors, with slow-progressing C57-G93A mice potentially having more favorable spinal cord bioenergetic profiles than 129S-G93A. These genetic background-associated metabolic differences together with the different early metabolic responses underscore the need to better characterize the impact of germline genetic variation on cellular responses to ALS gene mutations both before and after the onset of symptoms in order to understand their impact on disease development

Electric field control of magnetic properties and electron transport in BaTiO3-based multiferroic heterostructures

In this paper, we report on a purely electric mechanism for achieving the electric control of the interfacial spin polarization and magnetoresistance in multiferroic tunneling junctions. We investigate micrometric devices based on the Co/Fe/BaTiO3/La0.7Sr0.3MnO3 heterostructure, where Co/Fe and La0.7Sr0.3MnO3 are the magnetic electrodes and BaTiO3 acts both as a ferroelectric element and tunneling barrier. We show that, at 20 K, devices with a 2 nm thick BaTiO3 barrier present both tunneling electroresistance (TER = 12   ±   0.1%) and tunneling magnetoresistance (TMR). The latter depends on the direction of the BaTiO3 polarization, displaying a sizable change of the TMR from  -0.32   ±   0.05% for the polarization pointing towards Fe, to  -0.12   ±   0.05% for the opposite direction. This is consistent with the on-off switching of the Fe magnetization at the Fe/BaTiO3 interface, driven by the BaTiO3 polarization, we have previously demonstrated in x-ray magnetic circular dichroism experiments

Inhibition of chemotaxis by S-3-deazaadenosylhomocysteine in a mouse macrophage cell line

Chemotaxis by a macrophage cell line, RAW264, is specifically inhibited by the intracellular accumulation of 3-deazaadenosylhomocysteine (3-deaza-AdoHcy). Intracellular accumulation of 3-deaza-AdoHcy is the result of incubation of the cells with 3-deazaadenosine, a compound that can function both as a substrate and as an inhibitor of adenosylhomocysteine (AdoHcy) hydrolase. Accumulation of AdoHcy per se, brought about in chemotactic cell lines by incubation with either 3-deazaadenosine or with 3-deazaaristeromycin, does not affect chemotaxis. The specific role of 3-deazaadenosine as an inhibitor of macrophage cell line chemotaxis is supported by the following findings. Another macrophage cell line, RAW309CR, is resistant to the inhibition of chemotaxis by 3-deazaadenosine, and the resistance can be ascribed to the failure to accumulate 3-deaza-AdoHcy in this cell line. It is noteworthy that both RAW264 and RAW309CR accumulate similar amounts of AdoHcy after incubation with 3-deazaadenosine. The difference in the accumulation of 3-deaza-AdoHcy in RAW264 and RAW309CR is explained by the finding that sonicates of RAW264 rapidly form 3-deaza-AdoHcy but sonicates of RAW309CR do not. Both hydrolysis of AdoHcy and the inhibition of the hydrolysis of AdoHcy by 3-deazaadenosine are the same in sonicates of the two macrophage cell lines

The CO2 system in the Mediterranean Sea: a basin wide perspective.

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Entropy of three-dimensional asymptotically flat cosmological solutions

The thermodynamics of three-dimensional asymptotically flat cosmological solutions that play the same role than the BTZ black holes in the anti-de Sitter case is derived and explained from holographic properties of flat space. It is shown to coincide with the flat-space limit of the thermodynamics of the inner black hole horizon on the one hand and the semi-classical approximation to the gravitational partition function associated to the entropy of the outer horizon on the other. This leads to the insight that it is the Massieu function that is universal in the sense that it can be computed at either horizon.Comment: 16 pages Latex file, v2: references added, cosmetic changes, v3: 1 reference adde

A Quantitative Chemicals' Mixture Risk Assessment Approach For Contaminants Of Emerging Concern Management In Drinking Water

Uncertainties on occurrence and hazard of mixtures of Contaminants of Emerging Concern (CECs) in drinking water (DW) challenge water utilities and decision makers in prioritizing these compounds in, respectively, interventions for the optimization of DW treatment and DW regulations. Continuous development of quantitative risk assessment procedures addressing adverse effects of CECs supports decision-making regarding mitigation actions in minimizing health risks. We propose a novel, quantitative chemical risk assessment (QCRA) approach for mixtures of CECs in DW. The risks are evaluated with the aid of the benchmark quotient probabilistic distribution and including uncertainties in both (i) exposure assessment using occurrence data of different DW sources and simulating DW treatment by granular activated carbon and (ii) hazard assessment steps. The QCRA was applied to compare risks deriving from the presence of alkylphenols mixtures in tap or bottled DW, and to evaluate how actual DW consumption habits affect health risks