9 research outputs found

    Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

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    The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

    Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

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    The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

    Removal of phenol compounds from olive mill wastewater using Phanerochaete chrysosporium, Aspergillus niger, Aspergillus terreus and Geotrichum candidum

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    The manufacturing process of olive oil yields a liquid waste called ‘olive mill wastewater’ (OMW). This waste has a high polluting power as well as a high antibacterial activity exerted, among others, by various phenolic compounds. Among the methods for the purification of OMW, biological systems show some advantages that make these particularly suitable. However, the presence of phenolic inhibitors requires the use of microorganisms able to utilise aromatic compounds. The capability and kinetic behaviour of several fungi to deal with such a waste reducing the phenol content of OMW was studied. The removal of total phenols relative to the total organic load consumed, which might indicate a measure of the selectivity with which the microorganisms remove phenols among other organic compounds present, indicates the sequence: Phanerochaete chrysosporium>Aspergillus niger>Aspergillus terreus

    Sources, distribution, and acidity of sulfate–ammonium aerosol in the Arctic in winter–spring

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    We use GEOS-Chem chemical transport model simulations of sulfate–ammonium aerosol data from the NASA ARCTAS and NOAA ARCPAC aircraft campaigns in the North American Arctic in April 2008, together with longer-term data from surface sites, to better understand aerosol sources in the Arctic in winter–spring and the implications for aerosol acidity. Arctic pollution is dominated by transport from mid-latitudes, and we test the relevant ammonia and sulfur dioxide emission inventories in the model by comparison with wet deposition flux data over the source continents. We find that a complicated mix of natural and anthropogenic sources with different vertical signatures is responsible for sulfate concentrations in the Arctic. East Asian pollution influence is weak in winter but becomes important in spring through transport in the free troposphere. European influence is important at all altitudes but never dominant. West Asia (non-Arctic Russia and Kazakhstan) is the largest contributor to Arctic sulfate in surface air in winter, reflecting a southward extension of the Arctic front over that region. Ammonium in Arctic spring mostly originates from anthropogenic sources in East Asia and Europe, with added contribution from boreal fires, resulting in a more neutralized aerosol in the free troposphere than at the surface. The ARCTAS and ARCPAC data indicate a median aerosol neutralization fraction [NH4+]/(2[SO42-] + [NO3-]) of 0.5 mol mol-1 below 2 km and 0.7 mol mol-1 above. We find that East Asian and European aerosol transported to the Arctic is mostly neutralized, whereas West Asian and North American aerosol is highly acidic. Growth of sulfur emissions in West Asia may be responsible for the observed increase in aerosol acidity at Barrow over the past decade. As global sulfur emissions decline over the next decades, increasing aerosol neutralization in the Arctic is expected, potentially accelerating Arctic warming through indirect radiative forcing and feedbacks

    Genetic Engineering and Nitrogen Fixation

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    Nitrogen is extremely important in agriculture because it is a constituent of proteins, nucleic acids and other essential molecules in all organisms. Most of this nitrogen is derived from reduced or oxidized forms of N in the soil by growing plants, because plants and animals are unable to utilize N2, which is abundant in the atmosphere. Under most cropping conditions N is limiting for growth and is provided in fertilizers, usually at rates of between 50 and 300 kg of N per ha per year (Anonymous, 1979). The only other sources available to plants are from decomposing organic matter, soil reserves, biological nitrogen fixation, the little that is deposited in rainfall and from other sources such as automobile exhausts. Biological nitrogen fixation, the enzymic conversion of N2 gas to ammonia, is much the most important source of fixed nitrogen entering those soils which receive less than about 5 kg N per ha per year from fertilizers. The reduction of N2 is catalysed by the nitrogenase system, which is very similar in composition and function in all prokaryotes which produce it Indeed, subunits of nitrogenase obtained from different nitrogen-fixing species can often be mixed to produce a functional system (Emerich and Burris, 1978). In addition, DNA coding for the structural proteins is so highly conserved in sequence that this coding has been used in hybridization experiments to demonstrate the presence of these genes in all nitrogen-fixing species of prokaryotes tested (Mazur, Rice and Haselkorn, 1980; Ruvkun and Ausubel, 1980). Nitrogenase is found only in prokaryotic micro-organisms and thus eukaryotes, such as plants!» can benefit from N2 fixation only jf they interact with N2-fixing species of micro-organism or obtain the fixed N after the death of the organisms. Nitrogenase functions only under anaerobic conditions because it is irreversibly inactivated by oxygen. The fixation ofN2 requires large amounts of energy, about 30 moles of ATP per mole N2 reduced (Hill, 1976; Schubert and Wolk, 1982), and thus can act as a major drain for energy produced by N2-fixing micro-organisnls. The requirement for an anaerobic environment and large amounts of energy presents problems to the micro-organisms that fix N2 and to the geneticists who wish to extend the range of N2..fixing organisms. Many micro..organisms fix N2 anaerobically and thus avoid the oxygen problem. However, energy production from organic compounds is usually much more efficient when they are metabolized by oxidative phosphorylation. Thus, in general, nitrogen fixation under aerobic or microaerobic conditions should be more efficient, unless too much energy is lost in protecting the enzyme from oxygen or replacing oxygen-damaged proteins. An important consequence of the large energy cost for biological nitrogen fixation is that the activity of nitrogenase needs to be regulated very carefully to ensure that only the required amount of fixed N is produced. We discuss the regulation of N2 fixation in Klebsiella pneumoniae in some detail in this chapter because a full understanding of how nitrogenase is regulated will be necessary if the transfer of N 2 fixation genes (nij') into other species, or even plants, is to be beneficial to the recipient organism. The preceding remarks about the energy requirement and oxygen stability of nitrogenase point to two of the most important problems that will be faced in transferring nij"genes to new hosts. In this review we will discuss other potential problems and show how our knowledge of the genetics of nitrogen fixation might be exploited in future
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